Transcript of Clinical Trials Explained and Explored Presented By: Jerry Call March 11, 2013.
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- Clinical Trials Explained and Explored Presented By: Jerry Call
March 11, 2013
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- What is a Clinical Trial? Health-related research study
Requires ethics review (IRB) Follows a pre-defined protocol
Requires informed consent Only 2-4% of cancer patients participate
in clinical trials
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- Why do Patients Participate in Trials*? 89%-Obtaining possible
benefit very important 17%-Helping future cancer
patients/treatments Other factors cited as very important o
66%-Trust in doctor o 66%-Being treated by the latest treatment
available o 61%-Better standard of care and closer follow-up 71%
stated that surviving for as long as possible was the most
important thing for them *Survey of 38 patients participating in
phase I and phase II trials British Journal of Cancer (2005) 92,
1001-1005
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- May not be effective Side effects Additional testing, time and
travel (travel expenses) Some costs may not be covered by insurance
Option to access treatment after standard treatments fail Receive
treatment at a major GIST trial center Help future patients
BenefitsRisks
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- Clinical Trial Phases Approx 10% of drugs that start get
approved Phase II Further defines the safety and begins to evaluate
effectiveness Phase III Compare a new agent with the current
standard treatment Randomized to groups Phase IV o Usually take
place after the treatment is approved o Further evaluate long-term
safety and effectiveness Phase I o First step in humans o
Increasing doses (cohorts) determine safe dose o Evaluate route of
administration o Side effects
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- FDA Procedures that look like trials Compassionate access
Expanded access Single patient IND Treatment use o Example; Sutent
Treatment Use protocol 2004 - 2005
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- High Patient Interest in GIST Trials Success of Gleevec
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- GIST Survival-Historical vs. Current Therapy* *Lancet 2004;
1127-134
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- High Patient Interest in GIST Trials Success of Gleevec
Educated patient population o Internet-based support groups
Patients continue to join trials of new therapies for GIST o But at
a declining rate? o Early success- high expectations o GIST
patients spoiled by the initial success Off-Label drug access
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- Factors Affecting Choice in Trials Location Travel o How far? o
How often? o How long do you have to stay? Phase Mutation type
Eligibility o Inclusion/exclusion o Insurance coverage o National
health care issues Placebo vs. non- placebo Early perception o
Efficacy, side effects, etc
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- Navigating Clinical Trials Phase l: Starting at the right
dosage level Determining Eligibility Logistic and Financial Issues
o Where is the trial site? o Am I eligible to go there? o How often
to I have to go there? o For how long? o At what costs?
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- Previous Treatment Exclusions Participation in some trials may
prevent entry into other trials Examples Treatment with an HSP90
inhibitor may exclude you from trials with a different HSP90
inhibitor Treatment with a VEGFR inhibitor may prevent treatment
with a second VEGFR/KIT inhibitor May require some planning to
sequence trials
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- Treatment Phases Recently Diagnosed Stable Disease 2 nd Line 3
rd Line and beyond
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- Recently Diagnosed Neoadjuvant trials o Does drug therapy
before surgery make surgery easier? Adjuvant trials o Does Gleevec
after surgery prevent or delay a recurrence of GIST First Line
Trials o Is another drug better than Gleevec when given to new
patients? o Plasma levels? o Is another drug more tolerable? o By
genotype
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- 1 st line Trials Masitinib o Phase III o USA Florida Ohio
Crenolanib (D842V mutation only) o Fox Chase o OHSU Dasatinib
(Sprycel) o Recently closed
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- Stable Disease Surgery for metastatic GIST that is stable?
Difficult to randomize patients to surgery
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- 2 nd Line Trials Sutent + TH-302 Masitinib vs Sutent o Phase 3
trial recently opened; 50 sites. 2nd line means After Failure of
Gleevec
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- Resistant to Gleevec 1 st Line o Surgery, RFA, Ablation for
limited progression o 400 mg800 mg 2 nd Line o Sutent 3 rd Line o
Stivarga (regorafenib) 4th Line & beyond o Clinical trials o
Off-label o Treatment Use Trials (expanded access)
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- Target KIT and secondary mutations Higher dose IM or Sutent
Much not known CP-868,596 (ph II trial) Dasatinib? HSP90 or PI3K
inhibitor Potent WT KIT inhibitors IGF-1R SDH ?
MutationCharacteristicsPossible Solutions Little clinical data Some
in-vitro data
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- Failure to Inhibit KIT-secondary mutations Possible Solutions:
Different KIT inhibitor with activity against both the primary and
secondary mutation. Possibilities include: Sutent (approved in US)
Stivarga (approved in US) Dovitinib DCC-2618 (Deciphera) Destroy
KIT protein STA-9090, AUY922 Combinations; Gleevec + AT13387,
BKM120, etc In addition to the initial mutation, secondary
mutations that promote resistance to Gleevec can occur. Prior to
treatment with Gleevec none of 112 GIST samples had more than one
activating mutation in KIT or PDGFRA (Heinrich MC, et al. J Clin
Oncol 2003. 21:4342-49) Initial and secondary KIT mutations Ligand
binding domain Exon 9-Extracellular domain Exon 11-Juxtamembrane
domain Exon 13-Tyrosine kinase domain 1 Exon 17-Tyrosine kinase
domain 2 Kinase insert Cell membrane Common initial mutations
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- INDINNBrand NameManufacturer
STI-571ImatinibGleevec/GlivecNovartis SU11248SunitinibSutentPfizer
AMN107NilotinibTasignaNovartis Bay 43-9006SorafenibNexavarBayer BMS
354825DasatinibSprycelBristol-Myers Squibb Bay
73-4506RegorafenibStivargaBayer GW786034B
PazopanibVotrientGlaxoSmithKline STA-9090GanetespibSynta
AB1010MasitinibAB Science OSI 906LinsitinibOSI Pharmaceuticals
LBH589PanobinostatNovartis RAD001EverolimusAfinitorNovartis
L-001079038VorinostatZolinzaMerck Drugs and Names IND
Investigational New Drug INN International Non-proprietary
Name
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- Drugs and Names (Cont.) StemMeaning -tinib = Tyrosine Kinase
Inhibitor (imatinib, sunitinib, regorafenib) -mab = Monoclonal
Antibody (ipilimumab) -rolimus = Rapamycin Derivatives (mTOR
inhibitors) (everolimus) -inostat = Histone Deacetylase (HDAC)
Inhibitors (vorinostat) World Health Organization (WHO)
International Nonproprietary Names (INN) for pharmaceutical
substances, Stem Book 2009 United States Adopted Names (USAN) are
unique nonproprietary names assigned to pharmaceuticals marketed in
the United States. Each name is assigned by the USAN Council, which
is co-sponsored by the American Medical Association (AMA), the
United States Pharmacopeial Convention (USP), and the American
Pharmacists Association (APhA). As a general rule, the application
for a USAN should be forwarded to the USAN Council after the
Investigational New Drug (IND) has been approved by the FDA and
clinical trials have begun. Reference
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- NCCN Clinical Practice Guidelines for GIST NCCN Guidelines
Version 2.2012 5/24/2012 - Soft Tissue Sarcoma - Discussion -
Gastrointestinal Stromal Tumors - Progressive Disease: Page MS-30
"Any patients who has progression of GIST despite prior therapy or
who has a recurrence, regardless of presentation, should be
considered a candidate for enrollment in a clinical trial, if an
appropriate trial is available." Reference SARC-E: Systemic agents
and regimens with activity in Soft Tissue Sarcoma: GIST Imatinib
Sunitinib Disease progression after Imatinib & Sunitinib
Sorafenib Nilotinib Dasatinib
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- Trials DrugCategoryActionStage STA9090 (I.V.)
HSP90iWide-Spectrum KIT inhibitor Phase 2 Multiple drugs (most
oral) PI3KiDownstreamPhase 1 Linsitinib (OSI-906) Multiple drugs
(I.V. & oral) IGF1RiAlternate Pathway Phase 2 Deciphera (oral?)
KIT/PDGFRAWide-Spectrum KIT inhibitor Preclinical Imatinib +
ipilimumabKIT/PDGFRAKIT inhibitorFirst-line phase 3
MasitinibKIT/PDGFRAKIT inhibitorFirst-line phase 3
GleevecKIT/PDGFRAKIT inhibitorFirst-line Plasma level trial
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- Immunotherapy Dasatinib + ipilimumab (Yervoy) (Memorial
Sloan-Kettering (New York) Imatinib + ipilimumab MD Anderson
(Houston) Ipilimumab is approved for melanoma Blocks CTLA-4
receptor on T-cells (enhances T-cell activity) Imatinib positive
effect on immunotherapy via inhibition of IDO. IDO inhibits cd8+
T-cells Phase I plus expansion (MSKCC) o Phase I open to all stages
o Expansion open to resistant GIST
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- Pediatric-type GIST Sutent o Phase 1/2 o 6 years to 21 years
old o 6 yrs to
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- GIST Stages Gleevec/Sutent resistance (3 rd line and beyond)
Adjuvant Gleevec trials First-line trials Neo-adjuvant Gleevec
Second-line trials Other o Resistant to 400 mg Gleevec o Palliative
o Surgery (stable mets)
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- Trials by Genotype Pediatric-type GIST o IGF1R - Linsitinib o
SDH no trials yet PDGFRA o D842V - Crenolanib o IMC-3G3 monoclonal
antibody PDGFRA mutation arm No PDGFRA mutation arm (KIT mutation
& wildtype GIST) Exon 9 o Korean Study 400 mg IM for 4 wks, 600
mg for 4 wks, then 800 mg IM
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- AKT/mTOR MAPK KIT PI3K Jak/Stat 3 Survive-grow
SurviveProliferate PLC gamma PI3K Drugs in phase 1 trials KIT and
downstream Pathways are often targets in clinical trials PKC-
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- KIT Imatinib-sunitinib-regorafenib-nilotinib-sorafenib
pazopanib -masitinib-HSP-90 inhibitors (indirect) PI3K AKT
Perifosine mTOR RAD001-CCI779 AP-23573-Rapamycin PKC- RAS
R115777-SCH66336 RAF-1 regorafenib MEK MAPK PTEN BCL-2 Gentasense
BCL-X L BAD Src/Fyn/Lyn dasatinib Survive Proliferate VEGF
Avastin-sunitinib-regorafenib sorafenib-pazopanib New blood vessel
growth
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- General Trial Issues Right now there are limited Phase 3
Options Off Label use not formally reported outside clinical trial
setting Personalized GIST Treatment o GIST may be 10 diseases Jaap
Verweij, MD ASCO 2011 o Volunteer pool more critical with multiple
smaller groups Clinician awareness o Patients need to ask what
trials are available Trials without mutant KIT/PDGFRA Coverage
Washout periods
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- How does the new treatment work differently for you? Which
trial offers the best chance of survival? What are the chances it
will benefit you? What are the options if the trial does not work
for you? Will this trial limit future options? How much time do you
have to decide? If phase 1, will the dose be therapeutic? Ask
Questions
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- High Stakes Decision Making* 1.Allow yourself the time to
decide. 2.Get emotional support. 3.Make sense of controversies.
4.Manage your decision like you manage other complex projects.
5.Give yourself permission to experiment. 6.Recognize your
preferences. 7.Remain vigilant about ignorance. Seek those who will
teach and learn with you. 8.Delegate. 9.Keep records. 10.Keep your
sense of humor. *Top Ten Decision Lessons from the Community Breast
Health Project (CBHP) in Palo Alto, CA By Jeff Belkora, September
1997 http://www.guidesmith.org/top-ten-lessons /
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- Finding Clinical Trials GIST centers, trial coordinators,
doctors, websites http://www.liferaftgroup.org/treat_trials.html
www.clinicaltrials.gov www.emergingmed.com
http://www.gistsupport.org/
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- Help Understanding Trials Jim Hughes LRG Clinical Trials
Coordinator 847 866-8360 Jerry Call LRG Science Director 303
835-1745