# Presentation: 798184

## FDA Oncologic Drugs Advisory CommitteePediatric Oncology Subcommittee

***Endpoints for New Drugs to Treat***
***Pediatric Brain Tumors***
**6 December 2006**

## Public Workshop on Brain Tumor 

**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**
**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**

## 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**

## 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

**Survival**
**Disease stabilization**
**Clinical Response**
**Radiographic response**
**Quality of life**

***H Fine at Brain T Endpoints Workshop, January 2006***

## 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 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 

| Variable | N | Minimum | Lower
Quartile | Mean | Median | Upper
Quartile | Maximum |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Pre RT
Post RT
difference | 17
17
17 | 0.75
0.86
-1.21 | 1.34
1.14
0.00 | 1.80
1.34
0.46 | 1.75
1.26
0.35 | 2.03
1.46
0.80 | 3.11
2.77
2.04 |

**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 59774****Diffusion Ratio Pre-RT and Post-RT**

**February 2003**
**Ratio 3.11**

**May 2003**
**Ratio 1.07**

-  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

**Notes:**
Trends without statistical significance

## PBTC-007 3319 Tumor Progression

**PBTC-007 3319 ****Tumor Progression**

**7/24/02**

**7/25/03**

**1.53**

**1.13**

- 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

**PBTC-007: 3319    Progressive Disease**

**7/24/02**
**.91**

**7/25/03**
**1.3**

- - PBTC NIC, T. Young Poussaint

## 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

**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

**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% |
| recurrent | 9% | 14% |

***Ballman KV et al, Neuro-Oncol, NOV ‘06***

## 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

**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***
- 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

**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)

**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 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
**  **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?

## Kaplan-Meier Estimates of Overall Survival According to Treatment Group

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

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

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

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

***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

**Notes:**
Is ? chemobrain fatigue or is fatigue one of a constellation of symptoms that comprise chemobrain
DO YOU MENTION SOMETHING ABOUT CHEMO VS XRT VS BOTH....?

## 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?
**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;352:987-996**

## Disposition of Patients and Intensity of Treatment

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

## Stamatakos GS et al, Br J Radiol 79, 2006

***Stamatakos GS et al, Br J Radiol 79, 2006***