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FDA Oncologic Drugs Advisory Committee Pediatric Oncology Subcommittee

FDA Oncologic Drugs Advisory Committee Pediatric Oncology Subcommittee. Endpoints for New Drugs to Treat Pediatric Brain Tumors 6 December 2006. Report on. Public Workshop on Brain Tumor Clinical Trials Endpoints. 20 January 2006. Sponsored by FDA – AACR – ASCO . Larry E. Kun, MD

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FDA Oncologic Drugs Advisory Committee Pediatric Oncology Subcommittee

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  1. FDA Oncologic Drugs Advisory CommitteePediatric Oncology Subcommittee Endpoints for New Drugs to Treat Pediatric Brain Tumors 6 December 2006

  2. Report on Public Workshop on Brain Tumor Clinical Trials Endpoints 20 January 2006 Sponsored by FDA – AACR – ASCO Larry E. Kun, MD St. Jude Children’s Research Hospital Pediatric Brain Tumor Consortium

  3. FDA Workshop on Brain Tumor Clinical Trials Endpoints Purpose – Consider pros and cons of a number of endpoints for trials intended to support approval of new drugs for primary CNS tumors Goal – Advise re establishing a set of principles on current/future standards of efficacy Focus – Endpoints that can now or in the near future be incorporated into clinical trials

  4. FDA Workshop on Brain Tumor Clinical Trials Endpoints - Agenda FDA Introduction and Regulatory Background - Richard Pazdur, FDA - Edwin Rock, FDA Overview: Classifications, Therapies, Issues, Efficacy Endpoints - Howard Fine, NOB Imaging-Based Endpoints, Outcomes MRI Surrogate Markers of Brain Tumor Therapeutic Response - James Provenzale, Duke 18FDG-PET: Brain Tumor Measurements in Assessing Response - Nicholas Patronas, Diagnostic Radiology, NIH Clinical Center Response and Progression-Free Survival Endpoints - Karla Ballman, Mayo Clinic and NCCTG PFS – A Clinically Relevant Endpoint for Clinical Trials in Malignant Glioma? - Kathleen Lamborn, UCSF and NABTC

  5. FDA Workshop on Brain Tumor Clinical Trials Endpoints - Agenda Patient-Reported Outcomes Cognitive Testing and Patient-Reported Outcomes - Christina Meyers, M D Anderson Biomarker and Endpoint Research Priorities - Jeffrey Abrams, CTEP; Lalitha Shankar, CIP; Tracy Lugo-Lively, Ca Diagnosis Program

  6. Human Brain Tumors: Simplified Classification • Primary brain tumors • Gliomas (e.g., astrocytomas) “Benign” gliomas, WHO grade I (e.g., pilocytic astrocytoma) Malignant gliomas, WHO grades II – IV (e.g., anaplastic oligodendroglioma, glioblastoma) H Fine at Brain T Endpoints Workshop, January 2006

  7. Clinically Meaningful Endpoints for Patients with Brain Tumors • Survival • Disease stabilization • Clinical Response • Radiographic response • Quality of life H Fine at Brain T Endpoints Workshop, January 2006

  8. MRI in Gliomas - James Provenzale • preferred imaging modality: sensitivity, • 3-dimensional data, albeit technically complex re uniformity and reproducibility • endpoints • size: single diameter at widest point per RECIST vs volumetrics • enhancement: indicative of alterations in BBB permeability; susceptible to differences in contrast dose, administration, interval to imaging

  9. MRI in Gliomas - James Provenzale • recommended imaging parameters for gliomas – physiologic measures • MR spectroscopy: metabolic profiles • MR diffusion: rate of diffusion of water molecules; presence of tumor restricts diffusion • valid measure of therapy-induced changes • changes indicative of “response” and measured relatively early • MR perfusion: blood volume and permeability measurement in tumor • monitoring effects of anti-angiogenesis agents

  10. PBTC 006: Stratum 1 Diffusion Ratio Pre-RT and Post-RT Pre- and Post-RT diffusion ratio measurements differ significantly (p value= 0.0155) Radiation therapy is reducing the diffusion ratio - PBTC NIC, T. Young Poussaint

  11. PBTC 006: Stratum 1 59774Diffusion Ratio Pre-RT and Post-RT February 2003 Ratio 3.11 May 2003 Ratio 1.07 • PBTC NIC • T. Young Poussaint

  12. PBTC-007 A Trial of ZD1839 (IressaTM) and Radiation in Pediatric Patients Newly Diagnosed with Brain Stem Tumors Image Variables Over Time • Diffusion ratio stable for stable patients • Diffusion ratio decreases for PD patients PBTC NIC – T. Young Poussaint

  13. PBTC-007 3319 Tumor Progression 1.53 7/24/02 7/25/03 1.13 • PBTC NIC, • T. Young Poussaint

  14. PBTC-007 Stratum 1AImage Variables Over Time • Perfusion ratio increases in both but higher in stable group - PBTC NIC, T. Young Poussaint

  15. PBTC-007: 3319 Progressive Disease 7/24/02 .91 7/25/03 1.3 - PBTC NIC, T. Young Poussaint

  16. 18FDG-PET in Brain Tumors- Nicholas Patronas • quantitative measures of tumor burden, response in CNS tumors problematic • SUV (standardized uptake value) used in PET more difficult in highly metabolically active brain • technical factors complicate serial and cross-institutional quantitative measures • segmentation techniques superior to diameter in tumor volume measurement

  17. Response and PFS Endpoints in Gliomas • comparisons of unidimensional (RECIST), bidimensional (WHO), computer-calculated area, volume parameters • agreement amongst methods “moderate at best” • 1D = 2D • no evidence of association between response and survival • association between progression and survival for enhancing tumors • relationship between PFS at 6 months and OS at 12 months in ph II GBM trials (new diagnosed, recurrent GBM, n = 1359 patients from 12 NCCTG trials) - NCCTG

  18. Phase II Endpoint in GBM ̶ 6 month PFS and 1 year OS 11 phase II NCCTG studies, n = 1348 adults with newGBM (RT + “pharmaceutical therapy”) – 97% dead 16 phase II NCCTG studies, n = 345 adults with recurrent GBM (drug therapy) – 95% dead statistical models testing association between PSF 6 and OS 12  extremely strong association PFS 6 recommended as a reasonable endpoint for phase II GBM trials Ballman KV et al, Neuro-Oncol, NOV ‘06

  19. PFS – A Clinically Relevant Endpoint In Clinical Trials Testing Therapies for Recurrent Malignant Gliomas?- Kathleen Lamborn • data from 13 ph II trials, n = 611 • progression status at 9, 18, 26 weeks strongly predicted survival time • delay in time to progression  improved survival • parallel findings in cohort at UCSF studied at first progression • phase 3 trial in GBM using PFS-6 months would require 1.5 years of accrual vs. 3.5 years for OS in AA, 2.5 years vs. 4.2 years - NABTC

  20. Problems in Measuring PFS • post-irradiation changes at 2-4 (? 2-8) weeks post-RT: interval intralesional necrosis or tumor “swelling” provides false measure of tumor size for subsequent comparisons • suggestion: discount post-RT scan in favor of baseline at 2 months post-RT

  21. Problems in Measuring PFS • Debate:? any imaging modality(ies) validatedre efficacy assessment vs. convincing multi-institutional data using 1D or 2D measurement(s) in contrast-enhancing tumors correlating PFS-6 with OS-12 • convincing data in both newly diagnosed and recurrent settings reassuring • debate of “inter-institutional variability” vs. “well-designed multi-site study with standardized criteria” re imaging compliance, reliability • local modalities belie use of imaging endpoints (Gliadel®, CED trials)

  22. Key Issues re Clinical Status and PFS Assessment • all studies reporting PFS combine “neurologic stability” with imaging findings • debate re validity of physician assessment, clinical judgment as objective observed endpoints • does freedom from progression itself constitute a clinical benefit to the patient?

  23. Clinical Trials Endpoints for Approval:Patient-Reported Outcomes (PROs) • cognitive function • tumor-specific symptoms • quality of life instruments • general QoL measures, health-related QoL • role for patient self-reported symptom assessment triggering imaging • toward serial symptom and HR-QoL assessments • ? composite endpoint of patient function, neuroimaging • value of steroid reduction as an endpoint • PROs used as basis for approvalin neurology- and psychiatry-based drugs – ph III, blinded trials

  24. Clinically Meaningful Endpoints for Patients with Brain Tumors • Survival • Absolutely, • assuming treatment-related toxicity is not prohibitive • Progression free survival • only if a surrogate for some other clear clinical benefit • Radiographic response • only if a surrogate for some other clear clinical benefit • Clinical response and Quality of Life • Maybe - • what are the metrics for brain tumor patients? H Fine at Brain T Endpoints Workshop, January 2006

  25. FDA Approvals in Adult Malignant Gliomas Gliadel® - carmustine wafers ph III survival advantage = 2-3 months in newly diagnosed, recurrent GBM Temodar® - temozolomide ph III survival advantage = increased survival time of 2.5 months, increased 2-year survival of 18% what therapeutic outcomes are clinically meaningful to patients with gliomas? what clinical trials endpoints are representative of those outcomes? how can such endpoints be objectively, reproducibly measured?

  26. Kaplan-Meier Estimates of Overall Survival According to Treatment Group Stupp, R. et al. N Engl J Med 2005;352:987-996

  27. Kaplan-Meier Estimates of Progression-free Survival According to Treatment Group Stupp, R. et al. N Engl J Med 2005;352:987-996

  28. A. Onar and PBTC, NCI Workshop on BSG, May 2006

  29. A. Onar and PBTC, analysis following NCI Workshop on BSG, May 2006

  30. Cognitive Dysfunction • Net clinical benefit of cancer therapy includes “beneficial effects on disease-related symptoms and/or quality of life” (Working group of FDA & NCI members) • Maintaining function particularly important since long-term remission or cure is unlikely, or accompanied by significant disability C. Meyers, MDACC Presented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

  31. FDA Input in Brain Met Trial of Radiation Sensitizer • “Radiological response alone is not acceptable for approval. However, improvement in neurocognitive function or delay in neurocognitive progression are acceptable endpoints” C. Meyers, MDACC Presented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

  32. Analytic Validity of Cognitive TestsPediatric Brain Tumor Trials • Tests are developmentally appropriate • Selection guided in part by longitudinal design during which tests may change • Consideration of normal versus altered cognitive development after treatment in long-term survivors C. Meyers, MDACC Presented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

  33. Patient/Family Question, Observation • isthe benefit of extending survival overestimated when a patient’s neurocognitive function is seriously compromised and quality of life is poor? • patient representative noted that caring for his wife with GBM for 18 months confirmed for him that survival alone is not a good outcome measure

  34. Demographic Characteristics of the Patients at Baseline Stupp, R. et al. N Engl J Med 2005;352:987-996

  35. Disposition of Patients and Intensity of Treatment Stupp, R. et al. N Engl J Med 2005;352:987-996

  36. Stamatakos GS et al, Br J Radiol 79, 2006

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