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Nonclinical Perspective on Initiating Phase 1 Studies for Biological Oncology Products – Case Studies

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.

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Nonclinical Perspective on Initiating Phase 1 Studies for Biological Oncology Products – Case Studies

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Anti-GFR MAb – 4 Weeks

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

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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

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