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%

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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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