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 St. Jude Children’s Research Hospital Pediatric Brain Tumor Consortium

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

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 - Howard Fine, NOB Imaging-Based Endpoints, Outcomes MRI Surrogate Markers of Brain Tumor Therapeutic Response - James Provenzale, - James Provenzale, Duke 18 FDG-PET: Brain Tumor Measurements in Assessing Response - Nicholas Patronas, - Nicholas Patronas, Diagnostic Radiology, NIH Clinical Center Response and Progression-Free Survival Endpoints - Karla Ballman, - Karla Ballman, Mayo Clinic and NCCTG PFS – A Clinically Relevant Endpoint for Clinical Trials in Malignant Glioma? - Kathleen Lamborn, - Kathleen Lamborn, UCSF and NABTC

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

Human Brain Tumors: Simplified Classification Primary brain tumors Gliomas (e.g., astrocytomas)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

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

MRI in Gliomas MRI in Gliomas - James Provenzale preferred imaging modality: sensitivity, 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

MRI in Gliomas MRI in Gliomas - James Provenzale recommended imaging parameters for gliomas – physiologic measures 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

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

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

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

PBTC Tumor Progression 7/24/02 7/25/ PBTC NIC, T. Young Poussaint

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

PBTC-007: 3319 Progressive Disease 7/24/02.917/25/ PBTC NIC, T. Young Poussaint

18 FDG-PET in Brain Tumors 18 FDG-PET in Brain Tumors - Nicholas Patronas quantitative measures of tumor burden, response in CNS tumors problematic 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 segmentation techniques superior to diameter in tumor volume measurement

Response and PFS Endpoints in Gliomas comparisons of unidimensional (RECIST), bidimensional (WHO), computer-calculated area, volume parameters 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) 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

Phase II Endpoint in GBM ̶ 6 month PFS and 1 year OS 11 phase II NCCTG studies, n = 1348 adults with new GBM (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 pt PFS 6 OS 12 new dx 43%41% recurrent9%14% Ballman KV et al, Neuro-Oncol, NOV ‘06

PFS – A Clinically Relevant Endpoint In Clinical Trials Testing Therapies for Recurrent Malignant Gliomas? PFS – A Clinically Relevant Endpoint In Clinical Trials Testing Therapies for Recurrent Malignant Gliomas? - Kathleen Lamborn data from 13 ph II trials, n = 611 data from 13 ph II trials, n = 611 progression status at 9, 18, 26 weeks strongly predicted survival time 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 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

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 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

Problems in Measuring PFS Debate: ? any imaging modality(ies) validated re efficacy assessment vs. convincing multi-institutional data using 1D or 2D measurement(s) in contrast-enhancing tumors correlating PFS-6 with OS-12 Debate: ? any imaging modality(ies) validated re 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) local modalities belie use of imaging endpoints (Gliadel®, CED trials)

Key Issues re Clinical Status and PFS Assessment all studies reporting PFS combine “neurologic stability” with imaging findings 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? does freedom from progression itself constitute a clinical benefit to the patient?

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

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

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

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

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

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

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

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

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

Analytic Validity of Cognitive Tests Pediatric 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

Patient/Family Question, Observation is the benefit of extending survival overestimated when a patient’s neurocognitive function is seriously compromised and quality of life is poor? is the 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 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

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

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

Stamatakos GS et al, Br J Radiol 79, 2006