HCC-MUSC Phase I Program Development

Melanie B. Thomas, M.D.

Associate Director of Clinical Investigations Hollings Cancer Center Associate Professor of Medicine Division of Hematology-Oncology

Clinicians Perspective: Why do we need BIOMARKERS in Clinical Trials?

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90% of drugs that enter Phase II clinical trials will fail.

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21% of all drugs that enter Phase I testing ever reach the market.

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2-4% of newly-diagnosed adult cancer patients enroll in clinical trials.

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Of over 700,000 physicians in the US, only 4% of them have participated in clinical trials since 1988.

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Tumor shrinkage (RR), the primary endpoint of most Phase II trials, is a poor biologic signal

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The likelihood of new anti-cancer agent that enter Phase 1 trials reaching the commercial market?

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1993 - 14%

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2008 - 8%

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The failure rate of Phase III cancer trials:

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1998 - 20% 2008 - 50%

Example of anti-tumor activity, but not “response” by RECIST Criteria

CT abdomen, 63 year old woman with hypervascular hepatocellular carcinoma, right lobe

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Decreased tumor vascularity, increased necrosis after 8, 16 weeks treatment with targeted agents bevacizumab and erlotinib.

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Linking Targeted Agents to Molecular Targets: What is the Evidence:

Agent Target Trastuzumab Bevacizumab EGFR mAb EGFR TKI Sorafenib Sunitinib Bortezomib Imatinib HER2 receptor Serum VEGF A ligand Extra-cellular domain EGFR Intracellular phosphorylation site Raf-ras pathway VEGF Raf-ras pathway VEGF mtor C-kit Tumor type Her2 overexpressing breast cancer Metastatic colorectal, lung, breast cancers Colorectal in irintecan refractory NSCLCa pancreatic Effect Improves survival Decreases recurrence as adjuvant therapy Improves survival, TTP in metastatic colon, lung, breast cancers Target Validation yes no Improves survival, TTP in metastatic colon Kras mutants do not benefit from EGFR inhibitors Improves survival NSCLA, 2nd line Improves PFS in pancreatic ca by <2 wks EGFR mutations in minority of patients predict for benefit GIST RCC GIST RCC no no Myeloma no GIST CML yes

Drug Clinical Development - Overview

IND BLA/ NDA/ MA Drug Discovery Development R & D Genomics Proteomics High-thru screening DNA Arrays Preclinical Phase 1

GLP

Proof of Concept Animal Toxicology Animal Metabolism studies Production Purification Preparation for cGMP cGMPs initiated QA / QC Safety, Dose Production Purification Formulation Characterization, Stability Phase 2 Phase 3 Safety PK QA / QC Effectiveness Production Purification Formulation Stability

GMP

Full cGMP QA / QC Efficacy Safety Production Formulation Stability Release Tests Validation

Clinical Trials - Phases

Phase I II III IV Purpose Subjects Size Length (per phase) Safety, tolerabiltity, bioactivity, drug-drug interaction Healthy volunteers or subj. w/ indications Short-term side effects & efficacy Safety & efficacy Basis for labeling, new formulations Subjects with indications Subjects with indications 20-80 Several hundred Hundreds thousands 6-12 mos 1-2 yrs 2-3 yrs New indications, QoL, surveillance Subjects with indications Hundreds thousands 1-5 yrs

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  Efficacy    Tumor shrinkage (RR), Progression-free survical, overall survival Symptom palliation, QOL  Single arm with historical controls  Randomized PII  Phase IIa – proof of concept, pilot, feasibility, usually healthy volunteers  Phase IIb – well-controlled in target population  Seek to identify a “signal” of benefit to pave the way for “pivotal trials”

Phase III

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2 or 3 studies are pivotal (critical) studies

To prove safety and efficacy of primary endpoints Double-blind, positive or placebo control, multi-center Study population resembles the intended population  Support package labeling New 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 IV

 Post-licensure studies to confirm the safety in large population (after NDA is filed)  Phase IV commitments  Possible types of studies  Compared versus competition      Post-marketing surveillance Special population Rare event incidences Additional long-term usage safety data Pharmacoecomonic and Quality of Life (QoL) 21 CFR 312.85

There Are Many Types of Phase I Trials Study Type

First in human subjects Combinations of approved + new agents Combination of already approved single agents New agents in special populations Re-evaluate established dose(s) when late toxicity has emerged

Comments

Detailed study design based on preclinical large animal toxicity.

Slow dose escalation.

Extensive subject monitoring Fix dose of approved drug, dose-escalate new agent Overlapping toxicity, expected, unexpected Renal, hepatic dysfunction Children, elderly, poor PS Cumulative neuropathy, other neurologic effects.

Current Phase I Trials

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Upcoming Phase I Trials

Investigator Initiated Trials

15

Investigator Initiated Trials

HCC-MUSC Phase I Clinical Research Support Services

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HCC Phase I portfolio:

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2007 7 - trials

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2011 – 13 trials

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HCC Clinical Trials Office

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Review and process Confidentiality Agreements

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Assist investigators with reviewing industry trials

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Coordinate all Regulatory submissions

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PRC, IRB, INDs, ongoing Compliance monitoring

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Negotiate, resolve COI issues

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Coordinate study-specific training, forms, data management

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Management multi-site studies

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Seasoned staff to screen, evaluate, enroll patients

HCC-MUSC Phase I Clinical Research Support Services

 Clinical & Translational Research Center    Outpatient unit for early-phase trials (exam, treatment rooms, lab draws, ECG etc).

Priority inpatient bed assignment, dedicated unit Nursing support services on study-specific basis.

 Specialized services  Sample procurement, processing, banking, shipping (PK, PD, biomarkers) for in-house or external analysis  Clean 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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