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COG CNS Committee

2003-2007Ian Pollack

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Identify biological characteristics ofchildhood CNS tumors that influencetreatment response, and initiate risk-adaptedstratification.

Develop comprehensive treatmentapproaches to improve survival and quality oflife for children with primary CNS tumors.

Identify effective therapies for CNS tumorsresistant to prior treatments.

Define and validate strategies for reducingtreatment-related long-term sequelae.

Scientific Goals

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3

Medullo

PNET

Infant

Tumors

GermCell

Ependymoma

Low-Grade

Glioma

High-Grade

Glioma

Brainstem

Glioma

Optimize

Chemo to

Reduce

Sequelae

AAA999999666111

ACNS0331

CCCCCCGGG---

999999777000333AAACCCNNNSSS---

000222333222AAACCCNNNSSS---

000444222111AAA999999555222

Optimize RT

DeliveryACNS0331 PPP999999333444

AAACCCNNNSSS---

000111222111AAACCCNNNSSS---

000222222111

Chemo-RT

CCCCCCGGG---999999777000111

AAACCCNNNSSS000333333222

PPPOOOGGG---999666333111

AAACCCNNNSSS000333333333 AAACCCNNNSSS---000111222666

CCCCCCGGG---999777111222

CCCC

CCG

GG-

--999888000222PPPOOOGGG---999888333666

AAACCCNNNSSS000111222666

AAACCCNNNSSS000222222222AAACCCNNNSSS000222222444

Intensifying

ChemoCCCCCCGGG---999999777000222

CCCCCCGGG---

999999777000333

AAACCCNNNSSS000333333444

AAACCCNNNSSS---

000111222222

AAACCCNNNSSS---

000111222111

AAACCCNNNSSS---

000222222333

AAADDDVVVLLL000000111111

ACNS0423

AAACCCNNNSSS000222333111

CNS Committee Cross-Study

Therapeutic Hypotheses

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Observation that the use of adjuvantchemotherapy permits CSRT dose reduction

to 2340 cGy with >75% survival for M0

medulloblastoma.

Demonstration that extent of resection is

associated with outcome for children with

medulloblastoma,ependymoma, low- and

high-grade glioma. Initiation of the largest biological study to date

of high-grade gliomas of childhood, and

preliminary delineation of prognostic factors.

Cooperative Group Scientific

Accomplishments

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5

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10

Survival

POG-8631/CCG-923 (Reduced

DoseXRTAlone, N=46)

CCG-9892 (Reduced

XRT+ Chemo, N=65)

POG-8631/CCG-923 (Standard

Dose XRTAlone, N=42)

Packer et al. JCO 17: 2127, 1999; Thomas et al. JCO 18: 3004, 2000Years Post Onstudy

Reduced Dose Radiotherapy Is Feasible in

Standard-Risk Medulloblastomas If

Combined with Adjuvant Chemotherapy

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6

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12

Years Post Onstudy

Event-Free

Sur

vival

>90% Resection (N=66)

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Determination that moderately intensive chemoimproves survival for poor-risk medullo/PNET.

Identification of molecular factors correlatedwith outcome of infant tumors.

Documentation that building upon inductionchemo in infant tumors with high-doseconsolidation or focal irradiation improves

outcome. However, despite improvements in the

prognosis of some tumor types, others remainresistant and late effects remain a concern.

Scientific Accomplishments

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Management of Average-Risk

Medulloblastomas1) Post fossa location

2) M0

3) < 1.5 cm2Residual

A9961

2340 cGy CSRT

5580 cGy Local RT

CCNU

CPDDVCR

CPM

CPDDVCR N > 400

Has provided a platform for additional study developmentGoals: 1) Further CSRT dose reduction by modifying chemo

2) Target volume reduction (boost site) using conformal RT

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A9961 Progression-Free Survival from Study Entry

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6 7

Time (Years)

Per

centProgression-Free

RegA RegB

p=0.49

86% +/- 2.5%

84% +/- 3%

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Accuracy of Staging Strongly Influences

Effectiveness of Reduced Dose Therapy

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Overall Survival for A9961 by Anaplasia

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10

Years from study entry

Prob

ability

No Anaplasia (n=300)

Anaplasia (n=55)

p=0.04

Figures 5 and 6 were based on all patients on A9961 with anaplasia information (including those

ineligible by central review due to dissemination or excess residual).

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RT Dose Reduction for Average-Risk

Medulloblastoma (

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ACNS0331

Activation 4/04

RT Dose Reduction for Average-Risk

Medulloblastoma (>8 yrs)

2340 cGy CSRT

w/ VCR

Conformal tumor

bed boost (5400 cGy)

Conformal post fossa

boost (5400 cGy)

CCNU, CPDD, VCR

alt. with CPM, VCR

Both strata include prospective

Trk C and erbB2/4 analysis,

expression profiling, andhistological review to identify ~

20% of tumors that are notbiologically average risk SPECIMEN SUBMISSION

STRONGLY ENCOURAGED.

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High-Risk PNET

Radiosensitization Study

Craniospinal (36 Gy) XRT Boost (18 Gy) XRT

Carbo Carbo Carbo (Carbo) (Carbo) (Carbo)VCR VCR VCR VCR VCR VCR

week 1 2 3 4 5 6

CPMVCR

CDDPCPMVCR(CCG-99701)

Phase I MTD establishedPhase II completed 12/04

ACNS0332

Protocol approved by

CTEP/PCIRB

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3 yr OS: 81 5%

99701 Overall Survival for Metastatic MB

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7

Years from study entry

Proba

bility

n=58

3 yr OS: 81 + 5%

2

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3 yr OS is 89 5%

3 yr OS is 64 12%

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7

Years from study entry

Probability

Anaplasia (n=19)

No Anaplasia (n=39)

p=0.008

3 yr OS: 89 5%

3 yr OS: 64 12%

Overall Survival by Anaplasia

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Progressive DiseaseHigh-risk, Unresectable

< 10 years

A9952

Non-NF1

CarboplatinVCR

6-thioguanineProcarbazine

CCNUVCR

NF1

Management of Low-Grade Glioma

N=250

randomized, 350 total

New Studies

Carbo/VCR/TMZ pilot

ACNS0223 (protocolopened 7/04;

recently opened

groupwide - 32 pts)Conformal RT pilot

ACNS0221

(recently open)

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4

YEARS

Event-FreeSurvival

Regimen A (N=32)

Regimen B (N=31)

CCG-9941

Jennings et al. JCO, 2002

AA

Intensive Chemotherapy Followed by

Irradiation Fails to Alter Prognosis in Newly

Diagnosed Brainstem Glioma

Uniformly poor results of all

recent studies provide for reliable

natural history control data.

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Phase I/II Studies of Radiosensitization

and Chemo-Radiotherapy for Brainstem

Gliomas

Temozolomide (ACNS0126)closed 8/05

accrued at twice rate projected (60/yr)

standardized BSG stats (SPRT), imaging,response analysis in collaboration with PBTC

Topotecan (ACNS 0224)protocol opened

10/10/05

Gadolinium texaphyrin Phase I completed (CCG-09712)

Phase II protocol approved by CTEP/PCIRB - in queue to

open (ACNS0222)

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Combined Chemoradiotherapy for Non-

Brainstem High-Grade Glioma(ACNS0126)

Sequential study design Temozolomide qd w/RT, 5d schedule p-RT - done

Natural history control (CCG-945 centrally

reviewed cohort)

100 pts each, 12-18 months accrual EFS endpoint

Accrued at twice rate projected

Preliminary results available

Temozolomide + anti-angiogenic/signaling

inhibitor/other chemotherapeutic agent

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One year (GBM)

945

(53)

126

(51)

p-value Stupp

(287)

EFS 32% 33% .47 27%

OS 60% 64% .33 61%

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Differences in MGMT Expression are

Noted Among Childhood Malignant

Gliomas and Correlate with PromoterMethylation

2

1 3

4

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Overall Survival for HGG by MGMT

0.00

0.25

0.50

0.75

1.00

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Years from study entry

Probab

ility

No overexpression of MGMT (n=48)

Overexpression of MGMT (n=22)

p=0.032

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Builds upon ADVL0011

(CCNU/temozolomide) (1CR, 1 near CR, 2 PR,

3 MR among 27 pts during induction MTD 90 mg/m2CCNU and 160 mg/m2x 5 TMD

q6wk

ACNS0423, opened 3/21/05has accrued 58

pts

A third study (ACNS0622) is under

development (TMZ/irinotecan)

Combined Chemoradiotherapy for Non-

Brainstem High-Grade Glioma (ACNS0423)

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Management of Germinomas(ACNS 0232)Approved by CTEP/CIRB

Endpoints:EFS, QOL, Neuropsych

Biopsy Confirmation-Markers

Std RT (45Gy)

21Gy Whole ventricular24 Gy boost to 1osite

(30Gy CSR/15Gy 1ofor disseminated)

< CR

40.5 Gy to 1

o

site(24 Gy CSR/16.5 Gy 1ofor disseminated)

CR

30 Gy to 1

o

site(21Gy CSR/9 Gy 1ofor disseminated)

Chemotherapy(Carbo/etoposide)

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Management Paradigm for

NGGCTs (ACNS0122)Tissue Diagnosis

(Open/Stereo Bx)

+ Markers

Induction ChemoCarbo/VP alt with

Ifos/VP x 3

CR(60%)

< CR(40%)

RT36 Gy CS Axis

54 Gy Tumor Bed

PBSC Harvest

High Dose

ChemoThiotepa/VP16

Second LookSurgery

Activation 1/04

46 pts accrued

E d M t S h

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Ependymoma Management SchemaACNS0121 (Opened 8/25/03)

Ependymoma

Central Pathology Review

Observation

Extent of Resection: GTR 1

Differentiated Histology

Supratentorial

Extent of Resection: STR

Any Histology

Any Location

Chemotherapy

Carboplatin/Vincristine

Cyclophosphamide/EtoposideDuration: 7 weeks

Response Evaluation

(PD/SD/PR/CR)

Conformal Radiation Therapy

Total Dose: 59.4 Gy

Clinical Target Volume: 1.0 cm

Unresectable

Conformal Radiation Therapy

Total Dose: 59.4 Gy

Clinical Target Volume: 1.0 cm

Second Surgery

Surgery Endpoint 1: Resectability

Surgery Endpoint 2: Morbidity

Resectable

Extent of Resection: NTR/GTR 2

Any Histology

Any Location

Extent of Resection: GTR 1

Anaplastic Histology Supratentorial

Any Histology Infratentorial

Conformal Radiation Therapy

Total Dose: 59.4 GyClinical Target Volume: 1.0 cm

Novel Features

1) Observation arm

2) Histo-based stratification

3) Chemo to increase rate of

GTR via 2nd-look surgery

4) Group-wide conformal RT

(270 pts accrued, twicero ected rate5/62/76/127

CCG 99 03 Ph I/II S d f I i

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CCG-99703: Phase I/II Study of Intensive

Consolidation Chemo with PBSC Support

In fant B rain Tumors

Completed: Results Pending

Surgery

Induction Chemotherapy(9921 Regimen A)

PBSC harvesting

ConsolidationCBDCA/Thio/VCR x 3 courses

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Event-Free Survival

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8

Years from study entry

Probabi

lity CCG-99703 (n=92)

CCG-9921 (n=284)

Logrank p=0.025

Event-Free Survival 99703 v 9921

01/16/06

BIOLOGICAL STRATIFICATION OF INFANT

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0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6

Years Post Onstudy

Survival

Rhabdoid (N=16)

Non-Rhabdoid PNET (N=94)

CCG-9921

p=0.02

BIOLOGICAL STRATIFICATION OF INFANT

TUMORS: AT/RTs are prognostically distinct

from PNETs and warrant distinct therapy

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Histologicdiagnosis:PNET

FISH:Deletion 22

INI1 mutation analysis:Single base pair change

Molecular Evaluation (FISH and Mutation

Analysis) Will Be Included for Stratification on

All Infant Malignant Tumor Studies

Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002

M t f M0 I f t

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Management of M0 Infant

Medulloblastomas (P9934)

Resection

Staging8-36 months

Induction

Chemotherapy4 4-wk cycles

Focal conformal RT(Age & response-adjusted)

Maintenance

Chemotherapy

Second

Surgery

Endpoints:Survival vs. P8633/9233

Neuropsych and endocrine outcome

Safety of 2nd-look surgery

Separate studies for M+

medullo (ACNS0334 (in queue

to open)) and AT/RT(ACNS0333 (Protocol to

CTEP ))SPECIMEN SUBMISSION

MANDATORY

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Biologically based concepts for high-

risk/refractory malignant brain tumors

Examples:

Disruption of growth factor-mediated signal

transduction R115777 (ACNS0226) - 97

Tarceva (ADVL0214) - 46

Cilengitide (ACNS0621)in development

Tarceva/Avastin (ADVL0526)in development

Induction of maturation (e.g., 13-cis-RA)

medullo (ACNS0332)in queue to open