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2013N180486_02 CONFIDENTIAL The GlaxoSmithKline group of companies 200980 1 TITLE PAGE Division: Worldwide Development Information Type: Protocol Amendment Title: An open label positron emission tomography (PET) imaging study using 89Zirconium to investigate the biodistribution of anti-HER3 monoclonal antibody (mAb) GSK2849330 and characterize its dose receptor occupancy relationship in subjects with advanced HER3-positive solid tumors Compound Number: GSK2849330 Development Phase: 1 Effective Date: 30-APR-2015 Protocol Amendment Number: 02 Author (s): Revision Chronology GlaxoSmithKline Document Number Date Version 2013N180486_00 2014-JUN-06 Original 2013N180486_01 2014-OCT-06 Amendment No. 1 Insertion of correct medical monitor details, single follow-up visit to reduce burden on patients, removal of unnecessarty valvular toxicity stopping criteria, and minor corrections and clarifications of texts 2013N180486_02 2015-APR-30 Amendment No. 2 Inclusion of filter during administration of GSK2849330, updating medical monitor contact details, minor corrections. Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 2016N304736_00 PPD
Transcript of TITLE PAGE - Amazon S3 · In some countries, the clinical trial sponsor may be the local...
2013N180486_02 CONFIDENTIALThe GlaxoSmithKline group of companies 200980
1
TITLE PAGE
Division: Worldwide DevelopmentInformation Type: Protocol Amendment
Title: An open label positron emission tomography (PET) imaging study using 89Zirconium to investigate the biodistribution of anti-HER3 monoclonal antibody (mAb) GSK2849330 and characterize its dose receptor occupancy relationship in subjects with advanced HER3-positive solid tumors
Compound Number: GSK2849330
Development Phase: 1
Effective Date: 30-APR-2015
Protocol Amendment Number: 02
Author (s):
Revision Chronology
GlaxoSmithKlineDocument Number
Date Version
2013N180486_00 2014-JUN-06 Original
2013N180486_01 2014-OCT-06 Amendment No. 1
Insertion of correct medical monitor details, single follow-up visit to reduce burden on patients, removal of unnecessarty valvular toxicity stopping criteria, and minor corrections and clarifications of texts
2013N180486_02 2015-APR-30 Amendment No. 2
Inclusion of filter during administration of GSK2849330, updating medical monitor contact details, minor corrections.
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role Name Day Time Phone Number
After-hours Phone/Cell/Pager Number
Fax Number GSK Address
Primary Medical Monitor
709 Swedeland Rd, King of Prussia, PA 19406USA
Secondary Medical Monitor
n/a1250 S Collegeville Road Collegeville, PA 19426 USA
Tertiary Medical Monitor
n/a
Gunnels Wood RoadStevenage Herts, SG1 2NY
Sponsor Registered Address:
GlaxoSmithKlineIron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UKTelephone:
GlaxoSmithKlineFive Moore Drive P.O. 13398Research Triangle Park, NC 27709-3398, USATelephone:
GlaxoSmithKline1250 South Collegeville RoadCollegeville, PA 19426, USATelephone Number:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.
Regulatory Agency Identifying Number(s):
Compound Number IND Number EudraCT Number
GSK2849330 2013-004546-42
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200980
I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature Date
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
1. INTRODUCTION....................................................................................................131.1. Background ................................................................................................131.2. GSK2849330 ..............................................................................................14
1.2.1. GSK2849330 Background ...........................................................141.2.2. Pharmacokinetics of GSK2849330 ..............................................151.2.3. Safety of GSK2849330 ................................................................15
1.3. Summary of Risk Management...................................................................151.3.1. GSK2849330-specific risks..........................................................151.3.2. Ionising radiation..........................................................................16
2. OBJECTIVES AND ENDPOINTS...........................................................................17
3. INVESTIGATIONAL PLAN.....................................................................................183.1. Study Schematic.........................................................................................183.2. Discussion of Study Design ........................................................................193.3. Pre-screening .............................................................................................203.4. Part 1: Imaging Phase ................................................................................21
3.4.1. Imaging dose selection ................................................................223.4.1.1. PET/CT scans: ...........................................................23
3.5. Part 2: Continuation Phase .........................................................................233.6. Intra-subject Dose-Escalation .....................................................................233.7. Rationale ....................................................................................................24
3.7.1. Rationale for Study ......................................................................243.7.2. Rationale for Population...............................................................243.7.3. Rationale for Dose .......................................................................243.7.4. Rationale for Endpoints................................................................25
3.8. Study Treatment .........................................................................................253.8.1. Treatment Assignment.................................................................25
3.9. Dosage and Administration of Study Treatment(s)......................................253.9.1. Blinding........................................................................................26
3.10. Safety Management Guidelines ..................................................................263.10.1. Liver Chemistry Stopping Criteria ................................................26
3.10.1.1. Liver Chemistry Follow-up Procedures .......................273.10.2. QTc Stopping Criteria ..................................................................293.10.3. Left Ventricular Ejection Fraction (LVEF) Stopping Criteria..........29
3.11. Guidelines for Events of Special Interest and Dose Modifications...............303.11.1. Management of Infusion Reactions..............................................303.11.2. Allergic Reaction Management ....................................................313.11.3. Diarrhea Management .................................................................313.11.4. Dose Modifications ......................................................................323.11.5. Dose Reductions .........................................................................32
4. INVESTIGATIONAL PRODUCT(S) ........................................................................324.1. Description of Investigational Product(s).....................................................334.2. Preparation/Handling/Storage of GSK2849330 GSK Investigational
Product .......................................................................................................34
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4.3. Preparation/Handling/Storage of 89Zr-GSK2849330 GSK Investigational Product................................................................................34
4.4. Product Accountability ................................................................................344.5. Treatment Compliance................................................................................354.6. Treatment of Investigational Product Overdose ..........................................35
5. STUDY POPULATION ...........................................................................................355.1. Number of Subjects ....................................................................................355.2. Subject Selection Criteria............................................................................36
5.2.1. Pre-screening Inclusion Criteria ...................................................365.2.2. Screening Inclusion Criteria .........................................................375.2.3. Exclusion Criteria.........................................................................39
6. COMPLETION OR WITHDRAWAL OF SUBJECTS...............................................406.1. Screen Failures...........................................................................................406.2. Subject Completion Criteria ........................................................................406.3. Permanent Discontinuation from Study Treatment......................................406.4. Study Completion .......................................................................................416.5. Treatment after the End of the Study ..........................................................41
7. STUDY ASSESSMENTS AND PROCEDURES .....................................................417.1. Time and Events Table(s)...........................................................................427.2. Demographic/Medical History and Baseline Assessments..........................47
7.2.1. Critical Baseline Assessments .....................................................477.3. Safety Evaluations ......................................................................................47
7.3.1. Physical Examinations .................................................................477.3.2. ECOG Performance Status..........................................................477.3.3. Vital Signs....................................................................................477.3.4. Electrocardiogram........................................................................487.3.5. Echocardiogram and/or Multi-gated Acquisition (MUGA)
Scans ..........................................................................................487.3.6. Laboratory Assessments .............................................................487.3.7. Pregnancy Testing and Reporting................................................49
7.4. Pharmacokinetics .......................................................................................507.4.1. Blood Sample Collection for Pharmacokinetics............................507.4.2. Pharmacokinetic Sample Analysis ...............................................50
7.5. Image Analysis ...........................................................................................517.6. Immunogenicity...........................................................................................51
7.6.1. Blood Sample Collection..............................................................517.6.2. Sample Analysis ..........................................................................51
7.7. Translational Research...............................................................................527.7.1. Tumor Tissue for HER3 expression Pre-screening ......................52
7.8. Evaluation of Anti-Cancer Activity ...............................................................527.8.1. Tumor Marker(s) ..........................................................................53
8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................538.1. Definition of an AE......................................................................................538.2. Definition of an SAE....................................................................................54
8.2.1. Sentinel Events............................................................................558.3. Laboratory and Other Safety Assessment Abnormalities Reported
as AEs and SAEs .......................................................................................558.3.1. Cardiovascular Events .................................................................56
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8.4. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs .....................................................................................56
8.5. Time Period and Frequency of Detecting AEs and SAEs............................578.5.1. Method of Detecting AEs and SAEs.............................................578.5.2. Prompt Reporting of SAEs and Other Events to GSK ..................578.5.3. Regulatory reporting requirements for SAEs................................59
9. LIVER CHEMISTRY FOLLOW-UP PROCEDURES...............................................599.1. Liver Chemistry Testing Procedures ...........................................................599.2. Liver Chemistry Monitoring Criteria .............................................................609.3. Drug Restart/Rechallenge Following Liver Events that are Possibly
Related to Study Drug(s) ............................................................................609.4. Drug Restart Following Transient, Resolving Liver Events Not
Related to Study Drug(s) ............................................................................61
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................6110.1. Permitted Medication(s) ..............................................................................6210.2. Prohibited Medication(s) and Non-Drug Therapies .....................................62
11. LIFESTYLE AND/OR DIETARY RESTRICTIONS..................................................6211.1. Contraception .............................................................................................62
11.1.1. Female Subjects ..........................................................................6211.1.2. Male Subjects ..............................................................................63
11.2. Lactation Restrictions..................................................................................64
12. DATA MANAGEMENT ...........................................................................................64
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................6413.1. Hypothesis(es)............................................................................................6413.2. Sample Size Determination and Sensitivity.................................................65
13.2.1. Sample Size Re-estimation..........................................................6513.3. Data Analysis Considerations .....................................................................65
13.3.1. Analysis Populations....................................................................6513.3.2. Interim analyses and their timings................................................65
13.3.2.1. Immediate in-stream analysis .....................................6613.3.2.2. Analysis of Dosimetry data .........................................6613.3.2.3. Expansion phase in-stream analysis ..........................6613.3.2.4. Interim analysis at the end of part 1............................66
13.3.3. Final Analyses .............................................................................6613.4. Key Elements of Analysis Plan ...................................................................66
13.4.1. Anti-Cancer Activity Analyses ......................................................6713.4.2. Safety Analyses ...........................................................................67
13.4.2.1. Extent of Exposure .....................................................6713.4.2.2. Adverse Events ..........................................................6713.4.2.3. Clinical Laboratory Evaluations ..................................6813.4.2.4. Other Safety Measures...............................................68
13.4.3. Pharmacodynamic/Biomarker Analyses.......................................6813.4.4. Pharmacokinetic Analyses...........................................................68
13.4.4.1. Pharmacokinetic Parameters......................................6813.4.4.2. Statistical Analysis of Pharmacokinetic Data ..............6913.4.4.3. Statistical Analysis of Population
Pharmacokinetics .......................................................69
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13.4.5. Pharmacokinetic/Pharmacodynamic Analyses.............................6913.4.5.1. Translational Research Analyses ...............................70
14. STUDY CONDUCT CONSIDERATIONS ...............................................................7014.1. Posting of Information on Clinicaltrials.gov..................................................7014.2. Regulatory and Ethical Considerations, Including the Informed
Consent Process ........................................................................................7114.3. Urgent Safety Measures .............................................................................7114.4. Quality Control (Study Monitoring) ..............................................................7114.5. Quality Assurance.......................................................................................7214.6. Study and Site Closure ...............................................................................7214.7. Records Retention ......................................................................................7214.8. Provision of Study Results to Investigators, Posting of Information
on Publicly Available Clinical Trials Registers and Publication ....................73
15. REFERENCES.......................................................................................................74
16. APPENDICES ........................................................................................................7516.1. Appendix 1: PHYSICAL, CHEMICAL AND PHARMACEUTICAL
PROPERTIES AND FORMULATION - 89Zr-GSK2849330 SOLUTION FOR INJECTION .....................................................................75
16.2. Appendix 2: NYHA Functional Classification System .................................7816.3. Appendix 3: COCKCROFT-GAULT FORMULA .........................................7916.4. Appendix 4: ECOG Performance Status1 ....................................................8016.5. Appendix 5: Liver Safety Drug Restart Guidelines ......................................8116.6. Appendix 6: Urine Protein Creatinine (UPC) Ratio .....................................8516.7. Appendix 7: Protocol Amendment 1 – summary of changes ......................8616.8. Appendix 8: Protocol Amendment 2 – summary of changes ....................107
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LIST OF ABBREVIATIONS
%AUCex Percentage of AUC(0-) obtained by extrapolation
-HCG Beta-Human Chorionic Gonadotropin
M Micromolar
µg MicrogramµL Microliter89Zr Zirconium-89ABC’s Airway, breathing, and circulation from basic life supportADCC Antibody-dependent cell-mediated cytotoxicityAE(s) Adverse Event(s)ALP Alkaline phosphataseALT Alanine aminotransferaseANC Absolute neutrophil countAST Aspartate aminotransferase
AUC(0-) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time
AUC(0-) Area under the concentration-time curve over the dosing interval
AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments
AUC(0-x) Area under the concentration-time curve from zero (pre-dose) to some fixed nominal time x
BP Blood pressureBUN Blood urea nitrogenCBC Complete blood countCDC Complement dependent cytotoxicityCI Confidence IntervalCmax Maximum observed concentration CO2 Carbon dioxideCPK Creatine phosphokinaseCPMS Clinical Pharmacokinetic Modeling and SimulationCPR Cardio pulmonary resuscitationCPSR Clinical Pharmacology Study ReportCR Complete responseCRC Colorectal CancerCT Computed tomographyCV Coefficient of varianceCτ Pre-dose (trough) concentration at the end of the dosing intervalDMPK Drug Metabolism and PharmacokineticsDNA Deoxyribonucleic acidEC Ethics committeeECD Extracellular domainECG(s) Electrocardiogram(s)ECHO EchocardiogramECL Electrochemiluminescent
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ECOG Eastern Cooperative Oncology GroupeCRF Electronic case report formFSH Follicle Stimulating HormoneFTIH First time in humansGCP Good Clinical PracticeGGT Gamma glutamyltransferaseGI Gastrointestinal GLP Good Laboratory PracticeGSK GlaxoSmithKlineh/hr Hour(s)HBV Hepatitis B VirusHCC Hepatocellular CarcinomaHCV Hepatitis C VirusHER Human Epidermal Growth Factor Receptor HIV Human Immunodeficiency VirusHPLC High-performance liquid chromatographyHR Heart rateHRT Hormone replacement therapyIB Investigator’s BrochureICF Informed consent formICH International Conference on HarmonizationIEC Independent Ethics CommitteeIg ImmunoglobulinIgM Immunoglobulin MIHC ImmunohistochemistryIMP Investigational Medicinal ProductIND Investigational New DrugINR International normalization ratioIP Investigational ProductIRB Institutional Review BoardIU International UnitIV Intravenouskg KilogramKm Concentration at half maximal activity or rate L LiterLDH Lactate dehydrogenaseLH Luteinizing hormoneLLN Lower limit of normalln Naperian (natural) logarithmLSLV Last subject’s last visitLVEF Left Ventricular Ejection FractionmAb Monoclonal antibodyMBq MegaBequerelMCH Mean corpuscular hemoglobinMCHC Mean corpuscular hemoglobin concentrationMCV Mean corpuscular volume
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MDRD Modification of diet in renal diseaseMedDRA Medical Dictionary for Regulatory Activitiesmg MilligramsmL MilliliterMRI Magnetic resonance imagingMSDS Material Safety Data Sheetmsec MillisecondsmSv milliSievertMUGA Multi gated acquisition scanNA Not applicableNCI-CTCAE National Cancer Institute - Common Terminology Criteria for Adverse
Eventsng NanogramNK Natural killer cellsNSAID Nonsteroidal anti-inflammatory drugNSCLC Non-small cell lung cancerNYHA New York Heart AssociationORR Overall response rateOTC Over the counterPCI Potential clinical importancePd Progressive diseasePD PharmacodynamicPES PolyethersulfonePET Positron Emission Tomographypg PicogramPGx PharmacogeneticsPK PharmacokineticpM PicomolarPO PolyolefinPR Partial responsePT Prothrombin timePTT Partial thromboplastin timePVC Polymerizing vinyl chlorideQ Distributional clearanceQTc Corrected QT interval durationQTcF QT interval corrected for heart rate by Fridericia’s formulaRAP Reporting and Analysis PlanRBC Red blood cellsRNA Ribonucleic acidRoI Region of Interest
RP2D Recommended Phase 2 DoseRTK(s) Receptor Tyrosine Kinase(s)RT-PCR Reverse transcription-polymerase chain reactionSAE Serious adverse event(s)SD Stable disease or standard deviationSPM Study Procedures Manual
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SUV Standardized Uptake Valuet Time of last observed quantifiable concentrationt1/2 Half-lifetmax Time of occurrence of CmaxUK United KingdomULN Upper limit of normalUPC Urine protein creatinineUS/USA United States/United States of AmericaV Volume of distributionVm Maximal rate VUMC VU University Medical Centre AmsterdamWBC White blood cellsτ Dosing interval
Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of companies
NONE WinNonlin
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1. INTRODUCTION
1.1. Background
The epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) is comprised of HER1 (EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Whilst EGFR and HER2 already have established roles in oncogenic signaling there is now accumulating evidence of a role for the kinase deficient HER3 in driving malignant growth. Forming a heterodimer with another kinase proficient RTKs such as HER2, HER3 is capable of potent signaling through the phospho-inositide 3-kinase (PI3K) pathway leading to proliferation. Signaling can occur in a ligand-dependent or independent manner and can allow escape of tumor growth from inhibition of partner RTKs. Over expression of HER3 is correlated with adverse prognosis in a number of malignancies (colorectal, gastric, breast, ovarian, melanoma, pancreatic, cervical and cancers of the head and neck) and activating mutations were found to be present in around 11% of colonic and gastric cancers. Signaling through this receptor is an attractive target as it promotes malignant growth and acts as a means of resistance to other established therapeutics.
It is therefore desirable to develop agents that are capable of targeting HER3 as they are expected to provide clinical benefit either alone or in combination with other agents. Monoclonal antibodies offer an ideal means of blocking both ligand-dependent and independent signaling as well as targeting cells over-expressing HER3 for destruction by immune effectors via antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). To this end GSK2849330, a monoclonal antibody specific to HER3, is being developed. A first time in human (FTIH) study is being undertaken to assess the safety, tolerability and pharmacokinetics of GSK2849330 as well as looking for preliminary evidence of target engagement (including total HER3 and phosphorylated HER3) in subjects with advanced HER3-positive tumors. An understanding of the distribution of GSK2849330 into tumor tissue and its interaction with HER3 would greatly facilitate development of this monoclonal antibody (mAb) as a drug, helping to determine an optimal dose level to be taken forward for further clinical development.
Positron Emission Tomography (PET) scanning is ideal for this application being both quantitative and capable of assessing antibody binding sites throughout the body. Labeling antibodies with the radionuclide 89Zr allows them to be tracked by PET scanning and has previously been used to monitor the distribution of the anti-HER2 antibody trastuzumab to HER2-positive breast cancer deposits (Dijkers, 2010). The half-life of 89Zr is 3.3 days allowing imaging to take place over a timeframe that is relevant to the bio-distribution of monoclonal antibodies. Internalization and degradation of labeled antibody causes the zirconium to be retained within the cell. This residualising property allows the measured tissue signal to be related to the local exposure to the labeled antibody over time. Taking readings at more than one time point and relating these to both the area under concentration-time curve (AUC) and plasma concentration of drug allows an estimate of the rate of internalization to be made. Using a low total dose of drug initially allows maximal internalization of the radiolabeled antibody and can establish a baseline of uptake. Subsequent co-administration of a larger dose of unlabeled mAb along with radiolabeled mAb will result in increased competition for receptor
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binding. At sufficient concentrations of unlabeled mAb this will lead to inhibition of radiolabeled mAb uptake and diminishment of the internalized component of the signal. The degree of inhibition for each site can be established by comparison to the initial baseline scans. Assessing the effect of different dose levels of unlabeled antibody allows characterization of the dose-dependency of receptor-mediated clearance at a given site. From this a prediction of the dose required to saturate the target in the site of interest can be derived. This information is complementary to the endpoints of the FTIH study. Data generated from PET imaging will allow assessment of the bio-distribution of antibody as well as target binding, events which take place upstream of other pharmacodynamic measurements and therefore not subject to the same potential confounding factors. This information will form part of a package of information which can be used to select a suitable dose to take forward for further development of GSK2849330.
1.2. GSK2849330
1.2.1. GSK2849330 Background
Detailed information concerning the biology, pharmacology, pharmacokinetics (PK), and safety can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document Number 2013N168399_00]. GSK2849330 is a humanized IgG1/IgG3 monoclonal antibody (mAb) with a molecular mass of approximately 145 kDa. GSK2849330 selectively binds HER3 at Domain III which resides in the extracellular domain (ECD) of the protein. HER3 sequences are 99% identical (99% homologous) between human and cynomolgus monkey, and 91% identical (94% homologous) between human and rat or mouse. The binding affinity of GSK2849330 for HER3 across these species is comparable: human: 2.1 nM; cynomolgus monkey: 1.7 nM; mouse: 4.1 nM; rat: 3.4 nM. In addition to directly blocking ligand (heregulin) binding to the HER3 ECD, the antibody also sterically prevents the receptor from adopting the extended conformation that is required for dimerization, a prerequisite for receptor activation.
GSK2849330 is a glyco-engineered antibody with enhanced potency for ADCC and CDC. ADCC causes tumor cell lysis upon binding of antibody to target, followed by engagement of cytotoxic T-cells and natural killer (NK) effector cells via their FcRIIIA receptors. Perforin, granulysin and serine proteases released from cytoplasmic granules within cytotoxic T-cells and NK cells produce tumor cell lysis. CDC, considered one of the most powerful cell-killing mechanisms of antibodies, [Walport, 2001] results from assembly of the ‘membrane attack complex’ that punches holes in the target cell membrane leading to tumor cell lysis. Compared with a wild-type antibody, GSK2849330 has a 16-18 fold greater binding affinity to human FcRIIIA (responsible for initiating ADCC) and a 17-fold higher affinity to human complement protein (C1q, responsible for initiating CDC). These increased binding affinities translated to enhanced potency of GSK2849330, compared to wild type antibody, in cell-based assays for ADCC and CDC (see IB for details [GlaxoSmithKline Document Number 2013N168399_00]).
In summary, there are three main potential antitumor modes of action when GSK2849330 is administered as monotherapy: a) inhibition of signaling; b) ADCC and c) CDC. The latter two mechanisms provide an opportunity for differentiation from non-ADCC and non-CDC- enhanced HER3-directed mAbs in clinical development, based on direct
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killing of both dividing and non-dividing cells, which may be independent of inhibition of downstream signalling.
1.2.2. Pharmacokinetics of GSK2849330
Details of pre-clinical PK are given in the IB [GlaxoSmithKline Document number 2013N168399_00]. Clinical PK data from the FTIH study will be used to inform this study as they become available.
1.2.3. Safety of GSK2849330
Details of pre-clinical toxicology of GSK2849330 are given in the IB GlaxoSmithKline Document Number 2013N168399_00]. Clinical safety data from the FTIH will be utilized to guide dosing in this study as it becomes available. No dose level will be explored in this study unless it has been cleared as being safe and tolerable by the FTIH study team.
1.3. Summary of Risk Management
1.3.1. GSK2849330-specific risks
The anticipated adverse event(s) (AEs) include:
Gastrointestinal (GI): Mild GI hazard/diarrhea (multifocal ulceration of the cecum and colon, and abnormal fecal consistency), was observed in monkeys. High-grade diarrhea has not been reported with other HER3-targeting agents that have already been tested in the clinic; however precautions have been added to the protocol in the event that unexpected GI toxicity is observed with GSK2849330. Medical history, physical examination and clinical laboratory assessments will be used to identify and assess toxicity in the GI tract. Supportive therapy will be provided according to the diarrhea management guidelines provided in Section 3.11.3 and standard medical practice. Treatment with GSK2849330 will be withheld for clinically significant toxicity.
Prostate: Reversible decreases in prostate weight and serum testosterone and Luteinizing Hormone (LH) concentrations were seen in rats given GSK2849330. Decreases in prostate weight may represent inhibited or reduced androgen receptor activation. No clinical consequences are expected from decreased prostate volume and no clinical signals relating to prostate have emerged from ongoing studies with other agents that target HER3. However, serial measurement of testosterone and LH will be performed in male study subjects to explore for clinical correlation.
Infusion-related and immune-mediated side effects: As GSK2849330 is a fully humanized antibody it is considered unlikely for acute allergic reactions to occur in response to GSK2849330 exposure. However there is a risk of infusion-related or acute allergic reactions during administration of IV immunoglobulins, including monoclonal antibodies. Subjects must be monitored closely for signs and symptoms of infusion-related and acute allergic reactions and/or anaphylaxis following the administration of GSK2849330. It is required that
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appropriate procedures for the management of these side effects are in place and ready to be instituted based on clinical need, see Section 3.11.1 and Section 3.11.2 for further details on management.
Further information on these potential risks can be found in the IB for GSK2849330 [GlaxoSmithKline Document Number 2013N168399_00]
1.3.2. Ionising radiation
The radiation exposure from PET/ computed tomography (CT) scanning comes from two sources, the radionuclide injected for PET scanning and the exposure to x-rays that make up the CT scan component of the PET/CT.
Effective dose per low dose co-localising CT scan is 2.9mSv
Previous studies using 89Zr labeled IgG1 monocloncal antibodies have measured effective dose of between 0.5-0.66mSv/MBq of administered 89Zr-mAb [Börjesson, 2009].
Each administration of radiolabelled drug will have an activity of up to 37 MBq. Each subject will receive 2 radiolabelled doses.
The estimated total effective dose from both administrations of radionuclide is therefore expected to be between 37 (37MBq x 0.5mSv/Bq x 2 doses) and 48.8mSv (37MBq x 0.66mSv/Bq x 2 doses). The dose from low dose co-localising CT scans is estimated at 17.4mSv for the two subjects receiving six scans and a maximum of 14.5mSv for all other subjects (who receive up to 5 scans). Total radiation dose attributable to PET scanning procedures is therefore estimated to be between 54.4mSv and 66.2mSv for the two subjects receiving six scans and between 51.5mSV and 63.3mSv for all other subjects.
Where use of echocardiography is not possible, additional trial specific radiation exposure may come from the use of multi gated acquisition scan (MUGA) to assess left ventricular ejection fraction (LVEF). Each MUGA scan is estimated to have an effective dose of 3.5mSv. LVEF assessment will be carried out at screening, after four weeks and the every eight weeks or more frequently if clinically indicated.
The additional risk of developing a secondary malignancy due to trial specific radiation exposure over the remaining lifespan of subjects participating in this study is considered to be low and in line with the risk from standard of care procedures. In subjects with advanced solid malignancies lacking standard therapeutic alternatives the potential benefit from receiving GSK2849330 is anticipated to be greater than the potential risk from the radiation exposure above that deemed necessary for standard of care. Once an effective drug dose for imaging is established, data from the first three subjects to have representative scans in this study will be used to help refine estimates of dosimetry for 89Zr-GSK2849330.
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2. OBJECTIVES AND ENDPOINTS
Objective Endpoint(s)Primary
1.1Measure in vivo biodistribution of 89Zr -GSK2849330 in subjects with HER3 positive tumors.
Quantitative parameters derived from PET-CT images to assess uptake in tumor tissue and normal tissues of interest:o SUV (peak, mean) for each region of
interest (organ or lesion)o Volume of region of interest
Secondary
2.1
Establish dose-dependency of inhibition of target-mediated uptake of 89Zr-GSK2849330 by unlabeled GSK2849330 in HER3 positive tumors.
PET-CT images showing anatomical localization of radiolabelParameters from a pharmacometric model
estimating uptake to tumorsChange in uptake parameters in response to the
dose difference between dose 1 and 2. Blood radioactivity concentration:
o Whole blood SUVo Plasma SUVo Features of tumor : Central necrosis. Irregular shape Non-uniform uptake Lesion id (maps to RECIST assessments)
2.2To help further characterize the PK of GSK2849330 following IV administration.
o GSK2849330 PK parameters
2.3Measure dosimetry of 89Zr-GSK2849330 in subjects with advanced HER3-positive tumors
The following endpoints will be derived and provided for each subject for which dosimetry data is collected:o Organ dose (mSv)o Recorded for each organo Effective dose (mSv)o A single value for each subject
2.4 Safety and tolerability of GSK2849330
Adverse events (AEs), serious adverse events (SAEs), changes in laboratory values, electrocardiograms (ECGs), left ventricular ejection fraction (LVEF) and vital signs.
2.5To help further evaluate the immunogenicity of GSK2849330 following IV administration.
Antibodies to GSK2849330 assessed in serum.
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Objective Endpoint(s)Exploratory
3.1
Explore association of target-mediated uptake in tumor tissue with other factors such as level of HER3 IHC, size, site and histology of tumor.
H score or other measure of HER3 intensity from IHC
Tumor histology and molecular sub-type (when known)
3.2
Explore association between target mediated uptake in tumor tissue and change in tumor volume and growth rate
Tumor volume
Tumor growth rate
3.3
Develop a model of global distribution and clearance of GSK2849330 in subjects with advanced HER3-positive solid tumors.
Radioactivity measurements in tumor tissue, normal tissues of interest and blood at different time points and dose levels in a global model of tissue distribution and clearance
3.4Explore preliminary tumor outcomes and preliminary evidence of benefit following treatment with GSK2849330
Clinical benefit as assessed by overall response rate (ORR), tumor markers, and other measures of clinical benefit.
3. INVESTIGATIONAL PLAN
3.1. Study Schematic
The total number of PET scans will be no greater than five in the majority of subjects with two subjects during the course of the study receiving the same dose for dose 1 and dose 2 undergoing six scans to assess intra-subject variability.
Timing of PET scans may be adjusted as data emerge to enable generation of an optimal data set.
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3.2. Discussion of Study Design
This is an open label, PET imaging study of the anti-HER3 monoclonal antibody GSK2849330 labeled with 89Zr in subjects with advanced solid tumors expressing HER3. The study will be run in a staggered fashion with the FTIH study of GSK2849330 and will utilise safety and tolerability data from the FTIH study. Dose levels of GSK2849330 will only be used in this imaging study once cleared by the FTIH study team as safe and tolerable. Each subject will take part in an initial imaging phase, Part 1, followed by a treatment continuation phase, Part 2, as depicted below.
Part 1Imaging Phase
1. Eligible subjects will receive a dose of 89Zr-GSK2849330, Dose 1, with an activity of no more than 37MBq and a variable total dose of GSK2849330.
2. 2 - 4 PET scans will be acquired within 7 days. Blood samples will be collected for measurement of radioactivity and PK analysis
3. Two weeks after Dose 1 subjects will receive a second dose of 89Zr-GSK2849330, Dose 2, with an activity of no more than 37MBq and a variable total dose of GSK2849330. A blood sample for radioactivity and PK measurement will be collected just prior to Dose 2.
4. 2 - 4 PET scans will be acquired within 7 days. Blood samples will be collected for measurement of radioactivity and PK analysis.
Part 2
Continuation PhaseSubjects will continue dosing with unlabeled GSK2849330 at either the recommended phase 2
dose (RP2D), or if the RP2D has not yet been established a dose level will be selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have
previously been cleared as being safe and tolerable by the FTIH study.
Data will be collected on safety, tolerability and clinical response.
In part 1, the imaging phase, the study will use GSK2849330 radiolabeled with 89Zr (89Zr-GSK2849330). Subjects with advanced HER3-positive solid tumors will receive two doses with no more than 37MBq of 89Zirconium for each dose approximately two weeks apart (the delay being necessary to ensure decay of previously administered radioactivity). The total drug mass administered with each dose will be varied but will not exceed a maximum of 30mg/kg per dose, the highest dose level planned in the FTIH study. PET scans together with accompanying attenuation correction CT scans will be acquired in the seven days following each dose of 89Zr-GSK2849330. The distribution and timings of the scans may be varied but the total number of scans throughout the imaging phase will be no more than five in the majority of subjects, see Section 3.1.
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Blood samples will be taken for radioactivity measurements, safety laboratory, and PK analysis.
The initial aim will be to establish a dose of drug optimal for imaging uptake of 89Zr-GSK2849330 into HER3 expressing tissues and tumors. Visual and quantitative analysis of the scans taken following each dose received by the first subject(s) will be used to select a suitable dose for use in subsequent subjects as Dose 1. This dose will be used to establish a baseline uptake of 89Zr-GSK2849330 in tumors. Dose 2 will then be varied to inhibit the target-mediated uptake of radiolabeled antibody by tumor tissue aiming to explore a range of inhibition of specific uptake. Understanding the dose-dependency of this relationship will be used to predict a dose likely to achieve maximal inhibition of target-mediated clearance in tumor.
During the course of the study two subjects will be selected to undergo a total of six scans. These two subjects will receive the same dose of GSK2849330 for both Dose 1 and Dose 2 and will help to assess intra-subject variability. The rest of the subjects will have no more than five PET scans in total.
Dosimetry will be measured following Dose 1 for the first three subjects to have the selected imaging dose.
Once subjects have completed part 1 of the study they will move on to a maintenance phase, part 2, where they will continue dosing with GSK2849330 at the Recommended Phase II Dose (RP2D). If the RP2D has not yet been established, a dose level will be selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study. Dosing will continue until study discontinuation due to disease progression, death, unacceptable toxicity, withdrawal of subject consent, major deviations from protocol or at the investigator’s discretion or if the study or development of the asset is terminated. Intra-subject dose escalation will be allowed in the maintenance phase based on the data from the FTIH study. Subjects in the maintenance phase will continue to have safety and tolerability data collected per the schedule of events along with clinical assessments.
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table (Section 7.1), are essential.
Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.
3.3. Pre-screening
Subjects will be required to undergo pre-screening to determine if their tumor is HER3 expressing by immunohistochemistry (IHC), (details regarding HER3 expression requirements will be described in the SPM). Subjects with advanced solid tumors will sign an Informed Consent Form (ICF) to allow for pre-screening of archival tumor or tissue from fresh tumor biopsies for HER3 expression by an analytically validated IHC
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assay in a central laboratory. Pre-screening and screening assessments may take place concurrently provided appropriate consents have been documented in writing.
3.4. Part 1: Imaging Phase
An initial range of six dose levels will be explored as shown in Table 1. The two lowest dose levels, A and B, will be fixed total amounts of drug made up by the addition of unlabelled GSK2849330 to the radiolabeled GSK2849330 and given as a single short IV infusion injection of approximately 10 minutes duration. Dose levels C, D, E and F will be weight-adjusted and will be given as two separate IV infusions. First an infusion of unlabeled GSK2849330 lasting approximately 1 hour, followed within 2 hours (preferably within 1 hour) of the end of the first infusion, by the 89Zr-GSK2849330 containing infusion injection (lasting approximately 10 minutes). The 89Zr-GSK2849330 containing infusion will contain either 8mg or 24mg of GSK2849330, ie:
Total dose (mg) = (dose level (mg/kg) x weight (kg))
GSK2849330 (mg) = Total dose (mg) – 89Zr-GSK2849330 (8mg or 24mg)
For example,
A subject weighing 68kg and receiving Dose level D, 3mg/kg (Total dose = 3mg/kg x 68kg = 204mg) could receive:
180mg GSK2849330, followed by 24mg 89Zr-GSK2849330 to give a total dose of 204mg
OR
196mg GSK2849330, followed by 8mg 89Zr-GSK2849330 to give a total dose of 204mg
Other dose levels may be explored depending on information obtained during the study or from emerging information from the first time in human study HER117158 but will not exceed 30mg/kg.
Table 1 Proposed Dose levels of GSK2849330 for Part 1
Dose level Total amount of GSK2849330 per dose (labelled + unlabelled drug)
Proposed interval (if used as Dose 2) before starting Part 2
Planned first Dose in Continuation Phase
A 8mg 1 week Day 22B 24mg 1 week Day 22C 1mg/kg 1 week Day 22D 3mg/kg 2 weeks Day 29E 10mg/kg 2 weeks Day 29F 30mg/kg 2 weeks Day 29NB: Dose level and dose interval may be adjusted based on emerging data
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3.4.1. Imaging dose selection
The initial goal will be to establish a suitable imaging dose to use for Dose 1. The aim will be to achieve the lowest dose that achieves good uptake of 89Zr-GSK2849330 into HER3 expressing tissues and tumors. Given the expected non-linear nature of target-mediated clearance for this mAb, low doses may be cleared too rapidly to allow meaningful measurements to be taken. However, to establish a maximal baseline uptake of radiolabeled mAb the dose used should be sufficiently low to avoid limiting uptake through competition from unlabeled mAb. Dose levels will be explored until a suitable dose is identified. Doses and scan times (time given from the completion of the 89Zr-GSK2849330 containing infusion) for the first two subjects are outlined below although these may change as more information becomes available. Visual and quantitative analysis of the scans and blood measurements will be undertaken following each dose to select a dose which allows good uptake into HER3 expressing tissue and tumor.
Subject (5 scans total):
1st Dose = 8mg, PET Scans: 3hrs (1hrs), 48hrs (6hrs), 120hrs (6hrs).
2nd Dose = 24mg, PET Scans: 48hrs (6hrs), 120hrs ( 6hrs).
Subject (5 scans total):
1st Dose = Dose 24mg, PET Scans: 3hrs (4hrs), 48hrs (6hrs), 120hrs (6hrs).
2nd Dose = Dose 1mg/kg, PET Scans: 48hrs (6hrs), 120hrs ( 6hrs).
The dose levels explored and the timings of scans may be altered based on emergent data as it becomes available. If no suitable dose is established in the first two subjects further dose levels may be explored until one is found.
Once a dose level for Dose 1 has been identified this will be used to measure the baseline uptake of 89Zr-GSK2849330 by tumor tissue in each subject. Dosimetry will be measured for the first three representative subjects treated at this dose. Dose 2 will be varied to explore the dose-dependency of inhibition of specific uptake looking to cover a range of inhibition of baseline uptake. Subjects will be recruited to available dose levels as determined by the study team on the basis of available evidence to maximise the information obtained from each new subject, (a dose level is available for use in this study once it has been cleared as being safe and tolerable by the FTIH study team). Quantitative analysis of the results of each subject will be undertaken as they become available and may be used to alter the range of dose levels recruited to or establish new doses to a maximum of 30mg/kg to allow optimum coverage of the inhibition of uptake curve. If this range of inhibition is not achieved by the available dose levels then Dose 1 may be increased to explore higher cumulative dose levels. During the course of the study two subjects will undergo a total of six scans and will receive the same dose of GSK2849330 for Dose 1 and Dose 2 to assess intra-subject variability.
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3.4.1.1. PET/CT scans:
Details on the procedures for the acquisition of PET scans and attenuation correction CT scans will be included in the SPM. Scans will be acquired following each dose containing 89Zr-GSK2849330. Each PET scan requires the patient to lie still on the PET couch during the acquisition which typically lasts for about 45-60 minutes. For subjects having dosimetry measured the timings of the scans after Dose 1 will remain as the timings for the first two subjects. For subsequent subjects these timings may be changed as new information becomes available on the PK of GSK2849330 and on the basis of information obtained from previous scanning runs Quantitative analysis of scans will be undertaken for each subject when available to determine the activity values for each tissue and region of interest at each time point. Blood samples will be taken across this period to allow measurements of blood radioactivity and for PK analysis as indicated in the time and events table (Section 7.1).
3.5. Part 2: Continuation Phase
Once a subject has completed Part 1 they will not receive any further doses containing 89Zr-GSK2849330 but will continue to receive GSK2849330. The dose level and interval given will be the RP2D if established. If the RP2D has not yet been established a dose level felt most likely to give clinical benefit will be selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study, see Table 2 for list of potential dose levels. Alternative dosing levels and intervals may be used if established by the FTIH study. The timing of the first dose on the continuation phase will be determined by the interval required following Dose 2 during the imaging phase. If Dose 2 is at or below a level cleared for 1 weekly dosing then the first continuation dose may be given on Day 22. If Dose 2 is at a level only cleared for 2 weekly dosing the first continuation dose may be given on Day 29.
The interval between doses will never be less than that cleared by the FTIH study. Safety endpoints will be collected along with assessments of clinical response and tumor growth rate. Response will be defined either as Complete Response (CR) or Partial Response (PR) as per RECIST 1.1 guidelines.
Table 2 Proposed Dose levels of GSK2849330 for Part 2
Dose level Dose GSK2849330 Dosing IntervalG 1.4mg/kg 7 daysH 3mg/kg 14 daysI 10mg/kg 14 daysJ 30mg/kg 21 daysK 30mg/kg 14 daysNB: Dose level and dose interval may be adjusted based on emerging data
3.6. Intra-subject Dose-Escalation
Once on the treatment continuation phase a subject’s dose level may be increased up to the highest dose level that has previously been confirmed by the FTIH study team as
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being safe and tolerable. Intra-subject dose escalations will be allowed provided that the subject has not experienced toxicity greater than Grade 2 NCI-CTCAE, version 4.0 [Common Terminology Criteria for Adverse Events, Version 4, 2009] or the occurrence of significant AEs, and prior approval has been obtained from a GSK medical monitor. Subjects will be permitted to increase dose levels multiple times provided the above criteria are met. Any dose escalations must be agreed upon by the investigator and GSK medical monitor, and must be documented on a dose escalation decision form (see the SPM) with copies maintained at the site and in the study files.
3.7. Rationale
3.7.1. Rationale for Study
HER3 expression is associated with poor prognosis in a number of tumor types and signaling via this pathway is a common mechanism of resistance to a number of other therapies including HER2 and EGFR directed treatments. There is considerable unmet medical need across the tumor types where HER3 is expressed and GSK2849330 a mAb offers a unique therapeutic approach with enhanced ADCC and CDC capabilities.
PET imaging is a feasible way of obtaining quantitative information on the levels of drug present in tissues throughout the body simultaneously and at multiple time points without being as invasive as multiple biopsies or micro-dialysis. 89Zirconium is an ideal choice of radionuclide both due to its spectrum of emission and due to its half-life of 78.4hrs allowing measurements to be taken over a timeframe relevant to the bio-distribution of mAbs. The residualizing nature of this radionuclide also allows an assessment of total tumor uptake of mAb. This will allow measurements of the interaction of GSK2849330 with cell surface HER3, information which will complement the data from the FTIH study on downstream PD markers. Data on the saturation of target mediated uptake will be combined with the information obtained from the FTIH study to support selection of an effective dose to take forward for further clinical development.
3.7.2. Rationale for Population
Subjects will be selected on the basis of HER3 expression on the cell membrane of the invasive component of the tumor. Expression of receptor is a pre-requisite for binding by drug and therefore required for both potential clinical benefit and uptake of 89Zr-GSK2849330 for imaging.
3.7.3. Rationale for Dose
The proposed doses of GSK2849330 used in this study are mirrored on the doses used in the FTIH study. Dose levels used in Part 1 have been selected by using half-log steps to give dose levels which cover the range of dose levels selected for the FTIH study as well as two dose levels below this to ensure adequate cover of the dose range. An adaptive approach will be used as discussed above to define an optimal imaging dose to use for Dose 1 and establish the range of doses to explore for Dose 2. The dose levels for use in Part 2 are those planned for use in the FTIH study.
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Refer to the IB [GlaxoSmithKline Document Number 2013N168399_00] for additional information on the preclinical biology and toxicology studies.
3.7.4. Rationale for Endpoints
PET endpoints will allow assessment of the drug exposure at each site at multiple time points. Using this data from regions of interest and blood at multiple time points will allow measurement of the rate of internalization of 89Zr-GSK2849330. Comparing the uptake of 89Zr-GSK2849330 in the same tumor at different total doses of GSK2849330 will help to predict a dose which will saturate target binding in tumor tissue. Dosimetry data will help to guide further studies using 89Zr-GSK2849330 and other 89Zr labeled mAbs. Data from tumor tissue and normal tissues can be combined with pharmacokinetic endpoints to give a global model of the disposition of the antibody to further help with understanding the pharmacokinetic properties of GSK2849330.
The safety endpoints for all parts of the study are designed to maximize subject safety, to allow for the identification and monitoring of emerging safety signals.
Efficacy endpoints and assessment of alterations in tumor growth rate will be collected to evaluate preliminary evidence of clinical benefit from treatment with GSK2849330.
3.8. Study Treatment
3.8.1. Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the duration of the study.
Upon completion of all the required screening assessments, eligible subjects will be enrolled and will receive GSK2849330. There is no placebo treatment in this study.
3.9. Dosage and Administration of Study Treatment(s)
Guidance for the monitoring and managing of infusion related reactions and allergic/hypersensitivity reactions, including anaphylaxis, are outlined in Section 3.11.1and Section 3.11.2.
PART 1, doses A & B
At the start of each scanning period a preparation containing 89Zr- GSK2849330, with a maximum total radioactivity of 37MBq, will be administered as a short intravenous infusion (injection over ca. 10 minutes).
PART 1, doses C to F
Unlabeled GSK2849330 will be given by IV infusion over a 1 hour period. If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms; the subject will receive appropriate medical
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treatment. When the subject’s condition is stable, the infusion may be restarted according to the judgment of the investigator. Upon restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
At the start of each scanning period a preparation containing 89Zr- GSK2849330, with a maximum total radioactivity of 37MBq, will be administered as a short intravenous infusion (injection over ca. 10 minutes). This will be commenced within two hours of completing the infusion of unlabeled GSK2849330 (preferably within one hour).
PART 2, all doses
GSK2849330 will be given by IV infusion over a 1 hour period. If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms; the subject will receive appropriate medical treatment. When the subject’s condition is stable, the infusion may be restarted according to the judgment of the investigator. Upon restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
Subjects should be monitored for at least 1 hour after the completion of the infusion and may be discharged if considered clinically stable and all other study procedures have been completed.
3.9.1. Blinding
This is an open-label study.
3.10. Safety Management Guidelines
3.10.1. Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology during administration of study treatment(s) and the follow-up period up to the first follow up visit 28 days from the last dose of GSK2849330. Study treatment(s) will be stopped if any of the following liver chemistry stopping criteria is/are met:
1. Alanine aminotransferase (ALT) 3 times upper limit of normal (ULN) and bilirubin 2 times ULN (or ALT 3 times ULN and international normalization ratio [INR] >1.5)
NOTE: Serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).
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2. ALT 5 times ULN.
3. ALT 3 times ULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain, tenderness or jaundice) or hypersensitivity (such as fever, rash or eosinophilia, other than that as described in Section 3.10.1 and Section 3.11.2).
4. ALT 3 times ULN persists for 4 weeks.
5. ALT 3 times ULN and cannot be monitored weekly for 4 weeks.
Subjects with ALT 3 times ULN and <5 times ULN and bilirubin <2 times ULN, who do not exhibit hepatitis symptoms or rash, can continue study treatment(s) as long as they can be monitored weekly for 4 weeks. See following section for details on weekly follow-up procedures for these subjects.
3.10.1.1. Liver Chemistry Follow-up Procedures
Refer to the diagram in Appendix 5 for a visual presentation of the procedures listed below.
The procedures listed below are to be followed if a subject meets the liver chemistry stopping criteria defined in Section 3.10.1:
Immediately and permanently withdraw the subject from study treatment.
Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to confirm the subject’s study treatment(s) cessation and follow-up.
Complete the “Safety Follow-Up Procedures” listed below.
Complete the liver event electronic case report forms (eCRFs). If the event also meets the criteria of a serious adverse event (SAE) (see Section 8.2), the SAE data collection tool will be completed separately with the relevant details.
Upon completion of the safety follow-up permanently withdraw the subject from the study and do not rechallenge with study treatment(s).
Safety Follow-Up Procedures for subjects with ALT 3 times ULN:
Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase [AST], alkaline phosphatase [ALP], and bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3 times ULN and bilirubin 2 times ULN (or ALT 3 times ULN and INR >1.5):
This event is considered an SAE (see Section 8.2). Serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).
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Make every reasonable attempt to have subjects return to the clinic within 24 hours for repeat liver chemistries, additional testing, and close monitoring (with specialist or hepatology consultation recommended).
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3 times ULN, every attempt must be made to also obtain the following:
Viral hepatitis serology including:
Hepatitis A Immunoglobulin M (IgM) antibody.
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).
Hepatitis C ribonucleic acid (RNA).
Cytomegalovirus IgM antibody.
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing).
Hepatitis E IgM antibody (if subject resides outside the United States (US) or Canada, or has traveled outside US or Canada in past 3 months).
Blood sample for PK analysis, obtained within 45 days of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment(s) prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are included in the SPM.
Serum creatine phosphokinase and lactate dehydrogenase.
Fractionate bilirubin, if total bilirubin 2 times ULN.
Obtain complete blood count with differential to assess eosinophilia
Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia, on the AE eCRF.
Record use of concomitant medication(s), acetaminophen, herbal remedies, other over-the-counter medication(s), or putative hepatotoxins on the Concomitant Medications eCRF.
Record alcohol use on the Liver Events eCRF.
The following are required for subjects with ALT 3 times ULN and bilirubin 2 times ULN but are optional for other abnormal liver chemistries:
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.
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Liver imaging (ultrasound, magnetic resonance imaging [MRI] or computed tomography [CT] scan) to evaluate liver disease.
Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are performed.
Serum acetaminophen adduct high-performance liquid chromatography (HPLC) assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week, [James, 2009]).
Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793.
3.10.2. QTc Stopping Criteria
If a subject meets the QTc1 interval duration criteria below, study treatment(s) will be withheld.
QT interval corrected for heart rate (HR) by Fredericia’s formula (QTcF) >530 msec1Based on average QTc value of triplicate ECGs to include manual over-read. For example, if an ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period (e.g., within approximately 10 minutes of the abnormal ECG, if possible, and approximately 10 minutes apart from each other), and then use the averaged QTc values of the 3 ECGs to determine whether the subjects should have study treatment(s) withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on the study treatment(s) if the investigator and GSK Medical Monitor agree that the subject will benefit from further treatment.
3.10.3. Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
Echocardiography (ECHO) or MUGA must be performed at Screening and as outlined in the Time and Events Tables (Section 7.1). Subjects who have an asymptomatic, absolute decrease of >15% in LVEF compared with baseline or an absolute decrease of >10% in LVEF compared with baseline and the ejection fraction is below 50% should temporarily discontinue GSK2849330 and have a repeat evaluation of LVEF within 1 week. ECHO should be repeated every 1 to 2 weeks for 4 weeks or until LVEF recovery to within15% of baseline or to above 50% and within 10% of baseline depending on which stopping criteria above were met.
If the LVEF recovers (defined as absolute decrease 15% compared to baseline or 50% and absolute decrease 10% compared with baseline) at any time during the next 4 weeks, after consultation and approval of the GSK Medical Monitor, the subject may be restarted on GSK2849330 at a reduced dose. For such subjects, monitoring of LVEF will be performed 2, 4, and 8 weeks after rechallenge, and then per protocol.
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If repeat LVEF does not recover within 4 weeks, treatment with GSK2849330 should be permanently discontinued. Ejection fraction should be monitored every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must discontinue treatment with GSK2849330. Ejection fraction should be monitored every 4 weeks for a total of 16 weeks or until resolution. If recovery occurs (LVEF 50% and symptom resolution) within 4 weeks, treatment with GSK2849330 may be restarted at a reduced dose if the subject is receiving clinical benefit and in consultation with the GSK Medical Monitor.
Copies of all ECHOs/MUGAs and cardiology consultations performed on subjects who experience a >15% decrease in LVEF from baseline or >10% decrease in LVEF from baseline and whose cardiac ejection fraction is < 50% will be required by GSK for review. Instructions for submitting qualifying ECHOs/MUGAs are provided in the SPM.
3.11. Guidelines for Events of Special Interest and Dose Modifications
The severity of AEs will be graded utilizing NCI-CTCAE, version 4.0 [Common Terminology Criteria for Adverse Events, 2009]. Guidelines for dose modifications and interruptions for management of common toxicities associated with the study treatment(s) are provided in this section.
3.11.1. Management of Infusion Reactions
As there is a risk of infusion reactions during administration of IVimmunoglobulins, including monoclonal antibodies, subjects will be monitored forsigns and symptoms of an infusion-related reaction (including Grade 1 to 2 fever, chills, headache, nausea, malaise) during infusion and for a minimum of 1 hr after administration of GSK2849330.
If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms and the subject will receive appropriate medical treatment. A serum sample should be collected within 3 hours for any subject experiencing an infusion reaction and stored for subsequent analysis of markers of immune activation. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
Treatment may include: Fevers/Myalgia: Use acetaminophen. If subject’s fever does not respond to
acetaminophen, consider a nonsteroidal anti-inflammatory drug (NSAID) such as indomethacin. Consider pre-medicate with acetaminophen (paracetamol) for subsequent doses.
Chills/rigors: Use warming blankets as initial maneuver; consider IV meperidine (pethidine) if chills persist.
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Nausea/vomiting: consider 5-HT3 antagonists, prochlorperazine, lorazepam; some agents may cause hypotension and altered mental status, therefore, use with caution.
Monitoring for allergic reactions and the management of anaphylaxis is outlined in Section 3.11.2.
3.11.2. Allergic Reaction Management
As GSK2849330 is a fully humanized antibody, it is considered unlikely for acute allergic reactions to occur in response to GSK2849330 exposure; however, all subjects will be monitored carefully for evidence of allergic response. A subject that exhibits signs or symptoms of severe hypersensitivity or anaphylaxis will receive appropriate medical treatment and will not proceed with injection of 89Zr-GSK2849330 and will not receive further doses of GSK2849330 but will continue to be followed up for safety analyses as per time and events table Section 7.1. A serum sample should be collected within 3 hours for any subject experiencing an allergic reaction and stored for subsequent analysis of markers of immune activation.
In accordance with the preparedness for treatment of anaphylaxis, emergency resuscitation equipment, advanced cardiac life support equipment, and medications must be readily accessible during GSK2849330 administration.
It is important to recognize early signs of an anaphylaxis reaction and appropriate treatment must begin immediately to prevent progression to severe anaphylaxis. Subjects will be closely monitored in an appropriate setting for early signs of dyspnea and edema. Antihistamines, such as diphenhydramine; and corticosteroids such as prednisolone may be given to reduce symptoms.
If more severe clinical signs arise, immediate assessment of the ABC's (airway, breathing, and circulation from Basic Life Support) will be done in all suspected anaphylactic reactions. Cardio-Pulmonary Resuscitation (CPR) will be initiated if needed. Epinephrine will be given by injection without delay. Emergency interventions may include endotracheal intubation or tracheostomy. Treatment for shock will include IV fluids and medications that support the actions of the heart and circulatory system.
3.11.3. Diarrhea Management
If episodes of diarrhea occur, causes for the diarrhea other than the study treatment such as concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, partial bowel obstruction, etc., should be ruled out. Supportive measures should include the following as clinically indicated:
Dietary modifications (e.g. small, frequent meals, low fiber, and lactose-avoidance)
Maintain hydration with clear liquids or IV fluids as needed
Loperamide and/or oral antibiotics
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Additional recommended guidelines for the treatment of study treatment induced diarrhea are provided in Benson, et.al. [Benson, 2004].
3.11.4. Dose Modifications
In the case of an event that meets the any of the following criteria and is not clearly unrelated to treatment or in the event of any other clinically significant drug-related toxicity, treatment will be stopped and supportive therapy administered as clinically indicated:
a. Grade 3 or greater non-hematologic toxicity as described in Common National Cancer Institute-Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 [2009] that cannot be controlled with routine supportive measures (e.g. antiemetics, antidiarrheals, antihistamines).
b. Grade 4 neutropenia lasting >5 days.
c. Febrile neutropenia, of any Grade or duration as defined by NCI-CTCAE version 4.0 [2009].
d. Grade 4 thrombocytopenia.
e. ALT >3x upper limit of normal (ULN) with bilirubin >2x ULN.
f. Grade 3 or greater decrease in left ventricular ejection fraction (LVEF).
If clinically significant drug-related toxicity is present, treatment should be delayed until the toxicity resolves (with or without supportive therapy) to baseline or ≤Grade 1. If the toxicity does not resolve to ≤Grade 1 or baseline within 2 weeks, withdrawal from the trial is recommended unless otherwise agreed to by a GSK Medical Monitor and the investigator based on evidence of clinical benefit.
3.11.5. Dose Reductions
A subject who experiences toxicity meeting the criteria listed in Section 3.11.4 or any other clinically significant toxicity at any time during treatment with GSK2849330 will have their dose reduced to the next lower dose level. Any subject who experiences one or more recurrent clinically significant toxicities after the initial dose reduction may have one further dose reduction except where noted otherwise. Subjects who continue to experience clinically significant toxicity despite two dose reductions (i.e., unacceptable toxicity) will be discontinued from the study.
4. INVESTIGATIONAL PRODUCT(S)
The term ‘study treatment’ is used throughout the protocol to describe the investigational product (IP) received by the subject as per the protocol design.
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4.1. Description of Investigational Product(s)
Product name : GSK2849330 solution for infusion 100 mg/mL
Formulation description:Solution containing 100 mg/ml GSK2849330 in 1 mL or 5mL for injection
Dosage form :Solution for Infusion. The solution is stored at 2-8C, protected from light.
Unit dose strength(s)/Dose Level(s):IV/100 mg/mL (refer to Section 3.4 and Section 3.5 for dose levels)
Physical Description: GSK2849330 solution for infusion is clear to opalescent, colourless to pale yellow or pale brown in color.
Route/Administration/ Duration:
IV infusion lasting approximately 1 hour (see Section 3.9).
Dosing instructions:
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate concentration for the dose. Deliver the entire contents of the IV bag to the subject.
Manufacturer/ Source of Procurement: GSK
GSK2849330 will be provided to sites by GSK. The contents of the label will be in accordance with all applicable regulatory requirements.
89Zirconium labeled GSK2849330 will be prepared at the VUMC site by study staff. Details of 89Zirconium labeled GSK2849330 can be found in the relevant investigational medicinal product dossier and Appendix 1.
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4.2. Preparation/Handling/Storage of GSK2849330 GSK Investigational Product
Preparation
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate concentration for the dose. Deliver the entire contents of the IV bag to the subject. The administration kits can be polymerizing vinyl chloride (PVC), or polyolefin (PO). An inline filtration set will be used for this study.
Handling
Under normal conditions of handling and administration, IP is not expected to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.
Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists.
In the case of unintentional occupational exposure notify the study monitor, the GSK Medical Monitor and/or the study manager.
Refer to the SPM for detailed procedures for the disposal and/or return of unused study treatments.
Storage
GSK2849330 must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the GSK2849330 will be limited to the investigator and authorized site staff. GSK2849330 must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.
GSK2849330 is to be stored at a temperature range of 2C to 8C. Maintenance of a temperature log (manual or automated) is required.
4.3. Preparation/Handling/Storage of 89Zr-GSK2849330 GSK Investigational Product
Details of 89Zirconium labeled GSK2849330 can be found in the relevant investigational medicinal product document and Appendix 1.
Refer to the SPM for detailed procedures for the preparation, handling, storage of 89Zr-GSK2849330 as well as the disposal of any unused 89Zr-GSK2849330.
4.4. Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of IP
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dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study. Refer to the SPM for further detailed instructions on product accountability.
4.5. Treatment Compliance
GSK2849330 will be administered IV to subjects at the study site. Administration will be documented in the source documents and reported in the eCRF.
Treatment start and stop dates, including dates and reasons for treatment delays and/or dose modifications will also be recorded in the dosing eCRF.
4.6. Treatment of Investigational Product Overdose
In the event of an overdose (defined as administration of more than the protocol-specified dose) of GSK2849330, the investigator should:
contact the GSK Medical Monitor immediately
closely monitor the subject for AEs/SAEs and laboratory abnormalities for at least 45 days or 5 half lives [whichever is longer] for GSK2849330
obtain a plasma sample for PK analysis within 30 days from the date of the last dose of study treatment if requested by the GSK Medical Monitor (determined on a case-by-case basis)
document the quantity of the excess dose as well as the duration of the overdosing in the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in consultation with the GSK Medical Monitor based on the clinical evaluation of the subject.
5. STUDY POPULATION
5.1. Number of Subjects
Approximately 12-15 subjects will be recruited as follows:
The initial aim will be to establish a low dose of GSK2849330 suitable for imaging to establish a baseline of tissue and tumor uptake of 89Zr-GSK2849330 in subsequent subjects. This will require between 1 - 3 subjects. Estimation of intra-subject variability will be undertaken in 2 subjects during the course of the study who will receive the same dose of GSK2849330 in Dose 1 and Dose 2 and receive a total of 6 PET scans.
Once the initial dose to measure baseline of uptake is established the second dose will be varied to estimate the relationship between the dose of GSK2849330 and the inhibition of 89Zr-GSK2849330 uptake by tumor in order to predict an optimal dose of GSK2849330 which will lead to saturation of target binding. This is estimated to require between 3 - 4 subjects.
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Once doses have been established which achieve low, medium and high levels of inhibition of uptake 89Zr-GSK2849330 by tumors, a further 6 subjects will be studied across the dose range to improve the estimation of this relationship and to assess the reproducibility of the findings.
In-stream analysis of data will be used to ensure each new subject recruited receives a dose predicted to be informative in the estimation of the optimal saturating dose. Recruitment to different dose levels may alter from the above guide but will not exceed a total number of fifteen subjects.
5.2. Subject Selection Criteria
Specific information regarding warnings, precautions, contraindications, adverse events (AEs), and other pertinent information on the GSK study treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline Document Number 2013N168399_00]
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.2.1. Pre-screening Inclusion Criteria
Subjects will be eligible for inclusion in pre-screening for the study if all of the following criteria apply:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject is willing to undergo a fresh tumor biopsy for HER3 IHC analysis
5. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor malignancy for which no standard therapeutic alternatives exist. Eligible tumor types include, but are not limited to the following list:
Bladder cancer
Breast cancer
Castrate-resistant prostate cancer
Cervical cancer
Colorectal cancer (CRC)
Gastric cancer
Hepatocellular carcinoma (HCC)
Melanoma
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Non-small cell lung cancer (NSCLC)
Ovarian cancer
Pancreatic cancer
Squamous cancers of the head and neck region (including parotid and nasopharynx)
Additional tumor types will be considered at the discretion of a GSK medical monitor provided there is evidence that the HER3 IHC positivity in that tumor type is reliably validated.
5.2.2. Screening Inclusion Criteria
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Subjects must have tumors with documented HER3 expression on the cell surface (1+,2+ or 3+) of the invasive component of tumor (either on archival tissue or a fresh biopsy) using an analytically validated IHC assay by central laboratory.
4. ECOG performance status of 0 or 1
5. Histologically or cytologically confirmed diagnosis of solid tumor malignancy for which no standard therapeutic alternatives exist.
6. Adequate baseline organ function defined by:
SYSTEM LABORATORY VALUES
Hematologic
ANC 1.5 x 109/L
Hemoglobin 9 g/dL
Platelets 75 x 109/L
PT/INR and PTT 1.3x ULN
Hepatic
Albumin 2.5 g/dL
Total bilirubin 1.5 X ULN
AST and ALT 2.5 X ULN
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SYSTEM LABORATORY VALUES
Renal
Serum creatinine
OR
Estimated glomerular filtration rate or 24-hr urine creatinine clearancea
ULN
Or
50mL/min
Cardiac
LVEF 50% by ECHO or MUGAb
Abbreviation(s): ANC, absolute neutrophils count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT/INR:prothrombin time/International Normalized Ratio, PTT: partial thromboplastin time,ULN, upper limit of normal, LLN, lower limit of normal
a. Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease (MDRD) equation (Appendix 4). When both a calculated and 24-hr creatinine clearance are available, the 24-hr value will be used.
b. ECHO is preferred method.
7. Subjects must have at least two measurable lesions on CT or MRI scan with a shortest axis of at least 20mm. These two lesions must not be cystic in nature, lie within the liver or have received treatment with local radiotherapy unless progression has been documented on a subsequent scan following radiotherapy.
8. If the subject is female, she must be of non-childbearing potential, i.e. have a current tubal ligation, hysterectomy, ovariectomy or be post menopausal, or if she is of childbearing potential, she must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in Section 11.1.1, from the time of the first dose of study treatment until 45 days or 5 half lives (whichever is longer) after the last dose of study treatment.
9. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 11.1.2. from the time of the first dose of study treatment until 45 days or 5 half lives (whichever is longer) after the last dose of study treatment to allow for clearance of GSK2849330 from seminal fluid.
NOTE: Laboratory results obtained during Screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the investigator may opt to retest the subject and the subsequent within range screening result may be used to confirm eligibility.
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5.2.3. Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Subjects with leptomeningeal or brain metastases unless previously treated and stable for at least two months and without the need for ongoing corticosteroids.
2. Prior HER3- directed treatment (HER2- or EGFR-directed treatment is acceptable).
3. Use of an investigational anti-cancer drug within 28 days, or 5 half lives, whichever is longer, preceding the first dose of GSK2849330 OR chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy within the last 4 weeks, except as noted above.
4. Unresolved toxicity greater than NCI-CTCAE, version 4.0 Grade 1 from previous anti-cancer therapy except alopecia and stable anemia (i.e. untransfused Hb 9.0 g/dL without the need for supportive transfusion within 2 weeks of screening) at the time of treatment allocation.
5. Known or suspected hypersensitivity reaction to prior biologic therapy (e.g. therapeutic monoclonal antibody) that in the opinion of the investigator is a contraindication to their participation in the study.
6. Current use of a prohibited medication or requires any of these medications duringtreatment
7. History or evidence of significant cardiovascular risk including any of the following:
LVEF<50%
A QT interval corrected for HR using the Fredericia’s formula (QTcF) 480 msec (≥500 msec for subjects with bundle branch block)
History or evidence of current clinically significant uncontrolled arrhythmias.
Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible.
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA).
8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed).
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9. Evidence of another active malignancy (excludes non-melanoma skin cancer). Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
10. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
11. Concurrent medical condition that in the investigator’s opinion would jeopardize compliance with the protocol.
12. Lactating female.
13. Receiving chronic immunosuppressive therapies (includes daily steroid doses in excess of 20 mg/day of prednisolone).
6. COMPLETION OR WITHDRAWAL OF SUBJECTS
6.1. Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but are never subsequently randomized (as such this also includes ‘pre-screen’ failures). In order to ensure transparent reporting of screen failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and respond to queries from Regulatory authorities, a minimal set of screen failure information is required including Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events.
6.2. Subject Completion Criteria
A subject will be considered to have completed the study if they complete screening assessments, at least two study treatments and the post-treatment follow-up visit or are receiving ongoing study treatment at the time of the Sponsor’s decision to close the study. The study will be considered as completed having met the study objectives, after 70% of subjects have died or 2 years after the last subject is enrolled. If subjects are still continuing to receive benefit from GSK2849330, plans will be developed to provide continued access to for those subjects.2
6.3. Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable toxicity, including meeting stopping criteria for liver chemistry defined in Section 3.10.1. In addition, study treatment may be permanently discontinued for any of the following reasons:
major deviation(s) from the protocol
request of the subject or proxy (withdrawal of consent by subject or proxy)
investigator’s discretion
a dose delay of > 2 weeks unless the investigator or GSK Medical Monitor agree that further treatment may benefit the subject
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intercurrent illness that prevents further administration of study treatment(s)
subject is lost to follow-up study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented in the subject’s medical records and electronic case report form (eCRF).
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event (AE)’ will be recorded as the primary reason for permanently discontinuation on the electronic case report form (eCRF).
Once a subject has permanently discontinued from study treatment, the subject will not be allowed to be retreated.
All subjects who discontinue from study treatment will have safety assessments at the time of discontinuation. At their follow up visit, subjects will have safety, immunogenicity and, where relevant, pregnancy assessments as specified in the Time and Events Table (see Section 7.1).
6.4. Study Completion
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s last visit.
6.5. Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the post-study care of the subject’s medical condition whether or not GSK is providing specific post-study treatment.
7. STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any study-specific procedures or assessments being performed. Procedures conducted as part of the subject’s routine clinical management (e.g. blood count, ECG, ECHO/MUGA) obtained prior to their signing the informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol and have been performed within the protocol-specified timeframe. However physical exam, medical history, ECOG performance status, and vital signs must be conducted after the informed consent is signed regardless of when these procedures may have been performed as part of routine clinical management.
The timing of each assessment is listed in the Time and Events Table (Section 7.1). The timing and number of the planned study assessments may be altered during the course of the study based on newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring for the following assessments: imaging, safety, PK or other assessments. The change in timing or addition of time points for any of the planned study assessments listed above must be approved and documented by GSK, but this will not constitute a protocol amendment. The institutional review board (IRB) or ethics committee (EC) will be informed of any safety issues that
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require alteration of the safety monitoring scheme. No more than 350ml of blood will be collected over a 30 day period, including any extra assessments that may be required.
Whenever vital signs, 12-lead electrocardiograms (ECGs) and blood draws are scheduled for the same nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, blood draws. The timing of the assessments should allow the blood draw to occur at the exact nominal time. Detailed procedures for obtaining each assessment are provided in the Study Procedures Manual (SPM).
After a subject has provided written informed consent for pre-screening, the investigator or other study personnel will determine if the subject is eligible for pre-screening in the study. This will be done by reviewing the pre-screening inclusion criteria (Section 5.2.1) and completing all of the pre-screening assessments outlined in the Time and Events Table (Section 7.1). Pre-screening assessments may be carried out over more than one day.
After a subject has provided written informed consent for the study and within 21 days of the first dose of study treatment, the investigator or other study personnel will determine if the subject is eligible for enrollment in the study. This will be done by reviewing the inclusion and exclusion criteria and completing all of the screening assessments outlined in the Time and Events Tables (Section 7.1). Screening assessments may be carried out over more than one day provided that all required assessments are completed within 21 days prior to the first dose of study treatment. Pre-screening and screening assessments may take place concurrently provided appropriate consents have been documented in writing.
7.1. Time and Events Table(s)
This section consists of the Time and Events Table(s) and supplemental footnotes to describe assessment windows and sequencing of study-specific assessments and procedures.
All subjects will take part in the Imaging Phase, Part 1, before proceeding to the continuation phase, Part 2. The start of the continuation phase, Part 2 Day 1, will be the first dose of GSK2849330 given during this phase.
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Table 3 Time and Events for Part 1 (Imaging Phase)
Procedures
Pre-screening
Screening
Part 1
Start of Continuation Phase - Part 23
First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day15
Day 16 to Day 21
- 21 day window5± 1 day window for each visit
Part 2 will start with the first dose given in the continuation phase. The timing of this dose should be discussed with the
sponsor study team.
Informed consent X X
Archival tissue X
Tumor biopsy X7
Baseline demographics X X
Medical history X X
Concurrent Medication Continuous
Pregnancy test4 X5 X
Physical examination X X8 X
Height (at screening only) and weight X X8 X
ECOG X X X8 X
Vital signs (BP, pulse rate, temperature) X X9 X15 X9 X15
12-lead ECG X X9 X9
Hematology/Clinical Chemistry X5 X8 X2 X X2
Serum sample for ImmunogenicityX16 X
Urinalysis X X X
ECHO6 X
PK and Radioactivity measurements (Blood)1 X X X X
Testosterone and LH10 X
Co-localising CT scan11 X X X X
PET Scan11 X X X X89Zr-GSK2849330 IV infusion X14 X14
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Procedures
Pre-screening
Screening
Part 1 Start of Continuation Phase -Part 23First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day 15
Day 16 to Day 21
- 21 day window5± 1 day window for each visit
GSK2849330 IV infusion X14 X14
AE assessment Continuous
Tumor markers 12 X
Disease assessment X5 X13
1. Samples for radioactivity and PK analysis to be taken: pre-dose, 1hr(15mins), 3hrs(30mins), 6hrs(1hr), 12hrs(2hrs), 24hrs(3hrs) after end of infusion 89Zr-GSK2849330 and just prior to commencing each PET scan (within 30mins of starting scan). Timing of sampling may be adjusted based on emerging data.
2. Safety labs taken pre-scan of final scan in each scanning period3. The window between dose 2 in Part 1 and dose 1 in Part 2 should never be less than the relevant dosing interval cleared by the FTIH study with other assessments adjusted
according relative to the timing of the first dose in Part 2, if in doubt this should be discussed with a GSK medical monitor.4. Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at Screening. Urine pregnancy test should be conducted pre-dose on day 15. 5. Within 21 days prior to first dose except for Hematology/Clinical Chemistry (14 days), pregnancy test (7 days). Disease assessment can be based on historical data from up
to 42 days prior to Day 1.6. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA
scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated.
7. Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.8. If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.9. Collect at pre-dose, 1, 3, and 6hr after the start of infusion. Where 2 infusions are given, timings are relative to the start of the first infusion10. To be conducted in male subject only11. PET scans and co-localising CT scans to be acquired as outlined in Section 3.4.1.112. See Section 7.8.1 and collect all tumor markers applicable for the subject’s primary tumor type.13. If disease assessment modality is CT then this should be performed on same day as last PET scan. IF assessment is via another modality this may be performed 7days
from the day of the last PET scan to allow scheduling. This disease assessment is to be used as baseline for subsequent comparison to assess markers of clinical response.14. 89Zr- GSK2849330 and GSK2849330 will be administered as a short infusion of a pre-made mixture for the 8mg and 24mg dose levels. For the higher weight adjusted dose
levels the total dose will be achieved by an infusion of unlabeled GSK2849330 over 1 hour followed by a short infusion containing 89Zr- GSK284933015. To be conducted on scanning days only16. Pre-dose
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Table 4 Time and events for Part 2 (Continuation Phase)
1, 2 or 3 weekly dosing schedule
ProceduresPart 2 - Continuation Phase Follow-up
Part 2 Day 1 Dosing days (frequency to be advised)35 ± 7 days after
last dose
GSK2849330 IV infusion1 X X
Vital signs (BP, pulse rate, temperature) X Every dosing visit X
Hematology/Clinical Chemistry X X
Pregnancy test2 XIf on 1 or 2 week dosing interval then every 4 weeks to coincide
with a dosing visit
If on 3 week dosing interval then every dosing visit
X
Physical examination X X
Weight X X
ECOG X X
12-lead ECG X X
Urinalysis X X
Serum sample for Immunogenicity XEvery 12 weeks from first dose in Part 2 to coincide with a dosing
visit 7 X
ECHO3 XEvery 8 -10 weeks
X
Testosterone and LH4 X
Tumor markers 5 X Every 8-12 weeks from the first dose in Part 2X
Disease assessment6 X8
Concurrent MedicationContinuous X
AE assessment Continuous
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1 For any subjects receiving a weekly dosing schedule the study treatment dosing window is 2 days. The study treatment dosing window is 3 days for subjects on a 2 or 3 weekly dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received.
2 Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the follow-up visit. Urine pregnancy test should be conducted pre-dose on Part 2 Day 1 then pre-dose every 3-4 weeks depending on dosing interval.
3 ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated. First ECHO/MUGA in Part 2 may be performed between 22 and 30 days from the first dose in Part 1, subsequent ECHO/MUGAs should be performed at 8-10 week intervals from this.
4 To be conducted in male subjects only5 Collect all tumor markers applicable for the subjects’ primary tumor type.6 Confirmatory assessments suggested at least four weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a subject’s next regularly
scheduled visit as appropriate.7 Immunogenicity samples will be collected every 12 weeks (14 days) from the first dose on the continuation phase for the first year and then every 24 weeks (14 days). An
immunogenicity sample will also be collected at the Post-study visit.8 If the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease has not been documented, a disease assessment
should be obtained at the time of withdrawal from study.
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7.2. Demographic/Medical History and Baseline Assessments
Demographic data will include gender, age, race, height, and weight. Medical, surgical, and treatment history including date [month (if available) and year] of first diagnosis, best response to prior systemic therapy, histology, and current sites of disease will be taken as part of the medical history and disease status. Details concerning concomitant medication will be recorded starting from screening through to the follow-up visit. At a minimum, the drug name, route of administration, dose and frequency of dosing, along with start and stop dates/times should be recorded.
7.2.1. Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed at baseline.
7.3. Safety Evaluations
Measurements used to evaluate safety will include physical examinations, vital signs (BP, temperature and pulse rate), 12-lead ECGs, echocardiography, clinical laboratory tests, , and monitoring for AEs. Planned time points for all safety assessments are provided in the Time and Events Tables (Section 7.1).
Additional, unplanned safety assessments may be performed during the course of the study as clinically indicated in the judgment of the investigator. Additional time points for safety tests may also be added during the course of the study based on newly available data to ensure appropriate safety monitoring.
7.3.1. Physical Examinations
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), spine and long bones, lymph nodes and extremities. Height (at screening only) and weight will also be measured and recorded.
7.3.2. ECOG Performance Status
The performance status will be assessed using the Eastern Cooperative Oncology Group (ECOG) scale (Appendix 4) as specified in the Time and Events Table (Section 7.1).
7.3.3. Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure (BP), temperature, and pulse rate. Vital signs should be measured after resting for at least 5 minutes in a semi-supine position. Vital signs will be measured more frequently if warranted by clinical condition of the subject. On days where vital signs are measured multiple times, temperature does not need to be repeated unless clinically indicated. Refer to the Study Procedures Manual (SPM) for details regarding measurement of vital signs.
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If a subject develops a fever within the immediate post-infusion period, refer to Section 3.11.1 and Section 3.11.2 for management of infusion reactions and allergic reactions.
7.3.4. Electrocardiogram
Single 12-lead electrocardiogram (ECGs) will be obtained at designated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTcF) intervals. At each assessment a 12-lead ECG will be performed by qualified personnel at the site after the subject has at least a 5 minute rest and is in a semi-recumbent or supine position.
All ECGs will be single assessments unless clinically significant abnormality is observed, in which case repeat ECG twice more, for a total of 3 ECGs within approximately 5-15 minutes. Manual calculation for all 3 ECGs should be done using Fridericia’s formula (QTcF=QT/RR1/3) in view of the complex relationship between QT and RR. Any clinical decisions should be based on the average of all three ECGs.
Refer to Section 3.10.2 for QTc withdrawal criteria.
Refer to the Study Procedures Manual (SPM) for details regarding ECG procedures.
7.3.5. Echocardiogram and/or Multi-gated Acquisition (MUGA) Scans
ECHO will be performed to assess cardiac ejection fraction as noted in the Time and Events Tables Section 7.1. Should electrocardiograph not be available or if echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA scan may be performed. However, whichever method is used at baseline should be used for the remaining assessments in the study. Additional ECHO assessments may be performed if clinically warranted. The evaluation of the echocardiographer should include an evaluation for LVEF.
Copies of all ECHOs performed on subjects who experience an absolute decrease >15% in LVEF compared to baseline or an absolute decrease >10% in LVEF compared to baseline concurrent with LVEF < 50% may be required by GSK for review.
7.3.6. Laboratory Assessments
All protocol required laboratory assessments, as defined in (Table 5), should be performed according to the Time and Events Table (Section 7.1). Details for the preparation and shipment of samples will be provided in the Study Procedures Manual (SPM).
Prior to administration of the first dose of study treatment, results of laboratory assessments should be reviewed. Any laboratory test with a value outside the normal range may be repeated (prior to the first dose) at the discretion of the investigator.
At the discretion of the investigator, additional laboratory samples may be taken as clinically necessary. If additional non-protocol specified laboratory assessments are performed at the institution’s local laboratory and result in a change in subject
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management or are considered clinically significant by the investigator (for example SAE or AE or dose modification) the results must be recorded in the subject’s eCRF.
All abnormal laboratory tests with values that are clinically significant during study participation or within 28 days after the last dose of study treatment should be repeated until the values return to within normal range or baseline or the subject starts subsequent treatment. All subjects who have a Grade 3 or 4 laboratory abnormality at time of study withdrawal must be followed until resolution to Grade 2 or less, unless it is unlikely to improve due to underlying disease or subsequent therapy.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed in Table 5:
Table 5 List of Clinical Laboratory Tests
HematologyPlatelet Count RBC Indices: Automated WBC Differential:Red blood cell (RBC) Count MCV NeutrophilsWhite blood cell (WBC) Count (absolute)
MCH Lymphocytes
Reticulocyte Count MCHC MonocytesHemoglobin EosinophilsHematocrit BasophilsClinical ChemistryBlood urea nitrogen (BUN)
Potassium Aspartate aminotransferase (AST)
Total and direct bilirubin
Creatinine Chloride Alanine aminotransferase (ALT)
Uric Acid
Glucose, fasting Total carbon dioxide (CO2)
Gamma glutamyl transferase (GGT)
Albumin
Sodium Calcium Alkaline phosphatase Total ProteinMagnesium PhosphateRoutine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstickMicroscopic examination (if blood or protein is abnormal)Other screening tests
Testosterone (male subjects only)Luteinizing Hormone (LH) (male subjectsonly)Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
7.3.7. Pregnancy Testing and Reporting
All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until the follow-up visit.
The need for a screening pregnancy test depends on whether a female subject is of childbearing potential or non-childbearing potential.
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If a female subject is of childbearing potential, she must have a serum Beta-human chorionic gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first dose of study treatment. Subjects with positive pregnancy test result must be excluded from the study. Subjects with negative pregnancy test result must agree to use an effective contraception method as described below during the study until 45 days or 5 half lives (whichever is longer) following the last dose of study treatment. Additional pregnancy tests will be performed as outlined in the Times and Events Table (see Section 7.1).
Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK.
7.4. Pharmacokinetics
For all subjects in Part 1, blood samples for analysis of radioactivity concentration (whole blood and plasma) and GSK2849330 concentrations will be collected prior to each dose of 89Zr –GSK2849330 , then at the following times following completion of the 89Zr –GSK2849330 containing infusion: 1hr, 3hrs, 6hrs, 12hrs and 24hrs. Additionally samples will be collected on days when subjects are attending for PET scanning just prior to scanning.
7.4.1. Blood Sample Collection for Pharmacokinetics
Blood samples of approximately 1 mL for pharmacokinetic (PK) analysis of GSK2849330 will be collected at the time points indicated in the Time and Events Schedule (Section 7.1). Each PK sample should be collected as close as possible to the planned time relative to the dose (i.e., time zero) administered to the subject on PK days. The actual date and time of each blood sample collection will be recorded.
Once preliminary PK data have been reviewed, the planned sample collection times may be revised and provided to sites in writing. Changes in PK sample collection times will not constitute a protocol amendment.
Details on PK blood sample collection, processing, storage and shipping procedures are provided in the Study Procedures Manual (SPM).
7.4.2. Pharmacokinetic Sample Analysis
Plasma analysis will be performed under the management of Bioanalytical Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics (DMPK), GSK. Concentrations of GSK2849330 will be determined in plasma samples using the currently approved
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analytical methodology. Raw data will be stored in the good laboratory practice (GLP) Archives, GSK.
7.5. Image Analysis
PET images will be reconstructed with the needed corrections to supply quantitative values whereby the average radioactivity concentration in any region of the body can be determined and expressed as standardized uptake value (SUV). This entity is equal to tissue radioactivity concentration normalized by administered amount of radioactivity per body weight.
The radioactivity concentrations will be determined in selected anatomical structures for each scan point for each of the two sessions and for each patient with due consideration having the same anatomical region covered.
Regions of interest (RoI) will be outlined to represent the tissue radioactivity concentration through the values of SUVmean and SUVpeak. Furthermore RoIs will be outlined to represent whole organs and include the volumes encircled.
The analyses will include up to 5 tumor lesions if judged able for accurate quantification and the major organs like liver, spleen, lung, heart, bone marrow and muscle. Further organs and structures may be included depending on ability for identification and adequate quantitative values.
Anonymised images and auxiliary data will be transferred to GSK and may be used for further analyses.
The mode of image analysis is further described in the SPM.
7.6. Immunogenicity
7.6.1. Blood Sample Collection
Serum samples for determination of anti- GSK2849330 antibodies will be taken from all subjects in this study at the time-points specified in the Time and Events Tables in Section 7.1.
7.6.2. Sample Analysis
Samples will be analyzed for the presence of anti-GSK2849330 antibodies using a validated immunoelectrochemiluminescent (ECL) assay. The assay involves screening,confirmation and titration steps (tiered-testing approach). Confirmed positive samples will be titrated to obtain the titer of the anti-GSK2849330 antibodies. Further antibody characterization may be performed, if needed. Results will be reported at the end of the study. Details on sample preparation, storage and analysis will be given in the SPM.
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7.7. Translational Research
7.7.1. Tumor Tissue for HER3 expression Pre-screening
A formalin-fixed, paraffin-embedded tumor tissue block taken at a metastatic site (preferably) or obtained at the time of original primary cancer diagnosis (biopsy or from definitive surgery) is required to be submitted to the central laboratory (Ventana Medical Systems) for determining HER3 (regardless of any local results). Alternatively, sites may send 15-20 freshly sectioned, unstained slides containing 5-micron thick sections. Refer to the SPM for details on tumor tissue sample preparation and shipping.
If archival tumor tissue is not available, a fresh biopsy is required for HER3 testing.
Intensity of HER3 staining on IHC as assessed by central laboratory will be correlated with rate of uptake of 89Zr-GSK2849330 as seen on PET scanning over multiple time-points.
7.8. Evaluation of Anti-Cancer Activity
Disease assessment may include imaging (e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], bone scan, plain radiography) and physical examination (as indicated for palpable/superficial lesions). Disease assessment will be completed within 42 days prior to the first dose of GSK2849330, at the end of Part 1 then every 8-12 weeks in Part 2. If the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease has not been documented, a disease assessment should also be obtained at the time of withdrawal from study. The disease assessment at the end of Part 1 will be used as a baseline for subsequent comparison for assessments of disease progression and response evaluation according to the definitions established in Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009]. Assessment of changes in tumor diameter, volume and growth rate may also be made. Where possible a baseline tumor growth rate may be established using the disease assessments made during screening and at the end of Part 1.
If the disease assessment at the end of Part 1 is made by CT scan it will be completed on the same day as the final PET scan is acquired. If another modality is used for disease assessment then a window of 7 days around the time of the last PET scan is allowed for scheduling purposes. See the Time and Events Table (Section 7.1) for the schedule of assessments of anti-cancer activity. Assessments must be performed on a calendar schedule and should not be affected by dose interruptions/delays. For post-baseline assessments, a window of 7 days is permitted to allow for flexible scheduling. If the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease has not been documented, a disease assessmentshould be obtained at the time of withdrawal from study.
Disease progression and response evaluations will be determined according to the definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009]. Subjects whose disease responds (either complete response [CR] or partial response [PR]) are recommended to have a confirmatory disease assessment performed at least 4 weeks after the date of assessment during which the
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response was demonstrated. More frequent disease assessments may be performed at the discretion of the investigator. To ensure comparability between the baseline and subsequent assessments, the same method of assessment and the same technique will be used when assessing response.
Anonymised images and auxiliary data will be transferred to GSK and may be used for further analyses.
7.8.1. Tumor Marker(s)
For subjects whose disease may be followed by well-characterized tumor markers, disease assessments should include results of tumor marker measurements.
Tumor marker values will be recorded in the electronic case report form (eCRF).
8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an adverse event (AE) or serious adverse event (SAE) as outlined in Section 8.1 and Section 8.2, respectively.
8.1. Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Note: An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits, abuse, or misuse. Examples of events meeting the definition of an AE include:
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or grade of the condition
New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study
Signs, symptoms, or the clinical sequelae of a suspected interaction
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/serious adverse event [SAE]).
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be reported as an AE or SAE. However, any signs and symptoms and/or clinical sequelae resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the definition of an AE or SAE.
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Events that do not meet the definition of an AE include:
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.
The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.
8.2. Definition of an SAE
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-subject setting. Complications that occur during hospitalization are adverse events (AEs). If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect.
f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the
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other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.
g. Protocol-Specific SAEs:
All events of possible study treatment-induced liver injury with hyperbilirubinemia defined as alanine aminotransferase (ALT) 3 times upper limit of normal (ULN) and bilirubin ≥2 times ULN (>35% direct) (or ALT ≥3 times ULN and international normalization ratio (INR) >1.5, if INR is measured) or termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants).
NOTE: Bilirubin fractionation is performed if testing is available. If testing is not available, record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin ≥2 times ULN, then the event is still reported as a serious adverse event (SAE). If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.
Any new primary cancers
8.2.1. Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been associated historically with adverse reactions for other drugs and is therefore worthy of heightened pharmacovigilance. The GSK Medical Monitor is accountable for reviewing all SAEs for possible Sentinel Events which is mandated at GSK. The GSK medical monitor may request additional clinical information on an urgent basis if a possible Sentinel Event is identified on SAE review. The current GSK-defined Sentinel Events are listed below:
Acquired Long QT Syndrome
Agranulocytosis/Severe Neutropenia
Anaphylaxis & Anaphylactoid Reactions
Hepatotoxicity
Acute Renal Failure
Seizure
Stevens Johnson syndrome/Toxic epidermal necrosis
8.3. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other safety assessments (e.g., electrocardiogram [ECGs], radiological scans, vital signs
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measurements) including those that worsen from baseline, and events felt to be clinically significant in the medical and scientific judgment of the investigator are to be recorded as an adverse event (AE) or serious adverse event (SAE), in accordance with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other safety assessment that led to an intervention, including permanent discontinuation of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE.
However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject's condition, are not to be reported as AEs or SAEs.
8.3.1. Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the following AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism
Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week of when the AE/SAE(s) are first reported.
8.4. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease progression or hospitalization due to disease progression) does not need to be reported as a serious adverse event (SAE). Death due to disease under study is to be recorded on the Death electronic case report form (eCRF). However, if the underlying disease (i.e., progression) is greater than that which would normally be expected for the subject, or if the investigator considers that there was a causal relationship between treatment with study treatment(s) or protocol design or procedures and the disease progression, then this must be reported as a SAE.
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8.5. Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an adverse event (AE) or serious adverse event (SAE).
AEs will be collected from the time the first dose of study treatment is administered until the follow-up visit following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice.
SAEs will be collected over the same time period as stated above for AEs. In addition, any SAE assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy), study treatment or GSK concomitant medication must be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 8.5.2.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that are ongoing until resolution or stabilization of the event or until the subject is lost to follow-up. At any time after 45days the investigator may report any AE that they believe possibly related to study treatment.
8.5.1. Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:
“How are you feeling?” or for pediatric studies, “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or for pediatric studies, “Has your child had any (other) medical problems or seem to act differently in any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?” or for pediatric studies, ”Has your child needed to take any medicines, other than those provided in this study, since his/her last visit/contact?”
8.5.2. Prompt Reporting of SAEs and Other Events to GSK
Serious adverse events (SAEs), pregnancies, and liver function abnormalities and any other events meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines the event meets the protocol definition for that event.
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Initial Reports Follow-up Information on a Previous Report
Type of Event Time Frame Documents Time Frame DocumentsAll SAEs 24 hours SAE data collection
tool24 hours Updated SAE data
collection tool
“CV events” and/or “death”
Initial and follow up
reports to be completed within one
week of when the
cardiovascular event or death
is reported
“CV events” and/or “death” data collection
tool(s) if applicable
Initial and follow up reports to be completed within
one week of when the cardiovascular event or death is
reported
Updated “CV events” and/or “death” data
collection tool(s) if applicable
Pregnancy 2 Weeks Pregnancy Notification Form
2 Weeks Pregnancy Follow-up Form
Liver chemistry abnormalities:
ALT 3 times ULN and bilirubin 2 times ULN (>35% direct) (or ALT 3 times ULN and INR
>1.5, if INR is measured)c
24 hoursa SAE data collection tool;
Liver Event eCRF and liver imaging
and/or biopsy eCRFs if
applicableb
24 hours Updated SAE data collection tool.
Updated Liver Event eCRFb
ALT 5 times ULN; ALT 3 times ULN with
hepatitis or rash or 3 times ULN 4 weeks
24 hoursa Liver Event eCRFb 24 hours Updated Liver Event eCRFb
ALT 3 times ULN and <5 times ULN and
bilirubin <2 times ULN
24 hoursa Liver Event eCRF does not need to be completed unless elevations persist
for 4 weeks or subject cannot be monitored weekly
for 4 weeksb
a. GSK to be notified at onset of liver chemistry elevations to discuss subject safety.b. Liver event documents should be completed as soon as possiblec. INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving
anticoagulants.
Methods for detecting, recording, evaluating, and following up on adverse events (AEs) and serious adverse events (SAEs) are provided in the Study Procedures Manual (SPM).
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8.5.3. Regulatory reporting requirements for SAEs
Prompt notification of serious adverse events (SAEs) by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, institutional review board (IRB)/ethics committee (EC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/EC, if appropriate according to local requirements.
9. LIVER CHEMISTRY FOLLOW-UP PROCEDURES
9.1. Liver Chemistry Testing Procedures
For subjects meeting any of the liver chemistry stopping criteria in Section 3.10.1, make every attempt to carry out the liver event follow-up assessments described below:
Viral hepatitis serology, including:
Hepatitis A IgM antibody
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM)
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, then obtain heterophile antibody or monospot testing)
Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days of the last dose of study drug(s). Record the date and time of the PK blood sample draw and the date and time of the last dose of study drug(s) prior the blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date or time of the last dose cannot be approximated, or if a PK sample cannot be collected within the 10-day period following the last dose, do not obtain a PK sample. Instructions for sample handling and shipping are found in the Study Procedures Manual (SPM).
Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin 2 X upper limit of normal (ULN).
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Obtain a complete blood count (CBC) with differential to assess eosinophilia.
Record the appearance or worsening of clinical symptoms indicative of hepatitis or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia as relevant on the AE eCRF.
Record the use of concomitant medications, including acetaminophen, herbal remedies or any other over the counter (OTC) medications, or any putative hepatotoxins, on the concomitant medication eCRF.
Record alcohol use on the liver event alcohol intake eCRF.
The following assessments are required for subjects with ALT 3 X ULN and bilirubin 2X ULN (>35% direct) but are optional for other abnormal liver chemistries:
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.
Liver imaging (ultrasound, magnetic resonance imaging [MRI] or computed tomography [CT]) to evaluate liver disease.
9.2. Liver Chemistry Monitoring Criteria
For subjects with ALT 3 X ULN but <5X ULN and bilirubin <2 X ULN, without symptoms indicative of hepatitis or rash, and who can be monitored safety for 4 weeks, the following actions should be taken:
Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to discuss subject safety.
Continue administration of study drug(s).
Evaluate liver chemistries (ALT, AST, alkaline phosphatise, bilirubin) weekly until they resolve, stabilize or return to within baseline levels.
If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5 (Section 3.10.1), then proceed as described in Section 9).
If, after 4 weeks of monitoring, ALT <3X ULN and bilirubin <2 X ULN, then monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.
9.3. Drug Restart/Rechallenge Following Liver Events that are Possibly Related to Study Drug(s)
Approval by the GSK Medical Monitor to restart/rechallenge study drug(s) may be considered where:
The subject is receiving compelling benefit, the benefit exceeds the risk, and no effective alternative therapy is available. Approval of restart/rechallenge by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) must be obtained, as required.
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If the restart/rechallenge is approved by GSK in writing, then the subject must be provided with a clear description of the possible benefits and risks of administration of study drug(s), including the possibility of a recurrence, a more severe liver injury or death.
The subject must also provide signed informed consent specifically for the study drug(s) restart/rechallenge. Documentation of the informed consent must be recorded in the subject’s study chart.
Study drug(s) must be administered at the dose specified by the GSK Medical Monitor.
Subjects approved by GSK for restart/rechallenge of study drug(s) must return to the clinic twice a week for evaluation of liver chemistry tests until stable liver chemistries have been demonstrated and laboratory monitoring may resume per protocol.
9.4. Drug Restart Following Transient, Resolving Liver Events Not Related to Study Drug(s)
Approval by the GSK Medical Monitor to restart study drug(s) may be considered where:
Liver chemistry abnormalities have a clear underlying cause (e.g., biliary obstruction, hypotension) and liver chemistries have improved to normal or are within 1.5 X baseline and ALT <3X ULN. Approval of restart by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) may be required.
If the restart/rechallenge is approved by GSK in writing, then the subject must be provided with a clear description of the possible benefits and risks of administration of study drug(s), including the possibility of a recurrence, a more severe liver injury or death.
The subject must also provide signed informed consent specifically for the study drug(s) restart/rechallenge. Documentation of the informed consent must be recorded in the subject’s study chart.
Study drug(s) must be administered at the dose specified by the GSK Medical Monitor.
Subjects approved by GSK for restart/rechallenge of study drug(s) must return to the clinic once a week for evaluation of liver chemistry tests until stable liver chemistries have been demonstrated and laboratory monitoring may resume per protocol.
If protocol-defined stopping criteria for liver chemistry abnormalities are met, study drug(s) administration must stop.
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new medications from the time of first dose of study treatment until the end of the study (Final
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Study Visit). Any concomitant medication(s), including non-prescription medication(s) and herbal product(s), taken during the study will be recorded in the electronic case report form (eCRF). Additionally, a complete list of all prior anti-cancer therapies will be recorded in the eCRF.
If future changes are made to the list of permitted/prohibited medications, formal documentation will be provided by GSK and stored in the study file. Any such changes will be communicated to the investigative sites in the form of a letter.
10.1. Permitted Medication(s)
Subjects should receive full supportive care during the study, including transfusion of blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, as appropriate. Growth factors (e.g. G-CSF) are permitted after discussion with the GSK medical monitor.
10.2. Prohibited Medication(s) and Non-Drug Therapies
Subjects should not receive other anticancer therapy (cytotoxic, surgery, tumor embolization, biologic, radiation, or hormone other than replacement) except where noted in the eligibility criteria while on treatment in this study.
Chronic immunosuppressive therapies including daily steroid doses in excess of 20 mg/day of prednisolone are prohibited while on treatment in this study.
11. LIFESTYLE AND/OR DIETARY RESTRICTIONS
11.1. Contraception
11.1.1. Female Subjects
A female of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy (ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicular stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant during the study and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of <1%.
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Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, through the dosing period, and for at least 45 days or 5 half lives (whichever is longer) after the last dose of study treatment.
Contraceptive Methods with a Failure Rate of <1%
Oral contraceptives (either combined or progesterone only) if not contraindicated for this subject population or per local practice.
Estrogenic vaginal ring if not contraindicated for this subject population or per local practice.
Percutaneous contraceptive patches if not contraindicated for this subject population or per local practice.
Implants of levonorgestrel if not contraindicated for this subject population or per local practice.
Injectable progesterone if not contraindicated for this subject population or per local practice.
Intrauterine device or intrauterine system that meets the <1% failure rate as stated in the product label
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.
Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository)
These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception.
11.1.2. Male Subjects
To prevent pregnancy in a female partner or to prevent exposure of any partner to the study treatment from a male subject’s semen, male subjects must use one of the following contraceptive methods:
Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
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post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, through the dosing period, and for at least 45 days or 5 half lives (whichever is longer) after the last dose of study treatment.
Condom (during non-vaginal intercourse with any partner - male or female) OR
Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)
11.2. Lactation Restrictions
Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for at least 45 days or 5 half lives (whichever is longer) following the last dose of study treatment.
12. DATA MANAGEMENT
For this study, data will be collected using defined electronic case report forms (eCRFs), transmitted electronically to GSK and combined with data provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g. removing errors and inconsistencies in the data. AEs and concomitant medications terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and an internal validated medication dictionary, GSK Drug. Electronic CRFs (eCRFs), including queries and audit trails, will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy.
Laboratory samples (i.e., hematology and clinical chemistry) will be analyzed by a laboratory local to the site and the results will be entered into the eCRF.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
13.1. Hypothesis(es)
As this is an exploratory study, where the primary objective is to measure in vivo biodistribution of 89Zr -GSK2849330 as assessed by positron emission tomography scanning, there are no formal hypotheses to be tested for the primary endpoint. In this study an estimation approach will be adopted to evaluate the objectives.
Modeling of the relationship between blocking dose and uptake will be performed by clinical pharmacokinetic modeling and simulation (CPMS).
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13.2. Sample Size Determination and Sensitivity
There are no formal calculations of power or sample size for this study. The sample size has been primarily based on feasibility.
Approximately 12 to 15 subjects in total are therefore expected to be enrolled into the study.
13.2.1. Sample Size Re-estimation
No sample size re-estimation is currently planned for this study as the sample size is based on feasibility.
It is worth noting that the current study design does allow adaptive changes to several design parameters:
o Dose level for dose 1o Blocking dose level for dose 2 (i.e. dose level 2 – dose level 1)o Timing and number of PET scans
13.3. Data Analysis Considerations
Statistical analyses will be performed by, or under the direct auspices of Clinical Statistics, GSK
13.3.1. Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 89Zr -GSK2849330 and/or GSK2849330. Safety and anti-cancer activity will be evaluated based on this analysis population.
The PK Population will consist of all subjects from the All Treated Population for whom a PK sample is obtained and analysed.
Additional analysis populations may be defined in the Reporting and Analysis Plan (RAP).
13.3.2. Interim analyses and their timings
Decision making for the development programme is time critical and therefore there are four types of interim analysis planned in this study, of increasing numbers of outputs:
Immediate in-stream analysis
Analysis of dosimetry data
Post dose-escalation in-stream analysis
Interim analysis after completion of part 1 of the study (the imaging phase).
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13.3.2.1. Immediate in-stream analysis
The following data may be reviewed on an ongoing basis:
PET results and blood radioactivity and drug concentration measurements and safety data
In addition the pharmacometric model estimating uptake for each tumor and dose-response model characterising the effect of dose on uptake may be reviewed if data allow. Both models will be developed by CPMS or designee.
Note that the time interval between dose choice and the results for a subject (likely to be around 6 weeks) will mean that not every choice of dose will be informed in this way and the study design will therefore accommodate this lag by specifying a default dosing plan which may be adjusted based on these results.
The study may be terminated if the PET parameters fail to identify the previously identified tumors after any instream analysis or if the study procedures do not seem to be effective.
13.3.2.2. Analysis of Dosimetry data
Dosimetry results will be listed once planned data is received.
13.3.2.3. Expansion phase in-stream analysis
To answer project-level questions relating to dose level in the dose expansion phase of the GSK2849330 first time in human study (HER117158) a report of data received so far will be produced at the appropriate time point. This time point will be driven by the needs of the first time in human study. Analysis will include that done for the in-stream analysis.
13.3.2.4. Interim analysis at the end of part 1.
After the imaging results of the last subject have been received, all imaging, dosimetry and other available results may be summarised by dose.
13.3.3. Final Analyses
Database freeze and final analysis will occur when all information has been collected from the study. Note that this will occur after the end of part 2 of the study, the continuation phase.
13.4. Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where applicable. Complete details will be documented in the Reporting and Analysis Plan (RAP). Any deviations from, or additions to, the original analysis plan described in this protocol will be documented in the RAP and final study report.
All data up to the time of study completion/withdrawal from study will be included in the analysis, regardless of duration of treatment.
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As the duration of treatment for a given subject will depend on efficacy and tolerability, the duration of follow-up will vary between subjects. Consequently there will be no imputation for missing data.
Demographic and baseline characteristics will be summarized.
13.4.1. Anti-Cancer Activity Analyses
The All Treated Population will be used for anti-cancer activity analyses. Since this is a Phase I study, anti-cancer activity will be evaluated based on clinical evidence and response criteria. Where appropriate, the lesion data will be listed for each subject. The percent change from baseline will be calculated for each subject and listed, along with their ORR, CR, PR, SD and PD according to standard RECIST 1.1. Response-evaluable subjects are defined as subjects with a baseline disease assessment at the end of part 1 and at least 1 post-part 2 dose disease assessment.
Response data will be listed and summarized as appropriate. Graphical exploration of any relationship between the subject’s tumor type specific markers and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 may also be conducted. In addition graphical exploration of the association between tumor characteristics including drug uptake and subsequent tumor size change and/or tumor growth rate will be conducted where data permit. Full details will be specified in the Reporting and Analysis Plan (RAP).
Note that this study’s collection of lesion data is complementary to that collected in HER117158, the first time in human study and the potential to combine data from these two studies to improve estimates of clinical benefit (for example clinical benefit ratio which includes CR, PR and SD for each dose level) of GSK2849330 will be considered.
13.4.2. Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially collected safety endpoints (e.g. laboratory tests, vital signs, electrocardiogram [ECGs]) will be summarized according to the scheduled, nominal visit at which they were collected and across all on-treatment time points using a “worst-case” analysis.
Complete details of the safety analyses will be provided in the Reporting and Analysis Plan (RAP).
13.4.2.1. Extent of Exposure
The number of subjects administered study treatment will be summarized according to the duration of therapy.
13.4.2.2. Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system organ class. Adverse events (AEs) will be graded by the investigator according to the
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National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), (version [4.0]) [NCI, 2009].
Events will be summarized by frequency and proportion of total subjects, by system organ class and preferred term. Separate summaries will be given for all AEs, treatment-related AEs, serious adverse events (SAEs) and AEs leading to discontinuation of study treatment. Adverse events (AEs), if listed in the NCI-CTCAE (version [4.0]) [NCI, 2009] will be summarized by the maximum grade. Otherwise, the AEs will be summarized by maximum intensity.
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following AEs of special interest will be listed separately: infusion reactions, allergic reaction and diarrhea. The incidence of deaths and the primary cause of death will be summarized.
13.4.2.3. Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and proportions according to National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) (version [4.0]) [NCI, 2009]. Laboratory test results outside the reference ranges that do not have an associated NCI-CTCAE criteria will be summarized at each scheduled assessment. Results will be flagged using toxicity grades,if available, or as normal or abnormal (high or low) with reference to standard reference ranges. Further details will be provided in the Reporting and Analysis Plan (RAP).
13.4.2.4. Other Safety Measures
Data for vital signs, electrocardiograms (ECGs), and echocardiograms (ECHOs) or MUGAs will be summarized based on NCI-CTCAE criteria or, where these don’t exist, by predetermined criteria identified to be of potential clinical concern (PCI). Vital signs will be listed for each subject at all measured time points. A descriptive summary including change from baseline pre-dose will also be presented. Individual profiles of BP will be plotted by time. Further details will be provided in the Reporting and Analysis Plan (RAP).
13.4.3. Pharmacodynamic/Biomarker Analyses
Primary and secondary pharmacodynamic/biomarker endpoints including imaging endpoints will be presented in graphical and/or tabular form, summarised descriptively and listed.
13.4.4. Pharmacokinetic Analyses
13.4.4.1. Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology Modeling and Simulation (CPMS) Department, GSK.
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Pharmacokinetic (PK) analysis of GSK2849330 concentration-time data will be conducted by non-compartmental methods by CPMS, Quantitative Sciences, GSK. The following PK parameters will be determined if data permit:
maximum observed plasma concentration (Cmax)
time to Cmax (tmax)
AUC(0-t), AUC(0-τ) (repeat dosing) and/or AUC(0-∞) (single dose)
apparent terminal phase elimination rate constant (z) (single dose)
apparent terminal phase half-life (t½) (single dose)
13.4.4.2. Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the non-compartmental PK parameters data will be the responsibility of Clinical Statistics, Quantitative Sciences, GSK. Statistical analysis of the exploratory compartmental PK parameters data will be the responsibility of CPMS, Quantitative Sciences, GSK. Plasma GSK2849330 concentration-time data from the dose escalation will be analyzed by non-compartmental methods with WinNonlin [Version number 5.2 or higher].From the plasma concentration-time data, the following PK parameters will be determined, as data permit: Cmax, tmax, AUC(0-t) and AUC(0 - τ), apparent terminal phase half-life (t1/2). Trough concentration (Cτ) samples collected on the specified days will be used to assess attainment of steady state. Plasma concentration-time data will be listed by dose and summarized using descriptive statistics (n, mean, standard deviation SD, median, minimum and maximum) by planned relative assessment time. Mean and/or median values will be plotted over time. Individual plasma and urinary (if available) PK parameters values as well as a descriptive summary (mean, SD, median, minimum, maximum, geometric mean, and the standard deviation, 95% confidence interval (CI) of log-transformed parameters (if applicable) by dose cohort will be reported. Cmax and AUC [AUC(0-∞), and AUC(0-τ)] will be plotted as a function of the dose administered. Further exploratory statistical analysis of any or all the pharmacokinetic endpoints may be performed as appropriate including dose proportionality.
13.4.4.3. Statistical Analysis of Population Pharmacokinetics
Statistical analysis of the population PK parameter data will be the responsibility of CPMS, Quantitative Sciences, GSK. Plasma concentration-time data from the expansion cohorts may be combined with data from the dose escalation and further analyzed using a population approach. A nonlinear mixed effect model may be used to determine population PK parameters and important covariates (biomarkers or disease related covariates).
13.4.5. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/Pharmacodynamic analysis will be the responsibility of the Clinical Pharmacology Modeling and Simulation (CPMS) Department, GSK. This analysis will
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be reported separately from the main clinical pharmacology study report (CPSR) with details specified in a separate RAP.
The intent of modeling is to predict a dose that maximizes the rate of GSK2849330 uptake into the tumor and for which the trough concentration in tumor is likely to be in the therapeutic range.
In order to quantify biodistribution in normal tissue as well as uptake to lesions by a method that considers each subject to be their own control, the study design mandates that each subject receive a first dose at a level that may not saturate distribution to normal tissue and which may be less than a therapeutic dose and a second dose that may saturate uptake to normal tissue to visualize uptake to lesions and is planned to be in the range currently deemed safe and potentially therapeutic based on information from the GSK2849330 First Time in Human Study.
Plasma concentrations of GSK2849330 over time will be analyzed using a nonlinear mixed effects modeling approach. The rate of uptake from plasma to lesion will be estimated from SUV observed for up to 5 lesions per subject in terms of a biodistribution model describing the uptake biophase, as data permit.
The trough concentration in tumor will be estimated according to a population biodistribution model based on the data from this study; important covariates such as sex and weight may be included in the model. Parameters may be informed by data from the FTIH study and historical data translated across compounds or species..
To achieve this goal, population covariate PK/PD models to characterize the biodistribution of GSK2849330 will be developed, as data permit, including
Uptake model including an equilibrated reversible compartment in communication with an irreversible compartment (e.g., Patlak, 1985).
Further details of the PK/PD analysis performed by CPMS and Clinical Statistics will be addressed in the respective Reporting and Analysis Plans (RAP).
13.4.5.1. Translational Research Analyses
If data permit the relationship between HER3 intensity by immunohistochemistry and tumor uptake will be explored.
Further details on the translational research analyses will be addressed in the Reporting and Analysis Plan (RAP).
14. STUDY CONDUCT CONSIDERATIONS
14.1. Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.
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14.2. Regulatory and Ethical Considerations, Including the Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate regulatory agency to conduct the study in accordance with International Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:
Institutional review board (IRB)/ethics committee (EC) review and approval of study protocol and any subsequent amendments
Subject informed consent
Investigator reporting requirements
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the study.
14.3. Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, and this new event is likely to affect the study of subjects, the Sponsor, and the investigator will take appropriate urgent safety measures to protect subjects against any immediate hazard.
The Sponsor will work with the investigator to ensure the Institutional review board (IRB)/ethics committee (EC) is notified.
14.4. Quality Control (Study Monitoring)
In accordance with applicable regulations, Good Clinical Practice (GCP) and GSK procedures, the site will be contacted prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the electronic case report form (eCRF) will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents and to allocate their time and the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:
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Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements.
14.5. Quality Assurance
To ensure compliance with International Conference on Harmonization Good Clinical Practice (ICH GCP) and all applicable regulatory requirements, GSK may conduct quality assurance audits of the site. Regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss any findings/relevant issues.
14.6. Study and Site Closure
The end of the study will be defined as the date of the last visit of the last subject enrolled.
Upon completion or termination of the study, the monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, International Conference on Harmonization Good Clinical Practice (ICH GCP), and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/EC promptly and provide the reason(s) for the suspension/termination.
GSK may also close study sites which fail to recruit subjects within a predefined timeframe, as defined within the Study Procedures Manual (SPM).
14.7. Records Retention
Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and
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must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.
14.8. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.
GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.
The results summary will be posted to the GSK Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.
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15. REFERENCES
Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for thetreatment of cancer treatment-induced diarrhea. J Clin Oncol. Jul 15 2004;22(14):2918-2926.
Börjesson PK, Jauw YW, de Bree R, Roos JC, Castelijns JA, Leemans CR, van Dongen GA, Boellaard R. Radiation dosimetry of 89Zr-labeled chimeric monoclonal antibody U36 as used for immuno-PET in head and neck cancer patients. J Nucl Med. 2009 Nov;50(11):1828-1836. doi: 10.2967/jnumed.109.065862. Epub 2009 Oct 16.
Dijkers EC et al. Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer. Clin Pharmacol Ther. 2010 May;87(5):586-592
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). European Journal of Cancer. 2009; 45: 228-247.
GlaxoSmithKline Document Number 2013N168399_00 Version 00. GSK2849330 Investigator's Brochure. Report Date: 29-JUL-2013.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 1779-1784.
NCI Common Terminology Criteria for Adverse Events, Version 4 DCTD, NCI, NIH, DHHS, 28 May 2009.
Patlak, C.S. & Blasberg, R.G. (April 1985). "Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations". Journal of Cerebral Blood Flow and Metabolism 5 (4): 584–590.
Walport MJ. Complement. First of two parts. N Engl J Med. Apr 5 2001;344(14):1058-1066.
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16. APPENDICES
16.1. Appendix 1: PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES AND FORMULATION -89Zr-GSK2849330 SOLUTION FOR INJECTION
Pharmaceutical Presentation
89Zr-GSK2849330 Solution for Injection is a sterile, preservative-free aqueous solution containing the active ingredient, 89Zr-GSK2849330.
89Zr-GSK2849330 is formed in situ, from the conjugation of the monoclonal antibody GSK2849330, with the bifunctional chelator, p-isothiocyanatobenzyl desferrioxamine followed by radiolabeling with the radio isotope, Zirconium 89. 89Zr-GSK2849330 is diluted with GSK2849330 Solution for Infusion (unlabelled GSK2849330) to provide one single 20 mL dose, with a target radioactivity of 37MBq and a total antibody concentration of 0.4 mg/mL or 1.2 mg/mL.
The medicinal product appears as a clear, colorless liquid for intravenous administration in a 20 mL clear glass, stoppered vial. The drug is supplied as a single use vial and is not formulated with a preservative.
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Physical, Chemical and Biological Properties of the Drug Substance
Active Ingredient: 89Zr-GSK2849330
Also referred to as 89Zr-Df-Bz-NCS-GSK2849330
(where Df-Bz-NCS is the bifunctional chelator p-isothiocyanatobenzyl desferrioxamine, GSK2849330 is the unlabelled monoclonal antibody, and Df-Bz-NCS-GSK2849330 is the chelator-mab conjugate)
Zirconium-89-p-thioureabenzyl desferrioxamine-GSK2849330
Other Names: Not applicable
Isotope Type: Zirconium-89 (89Zr)
Physical Form: Clear, colorless liquid
Nuclear and radio-physical Properties:
Half-life: 78.4 hours
Principle mode of disintegration: Beta decay
Principle gamma radiation: 909 keV
Summary of Manufacturing Process and Quality Assurance
89Zr-GSK2849330 Solution for Injection is manufactured and tested according to current Good Manufacturing Practice.
All reagents, solvents and other materials used in the 89Zr-GSK2849330 Solution for Injection preparation contain no materials of animal or human origin and are therefore safe with regard to viral and non-viral adventitious agents contamination.
List of Excipients
The medicinal product is manufactured in situ at the VUMC. 89Zr-GSK2849330 Solution for Injection is diluted with GSK2849330 Solution for Infusion to provide a total antibody concentration of 0.4 mg/mL or 1.2 mg/mL.
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Placebo
No placebo will be used in the clinical study.
Storage and Handling
The recommended storage conditions, and expiry date where required, for 89Zr-GSK2849330 Solution for Injection are stated on the product label.
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16.2. Appendix 2: NYHA Functional Classification System
The New York Heart Association (NYHA) Functional Classification: Class I, II, III or IV Heart Failure [NYHA, 1994] provides a simple way of classifying the extent of heart failure. It places subjects in one of 4 categories based on the level of limitation experienced during physical activity:
Class SymptomsClass I(Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea (shortness of breath).
Class II(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea.
Class III(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
Reference:
The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: Little, Brown & Co.; 1994:253-256.
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16.3. Appendix 3: COCKCROFT-GAULT FORMULA
ClCr (mL/min) = Q x (140 - age[yr]) x ideal body weight [kg]*72 x serum creatinine [mg/dL]
Q = 0.85 for femalesQ = 1.0 for males
OR
ClCr (mL/min) = K x (140 - age[yr]) x ideal body weight [kg]*Serum creatinine [umol/L]
K = 1.0 for females K = 1.23 for males
*Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]Ideal body weight:Males = 50.0 kg + (2.3 kg x each inch over 5 feet) or 50.0 kg + (0.906 kg x each cm over
152.4 cm)Females = 45.5 kg + (2.3 kg x each inch over 5 feet) or 45.5 kg + (0.906 kg x each cm over
152.4 cm)Example: Male, actual body weight = 90.0 kg, height = 68 inches
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg.This subject’s actual body weight is >30% over ideal body weight. Therefore, in this case, the subject’s ideal body weight of 68.4 kg should be used in calculating estimated CrCl.
Reference
Devine, BJ. Case Number 25 Gentamicin Therapy: Clinical Pharmacology Case Studies. Drug Intelligence and Clinical Pharmacy. 1974; 8:650-655
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16.4. Appendix 4: ECOG Performance Status1
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16.5. Appendix 5: Liver Safety Drug Restart Guidelines
Drug restart may be considered for a subject exhibiting compelling benefit for a critical medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and no alternative medicine available.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or rechallenge is associated with a 13% mortality across all drugs in prospective studies.1 Clinical outcomes vary by drug, with nearly 50% fatality with halothane readministered in one month of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. Risk factors for a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia), jaundice or bilirubin2xULN or INR>1.5 suggesting severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or evidence of drug-related preclinical liability / mitochondrial impairment3.
Drug Restart/Rechallenge Process (also see Figure 1)
1. Principal Investigator (PI) requests consideration of drug restart for a subject receiving compelling benefit from a critical or life-saving drug, who exhibits liver chemistry elevation meeting subject stopping criteria, with no alternative treatment.
2. GSK Medical Monitor & Clinical Safety Physician.to review the subject’s restart/rechallenge risk factors & complete checklist (see below).
Checklist for drug restart/rechallenge for critical medicine
(Following drug-induced liver injury, drug rechallenge is associated with 13% mortality across all drugs in prospective studies)
Yes No
Compelling benefit of the investigational product (IP) for this subject and no alternative therapy. Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after considering the following high risk factors:
• Initial liver injury event included:
– fever, rash, eosinophilia, or hypersensitivity
– or bilirubin2xULN (direct bilirubin >35% of total)
• Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct
bilirubin >35% of total, if available), or INR1.5
• Severe or fatal restart/rechallenge has earlier been observed
with IP If yes, please provide brief explanation:
• IP associated with known preclinical hepatic liability/ injury
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3. If GSK provides written approval for restart/rechallenge following the above review, the Principal Investigator (PI) must ensure the following:
The PI is to obtain Ethics Committee or Institutional Review Board review of drug re-initiation, as required.
PI must discuss the possible benefits and risks of drug re-initiation with the subject.
The subject must sign informed consent with a clear description of possible benefits and risks of drug administration, including recurrent liver injury or death. Consent specifically for the IP restart must be recorded in the study chart.
The drug must be reinitiated at GSK approved dose(s).
Subjects approved by GSK for restart of IP must return to the clinic twice a week for liver chemistry tests until stable, liver chemistries have been demonstrated and then laboratory monitoring may resume as per protocol. If protocol defined stopping criteria for liver chemistry elevations are met, study drug must be stopped.
The Ethics Committee or Institutional Review Board is to be informed of the subject’s outcome, as required.
GSK is to be notified of any adverse events, as per Section 8.5.2.
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Figure 1 GSK process for drug restart after possible drug-induced liver injury
References:
1. Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury:the attractive hazard. Expert Opin Drug Saf 2009;8:709–714.
2. Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: a systematic review. Hepatology 2010;52:2216–2222
3. Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury following positive drug rechallenge. Regul Toxicol Pharmacol 2009;54:84-90.
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Figure 2 Liver Safety Algorithm
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16.6. Appendix 6: Urine Protein Creatinine (UPC) Ratio
Clinical meaning of UPC
There is a good correlation between the ratio of protein concentration to creatinine concentration in a random urine sample and the amount of protein excreted over 24 hours. Creatinine excretion is fairly constant throughout the day regardless of changes in urine flow rate.
Normal protein excretion is <150 mg/24 hours and is similar for men and women.
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day.
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day.
Calculating UPC
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.
Example: Patient has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.
UPC ratio= (90 mg/dL) / (30 mg/dL) = 3
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 24-hour period.
Units for UPC ratio
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the same units (mg/dL, g/L, or μmol/L). If, for example, protein concentration is expressed in mg/dL and creatinine concentration is expressed in µmol/L, conversion of one of the concentration values is required. Conversion factors are:
From To Conversion Factor Conventional Units: mg/dL SI Units: µmol/L Multiply by 88.4SI Units: µmol/L Conventional Units: mg/dL Divide 88.4
References:
NKF: NKF KDOQI Guidelines [Internet]. National Kidney Foundation; nd. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Available from http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm
Xin G, Wang M, Jian L, Xu F, Wang H. Protein-to-creatinine ratio in spot urine samples as a predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39.
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16.7. Appendix 7: Protocol Amendment 1 – summary of changes
The protocol has been amended to:
Correct medical monitor information; Correct minor errors in the protocol; and Clarify sections of the protocol.
List of Specific Changes
Section: throughout the protocol
PREVIOUS TEXT
...tumour...
REVISED TEXT
...tumor...
Section: throughout the protocol
Acronyms defined on first use in text.
Section: Sponsor Contact Information
PREVIOUS TEXT
Role Name Day Time Phone Number
After-hours Phone/Cell/Pager Number
Fax Number GSK Address
Primary Medical Monitor
. Gunnels Wood RoadStevenage Herts, SG1 2NY
Secondary Medical Monitor
709 Swedeland RoadKing of Prussia, PA 19406
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PPD
PPD
PPD PPD PPD
PPD
PPD
PPD
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REVISED TEXT
Role Name Day Time Phone Number
After-hours Phone/Cell/Pager Number
Fax Number GSK Address
Primary Medical Monitor
Gunnels Wood RoadStevenage Herts, SG1 2NY
Secondary Medical Monitor
n/a 1250 S Collegeville Road Collegeville, PA 19426 USA
Tertiary Medical Monitor
n/a 709 Swedeland RoadKing of Prussia, PA 19406
Section: Abbreviations
Removed numerous abbreviations that were not used in the protocol
Section 1.1: Background
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The epidermal growth factor receptor (HER) family of receptor tyrosine kinases is comprised of...
...A FTIH study is being undertaken...
...Positron Emission Tomography (PET) scanning is ideal for this application being both quantitative and capable of assessing sites throughout the body.
...At sufficient concentations of unlabeled mAb...
REVISED TEXT
The epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs)is comprised of ...
...A first time in human (FTIH) study is being undertaken...
...Positron Emission Tomography (PET) scanning is ideal for this application being both quantitative and capable of assessing antibody binding sites throughout the body.
...At sufficient concentrations of unlabeled mAb...
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PPD
PPD
PPD
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Section: 1.2.1 GSK2849330 Background
PREVIOUS TEXT
... In summary, there are three main potential antitumor modes of action when GSK2849330 is administered as monotherapy: a) inhibition of signaling; b) ADCC and c) CDC. The latter two mechanisms provide an opportunity for differentiation from non-ADCC and CDC-enhanced HER3-directed mAbs in clinical development, based on direct killing of both dividing and non-dividing cells, which may be independent of inhibition of downstream signaling.
REVISED TEXT
...In summary, there are three main potential antitumor modes of action when GSK2849330 is administered as monotherapy: a) inhibition of signaling; b) ADCC and c) CDC. The latter two mechanisms provide an opportunity for differentiation from non-ADCC and non-CDC-enhanced HER3-directed mAbs in clinical development, based on direct killing of both dividing and non-dividing cells, which may be independent of inhibition of downstream signalling.
Section: 1.3.2 Ionising radiation
PREVIOUS TEXT
The radiation exposure from PET/CT scanning comes from two sources, the radionuclide injected for PET scanning and the exposure to x-rays that make up the CT scan component of the PET/CT.
Effective dose per low dose co-localising CT scan is 2.9mSv
Previous studies using 89Zr labeled IgG1 monocloncal antibodies have measured effective dose of between 0.5-0.66mSv/MBq of administered 89Zr-mAb [Börjesson, 2009].
The estimated total effective dose from both administrations of radionuclide is therefore expected to be between 37 and 48.8mSv. The dose from low dose co-localising CT scans is estimated at 17.4mSv for the two subjects receiving six scans and a maximum of 14.5mSv for all other subjects. Total radiation dose attributable to PET scanning procedures is therefore estimated to be between 54.4mSv and 66.2mSv for the two subjects receiving six scans and between 51.5mSV and 63.3mSv for all other subjects.. Additional trial specific radiation exposure may come from the use of MUGA scans to assess LVEF if use of echocardiography is not possible. Each MUGA scan is estimated to have an effective dose of 3.5mSv. LVEF assessment will be carried out at screening, after four weeks and the every eight weeks or more frequently if clinically indicated...
REVISED TEXT
The radiation exposure from PET/CT scanning comes from two sources, the radionuclide injected for PET scanning and the exposure to x-rays that make up the CT scan component of the PET/CT.
Effective dose per low dose co-localising CT scan is 2.9mSv
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Previous studies using 89Zr labeled IgG1 monocloncal antibodies have measured effective dose of between 0.5-0.66mSv/MBq of administered 89Zr-mAb [Börjesson, 2009].
Each administration of radiolabelled drug will have an activity of up to 37 MBq. Each subject will receive 2 radiolabelled doses.
The estimated total effective dose from both administrations of radionuclide is therefore expected to be between 37 (37MBq x 0.5mSv/Bq x 2 doses) and 48.8mSv (37MBq x 0.66mSv/Bq x 2 doses). The dose from low dose co-localising CT scans is estimated at 17.4mSv for the two subjects receiving six scans and a maximum of 14.5mSv for all other subjects (who receive up to 5 scans). Total radiation dose attributable to PET scanning procedures is therefore estimated to be between 54.4mSv and 66.2mSv for the two subjects receiving six scans and between 51.5mSV and 63.3mSv for all other subjects.
Where use of echocardiography is not possible, additional trial specific radiation exposure may come from the use of MUGA scans to assess LVEF. Each MUGA scan is estimated to have an effective dose of 3.5mSv. LVEF assessment will be carried out at screening, after four weeks and the every eight weeks or more frequently if clinically indicated...
Section: 3.2 Discussion of study design
PREVIOUS TEXT
Subjects will continue dosing with unlabeled GSK2849330 at either the RP2D if established or if the RP2D has not yet been established a dose level felt to most likely to give clinical benefit will be
selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study.
...Once subjects have completed part 1 of the study they will move on to a maintenance phase, part 2, where they will continue dosing with GSK2849330 at the Recommended Phase II Dose (RP2D) if established. If the RP2D has not yet been established a dose level felt to give the highest probability of clinical benefit will be selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study. Dosing will continue until study discontinuation due to disease progression, death, unacceptable toxicity, withdrawal of subject consent, major deviations from protocol or at the investigator’s discretion. Intra-subject dose escalation will be allowed in the maintenance phase based on the data from the FTIH study. Subjects in the maintenance phase will continue to have safety and tolerability data collected per the schedule of events along with clinical assessments.
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REVISED TEXT
Subjects will continue dosing with unlabeled GSK2849330 at either the recommended phase 2 dose (RP2D), or if the RP2D has not yet been established a dose level will be selected by the GSK
medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study.
...Once subjects have completed part 1 of the study they will move on to a maintenance phase, part 2, where they will continue dosing with GSK2849330 at the Recommended Phase II Dose (RP2D). If the RP2D has not yet been established, a dose level will be selected by the GSK medical monitor in consultation with the investigator(s). Any dose level selected must have previously been cleared as being safe and tolerable by the FTIH study. Dosing will continue until study discontinuation due to disease progression, death, unacceptable toxicity, withdrawal of subject consent, major deviations from protocol or at the investigator’s discretion or if the study or development of the asset is terminated. Intra-subject dose escalation will be allowed in the maintenance phase based on the data from the FTIH study. Subjects in the maintenance phase will continue to have safety and tolerability data collected per the schedule of events along with clinical assessments...
Section: .3.4 Part 1: Imaging phase
PREVIOUS TEXT
Each subject will receive two doses containing both labelled and unlabelled GSK2849330 during the imaging phase, each with an activity of no more than 37MBq. The total dose of GSK2849330 administered with each dose will be altered by varying the amount of unlabeled GSK2849330 given. An initial range of six dose levels will be explored as shown in Table 6. The two lowest dose levels, A and B, will be fixed total amounts of drug made up by the addition of unlabelled GSK2849330 to the radiolabeled GSK2849330 and given as a single short infusion. Dose levels C, D, E and F will be weight adjusted and will be given as two separate infusions. First an infusion of unlabeled GSK2849330 followed within 2 hours by the 89Zr-GSK2849330 containing infusion...
Table 6 Dose levels of GSK2849330 for Part 1
Dose level Total Dose GSK2849330
Minimum Interval following use as Dose 2
Planned first Dose in Continuation Phase
A 8mg 1 week Day 22B 24mg 1 week Day 22C 1mg/kg 1 week Day 22D 3mg/kg 2 weeks Day 29E 10mg/kg 2 weeks Day 29F 30mg/kg 2 weeks Day 29
REVISED TEXT
An initial range of six dose levels will be explored as shown in Table 6. The two lowest dose levels, A and B, will be fixed total amounts of drug made up by the addition of
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unlabelled GSK2849330 to the radiolabeled GSK2849330 and given as a single short IVinfusion injection of approximately 10 minutes duration. Dose levels C, D, E and F will be weight-adjusted and will be given as two separate IV infusions. First an infusionof unlabeled GSK2849330 lasting approximately 1 hour, followed within 2 hours (preferably within 1 hour) of the end of the first infusion, by the 89Zr-GSK2849330 containing infusion injection (lasting approximately 10 minutes)...
Table 1 Proposed Dose levels of GSK2849330 for Part 1
Dose level Total amount of GSK2849330 per dose (labelled + unlabelled drug)
Proposed interval (if used as Dose 2) before starting Part 2
Planned first Dose in Continuation Phase
A 8mg 1 week Day 22B 24mg 1 week Day 22C 1mg/kg 1 week Day 22D 3mg/kg 2 weeks Day 29E 10mg/kg 2 weeks Day 29F 30mg/kg 2 weeks Day 29NB: Dose level and dose interval may be adjusted based on emerging data
Section: 3.5 Part 2: Continuation phase
PREVIOUS TEXT
...If Dose 2 = 8mg, 24mg or 1mg/kg then first continuation dose = Day 22
If Dose 2 = 3, 10 or 30mg/kg then first continuation dose = Day 29
The interval between doses will never be less than that cleared by the FTIH study...
Table 2 Initial Dose levels of GSK2849330 for Part 2
Dose level Dose GSK2849330 Dosing IntervalG 1.4mg/kg 7 daysH 3mg/kg 14 daysI 10mg/kg 14 daysJ 30mg/kg 14 daysK 30mg/kg 21 days
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REVISED TEXT
The interval between doses will never be less than that cleared by the FTIH study...
Table 2 Proposed Dose levels of GSK2849330 for Part 2
Dose level Dose GSK2849330 Dosing IntervalG 1.4mg/kg 7 daysH 3mg/kg 14 daysI 10mg/kg 14 daysJ 30mg/kg 21 daysK 30mg/kg 14 daysNB: Dose level and dose interval may be adjusted based on emerging data
Section: 3.9 Dosage and administration of study treatment(s)
PREVIOUS TEXT
Unlabeled GSK2849330 will be given by IV infusion over a 1 hour period. If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms; the subject will receive appropriate medical treatment. When the subject’s condition is stable, the infusion may be restarted according to the judgment of the investigator. Upon restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
At the start of each scanning period a preparation containing 89Zr- GSK2849330, with a maximum total radioactivity of 37MBq and maximum total drug mass of 24mg, will be administered as a short intravenous infusion. This will be commenced within two hours of completing the infusion of unlabeled GSK2849330 (preferably within one hour) if both are being administered on the same day.
Guidance for the monitoring and managing of infusion related reactions and allergic/hypersensitivity reactions, including anaphylaxis, are outlined in Section 3.11.1 and Section 3.11.2.
Subjects should be monitored for at least 1 hour after the completion of the infusion and may be discharged if considered clinically stable and all other study procedures have been completed.
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REVISED TEXT
Guidance for the monitoring and managing of infusion related reactions and allergic/hypersensitivity reactions, including anaphylaxis, are outlined in Section 3.11.1 and Section 3.11.2.
PART 1, doses A & B
At the start of each scanning period a preparation containing 89Zr- GSK2849330, with a maximum total radioactivity of 37MBq, will be administered as a short intravenous infusion (injection over ca. 10 minutes).
PART 1, doses C to F
Unlabeled GSK2849330 will be given by IV infusion over a 1 hour period. If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms; the subject will receive appropriate medical treatment. When the subject’s condition is stable, the infusion may be restarted according to the judgment of the investigator. Upon restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
At the start of each scanning period a preparation containing 89Zr- GSK2849330, with a maximum total radioactivity of 37MBq, will be administered as a short intravenous infusion (injection over ca. 10 minutes). This will be commenced within two hours of completing the infusion of unlabeled GSK2849330 (preferably within one hour).
PART 2, all doses
GSK2849330 will be given by IV infusion over a 1 hour period. If an infusion-related reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the investigator or in consultation with a GSK medical monitor, depending on the severity of the symptoms; the subject will receive appropriate medical treatment. When the subject’s condition is stable, the infusion may be restarted according to the judgment of the investigator. Upon restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. For subsequent infusions, the investigator may provide premedication with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting infusion rate.
Subjects should be monitored for at least 1 hour after the completion of the infusion and may be discharged if considered clinically stable and all other study procedures have been completed.
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Section 3.10.3: Left Ventricular Ejection Fraction (LVEF) and Valvular Toxicity Stopping Criteria
PREVIOUS TEXT
Left Ventricular Ejection Fraction (LVEF) and Valvular Toxicity Stopping Criteria
REVISED TEXT
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
Section 3.10.3.2: Valvular Toxicity Stopping Criteria
SECTION REMOVED
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by ECHO/MUGA (Grade 2 mitral/tricuspid/aortic valvular toxicity per National Cancer Institute- Common Toxicity Criteria for Adverse Events [NCI-CTCAE], version 4.0) should temporarily discontinue GSK2849330 and have a repeat evaluation by ECHO/MUGA within 1 week. ECHO/MUGA should be repeated every 1 to 2 weeks for 4 weeks or until valve recovery to baseline.
If the valve recovers to baseline any time during the next 4 weeks after consultation and approval of the GSK Medical Monitor, the subject may be restarted on GSK2849330 at a reduced dose(s). For such subjects, monitoring of the valve via ECHO/MUGA will then be performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 16 weeks and then per protocol.
If repeat ECHO/MUGA does not reveal valve recovery to baseline within 4 weeks, then the subject should permanently discontinue GSK2849330. The valve should continue to be monitored via ECHO/MUGA every 4 weeks for 16 weeks or until resolution.
Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with symptoms controlled by medical intervention) valvular toxicity must discontinue GSK2849330. Valvular toxicity should continue to be monitored every 4 weeks for 16 weeks or until resolution. If recovery occurs (return to baseline via imaging AND symptom resolution) within 4 weeks, the subject may restart GSK2849330 at a reduced dose after consultation and approval of the GSK Medical Monitor.
ECHO/MUGA must be performed at baseline and at the final study visit. Copies of all ECHO(s)/MUGA(s) and cardiology consultations performed on subjects who experience valvular toxicity will be required by GSK for review. Instructions for submitting qualifying ECHOs are provided in the Study Procedures Manual (SPM)
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Section: 4.1 Description of Investigational Product(s)
PREVIOUS TEXT
Route/Administration/ Duration:
Delivered as an IV solution (see Section 3.9).
...89Zirconium labeled GSK2849330 will be prepared on site by study staff. Details of 89Zirconium labeled GSK2849330 can be found in the relevant investigational medicinal product document...
REVISED TEXT
Route/Administration/ Duration:
IV infusion lasting approximately 1 hour (see Section 3.9).
...89Zirconium labeled GSK2849330 will be prepared at the VUMC site by study staff. Details of 89Zirconium labeled GSK2849330 can be found in the relevant investigational medicinal product dossier...
Section: 5.2.3 Exclusion Criteria
PREVIOUS TEXT
3) Use of an investigational anti-cancer drug within 28 days preceding the first dose of GSK2849330 OR chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy within the last 4 weeks
REVISED TEXT
3) Use of an investigational anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of GSK2849330 OR chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy within the last 4 weeks except as noted above
Section: 6.1 Screen failures
PREVIOUS TEXT
Screen failures are defined as subjects who consent to participate in the clinical trial but are never subsequently randomized.
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REVISED TEXT
Screen failures are defined as subjects who consent to participate in the clinical trial but are never subsequently randomized (as such this also includes ‘pre-screen’ failures).
Section: 6.2 Subject completion criteria
PREVIOUS TEXT
A subject will be considered to have completed the study if they complete screening assessments, at least two study treatments and the post-treatment first follow-up visit or are receiving ongoing study treatment at the time of the Sponsor’s decision to close the study.
REVISED TEXT
A subject will be considered to have completed the study if they complete screening assessments, at least two study treatments and the post-treatment follow-up visit or are receiving ongoing study treatment at the time of the Sponsor’s decision to close the study. The study will be considered as completed having met the study objectives, after 70% of subjects have died or 2 years after the last subject is enrolled. If subjects are still continuing to receive benefit from GSK2849330, plans will be developed to provide continued access to for those subjects.
Section: 7.1 Time and Events table(s)
PREVIOUS TEXT
...All subjects will take part in the Imaging Phase, Part 1, before proceeding to the continuation phase, Part 2. The start of the continuation phase, Part 2 Day 1, will be the first dose of GSK2849330 given during this phase. The timing of this dose relative to the start of Part 1 will be driven by the dosing interval required following the dose given on Day 15, (Part 1 Dose 2):
If Part 1 Dose 2 ≤ 1.4mg/kg then the first dose in Part 2 will be Day 22(+ 1 day)
If Part 1 Dose 2 > 1.4mg/kg then the first dose in Part 2 will be Day 29 (1 day)
REVISED TEXT
...All subjects will take part in the Imaging Phase, Part 1, before proceeding to the continuation phase, Part 2. The start of the continuation phase, Part 2 Day 1, will be the first dose of GSK2849330 given during this phase.
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PREVIOUS TEXTTable 3 Time and Events for Part 1 (Imaging Phase)
Procedures
Pre-screening
Screening
Part 1
Start of Continuation Phase - Part 23
First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day 15
Day 16 to Day 21
- 21 day window5 ± 1 day window for each visit
Part 2 will start with the first dose given in the continuation phase. The timing of this dose should be discussed with the
sponsor study team.
will be driven by the dose given for Part 1 Dose 2:
Part 1 Dose 2
Start Part 2
≤1.4mg/kg Day 22 (+ 1day)
>1.4mg/kg Day 29 (1day)
Informed consent X X
Archival tissue X
Tumor biopsy X7
Baseline demographics X X
Medical history X X
Concurrent Medication Continuous
Pregnancy test4 X5 X
Physical examination X X8 X
Height (at screening only) and weight X X8 X
ECOG X X X8 X
Vital signs (BP, pulse rate, temperature) X X9 X X9 X
12-lead ECG X X9 X9
Hematology/Clinical Chemistry X5 X8 X2 X X2
Serum sample for ImmunogenicityX X
Urinalysis X X X
ECHO6 X
PK and Radioactivity measurements (Blood)1 X X X X
Testosterone and LH10 X
Co-localising CT scan11 X X X X
PET Scan11 X X X X
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89Zr-GSK2849330 IV infusion X14 X14
Procedures
Pre-screening
Screening
Part 1 Start of Continuation Phase -Part 23First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day 15
Day 16 to Day 21
- 21 day window5 ± 1 day window for each visit
GSK2849330 IV infusion X14 X14
AE assessment Continuous
Tumor markers 12 X
Disease assessment X5 X13
1. Samples for radioactivity and PK analysis to be taken: pre-dose, 1hr(15mins), 3hrs(30mins), 6hrs(1hr), 12hrs(2hrs), 24hrs(3hrs) after end of infusion 89Zr-GSK2849330 and just prior to commencing each PET scan (within 30mins of starting scan).
2. Safety labs taken pre-scan of final scan in each scanning period3. The window between dose 2 in Part 1 and dose 1 in Part 2 should never be less than the relevant dosing interval cleared by the FTIH study with other assessments adjusted
according relative to the timing of the first dose in Part 2, if in doubt this should be discussed with a GSK medical monitor.4. Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at Screening. Urine pregnancy test should be conducted pre-dose on day 15. 5. Within 21 days prior to first dose except for Hematology/Clinical Chemistry (14 days), pregnancy test (7 days), and Disease Assessment (42 days) prior to the first dose.6. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA
scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated.
7. Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.8. If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.9. Collect at pre-dose, 1, 3, and 6hr after the start of infusion. 10. To be conducted in male subject only11. PET scans and co-localising CT scans to be acquired as outlined in Section 3.312. See Section 7.8.1 and collect all tumor markers applicable for the subject’s primary tumor type.13. If disease assessment modality is CT then this should be performed on same day as last PET scan. IF assessment is via another modality this may be performed 7days
from the day of the last PET scan to allow scheduling. This disease assessment is to be used as baseline for subsequent comparison to assess markers of clinical response.14. 89Zr- GSK2849330 and GSK2849330 will be administered as a short infusion of a pre-made mixture for the 8mg and 24mg dose levels. For the higher weight adjusted dose
levels the total dose will be achieved by an infusion of unlabeled GSK2849330 over 1 hour followed by a short infusion containing 89Zr- GSK2849330
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REVISED TEXTTable 7 Time and Events for Part 1 (Imaging Phase)
Procedures
Pre-screening
Screening
Part 1
Start of Continuation Phase - Part 23
First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day 15
Day 16 to Day 21
- 21 day window5 ± 1 day window for each visit
Part 2 will start with the first dose given in the continuation phase. The timing of this dose should be discussed with the
sponsor study team.
Informed consent X X
Archival tissue X
Tumor biopsy X7
Baseline demographics X X
Medical history X X
Concurrent Medication Continuous
Pregnancy test4 X5 X
Physical examination X X8 X
Height (at screening only) and weight X X8 X
ECOG X X X8 X
Vital signs (BP, pulse rate, temperature) X X9 X15 X9 X15
12-lead ECG X X9 X9
Hematology/Clinical Chemistry X5 X8 X2 X X2
Serum sample for ImmunogenicityX16 X
Urinalysis X X X
ECHO6 X
PK and Radioactivity measurements (Blood)1 X X X X
Testosterone and LH10 X
Co-localising CT scan11 X X X X
PET Scan11 X X X X
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89Zr-GSK2849330 IV infusion X14 X14
Procedures
Pre-screening
Screening
Part 1 Start of Continuation Phase -Part 23First Scanning Period Second Scanning period
Day 1 Day 2 to Day 7Day 15
Day 16 to Day 21
- 21 day window5 ± 1 day window for each visit
GSK2849330 IV infusion X14 X14
AE assessment Continuous
Tumor markers 12 X
Disease assessment X5 X13
1. Samples for radioactivity and PK analysis to be taken: pre-dose, 1hr(15mins), 3hrs(30mins), 6hrs(1hr), 12hrs(2hrs), 24hrs(3hrs) after end of infusion 89Zr-GSK2849330 and just prior to commencing each PET scan (within 30mins of starting scan). Timing of sampling may be adjusted based on emerging data.
2. Safety labs taken pre-scan of final scan in each scanning period3. The window between dose 2 in Part 1 and dose 1 in Part 2 should never be less than the relevant dosing interval cleared by the FTIH study with other assessments adjusted
according relative to the timing of the first dose in Part 2, if in doubt this should be discussed with a GSK medical monitor.4. Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at Screening. Urine pregnancy test should be conducted pre-dose on day 15. 5. Within 21 days prior to first dose except for Hematology/Clinical Chemistry (14 days), pregnancy test (7 days). Disease assessment can be based on historical data from
up to 42 days prior to Day 1.6. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA
scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated.
7. Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.8. If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.9. Collect at pre-dose, 1, 3, and 6hr after the start of infusion. Where 2 infusions are given, timings are relative to the start of the first infusion10. To be conducted in male subject only11. PET scans and co-localising CT scans to be acquired as outlined in Section 3.4.1.112. See Section 7.8.1 and collect all tumor markers applicable for the subject’s primary tumor type.13. If disease assessment modality is CT then this should be performed on same day as last PET scan. IF assessment is via another modality this may be performed 7days
from the day of the last PET scan to allow scheduling. This disease assessment is to be used as baseline for subsequent comparison to assess markers of clinical response.14. 89Zr- GSK2849330 and GSK2849330 will be administered as a short infusion of a pre-made mixture for the 8mg and 24mg dose levels. For the higher weight adjusted dose
levels the total dose will be achieved by an infusion of unlabeled GSK2849330 over 1 hour followed by a short infusion containing 89Zr- GSK284933015. To be conducted on scanning days only16. Pre-dose
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PREVIOUS TEXTTable 4 Time and events for Part 2 (Continuation Phase)
1, 2 or 3 weekly dosing schedule
ProceduresPart 2 - Continuation Phase 1st Follow-up8 2nd Follow-up9
Part 2 Day 1 ± 7 days + 7 days
GSK2849330 IV infusion1 X
Dose level11 Dosing intervalG 1 week
H, I, J 2 weeksK 3 weeks
Vital signs (BP, pulse rate, temperature) X Every dosing visit X
Hematology/Clinical Chemistry X X
Pregnancy test2 XIf on 1 or 2 week dosing interval then every 4 weeks
to coincide with a dosing visit
If on 3 week dosing interval then every dosing visit
X X
Physical examination X X
Weight X X
ECOG X X
12-lead ECG X X
Urinalysis X X
Serum sample for Immunogenicity XEvery 12 weeks from first dose in Part 2 to coincide
with a dosing visit 7 X
ECHO3 XEvery 8 -10 weeks
X
Testosterone and LH4 X
Tumor markers 5 X Every 8-12 weeks from the first dose in Part 2X
Disease assessment6 X10
Medical history X
Concurrent MedicationContinuous X
AE assessment Continuous
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1 For any subjects receiving a weekly dosing schedule the study treatment dosing window is 2 days. The study treatment dosing window is 3 days for subjects on a 2 or 3 weekly dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received.
2 Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the 1st Follow-up, and 2nd Follow-up visits. Urine pregnancy test should be conducted pre-dose on Part 2 Day 1 then pre-dose every 3-4 weeks depending on dosing interval.
3 ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated. First ECHO/MUGA in Part 2 may be performed between 22 and 30 days from the first dose in Part 1, subsequent ECHO/MUGAs should be performed at 8-10 week intervals from this.
4 To be conducted in male subjects only5 Collect all tumor markers applicable for the subjects’ primary tumor type.6 Confirmatory assessments suggested at least four weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a subject’s next regularly
scheduled visit as appropriate.7 Immunogenicity samples will be collected every 12 weeks (14 days) from the first dose on the continuation phase for the first year and then every 24 weeks (14 days). An
immunogenicity sample will also be collected at the Post-study visit.8 The 1st follow-up visit should be approximately 28 days after the last dose of study treatment.9 The 2nd Follow-up visit should be at least 45 days or 5 half lives (whichever is longer) after the last dose of study treatment.10 If the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease has not been documented, a disease assessment
should be obtained at the time of withdrawal from study.11 See Table 2 for details of dose levels for use in Part 2.
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REVISED TEXTTable 4 Time and events for Part 2 (Continuation Phase)
1, 2 or 3 weekly dosing schedule
ProceduresPart 2 - Continuation Phase Follow-up
Part 2 Day 1 Dosing Days (frequency to be advised)35 ± 7 days after
last dose
GSK2849330 IV infusion1 X X
Vital signs (BP, pulse rate, temperature) X Every dosing visit X
Hematology/Clinical Chemistry X X
Pregnancy test2 XIf on 1 or 2 week dosing interval then every 4 weeks to coincide
with a dosing visit
If on 3 week dosing interval then every dosing visit
X
Physical examination X X
Weight X X
ECOG X X
12-lead ECG X X
Urinalysis X X
Serum sample for Immunogenicity XEvery 12 weeks from first dose in Part 2 to coincide with a dosing
visit 7 X
ECHO3 XEvery 8 -10 weeks
X
Testosterone and LH4 X
Tumor markers 5 X Every 8-12 weeks from the first dose in Part 2X
Disease assessment6 X8
Concurrent MedicationContinuous X
AE assessment Continuous
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1 For any subjects receiving a weekly dosing schedule the study treatment dosing window is 2 days. The study treatment dosing window is 3 days for subjects on a 2 or 3 weekly dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received.
2 Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the follow-up visit. Urine pregnancy test should be conducted pre-dose on Part 2 Day 1 then pre-dose every 3-4 weeks depending on dosing interval.
3 ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a MUGA scan may be performed. Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments should be performed more frequently if clinically indicated. First ECHO/MUGA in Part 2 may be performed between 22 and 30 days from the first dose in Part 1, subsequent ECHO/MUGAs should be performed at 8-10 week intervals from this.
4 To be conducted in male subjects only5 Collect all tumor markers applicable for the subjects’ primary tumor type.6 Confirmatory assessments suggested at least four weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a subject’s next regularly
scheduled visit as appropriate.7 Immunogenicity samples will be collected every 12 weeks (14 days) from the first dose on the continuation phase for the first year and then every 24 weeks (14 days). An
immunogenicity sample will also be collected at the Post-study visit.8 If the last radiographic assessment was more than 8 weeks prior to the subject’s withdrawal from study and progressive disease has not been documented, a disease assessment
should be obtained at the time of withdrawal from study.
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Section 7.2: Demographic/Medical History and Baseline Assessments
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...Details concerning concomitant medication will be recorded starting from screening through to the follow-up 1 visit...
REVISED TEXT
...Details concerning concomitant medication will be recorded starting from screening through to the follow-up visit...
Section 7.3.7: Pregnancy Testing and Reporting
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All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until the second follow-up visit.
REVISED TEXT
All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until the follow-up visit.
Section 8.5: Time Period and Frequency of Detecting AEs and SAEs
PREVIOUS TEXT
...AEs will be collected from the time the first dose of study treatment is administered until the second follow-up visit (45days or 5 half-lives from last dose of GSK2849330, whichever is longer) following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice.
REVISED TEXT
...AEs will be collected from the time the first dose of study treatment is administered until the follow-up visit following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice.
Section 13.3.2.3:Post dose-escalation in-stream analysis
PREVIOUS TEXT
Post dose-escalation in-stream analysis
To answer the project-level questions of what dose to take forward to the dose expansion phase of the GSK2849330 first time in human study (HER117158) a complete summaryof data received so far will be produced at the appropriate time point. .
REVISED TEXT
Expansion phase in-stream analysis
To answer project-level questions relating to dose level in the dose expansion phase of the GSK2849330 first time in human study (HER117158) a report of data received so far will be produced at the appropriate time point
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Section 13.4.5: Pharmacokinetic/Pharmacodynamic Analyses
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Further details of the PK/PD analysis performed by Clinical Statistics will be addressed in the Reporting and Analysis Plan (RAP).
REVISED TEXT
Further details of the PK/PD analysis performed by CPMS and Clinical Statistics will be addressed in the respective Reporting and Analysis Plans (RAP).
Section: 16.1 Appendix 1: Physical, Chemical and Pharmaceutical Properties and Formulation - 89Zr-GSK2849330 solution for injection
PREVIOUS TEXT
...The medicinal product is manufactured in situ.
REVISED TEXT
...The medicinal product is manufactured in situ at the VUMC
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16.8. Appendix 8: Protocol Amendment 2 – summary of changes
The protocol has been amended to:
Correct information relating to use of filter during administration Update medical monitor information; and Correct minor errors in the protocol.
List of Specific Changes
Medical Monitor and Sponsor contact information
PREVIOUS TEXT
Role Name Day Time Phone Number
After-hours Phone/Cell/Pager Number
Fax Number GSK Address
Primary Medical Monitor
Gunnels Wood RoadStevenage Herts, SG1 2NY
Secondary Medical Monitor
n/a 1250 S Collegeville Road Collegeville, PA 19426 USA
Tertiary Medical Monitor
n/a 709 Swedeland RoadKing of Prussia, PA 19406
REVISED TEXT
Role Name Day Time Phone Number
After-hours Phone/Cell/Pager Number
Fax Number GSK Address
Primary Medical Monitor
709 Swedeland Rd, King of Prussia, PA 19406USA
Secondary Medical Monitor
n/a1250 S Collegeville Road Collegeville, PA 19426 USA
Tertiary Medical Monitor
n/aGunnels Wood RoadStevenage Herts, SG1 2NY
Section 1.2.3: Safety of GSK2849330
PREVIOUS TEXT
Details of pre-clinical toxicology of GSK2849330 are given in Section 3.6.3 and the IB GlaxoSmithKline Document Number 2013N168399_00].
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PPD
PPD
PPD
PPDPPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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NEW TEXT
Details of pre-clinical toxicology of GSK2849330 are given in the IB GlaxoSmithKline Document Number 2013N168399_00].
Section 4.2: Preparation/Handling/Storage of GSK2849330 GSK Investigational Product
PREVIOUS TEXT
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate concentration for the dose. Deliver the entire contents of the IV bag to the subject. The administration kits can be polymerizing vinyl chloride (PVC), polyolefin (PO) or 0.22M polyethersulfone (PES). A filtration set will not be used for this study
REVISED TEXT
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate concentration for the dose. Deliver the entire contents of the IV bag to the subject. The administration kits can be polymerizing vinyl chloride (PVC), or polyolefin (PO). An inline filtration set will be used for this study.
Section: 6.3 . Permanent Discontinuation from Study Treatment
PREVIOUS TEXT
All subjects who discontinue from study treatment will have safety assessments at the time of discontinuation and follow up one (28 days post last dose) and immunogenicity and, where relevant, pregnancy assessments at follow up two (45 days or five half lives, whichever is greater) as specified in the Time and Events Table (see Section 7.1).
REVISED TEXT
All subjects who discontinue from study treatment will have safety assessments at the time of discontinuation. At their follow up visit, subjects will have safety, immunogenicity and, where relevant, pregnancy assessments as specified in the Time and Events Table (see Section 7.1).
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