HCC-MUSCPhase I Program
Development
Melanie B. Thomas, M.D.Associate Director of Clinical Investigations
Hollings Cancer CenterAssociate Professor of Medicine
Division of Hematology-Oncology
Clinicians Perspective:Why do we need BIOMARKERS in Clinical
Trials?
90% of drugs that enter Phase II clinical trials will fail.
21% of all drugs that enter Phase I testing ever reach the market.
2-4% of newly-diagnosed adult cancer patients enroll in clinical trials.
Of over 700,000 physicians in the US, only 4% of them have participated in clinical trials since 1988.
Tumor shrinkage (RR), the primary endpoint of most Phase II trials, is a poor biologic signal
The likelihood of new anti-cancer agent that enter Phase 1 trials reaching the commercial market? 1993 - 14% 2008 - 8%
The failure rate of Phase III cancer trials: 1998 - 20% 2008 - 50%
3
CT abdomen, 63 year old womanwith hypervascular hepatocellular carcinoma, right lobe.
Decreased tumor vascularity,increased necrosis after 8, 16 weeks treatment with targeted agents bevacizumab and erlotinib.
Example of anti-tumor activity, but not “response” by RECIST Criteria
Linking Targeted Agents to Molecular Targets:
What is the Evidence:
Agent Target Tumor type Effect Target Validation
Trastuzumab HER2 receptorHer2-
overexpressing breast cancer
Improves survival Decreases
recurrence as adjuvant therapy
yes
Bevacizumab Serum VEGF A ligandMetastatic
colorectal, lung, breast cancers
Improves survival, TTP in metastatic colon, lung, breast
cancers
no
EGFR mAb Extra-cellular domain EGFR
Colorectalin irintecan-refractory
Improves survival, TTP in metastatic
colon
Kras mutants do not benefit
from EGFR inhibitors
EGFR TKI Intracellular phosphorylation site
NSCLCapancreatic
Improves survival NSCLA, 2nd lineImproves PFS in pancreatic ca by <2 wks
EGFR mutations in minority of
patients predict for
benefit
Sorafenib Raf-ras pathwayVEGF
GISTRCC
no
Sunitinib Raf-ras pathwayVEGF
GISTRCC
no
Bortezomib mtor Myeloma no
Imatinib C-kitGISTCML
yes
Drug Clinical Development - Overview
R & DGenomicsProteomicsHigh-thru screeningDNA Arrays
Proof of ConceptAnimal ToxicologyAnimal Metabolism studiesProductionPurificationPreparation for cGMP
cGMPs initiatedQA / QCSafety, DoseProductionPurificationFormulationCharacterization, Stability
SafetyPKQA / QCEffectivenessProductionPurificationFormulationStability
Full cGMPQA / QCEfficacy SafetyProduction
FormulationStabilityRelease TestsValidation
DrugDiscovery
Development Preclinical Phase 1 Phase 2 Phase 3
INDIND
BLA/BLA/NDA/NDA/MAMA
GLP GMP
Clinical Trials - Phases
1-5 yrs1-5 yrs
HundredsHundreds--thousandthousandss
Subjects Subjects with with indicationsindications
New indications, New indications,
QoL, surveillanceQoL, surveillanceIVIV
2-3 yrs2-3 yrs
HundredsHundreds--thousandthousandss
Subjects Subjects with with indicationsindications
Safety & efficacy Safety & efficacy
Basis for labeling, Basis for labeling,
new formulationsnew formulationsIIIIII
1-2 yrs1-2 yrsSeveral Several hundredhundred
Subjects Subjects with with indicationsindications
Short-term side Short-term side
effects & efficacyeffects & efficacyIIII
6-12 6-12 mosmos20-8020-80
Healthy Healthy volunteers volunteers or subj. w/ or subj. w/ indicationsindications
Safety, Safety, tolerabiltity, tolerabiltity, bioactivity, bioactivity,
drug-drug drug-drug interactioninteraction
II
LengthLength(per (per
phase)phase)SizeSizeSubjectsSubjectsPurposePurposePhasePhase
Phase I
First time in human subjects
Small number of healthy volunteers or advanced disease patients who have no other options.
Establish safety profile and dosage range
Single and multi-dose studies
Pharmacokinetics / pharmacodynamics
Open label, often single center
Commonly performed ex-U.S.
Phase II
Safety, side effects
EfficacyTumor shrinkage (RR), Progression-free survical, overall survivalSymptom palliation, QOL
Single arm with historical controls
Randomized PIIPhase IIa – proof of concept, pilot, feasibility,
usually healthy volunteersPhase IIb – well-controlled in target
population
Seek to identify a “signal” of benefit to pave the way for “pivotal trials”
Phase III
2 or 3 studies are pivotal (critical) studiesTo prove safety and efficacy of primary endpointsDouble-blind, positive or placebo control, multi-centerStudy population resembles the intended populationSupport package labelingNew Drug Application (NDA)
Special population, concomitant medications, multiple illnesses, etc.
IIIb studies – post NDA-submission trial looking at additional indications
Pre-NDA meeting with the FDA near conclusion of Phase III
Phase III trials can change standard of care without formal FDA approval
Phase IVPost-licensure studies to confirm the safety in
large population (after NDA is filed)
Phase IV commitments
Possible types of studiesCompared versus competitionPost-marketing surveillanceSpecial populationRare event incidencesAdditional long-term usage safety dataPharmacoecomonic and Quality of Life (QoL)
21 CFR 312.85
There Are Many Types of Phase I Trials
Study Type CommentsFirst in human subjects Detailed study design
based on preclinical large animal toxicity.Slow dose escalation.Extensive subject monitoring
Combinations of approved + new agents
Fix dose of approved drug, dose-escalate new agent
Combination of already-approved single agents
Overlapping toxicity, expected, unexpected
New agents in special populations
Renal, hepatic dysfunctionChildren, elderly, poor PS
Re-evaluate established dose(s) when late toxicity has emerged
Cumulative neuropathy, other neurologic effects.
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Current Phase I Trials
Upcoming Phase I Trials
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Investigator Initiated Trials
Investigator Initiated Trials
HCC-MUSC Phase I Clinical Research Support Services
HCC Phase I portfolio: 2007 7 - trials 2011 – 13 trials
HCC Clinical Trials Office Review and process Confidentiality Agreements Assist investigators with reviewing industry trials Coordinate all Regulatory submissions
PRC, IRB, INDs, ongoing Compliance monitoring
Negotiate, resolve COI issues
Coordinate study-specific training, forms, data management
Management multi-site studies
Seasoned staff to screen, evaluate, enroll patients
HCC-MUSC Phase I Clinical Research Support Services
Clinical & Translational Research CenterOutpatient unit for early-phase trials (exam,
treatment rooms, lab draws, ECG etc).Priority inpatient bed assignment, dedicated unitNursing support services on study-specific basis.
Specialized servicesSample procurement, processing, banking, shipping
(PK, PD, biomarkers) for in-house or external analysisClean Room Facility: human cell isolation,
processing, vaccine development.
Developing Phase I “capacity” within HCC Infusion Center
Regular weekly Phase I meeting
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