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TPS3132 PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF …
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PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF SINGLE-AGENT BISPECIFIC ANTIBODY T-CELL ENGAGER GBR 1342 IN RELAPSED/REFRACTORY MULTIPLE MYELOMA JOSHUA RICHTER 1 ■ OLA LANDGREN 2 ■ JOHN KAUH 3 ■ JONATHAN BACK 4 ■ YACINE SALHI 3 ■ VENKATESHWAR REDDY 3 ■ ELIEL BAYEVER 3 ■ JESUS BERDEJA 5 1 JOHN THEURER CANCER CENTER, HACKENSACK UNIVERSITY MEDICAL CENTER, HACKENSACK, NEW JERSEY, USA ■ 2 MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, NEW YORK, USA ■ 3 GLENMARK PHARMACEUTICALS INC, MAHWAH, NEW JERSEY, USA ■ 4 GLENMARK PHARMACEUTICALS SA, LA CHAUX-DE-FONDS, SWITZERLAND ■ 5 SARAH CANNON RESEARCH INSTITUTE, NASHVILLE, TENNESSEE, USA INTRODUCTION ◾ ◾ GBR 1342 is a novel CD3xCD38 bispecific antibody engineered (using the Glenmark Bispecific Engagement by Antibodies based on the T-cell receptor [BEAT®] platform) to direct T-cells to CD38-expressing myeloma cells by engaging the CD3 molecule on T lymphocytes and the CD38 antigen on tumor cells, thereby killing the bound target cells through redirected lysis (Figure 1) •◾ Includes a single chain, variable fragment arm with anti-CD38 specificity and a fragment antigen binding (Fab) arm with anti-CD3ε specificity •◾ Has full antibody-like pharmacokinetics with a long elimination half-life of approximately 110 hours (in rats), which is similar to IgG and therefore permits intermittent dosing •◾ Has low immunogenicity potential •◾ Fcγ receptor binding is engineered to reduce complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) effector functions Figure 1. GBR 1342 BEAT® Design and Redirected Lysis anti-CD3 anti-CD38 Redirected Lysis CD3+ T-cell Tumor Cell ◾ ◾ Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease 1 ◾ ◾ CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1 kappa (IgG1κ) monoclonal antibody 2-5 ◾ ◾ In preclinical studies, GBR 1342 demonstrated potent killing of CD38-overexpressing cancer cell lines, including multiple myeloma cell lines (Figure 2) •◾ A direct correlation was observed between CD38 expression levels and efficacy of killing by GBR 1342, with greater antigen expression resulting in more potent killing Figure 2. GBR 1342 Killing of Target Cells Correlates with CD38 Expression EC 50 (ng/mL) 0.1 1 10 Daudi RAJI RPMI8226 IM-9 NCI-H929 The ratio of effector (healthy donor PBMC): target cells was 10:1. CD38 expression on target cells decreases from left to right. EC 50 , 50% effective concentration; PBMC, peripheral blood mononuclear cell. ◾ ◾ In redirected lysis (RDL) assays, GBR 1342 demonstrated greater potency versus daratumumab on all cell lines tested, suggesting the redirecting ability of GBR 1342 affords more rapid and efficient T-cell cytotoxic activity (Figure 3) ◾ ◾ These data suggest that the unique mechanism of action of GBR 1342 may afford superior anti-tumor activity to patients with multiple myeloma compared with conventional CD38-targeting therapies (e.g., daratumumab 1 ) Figure 3. Comparison of GBR 1342 and Daratumumab Potency in RDL Assays % of Specific Killing -50 0 50 100 % of Specific Killing -50 0 50 100 Log Antibody Concentration (pM) -4 -2 0 2 4 Log Antibody Concentration (pM) -4 -2 0 2 4 % of Specific Killing -50 0 50 100 Log Antibody Concentration (pM) -4 -2 0 2 4 % of Specific Killing 0 50 100 Log Antibody Concentration (pM) -4 -2 0 2 4 RPMI8226 Daudi IM-9 NCI-H929 GBR 1342 daratumumab GBR 1342 daratumumab GBR 1342 daratumumab GBR 1342 daratumumab Graphs show non-linear curve fitting from each PBMC donor with the indicated target cell lines; the results represent at least 2 independent experiments per cell line. PBMC, peripheral blood mononuclear cell; RDL, redirected lysis. STUDY STATUS ◾ ◾ The first clinical study of GBR 1342 (GBR 1342-101; NCT03309111) is currently recruiting and enrolling patients in the United States STUDY OBJECTIVES ◾ ◾ This two-part, first-in-human clinical study of GBR 1342 aims to: 1. Evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma 2. Further elucidate the safety, tolerability, and preliminary clinical activity (objective response, pharmacokinetics [PK], immunogenicity) of GBR 1342 at the MTD ◾ ◾ The study additionally aims to characterize the immunomodulatory effects triggered by GBR 1342 STUDY DESIGN ◾ ◾ Phase I, multicenter, open-label, two-part, dose-escalation study of GBR 1342 monotherapy in subjects with previously treated multiple myeloma ◾ ◾ The study is being conducted in compliance with Good Clinical Practice, 6 International Council on Harmonisation guidelines, 7 and the Declaration of Helsinki 8 ◾ ◾ The protocol and informed consent were approved by local institutional review boards and written informed consent was obtained from all subjects prior to entering the study Part 1: Dose-Finding Study ◾ ◾ Currently enrolling approximately 60 adult subjects with multiple myeloma who have received prior therapies Part 2: Expansion Study ◾ ◾ Plans to enroll an additional 65 subjects with multiple myeloma who have received prior therapies ◾ ◾ Subjects will be treated at the MTD identified in Part 1 to further evaluate the safety, PK, and preliminary anti-tumor activity of GBR 1342 until disease progression or unacceptable toxicity occurs STUDY SUBJECTS (PART 1) Key Inclusion Criteria ◾ ◾ Adults ≥18 years without therapeutic options of known or proven benefit, in the opinion of the Investigator ◾ ◾ Measurable disease, defined as any quantifiable monoclonal protein value by ≥1 of the following measures: •◾ Serum M protein ≥10 g/L (for IgA ≥5 g/L), or •◾ Urine light-chain (M protein) of ≥200 mg/24 hours, or •◾ Serum free light chain (sFLC) assay: involved free light chain (FLC) level ≥10 mg/dL provided sFLC ratio is abnormal ◾ ◾ Eastern Cooperative Oncology Group (ECOG) performance-status score of ≤2 ◾ ◾ Absolute neutrophil count ≥1000/mm 3 , platelet count ≥20×10 9 /L, and hemoglobin ≥7.5 g/dL (unless decreases are caused by myeloma, defined by bone marrow infiltration of >50%) ◾ ◾ Serum creatinine ≤2x upper limit of normal (ULN) or creatinine clearance ≥20 mL/minute/1.73 m 2 of body surface area, serum alanine aminotransferase and alkaline phosphatase ≤3.5x ULN, and bilirubin ≤2.5x ULN Key Exclusion Criteria ◾ ◾ Any condition that would interfere with evaluation of the study drug or results, as determined by the Investigator, or a diagnosis of another malignancy that requires active therapy ◾ ◾ Active infectious disease considered by the Investigator to be incompatible with the protocol; known to be seropositive for human immunodeficiency virus; or history of a positive result for hepatitis B surface antigen (HbsAg) or antibody to hepatitis C virus (anti-HCV) ◾ ◾ Evidence of clinically significant cardiovascular and respiratory conditions, including myocardial infarction within 1 year, uncontrolled or unstable angina, congestive heart failure (New York Heart Association Class III or IV), arrhythmia (Grade ≥2), QTcF interval longer than 470 ms, chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years ◾ ◾ Active central nervous system involvement ◾ ◾ Subjects not recovered to at least Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 from any therapy-related toxicities from previous chemo-, immune-, molecular-targeted, or radiotherapies, except in cases of liver metastases, Gilbert’s Syndrome, or alopecia ◾ ◾ Anti-myeloma treatment within 2 weeks or autologous stem cell transplantation within 12 weeks of Day 1 of dosing Cycle 1 (Part 1) ◾ ◾ Use of any investigational drug within 4 weeks of the start of study drug or concomitantly with study drug, except for investigational immune-stimulatory therapy (e.g., checkpoint-regulator targeted therapy) for which the minimum washout period should be 8 weeks ◾ ◾ Pregnant or breastfeeding ◾ ◾ Known allergy to any of the ingredients in the formulation (i.e., citrate, sucrose, Tween) or known allergy to any related class of compounds Dosing Schedule (Part 1) ◾ ◾ Based on previous in vitro studies and PK projections, the estimated safe starting dose of GBR 1342 in humans was determined to be 1 ng/kg ◾ ◾ Intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating doses ( Table 1) •◾ Cohorts 1-4: each consist of a single subject; targeted final doses range from 3 ng/kg (Cohort 1) to 60 ng/kg (Cohort 4) •◾ Cohorts 5-10: standard 3+3 design; targeted final doses range from 100 ng/kg (Cohort 5) to 1000 ng/kg (Cohort 10) Table 1. GBR 1342 Dose Escalation Scheme Cohort Days of Cycle Cycle 1 Cycle 2 Subsequent Cycle(s) Day 1 Day 15 Day 1 Day 15 Day 1 Day 15 Single Subject 1 1 3 3 3 3 3 2 3 10 10 10 10 10 3 10 30 30 30 30 30 4 30 60 60 60 60 60 3+3 5 60 100 100 100 100 100 6 100 200 200 200 200 200 7 200 400 400 400 400 400 8 400 600 600 600 600 600 9 600 800 800 800 800 800 10 800 1000 1000 1000 1000 1000 Doses are in ng/kg. Determination of Maximum Tolerable Dose (MTD) ◾ ◾ Dose escalation follows an accelerated design initially with 4 single subject cohorts (Cohorts 1-4) and switches to a classical 3+3 design with intra-subject dose escalation (Figure 4) ◾ ◾ Adverse events (AEs) constitute a dose limiting toxicity (DLT) if one of the following conditions applies •◾ Non-hematologic toxicity CTCAE Grade ≥3, except for: • Alopecia of any CTCAE grade • Any other CTCAE Grade ≥3 skin toxicity recovered to Grade ≤1 within 2 weeks after last dose • CTCAE Grade 3 fatigue recovered to Grade ≤2 within 2 weeks after last dose •◾ ≥1 hematologic toxicities: CTCAE Grade 3 hemolytic anemia; CTCAE Grade 4 anemia; CTCAE Grade 4 neutropenia lasting 7 days; CTCAE Grade 3 or 4 febrile neutropenia; CTCAE Grade 3 thrombocytopenia lasting more than 7 days •◾ Any other AE that in the opinion of the Data Safety Monitoring Committee constitutes a safety threat to the subject ◾ ◾ The observation period for DLT is the 28 days following the first administration of study drug (Day 1 of Cycle 1) ◾ ◾ Subjects will receive GBR 1342 treatment until either disease progression or unacceptable toxicity occurs Figure 4. Schematic for Determination of MTD Enter 3 Subjects 1 of 3 DLT Enter 3 More Subjects at This Dose Level 0 of 3 DLT Escalate to the Next Higher Dose 1 of 6 DLT b Escalate to the Next Higher Dose >1 of 6 DLT b Stop Dose Escalation ≥2 of 3 DLT Stop Dose Escalation Enter 3 More Subjects at Previous Dose to Confirm MTD with n=6 Subjects MTD is Previous Dose Enter 1 Subject 1 of 1 DLT Enter 5 More Subjects at This Dose Level 0 of 1 DLT Escalate to the Next Higher Dose 1 of 6 DLT a Escalate to the Next Higher Dose ≥2 of 6 DLT a Stop Dose Escalation MTD is Previous Dose MTD is Previous Dose Cohorts 1-4: Single Subject Cohorts 5-10: 3+3 Design a Includes the one subject who experienced DLT. b Includes the three subjects of which ≥1 experienced DLT. DLT, dose limiting toxicity; MTD, maximum tolerable dose. STUDY ENDPOINTS ◾ ◾ Primary endpoints •◾ Frequency and severity of AEs •◾ Number of DLTs during the first 28 days after the first administration of study drug (i.e., Cycle 1) (Part 1 only) •◾ Objective response to GBR 1342 according to International Myeloma Working Group (IMWG) response criteria 9 (Part 2 only) ◾ ◾ Secondary endpoints •◾ PK endpoints estimated after each dose administration, including: C max , t max , AUC 0-tau , AUC 0-t •◾ Objective response to GBR 1342 according to IMWG response criteria (Part 1 only) •◾ Anti-tumor activity of GBR 1342 (Part 2), including: progression free survival, time to treatment failure, time to disease progression, overall survival, duration of response, disease control rate, and duration of disease control compared with prior therapy •◾ Immunogenicity by anti-drug antibody formation assessed from baseline until end of treatment ◾ ◾ Exploratory endpoints •◾ Changes in pharmacodynamic biomarkers from baseline as surrogate markers for GBR 1342 activity, including: • Cellular biomarkers (CD3, CD4, CD8, CD25, CD38, CD69, and CD127) assessed by fluorescence- activated cell sorting (FACS) analysis of peripheral blood leukocytes • Cytokines (interleukin [IL]-2, IL-6, IL-10, interferon [IFN]-γ, tumor necrosis factor [TNF]) assessed in peripheral blood REFERENCES 1. Larocca A, Mina R, et al. Oncotarget. 2017;8(36):60656-72. 2. Lin P, Owens R, et al. Am J Clin Pathol. 2004;121(4):482-8. 3. Lokhorst HM, Plesner T, et al. NEJM. 2015;373(13):1207-19. 4. Lonial S, Weiss BM, et al. Lancet. 2016;387(10027):1551-60. 5. Krejcik J, Frerichs KA, et al. Clin Cancer Res. 2017;23(24):7498-511. 6. Guidance for Industry E6 Good Clinical Practice. [https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf] 7. ICH Harmonised Tripartite Guideline. [http://www.ich.org/products/guidelines.html] 8. World Medical Association. JAMA. 2013;310(20):2191-4. 9. Rajkumar SV, Harousseau JL, et al. Blood. 2011;117(18):4691-5. DISCLOSURES This study was sponsored by Glenmark Pharmaceuticals Inc., USA (Mahwah, NJ). Medical writing and editorial assistance were provided by Prescott Medical Communications Group (Chicago, IL) and funded by Glenmark Pharmaceuticals S.A., Switzerland. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from ASCO® and the authors of this poster. Corresponding author: Dr. J. Richter, [email protected] POSTER PRESENTED AT THE 54TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY | JUNE 1-5, 2018 | CHICAGO, IL TPS3132
Transcript of TPS3132 PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF …
PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF SINGLE-AGENT BISPECIFIC ANTIBODY T-CELL ENGAGER
GBR 1342 IN RELAPSED/REFRACTORY MULTIPLE MYELOMAJOSHUA RICHTER1 ■ OLA LANDGREN2 ■ JOHN KAUH3 ■ JONATHAN BACK4 ■ YACINE SALHI3 ■ VENKATESHWAR REDDY3 ■ ELIEL BAYEVER3 ■ JESUS BERDEJA5
1JOHN THEURER CANCER CENTER, HACKENSACK UNIVERSITY MEDICAL CENTER, HACKENSACK, NEW JERSEY, USA ■ 2MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, NEW YORK, USA ■ 3GLENMARK PHARMACEUTICALS INC, MAHWAH, NEW JERSEY, USA ■ 4GLENMARK PHARMACEUTICALS SA, LA CHAUX-DE-FONDS, SWITZERLAND ■
5SARAH CANNON RESEARCH INSTITUTE, NASHVILLE, TENNESSEE, USA
INTRODUCTION◾◾ GBR 1342 is a novel CD3xCD38 bispecific antibody engineered (using the Glenmark Bispecific Engagement by Antibodies based on the T-cell receptor [BEAT®] platform) to direct T-cells to CD38-expressing myeloma cells by engaging the CD3 molecule on T lymphocytes and the CD38 antigen on tumor cells, thereby killing the bound target cells through redirected lysis (Figure 1)
•◾ Includes a single chain, variable fragment arm with anti-CD38 specificity and a fragment antigen binding (Fab) arm with anti-CD3ε specificity
•◾ Has full antibody-like pharmacokinetics with a long elimination half-life of approximately 110 hours (in rats), which is similar to IgG and therefore permits intermittent dosing
•◾ Has low immunogenicity potential
•◾ Fcγ receptor binding is engineered to reduce complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) effector functions
Figure 1. GBR 1342 BEAT® Design and Redirected Lysis
anti-CD3
anti-CD38
RedirectedLysis
CD3+T-cell
TumorCell
◾◾ Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease1
◾◾ CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1 kappa (IgG1κ) monoclonal antibody2-5
◾◾ In preclinical studies, GBR 1342 demonstrated potent killing of CD38-overexpressing cancer cell lines, including multiple myeloma cell lines (Figure 2)
•◾ A direct correlation was observed between CD38 expression levels and efficacy of killing by GBR 1342, with greater antigen expression resulting in more potent killing
Figure 2. GBR 1342 Killing of Target Cells Correlates with CD38 Expression
EC5
0 (ng
/mL)
0.1
1
10
Daudi RAJI RPMI8226 IM-9 NCI-H929
The ratio of effector (healthy donor PBMC): target cells was 10:1.CD38 expression on target cells decreases from left to right.EC50, 50% effective concentration; PBMC, peripheral blood mononuclear cell.
◾◾ In redirected lysis (RDL) assays, GBR 1342 demonstrated greater potency versus daratumumab on all cell lines tested, suggesting the redirecting ability of GBR 1342 affords more rapid and efficient T-cell cytotoxic activity (Figure 3)
◾◾ These data suggest that the unique mechanism of action of GBR 1342 may afford superior anti-tumor activity to patients with multiple myeloma compared with conventional CD38-targeting therapies (e.g., daratumumab1)
Figure 3. Comparison of GBR 1342 and Daratumumab Potency in RDL Assays
% o
f Spe
cific
Kill
ing
-50
0
50
100
% o
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cific
Kill
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Log Antibody Concentration (pM)-4 -2 0 2 4
Log Antibody Concentration (pM)-4 -2 0 2 4
% o
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Log Antibody Concentration (pM)-4 -2 0 2 4
% o
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Log Antibody Concentration (pM)-4 -2 0 2 4
RPMI8226 Daudi IM-9 NCI-H929
GBR 1342daratumumab
GBR 1342daratumumab
GBR 1342daratumumab
GBR 1342daratumumab
Graphs show non-linear curve fitting from each PBMC donor with the indicated target cell lines; the results represent at least 2 independent experiments per cell line.PBMC, peripheral blood mononuclear cell; RDL, redirected lysis.
STUDY STATUS◾◾ The first clinical study of GBR 1342 (GBR 1342-101; NCT03309111) is currently recruiting and enrolling patients in the United States
STUDY OBJECTIVES◾◾ This two-part, first-in-human clinical study of GBR 1342 aims to:
1. Evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma
2. Further elucidate the safety, tolerability, and preliminary clinical activity (objective response, pharmacokinetics [PK], immunogenicity) of GBR 1342 at the MTD
◾◾ The study additionally aims to characterize the immunomodulatory effects triggered by GBR 1342
STUDY DESIGN◾◾ Phase I, multicenter, open-label, two-part, dose-escalation study of GBR 1342 monotherapy in subjects with previously treated multiple myeloma
◾◾ The study is being conducted in compliance with Good Clinical Practice,6 International Council on Harmonisation guidelines,7 and the Declaration of Helsinki8
◾◾ The protocol and informed consent were approved by local institutional review boards and written informed consent was obtained from all subjects prior to entering the study
Part 1: Dose-Finding Study ◾◾ Currently enrolling approximately 60 adult subjects with multiple myeloma who have received prior therapies
Part 2: Expansion Study◾◾ Plans to enroll an additional 65 subjects with multiple myeloma who have received prior therapies
◾◾ Subjects will be treated at the MTD identified in Part 1 to further evaluate the safety, PK, and preliminary anti-tumor activity of GBR 1342 until disease progression or unacceptable toxicity occurs
STUDY SUBJECTS (PART 1)Key Inclusion Criteria ◾◾ Adults ≥18 years without therapeutic options of known or proven benefit, in the opinion of the Investigator
◾◾ Measurable disease, defined as any quantifiable monoclonal protein value by ≥1 of the following measures:
•◾ Serum M protein ≥10 g/L (for IgA ≥5 g/L), or
•◾ Urine light-chain (M protein) of ≥200 mg/24 hours, or
•◾ Serum free light chain (sFLC) assay: involved free light chain (FLC) level ≥10 mg/dL provided sFLC ratio is abnormal
◾◾ Eastern Cooperative Oncology Group (ECOG) performance-status score of ≤2
◾◾ Absolute neutrophil count ≥1000/mm3, platelet count ≥20×109/L, and hemoglobin ≥7.5 g/dL (unless decreases are caused by myeloma, defined by bone marrow infiltration of >50%)
◾◾ Serum creatinine ≤2x upper limit of normal (ULN) or creatinine clearance ≥20 mL/minute/1.73 m2 of body surface area, serum alanine aminotransferase and alkaline phosphatase ≤3.5x ULN, and bilirubin ≤2.5x ULN
Key Exclusion Criteria◾◾ Any condition that would interfere with evaluation of the study drug or results, as determined by the Investigator, or a diagnosis of another malignancy that requires active therapy
◾◾ Active infectious disease considered by the Investigator to be incompatible with the protocol; known to be seropositive for human immunodeficiency virus; or history of a positive result for hepatitis B surface antigen (HbsAg) or antibody to hepatitis C virus (anti-HCV)
◾◾ Evidence of clinically significant cardiovascular and respiratory conditions, including myocardial infarction within 1 year, uncontrolled or unstable angina, congestive heart failure (New York Heart Association Class III or IV), arrhythmia (Grade ≥2), QTcF interval longer than 470 ms, chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years
◾◾ Active central nervous system involvement
◾◾ Subjects not recovered to at least Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤1 from any therapy-related toxicities from previous chemo-, immune-, molecular-targeted, or radiotherapies, except in cases of liver metastases, Gilbert’s Syndrome, or alopecia
◾◾ Anti-myeloma treatment within 2 weeks or autologous stem cell transplantation within 12 weeks of Day 1 of dosing Cycle 1 (Part 1)
◾◾ Use of any investigational drug within 4 weeks of the start of study drug or concomitantly with study drug, except for investigational immune-stimulatory therapy (e.g., checkpoint-regulator targeted therapy) for which the minimum washout period should be 8 weeks
◾◾ Pregnant or breastfeeding
◾◾ Known allergy to any of the ingredients in the formulation (i.e., citrate, sucrose, Tween) or known allergy to any related class of compounds
Dosing Schedule (Part 1)◾◾ Based on previous in vitro studies and PK projections, the estimated safe starting dose of GBR 1342 in humans was determined to be 1 ng/kg
◾◾ Intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating doses (Table 1)
•◾ Cohorts 1-4: each consist of a single subject; targeted final doses range from 3 ng/kg (Cohort 1) to 60 ng/kg (Cohort 4)
•◾ Cohorts 5-10: standard 3+3 design; targeted final doses range from 100 ng/kg (Cohort 5) to 1000 ng/kg (Cohort 10)
Table 1. GBR 1342 Dose Escalation Scheme
Cohort
Days of CycleCycle 1 Cycle 2 Subsequent Cycle(s)
Day 1 Day 15 Day 1 Day 15 Day 1 Day 15
SingleSubject
1 1 3 3 3 3 32 3 10 10 10 10 103 10 30 30 30 30 304 30 60 60 60 60 60
3+3
5 60 100 100 100 100 1006 100 200 200 200 200 2007 200 400 400 400 400 4008 400 600 600 600 600 6009 600 800 800 800 800 800
10 800 1000 1000 1000 1000 1000Doses are in ng/kg.
Determination of Maximum Tolerable Dose (MTD)◾◾ Dose escalation follows an accelerated design initially with 4 single subject cohorts (Cohorts 1-4) and switches to a classical 3+3 design with intra-subject dose escalation (Figure 4)
◾◾ Adverse events (AEs) constitute a dose limiting toxicity (DLT) if one of the following conditions applies
•◾ Non-hematologic toxicity CTCAE Grade ≥3, except for:
• Alopecia of any CTCAE grade
• Any other CTCAE Grade ≥3 skin toxicity recovered to Grade ≤1 within 2 weeks after last dose
• CTCAE Grade 3 fatigue recovered to Grade ≤2 within 2 weeks after last dose
•◾ ≥1 hematologic toxicities: CTCAE Grade 3 hemolytic anemia; CTCAE Grade 4 anemia; CTCAE Grade 4 neutropenia lasting 7 days; CTCAE Grade 3 or 4 febrile neutropenia; CTCAE Grade 3 thrombocytopenia lasting more than 7 days
•◾ Any other AE that in the opinion of the Data Safety Monitoring Committee constitutes a safety threat to the subject
◾◾ The observation period for DLT is the 28 days following the first administration of study drug (Day 1 of Cycle 1)
◾◾ Subjects will receive GBR 1342 treatment until either disease progression or unacceptable toxicity occurs
Figure 4. Schematic for Determination of MTD
Enter 3 Subjects
1 of 3 DLT
Enter 3 MoreSubjects at This
Dose Level
0 of 3 DLT
Escalate to theNext Higher
Dose
1 of 6 DLTb
Escalate to theNext Higher
Dose
>1 of 6 DLTb
Stop DoseEscalation
≥2 of 3 DLT
Stop DoseEscalation
Enter 3 MoreSubjects at
Previous Doseto Confirm MTD
with n=6Subjects
MTD isPrevious Dose
Enter 1 Subject
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MTD isPrevious Dose
MTD isPrevious Dose
Cohorts 1-4: Single Subject Cohorts 5-10: 3+3 Design
aIncludes the one subject who experienced DLT.bIncludes the three subjects of which ≥1 experienced DLT.DLT, dose limiting toxicity; MTD, maximum tolerable dose.
STUDY ENDPOINTS◾◾ Primary endpoints
•◾ Frequency and severity of AEs
•◾ Number of DLTs during the first 28 days after the first administration of study drug (i.e., Cycle 1) (Part 1 only)
•◾ Objective response to GBR 1342 according to International Myeloma Working Group (IMWG) response criteria9 (Part 2 only)
◾◾ Secondary endpoints
•◾ PK endpoints estimated after each dose administration, including: Cmax, tmax, AUC0-tau, AUC0-t
•◾ Objective response to GBR 1342 according to IMWG response criteria (Part 1 only)
•◾ Anti-tumor activity of GBR 1342 (Part 2), including: progression free survival, time to treatment failure, time to disease progression, overall survival, duration of response, disease control rate, and duration of disease control compared with prior therapy
•◾ Immunogenicity by anti-drug antibody formation assessed from baseline until end of treatment
◾◾ Exploratory endpoints
•◾ Changes in pharmacodynamic biomarkers from baseline as surrogate markers for GBR 1342 activity, including:
• Cellular biomarkers (CD3, CD4, CD8, CD25, CD38, CD69, and CD127) assessed by fluorescence-activated cell sorting (FACS) analysis of peripheral blood leukocytes
• Cytokines (interleukin [IL]-2, IL-6, IL-10, interferon [IFN]-γ, tumor necrosis factor [TNF]) assessed in peripheral blood
REFERENCES1. Larocca A, Mina R, et al. Oncotarget. 2017;8(36):60656-72.2. Lin P, Owens R, et al. Am J Clin Pathol. 2004;121(4):482-8.3. Lokhorst HM, Plesner T, et al. NEJM. 2015;373(13):1207-19.4. Lonial S, Weiss BM, et al. Lancet. 2016;387(10027):1551-60.5. Krejcik J, Frerichs KA, et al. Clin Cancer Res. 2017;23(24):7498-511.6. Guidance for Industry E6 Good Clinical Practice. [https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf]7. ICH Harmonised Tripartite Guideline. [http://www.ich.org/products/guidelines.html]8. World Medical Association. JAMA. 2013;310(20):2191-4.9. Rajkumar SV, Harousseau JL, et al. Blood. 2011;117(18):4691-5.
DISCLOSURESThis study was sponsored by Glenmark Pharmaceuticals Inc., USA (Mahwah, NJ). Medical writing and editorial assistance were provided by Prescott Medical Communications Group (Chicago, IL) and funded by Glenmark Pharmaceuticals S.A., Switzerland. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission from ASCO® and the authors of this poster.Corresponding author: Dr. J. Richter, [email protected]
C
POSTER PRESENTED AT THE 54TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY | JUNE 1-5, 2018 | CHICAGO, IL
TPS3132
