FDA Oncologic Drugs Advisory Committee Pediatric Oncology Subcommittee

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

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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

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FDA Workshop on Brain Tumor Clinical Trials Endpoints Purpose – Consider advantages and disadvantages of various endpoints for trials proposed to bolster endorsement of new medications for essential CNS tumors Goal – Advise re setting up an arrangement of standards on ebb and flow/future models of viability Focus – Endpoints that can now or sooner rather than later be fused into clinical trials

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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 18 FDG-PET: Brain Tumor Measurements in Assessing Response - Nicholas Patronas, Diagnostic Radiology, NIH Clinical Center Response and Progressi on-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

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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

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Human Brain Tumors: Simplified Classification Primary mind tumors Gliomas (e.g., astrocytomas) "Benevolent" gliomas, WHO review 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

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Clinically Meaningful Endpoints for Patients with Brain Tumors Survival Disease adjustment Clinical Response Radiographic reaction Quality of life H Fine at Brain T Endpoints Workshop, January 2006

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MRI in Gliomas - James Provenzale favored imaging methodology: affectability, 3-dimensional information, but in fact complex re consistency and reproducibility endpoints estimate: single breadth at most stretched out point per RECIST versus volumetrics upgrade: demonstrative of modifications in BBB penetrability; defenseless to contrasts interestingly dosage, organization, interim to imaging

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MRI in Gliomas - James Provenzale prescribed imaging parameters for gliomas – physiologic measures MR spectroscopy: metabolic profiles MR dissemination: rate of dispersion of water particles; nearness of tumor limits dispersion legitimate measure of treatment initiated changes characteristic of "reaction" and measured generally early MR perfusion: blood volume and porousness estimation in tumor observing impacts of hostile to angiogenesis specialists

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PBTC 006: Stratum 1 Diffusion Ratio Pre-RT and Post-RT Pre-and Post-RT dispersion proportion estimations vary fundamentally (p value= 0.0155) Radiation treatment is diminishing the dissemination proportion - PBTC NIC, T. Youthful Poussaint

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

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

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

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PBTC-007 Stratum 1A Image Variables Over Time Perfusion proportion increments in both however higher in stable gathering - PBTC NIC, T. Youthful Poussaint

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

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18 FDG-PET in Brain Tumors - Nicholas Patronas quantitative measures of tumor weight, reaction in CNS tumors tricky SUV (institutionalized take-up esteem) utilized as a part of PET more troublesome in profoundly metabolically dynamic cerebrum specialized components confound serial and cross-institutional quantitative measures division systems better than breadth in tumor volume estimation

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Response and PFS Endpoints in Gliomas examinations of unidimensional (RECIST), bidimensional (WHO), PC computed region, volume parameters understanding among techniques "direct, best case scenario" 1D = 2D no proof of relationship amongst reaction and survival relationship amongst movement and survival for upgrading tumors relationship between PFS at 6 months and OS at 12 months in ph II GBM trials (new analyzed, repetitive GBM, n = 1359 patients from 12 NCCTG trials) - NCCTG

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Phase II Endpoint in GBM ̶ 6 month PFS and 1 year OS 11 stage II NCCTG concentrates on, n = 1348 grown-ups with new GBM (RT + "pharmaceutical treatment") – 97% dead 16 stage II NCCTG ponders, n = 345 grown-ups with intermittent GBM (medicate treatment) – 95% dead factual models testing relationship between PSF 6 and OS 12 ��  to a great degree solid affiliation PFS 6 prescribed as a sensible endpoint for phase II GBM trials Ballman KV et al, Neuro-Oncol, NOV '06

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PFS – A Clinically Relevant Endpoint In Clinical Trials Testing Therapies for Recurrent Malignant Gliomas? - Kathleen Lamborn information from 13 ph II trials, n = 611 movement status at 9, 18, 26 weeks emphatically anticipated survival time delay so as to movement ��  enhanced survival parallel discoveries in companion at UCSF learned at first movement stage 3 trial in GBM utilizing PFS-6 months would require 1.5 years of collection versus 3.5 years for OS in AA, 2.5 years versus 4.2 years - NABTC

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Problems in Measuring PFS post-illumination changes at 2-4 (? 2-8) weeks post-RT: interim intralesional putrefaction or tumor "swelling" gives bogus measure of tumor size for ensuing examinations proposal: rebate post-RT filter for gauge at 2 months post-RT

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Problems in Measuring PFS Debate: ? any imaging modality(ies) approved re viability appraisal versus persuading multi-institutional information utilizing 1D or 2D measurement(s) interestingly upgrading tumors relating PFS-6 with OS-12 persuading information in both recently analyzed and intermittent settings consoling level headed discussion of "between institutional fluctuation" versus "very much outlined multi-site think about with institutionalized criteria" reimaging consistence, dependability neighborhood modalities give a false representation of utilization of imaging endpoints (Gliadel ®, CED trials)

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Key Issues re Clinical Status and PFS Assessment all studies reporting PFS consolidate "neurologic strength" with imaging discoveries discuss re legitimacy of doctor evaluation, clinical judgment as target watched endpoints does opportunity from movement itself constitute a clinical advantage to the patient?

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Clinical Trials Endpoints for Approval: Patient-Reported Outcomes (PROs) intellectual capacity tumor-particular side effects personal satisfaction instruments general QoL measures, wellbeing related QoL part for patient self-reported indication appraisal activating imaging toward serial manifestation and HR-QoL evaluations ? composite endpoint of patient capacity, neuroimaging estimation of steroid diminishment as an endpoint PROs utilized as reason for endorsement as a part of neurology-and psychiatry-based medications – ph III, blinded trials

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Clinically Meaningful Endpoints for Patients with Brain Tumors Survival Absolutely, accepting treatment-related lethality is not restrictive Progression free survival just if a surrogate for some other clear clinical advantage Radiographic reaction just if a surrogate for some other clear clinical advantage Clinical reaction and Quality of Life Maybe - what are the measurements for mind tumor patients? H Fine at Brain T Endpoints Workshop, January 2006

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FDA Approvals in Adult Malignant Gliomas Gliadel ® - carmustine wafers ph III survival advantage = 2-3 months in recently diagnosed, intermittent GBM Temodar® - temozolomide ph III survival advantage = expanded survival time of 2.5 months, expanded 2-year survival of 18% what restorative results are clinically meaningful to patients with gliomas? what clinical trials endpoints are representative of those results? by what means can such endpoints be impartially, reproducibly measured?

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

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

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

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

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Cognitive Dysfunction Net clinical advantage of malignancy treatment incorporates "advantageous consequences for ailment related side effects as well as personal satisfaction" (Working gathering of FDA & NCI individuals) Maintaining capacity especially imperative since long haul reduction or cure is impossible, or joined by critical handicap C. Meyers, MDACC Presented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

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FDA Input in Brain Met Trial of Radiation Sensitizer "Radiological reaction alone is not adequate for endorsement. Be that as it may, change in neurocognitive capacity or deferral in neurocognitive movement are satisfactory endpoints" C. Meyers, MDACC Presented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

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Analytic Validity of Cognitive Tests Pediatric Brain Tumor Trial

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