fda oncologic drugs advisory committee pediatric oncology subcommittee endpoints for new drugs to...

FDA Oncologic Drugs FDA Oncologic Drugs Advisory CommitteeAdvisory Committee

Pediatric Oncology Pediatric Oncology SubcommitteeSubcommittee

Endpoints for New Drugs to Endpoints for New Drugs to TreatTreat

Pediatric Brain TumorsPediatric Brain Tumors

6 December 20066 December 2006

Report onReport on

Public Workshop on Brain Tumor Public Workshop on Brain Tumor Clinical Trials EndpointsClinical Trials Endpoints

20 January 200620 January 2006

Sponsored by FDA – AACR – ASCO Sponsored by FDA – AACR – ASCO

Larry E. Kun, MDSt. Jude Children’s Research HospitalPediatric Brain Tumor Consortium

FDA Workshop on Brain Tumor FDA Workshop on Brain Tumor Clinical Trials EndpointsClinical Trials Endpoints

Purpose –Purpose –

Consider pros and cons of a number of Consider pros and cons of a number of endpoints for trials intended to endpoints for trials intended to support approval of new drugs for support approval of new drugs for primary CNS tumorsprimary CNS tumors

Goal –Goal –

Advise re establishing a set of Advise re establishing a set of principles on current/future standards principles on current/future standards of efficacyof efficacy

Focus –Focus –

Endpoints that can now or in the near Endpoints that can now or in the near future be incorporated into clinical future be incorporated into clinical trialstrials

FDA Workshop on Brain Tumor FDA Workshop on Brain Tumor Clinical Trials Endpoints - Clinical Trials Endpoints -

AgendaAgendaFDA Introduction and Regulatory BackgroundFDA Introduction and Regulatory Background

- Richard Pazdur, FDA- Richard Pazdur, FDA- Edwin Rock, FDA- Edwin Rock, FDA

Overview: Classifications, Therapies, Issues, Efficacy Overview: Classifications, Therapies, Issues, Efficacy EndpointsEndpoints

- Howard Fine, NOB- Howard Fine, NOB

Imaging-Based Endpoints, OutcomesImaging-Based Endpoints, OutcomesMRIMRI Surrogate Markers of Brain Tumor Therapeutic Surrogate Markers of Brain Tumor Therapeutic

ResponseResponse- James Provenzale, - James Provenzale, Duke

1818FDG-PET:FDG-PET: Brain Tumor Measurements in Assessing Brain Tumor Measurements in Assessing ResponseResponse

- Nicholas Patronas, - Nicholas Patronas, Diagnostic Radiology, NIH Clinical Center

Response and ProgressiResponse and Progression-Free Survival Endpointson-Free Survival Endpoints- Karla Ballman, - Karla Ballman, Mayo Clinic and NCCTG

PFS – A Clinically Relevant Endpoint for Clinical Trials in PFS – A Clinically Relevant Endpoint for Clinical Trials in Malignant Malignant Glioma?Glioma?

- Kathleen Lamborn, - Kathleen Lamborn, UCSF and NABTC

FDA Workshop on Brain Tumor FDA Workshop on Brain Tumor Clinical Trials Endpoints - Clinical Trials Endpoints -

AgendaAgenda

Patient-Reported OutcomesPatient-Reported OutcomesCognitive Testing and Patient-Reported OutcomesCognitive Testing and Patient-Reported Outcomes

- Christina Meyers, - Christina Meyers, M D Anderson

Biomarker and Endpoint Research PrioritiesBiomarker and Endpoint Research Priorities- Jeffrey Abrams, - Jeffrey Abrams, CTEP; Lalitha Shankar, ; Lalitha Shankar, CIP; ;

Tracy Lugo-Lively, Tracy Lugo-Lively, Ca Diagnosis Program

Human Brain Tumors: Human Brain Tumors: Simplified ClassificationSimplified Classification

Primary brain tumorsPrimary brain tumors•Gliomas (e.g., astrocytomas)Gliomas (e.g., astrocytomas)

““Benign” gliomas, Benign” gliomas, WHO grade I (e.g., WHO grade I (e.g., pilocytic pilocytic astrocytoma)astrocytoma) Malignant gliomas, WHO Malignant gliomas, WHO

grades II – IV (e.g., anaplastic grades II – IV (e.g., anaplastic oligodendroglioma, oligodendroglioma, glioblastoma)glioblastoma)

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

Clinically Meaningful Clinically Meaningful Endpoints for Patients Endpoints for Patients

with Brain Tumorswith Brain Tumors

SurvivalSurvival

Disease stabilizationDisease stabilization

Clinical ResponseClinical Response

Radiographic responseRadiographic response

Quality of lifeQuality of lifeH Fine at Brain T Endpoints Workshop, January 2006H Fine at Brain T Endpoints Workshop, January 2006

MRIMRI in Gliomas in Gliomas - James Provenzale

preferred imaging modality:preferred imaging modality: sensitivity, sensitivity,

3-dimensional data, albeit technically 3-dimensional data, albeit technically complex complex rere uniformity and uniformity and reproducibilityreproducibility– endpointsendpoints

size: size: single diameter at widest point per single diameter at widest point per RECIST vs volumetricsRECIST vs volumetrics

enhancement: enhancement: indicative of alterations in indicative of alterations in BBB permeability; susceptible to BBB permeability; susceptible to differences in contrast dose, differences in contrast dose, administration, interval to imagingadministration, interval to imaging

MRIMRI in Gliomas in Gliomas - James Provenzale

recommended imaging parameters for recommended imaging parameters for gliomas – gliomas – physiologic measuresphysiologic measures– MR MR spectroscopy: spectroscopy: metabolic profilesmetabolic profiles– MR MR diffusion: diffusion: rate of diffusion of water rate of diffusion of water

molecules; presence of tumor restricts molecules; presence of tumor restricts diffusiondiffusion

valid measure of therapy-induced changesvalid measure of therapy-induced changes

changes indicative of “response” and changes indicative of “response” and measured relatively earlymeasured relatively early

– MR MR perfusion: perfusion: blood volume and blood volume and permeability measurement in tumorpermeability measurement in tumor

monitoring effects of monitoring effects of anti-angiogenesisanti-angiogenesis agentsagents

PBTC 006: Stratum 1 Diffusion Ratio Pre-RT and Post-RT

VariableVariable NN MinimumMinimumLowerLower

QuartileQuartile MeanMean MedianMedianUpperUpper

QuartileQuartile MaximumMaximum

Pre RTPre RT

Post RTPost RT

differencdifferencee

1717

1717

1717

0.750.75

0.860.86

-1.21-1.21

1.341.34

1.141.14

0.000.00

1.801.80

1.341.34

0.460.46

1.751.75

1.261.26

0.350.35

2.032.03

1.461.46

0.800.80

3.113.11

2.772.77

2.042.04

Pre- and Post-RT diffusion ratio measurements differ significantly Pre- and Post-RT diffusion ratio measurements differ significantly

(p value= 0.0155)(p value= 0.0155)

Radiation therapy is reducing the diffusion ratioRadiation therapy is reducing the diffusion ratio

- PBTC NIC, T. Young Poussaint

PBTC 006: Stratum 1 59774Diffusion Ratio Pre-RT and Post-RT

February 2003February 2003

Ratio 3.11Ratio 3.11

May 2003May 2003

Ratio 1.07Ratio 1.07 - PBTC NICT. Young Poussaint

PBTC-007 A Trial of ZD1839 (IressaTM) PBTC-007 A Trial of ZD1839 (IressaTM) and Radiation in Pediatric Patients and Radiation in Pediatric Patients Newly Diagnosed with Brain Stem Newly Diagnosed with Brain Stem Tumors Image Variables Over TimeTumors Image Variables Over Time

Diffusion ratio Diffusion ratio stable for stable patientsstable for stable patients

Diffusion ratio Diffusion ratio decreases for PD patientsdecreases for PD patients

PBTC NIC – T. Young Poussaint

PBTC-007 3319 Tumor Progression

7/24/02

7/25/03

1.53

1.13

-PBTC NIC, T. Young Poussaint

PBTC-007 Stratum 1AImage Variables Over Time

Perfusion ratio increases in both but Perfusion ratio increases in both but higher in stable grouphigher in stable group

- PBTC NIC, T. Young Poussaint

PBTC-007: 3319 PBTC-007: 3319 Progressive DiseaseProgressive Disease

7/24/027/24/02

.91.91

7/25/037/25/03

1.31.3- PBTC NIC, T. Young Poussaint

1818FDG-PETFDG-PET in Brain in Brain TumorsTumors

- Nicholas Patronas

quantitative measures of tumor burden, quantitative measures of tumor burden, response in CNS tumors problematicresponse in CNS tumors problematic– SUV (standardized uptake value) used in PET SUV (standardized uptake value) used in PET

more difficult in highly metabolically active brainmore difficult in highly metabolically active brain– technical factors complicate serial and cross-technical factors complicate serial and cross-

institutional quantitative measuresinstitutional quantitative measures

segmentation techniques superior to segmentation techniques superior to diameter in tumor volume measurementdiameter in tumor volume measurement

Response and PFS Endpoints in Response and PFS Endpoints in GliomasGliomas

comparisons of comparisons of unidimensional (RECIST), unidimensional (RECIST), bidimensional (WHO), computer-bidimensional (WHO), computer-calculated area, volume parameterscalculated area, volume parameters– agreement amongst methods “moderate at best”agreement amongst methods “moderate at best”– 1D = 2D1D = 2D– no evidence of association between response and no evidence of association between response and

survivalsurvival– association between progression and survival for association between progression and survival for enhancingenhancing tumors tumors

relationship between relationship between PFS at 6 months and PFS at 6 months and OS at 12 months in ph II GBMOS at 12 months in ph II GBM trials trials (new (new diagnosed, recurrent GBM, n = 1359 patients from 12 diagnosed, recurrent GBM, n = 1359 patients from 12 NCCTG trials)NCCTG trials) - NCCTG- NCCTG

Phase II Endpoint in GBM Phase II Endpoint in GBM ̶ ̶

6 month PFS and 1 year 6 month PFS and 1 year OSOS11 phase II NCCTG studies, n = 1348 adults with 11 phase II NCCTG studies, n = 1348 adults with newnew GBM GBM (RT + “pharmaceutical therapy”) – (RT + “pharmaceutical therapy”) – 97% dead97% dead16 phase II NCCTG studies, n = 345 adults with 16 phase II NCCTG studies, n = 345 adults with

recurrent GBMrecurrent GBM (drug therapy) – 95% dead (drug therapy) – 95% dead

statistical models testing association between statistical models testing association between PSF 6 and OS 12 PSF 6 and OS 12 extremely strong extremely strong

associationassociation

PFS 6 recommended as a reasonable endpoint PFS 6 recommended as a reasonable endpoint for for phase II GBM trialsphase II GBM trials

ptpt PFS 6PFS 6 OS 12OS 12

new dxnew dx 43%43% 41%41%

recurrenrecurrentt

9%9% 14%14%

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

PFS – A Clinically Relevant PFS – A Clinically Relevant Endpoint In Clinical Trials Testing Endpoint In Clinical Trials Testing Therapies for Recurrent Malignant Therapies for Recurrent Malignant Gliomas?Gliomas?

- Kathleen Lamborndata from 13 ph II trials, n = 611data from 13 ph II trials, n = 611progression status at 9, 18, 26 progression status at 9, 18, 26

weeks strongly predicted survival weeks strongly predicted survival timetime– delay in time to progression delay in time to progression improved survival improved survival– parallel findings in cohort at UCSF studied at first parallel findings in cohort at UCSF studied at first

progressionprogression

phase 3 trial in GBM using PFS-6 phase 3 trial in GBM using PFS-6 months would require 1.5 years of months would require 1.5 years of accrual vs. 3.5 years for OS in AA, accrual vs. 3.5 years for OS in AA, 2.5 years vs. 4.2 years2.5 years vs. 4.2 years - NABTC- NABTC

Problems in Measuring Problems in Measuring PFSPFS

post-irradiation changes at 2-4 (? 2-8) post-irradiation changes at 2-4 (? 2-8) weeks post-RT: weeks post-RT: interval intralesional interval intralesional necrosis or tumor “swelling” provides necrosis or tumor “swelling” provides false measure of tumor size for false measure of tumor size for subsequent comparisonssubsequent comparisons

– suggestion: suggestion: discount post-RT scan in favor of discount post-RT scan in favor of

baseline at 2 baseline at 2 months post-RTmonths post-RT

Problems in Measuring Problems in Measuring PFSPFSDebate:Debate: ? any imaging modality(ies) ? any imaging modality(ies)

validatedvalidated rere efficacy assessment efficacy assessment vs.vs. convincing multi-institutional data using convincing multi-institutional data using 1D or 2D measurement(s) in contrast-1D or 2D measurement(s) in contrast-enhancing tumors correlating PFS-6 with enhancing tumors correlating PFS-6 with OS-12OS-12– convincing data in both newly diagnosed and convincing data in both newly diagnosed and

recurrent settings reassuringrecurrent settings reassuring– debate of “inter-institutional variability” debate of “inter-institutional variability” vs.vs. “well- “well-

designed multi-site study with standardized designed multi-site study with standardized criteria” re imaging compliance, reliabilitycriteria” re imaging compliance, reliability

local modalitieslocal modalities belie use of imaging belie use of imaging endpoints endpoints (Gliadel(Gliadel®, CED trials)®, CED trials)

Key Issues re Clinical Key Issues re Clinical Status Status and PFS Assessmentand PFS Assessmentall studies reporting PFS combine all studies reporting PFS combine

“neurologic stability”“neurologic stability” with with imaging findingsimaging findings– debate re validity of physician assessment, debate re validity of physician assessment,

clinical judgment as objective observed clinical judgment as objective observed endpointsendpoints

does freedom from progression does freedom from progression itself constitute a clinical benefit itself constitute a clinical benefit to the patient?to the patient?

Clinical Trials Endpoints for Clinical Trials Endpoints for Approval:Approval:Patient-Reported Outcomes (PROs)Patient-Reported Outcomes (PROs) cognitivecognitive function function tumor-specific tumor-specific symptomssymptoms quality of lifequality of life instruments instruments

– general QoL measures, health-related QoLgeneral QoL measures, health-related QoL

role for patient role for patient self-reported symptom self-reported symptom assessment triggering imagingassessment triggering imaging– toward serial symptom and HR-QoL assessmentstoward serial symptom and HR-QoL assessments

? ? composite endpointcomposite endpoint of patient function, of patient function, neuroimagingneuroimaging

value of value of steroid reductionsteroid reduction as an endpoint as an endpoint PROs used as basis for approvalPROs used as basis for approval in neurology- in neurology-

and psychiatry-based drugs – ph III, blinded trialsand psychiatry-based drugs – ph III, blinded trials

Clinically Meaningful Clinically Meaningful Endpoints for Patients with Endpoints for Patients with

Brain TumorsBrain TumorsSurvivalSurvival

– Absolutely, Absolutely,

assuming treatment-related toxicity is not assuming treatment-related toxicity is not prohibitiveprohibitive

Progression free survivalProgression free survival– only if a surrogate for some other clear clinical benefitonly if a surrogate for some other clear clinical benefit

Radiographic responseRadiographic response– only if a surrogate for some other clear clinical benefitonly if a surrogate for some other clear clinical benefit

Clinical response and Quality of LifeClinical response and Quality of Life– Maybe - Maybe -

what are the metrics for brain tumor patients?what are the metrics for brain tumor patients?

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

FDA Approvals in Adult FDA Approvals in Adult Malignant GliomasMalignant Gliomas

GliadelGliadel® ® - carmustine wafers- carmustine wafers– ph III survival advantage = 2-3 months in newly ph III survival advantage = 2-3 months in newly

diagnosed, recurrent GBMdiagnosed, recurrent GBM Temodar® Temodar® - temozolomide- temozolomide

– ph III survival advantage = increased survival ph III survival advantage = increased survival time of time of 2.5 months, increased 2-2.5 months, increased 2-year survival of 18%year survival of 18%

what therapeutic outcomes are what therapeutic outcomes are clinically clinically meaningful to patients meaningful to patients with gliomas?with gliomas? what clinical trials endpoints are what clinical trials endpoints are representative of those outcomes?representative of those outcomes?

– how can such endpoints be objectively, how can such endpoints be objectively, reproducibly reproducibly measured?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


Newly Diagnosed Brain Stem Glioma Patients

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.5 1 1.5 2 2.5 3

Years from Date on Study

Pro

babi

lity

Survival Progression Free Survival

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

Survival for Newly Diagnosed and Recurrent BSG Patients

0

0.10.2

0.3

0.4

0.50.6

0.7

0.80.9

1

0 6 12 18 24 30 36 42 48 54 60 66 72

Months from Diagnosis

Prob

abili

ty

No PD Reported NDBSGPD Reported NDBSGRecurrent BSG

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

Cognitive Dysfunction

Net clinical benefit of cancer therapy Net clinical benefit of cancer therapy includes “beneficial effects on disease-includes “beneficial effects on disease-related symptoms and/or quality of life” related symptoms and/or quality of life” (Working group of FDA & NCI members)(Working group of FDA & NCI members)

Maintaining function particularly Maintaining function particularly important since long-term remission or important since long-term remission or cure is unlikely, or accompanied by cure is unlikely, or accompanied by significant disabilitysignificant disability

C. Meyers, MDACCPresented at FDA Workshop on BT Clinical Trials Endpoints, 1.06

FDA Input in Brain Met Trial of Radiation Sensitizer

““Radiological response alone is Radiological response alone is not acceptable for approval. not acceptable for approval. However, improvement in However, improvement in neurocognitive function or neurocognitive function or delay in neurocognitive delay in neurocognitive progression are acceptable progression are acceptable endpoints”endpoints”


Analytic Validity of Cognitive Tests

Pediatric Brain Tumor TrialsTests are developmentally Tests are developmentally

appropriateappropriate– Selection guided in part by longitudinal design Selection guided in part by longitudinal design

during which tests may changeduring which tests may change

Consideration of normal versus Consideration of normal versus altered cognitive development altered cognitive development after treatment in long-term after treatment in long-term survivorssurvivors


Patient/Family Question, Patient/Family Question, ObservationObservation

isis the benefit of extending the benefit of extending survivalsurvival overestimated when a patient’s overestimated when a patient’s neurocognitive functionneurocognitive function is seriously is seriously compromised and compromised and quality of lifequality of life is is poor?poor?

patient representative noted patient representative noted that caring for his wife with GBM that caring for his wife with GBM for 18 months confirmed for him for 18 months confirmed for him that that survival alone is not a good survival alone is not a good outcome measureoutcome measure

Demographic Characteristics of the Patients at Baseline


Disposition of Patients and Intensity of Treatment


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

fda oncologic drugs advisory committee pediatric oncology subcommittee endpoints for new drugs to...

Documents