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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

FDA Oncologic Drugs Advisory CommitteePediatric Oncology Subcommittee

Endpoints for New Drugs to Treat

Pediatric Brain Tumors

6 December 2006

slide2

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

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

slide4

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

slide5

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

slide6

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

clinically meaningful endpoints for patients with brain tumors
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 james provenzale
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
mri in gliomas james provenzale9
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
pbtc 006 stratum 1 diffusion ratio pre rt and post rt
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

pbtc 006 stratum 1 59774 diffusion ratio pre rt and post rt
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
slide12
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 007 3319 tumor progression
PBTC-007 3319 Tumor Progression

1.53

7/24/02

7/25/03

1.13

  • PBTC NIC,
  • T. Young Poussaint
pbtc 007 stratum 1a image variables over time
PBTC-007 Stratum 1AImage Variables Over Time
  • Perfusion ratio increases in both but higher in stable group

- PBTC NIC, T. Young Poussaint

slide15

PBTC-007: 3319 Progressive Disease

7/24/02

.91

7/25/03

1.3

- PBTC NIC, T. Young Poussaint

18 fdg pet in brain tumors nicholas patronas
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
response and pfs endpoints in gliomas
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

phase ii endpoint in gbm 6 month pfs and 1 year os

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

slide19
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

problems in measuring pfs
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

problems in measuring pfs21
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)
key issues re clinical status and pfs assessment
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?
clinical trials endpoints for approval patient reported outcomes pros
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
clinically meaningful endpoints for patients with brain tumors24
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

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?

slide26

Kaplan-Meier Estimates of Overall Survival According to Treatment Group

Stupp, R. et al. N Engl J Med 2005;352:987-996

slide27

Kaplan-Meier Estimates of Progression-free Survival According to Treatment Group

Stupp, R. et al. N Engl J Med 2005;352:987-996

slide29

A. Onar and PBTC, analysis following

NCI Workshop on BSG, May 2006

cognitive dysfunction
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
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
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

patient family question observation
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
slide35

Demographic Characteristics of the Patients at Baseline

Stupp, R. et al. N Engl J Med 2005;352:987-996

slide36

Disposition of Patients and Intensity of Treatment

Stupp, R. et al. N Engl J Med 2005;352:987-996