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HCC-MUSC Phase I Program Development Melanie B. Thomas, M.D. Associate Director of Clinical Investigations Hollings Cancer Center Associate Professor of.

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Presentation on theme: "HCC-MUSC Phase I Program Development Melanie B. Thomas, M.D. Associate Director of Clinical Investigations Hollings Cancer Center Associate Professor of."— Presentation transcript:

1 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

2 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 3 CT abdomen, 63 year old woman with 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

4 Linking Targeted Agents to Molecular Targets: What is the Evidence: AgentTargetTumor typeEffect Target Validation Trastuzumab HER2 receptor Her2- overexpressing breast cancer Improves survival Decreases recurrence as adjuvant therapy yes Bevacizumab Serum VEGF A ligand Metastatic colorectal, lung, breast cancers Improves survival, TTP in metastatic colon, lung, breast cancers no EGFR mAb Extra-cellular domain EGFR Colorectal in irintecan- refractory Improves survival, TTP in metastatic colon Kras mutants do not benefit from EGFR inhibitors EGFR TKI Intracellular phosphorylation site NSCLCa pancreatic Improves survival NSCLA, 2nd line Improves PFS in pancreatic ca by <2 wks EGFR mutations in minority of patients predict for benefit Sorafenib Raf-ras pathway VEGF GIST RCC no Sunitinib Raf-ras pathway VEGF GIST RCC no Bortezomib mtorMyelomano Imatinib C-kit GIST CML yes

5 Drug Clinical Development - Overview R & D Genomics Proteomics High-thru screening DNA Arrays Proof of Concept Animal Toxicology Animal Metabolism studies Production Purification Preparation for cGMP cGMPs initiated QA / QC Safety, Dose Production Purification Formulation Characterization, Stability Safety PK QA / QC Effectiveness Production Purification Formulation Stability Full cGMP QA / QC Efficacy Safety Production Formulation Stability Release Tests Validation Drug Discovery DevelopmentPreclinical Phase 1Phase 2Phase 3 IND BLA/ NDA/ MA GLP GMP


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

8 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.

9 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”

10 Phase III 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

11 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

12 There Are Many Types of Phase I Trials Study Type Comments First in human subjectsDetailed 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 dysfunction Children, elderly, poor PS Re-evaluate established dose(s) when late toxicity has emerged Cumulative neuropathy, other neurologic effects.

13 13 Current Phase I Trials

14 Upcoming Phase I Trials

15 15 Investigator Initiated Trials


17 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

18 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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