Nonclinical Perspective on Initiating Phase 1 Studies for Biological Oncology Products – Case Studies Anne M. Pilaro, Ph.D. DBOP/OODP/CDER Oncology Drugs Advisory Committee March 13, 2006

Objectives Provide examples where nonclinical data identified different safety issues arising with continued vs. short-term treatment Discuss how resulting findings drove need for studies of longer duration from other sponsors with similar products Request input from ODAC on appropriate nonclinical study duration to support Phase 1 studies of biologic oncology products

Case Study I – MAb to Growth Factor Receptor MOA – inhibition of binding of growth factor to its receptor –GF receptor ubiquitously present on tumor and normal cells Several sponsors propose Phase 1 studies in advanced cancers Some sponsors propose treatment past the 4-5 weeks supported by animal data –based on objective tumor response

Case Study I – MAb to Growth Factor Receptor, cont’d Supporting toxicology done in monkeys –4-week or 7-week (1 sponsor) studies weight loss only overt toxicity observed dose-related thymic atrophy, lymphocyte depletion in all lymphoid organs by histopath no resolution in 2/4 studies after recovery –recovery data still pending for 1/4 studies –One sponsor – 4 week study completed still pre-IND phase, but early histopathologic indication of thymus changes

Case Study I – MAb to Growth Factor Receptor, cont’d Several sponsors conducted nonclinical studies with treatment out to 13 weeks –one sponsor (pre-IND) initiated early discussion with FDA based on findings in pilot study agreed to add extension groups at high-dose, control groups to continue treatment to 13 weeks –one sponsor – based on findings in 4 week study, conducted 13 week tox study at same dose levels increase in severity of weight loss; no new toxicities histopathology revealed dose-related thymic atrophy, lymphocyte depletion in all lymphoid organs, all groups added flow cytometry evaluations for lymphocyte profiles –4 weeks, 13 weeks, and recovery

Anti-GFR MAb – 4 Weeks

Anti-GFR MAb – 13 Weeks * * * * * * * * * p < 0.05 *

Anti-GFR MAb – Recovery * * * * * p < 0.05

Case Study I – MAb to Growth Factor Receptor, cont’d In absence of 13-week safety data, FDA requested sponsors to limit patient treatment –continuation of treatment for objective response (CR/PR) with no DLTs FDA requested all sponsors to submit longer term animal studies out to 13-weeks duration –prior to allowing indefinite extension of treatment in patients where risk:benefit ratio is less justifiable –will permit studies to be submitted on a “rolling toxicology” basis, i.e., in advance of treating patients for extended durations

Case Study II – Recombinant GF Receptor Antagonist MOA – inhibition of binding of GF to its receptor –target receptor on vascular, other cells Product biologically active in multiple test species, including rodent, monkey Phase 1 study in advanced/refractory solid tumors, or NHL –propose up to 6-months continuous treatment in all patients in absence of DLT

Case Study II – Recombinant GF Receptor Antagonist, cont’d 4-week toxicity studies in monkeys, rats –more frequent dosing than proposed clinical plan –dose-related renal pathology at 28 d in both species not readily detected by serum biochemistry proteinuria only detectable in rodents histopath, U/A findings not reversible –coagulopathies evident in both species –cardiac findings present in rats, single monkey –bone fractures, dental findings present only in rodents following completion of 4-week treatment mechanism of toxicities unknown –potentially related to exaggerated pharmacology and/or immunogenicity

Case Study II – Recombinant GF Receptor Antagonist, cont’d Clinical study amended to exclude patients with baseline renal, cardiac pathology Protocol to include extensive monitoring: –renal pathology (serum chemistry, serial U/A) –coagulation parameters –baseline/on-study cardiac enzymes, echo/MUGA –baseline/on-study evaluation of bone, collagen Sponsor to complete 13-week toxicology studies to support continuous treatment –clinically relevant doses and schedule –evaluate mechanism of renal pathology observed

Case Study III – MAb to Growth Factor Receptor Mechanism of action (MOA) – inhibition of binding of growth factor (GF) to its receptor –subsequent inhibition of tumor cell growth through blockade of GF-induced signaling Target receptor normally expressed by cells in GI tract, salivary glands, skin, eye MAb biologically active only in monkeys and humans –short-term pharmacology studies in human tumor xenograft models –pivotal toxicology study in monkeys mimicked the schedule for clinical use

Case Study III – MAb to Growth Factor Receptor, cont’d Dose- and duration-related toxicities, mortality observed –GI pathology, severe skin lesions, ocular effects –related to mechanism of action (inhibition of GF) –incidence, severity related to both dose of MAb, duration of treatment –non-clinical data not submitted until Phase 3 in clinical development monkey data not available to guide clinical monitoring, dose modification for toxicities clinical events related to mortality in monkeys (i.e., sepsis) may not have been adequately captured in patients during early clinical development

Case Study III – MAb to Growth Factor Receptor, cont’d Other sponsors with MAb to identical GF receptor for use in advanced cancer –in various stages of clinical development FDA recommendation for sponsors to conduct longer-term toxicology studies at clinically relevant exposure, duration –data to provide recommendations for clinical monitoring, dose modification –previous findings corroborated with one product similar, severe toxicities in monkeys at 6-months –data will eventually lead to class labeling

Safety Issue – Duration of Supporting Nonclinical Studies Three case studies where duration of animal toxicology studies was less than that proposed for Phase 1 studies –all cases had clinical, laboratory and/or histopath findings that suggested cumulative toxicity –renal toxicity in third case study may not be monitorable in the clinical population What should be the appropriate nonclinical study duration to support Phase 1 studies of biologic oncology products? –questions for ODAC deliberation and discussion

Conclusion Need to expedite development of novel oncology products –pre-IND meetings and advice –nonclinical study design features “rolling” toxicology study (e.g., 6-month study with interim data at 1, 3, 6 months and recovery) submission of in-life data (no histopathology) number of doses vs. duration of study –plan to include these approaches, ODAC recommendations in upcoming guidance