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COG CNS Committee 2003-2007 Ian Pollack

COG CNS Committee 2003-2007 Ian Pollack. Scientific Goals. Identify biological characteristics of childhood CNS tumors that influence treatment response, and initiate risk-adapted stratification .

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COG CNS Committee 2003-2007 Ian Pollack

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  1. COG CNS Committee 2003-2007 Ian Pollack

  2. Scientific Goals • Identify biological characteristics of childhood CNS tumors that influence treatment response, and initiate risk-adapted stratification. • Develop comprehensive treatment approaches to improve survival and quality of life for children with primary CNS tumors. • Identify effective therapies for CNS tumors resistant to prior treatments. • Define and validate strategies for reducing treatment-related long-term sequelae.

  3. CNS Committee Cross-Study Therapeutic Hypotheses

  4. Cooperative Group Scientific Accomplishments • Observation that the use of adjuvant chemotherapy 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.

  5. Reduced Dose Radiotherapy Is Feasible in Standard-Risk Medulloblastomas If Combined with Adjuvant Chemotherapy

  6. Amount of Residual Disease Is Associated with Outcome in Children with High-Grade Glioma CCG-945 Wisoff et al., J Neurosurg 89: 52, 1998

  7. Scientific Accomplishments • Determination that moderately intensive chemo improves survival for poor-risk medullo/PNET. • Identification of molecular factors correlated with outcome of infant tumors. • Documentation that building upon induction chemo in infant tumors with high-dose consolidation or focal irradiation improves outcome. • However, despite improvements in the prognosis of some tumor types, others remain resistant and late effects remain a concern.

  8. 1) Post fossa location 2) M0 3) < 1.5 cm2 Residual A9961 2340 cGy CSRT 5580 cGy Local RT CCNU CPDD VCR CPM CPDD VCR Management of Average-Risk Medulloblastomas N > 400 • Has provided a platform for additional study development • Goals: 1) Further CSRT dose reduction by modifying chemo • 2) Target volume reduction (boost site) using conformal RT

  9. A9961 Progression-Free Survival from Study Entry RegA RegB 100% 86% +/- 2.5% 90% 80% Percent Progression-Free 84% +/- 3% 70% 60% p=0.49 50% 0 1 2 3 4 5 6 7 Time (Years)

  10. Accuracy of Staging Strongly Influences Effectiveness of Reduced Dose Therapy

  11. 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).

  12. RT Dose Reduction for Average-Risk Medulloblastoma (<8 yrs) 1800 cGy CSRT with VCR 2340 cGy CSRT with VCR Conformal post fossa boost (5400 cGy) Conformal tumor bed boost (5400 cGy) ACNS0331 Activation 4/04 135 pts accrued CCNU, CPDD, VCR alt. with CPM, VCR

  13. RT Dose Reduction for Average-Risk Medulloblastoma (>8 yrs) Both strata include prospective Trk C and erbB2/4 analysis, expression profiling, and histological review to identify ~ 20% of tumors that are not biologically “average risk” – SPECIMEN SUBMISSION STRONGLY ENCOURAGED. 2340 cGy CSRT w/ VCR Conformal post fossa boost (5400 cGy) Conformal tumor bed boost (5400 cGy) ACNS0331 Activation 4/04 CCNU, CPDD, VCR alt. with CPM, VCR

  14. CDDP CPM VCR High-Risk PNET Radiosensitization Study Carbo Carbo Carbo (Carbo) (Carbo) (Carbo) VCR VCR VCR VCR VCR VCR Craniospinal (36 Gy) XRT Boost (18 Gy) XRT week 1 2 3 4 5 6 ACNS0332 Protocol approved by CTEP/PCIRB CPM VCR (CCG-99701) Phase I MTD established Phase II completed 12/04

  15. 99701 Overall Survival for Metastatic MB 1.00 n=58 0.75 Probability 0.50 0.25 0.00 0 1 2 3 4 5 6 7 Years from study entry 3 yr OS: 81 + 5% 2 3 yr OS: 81 ± 5%

  16. 1.00 No Anaplasia (n=39) 0.75 Anaplasia (n=19) Probability 0.50 0.25 p=0.008 0.00 0 1 2 3 4 5 6 7 Years from study entry Overall Survival by Anaplasia 3 yr OS is 89 ± 5% 3 yr OS: 89 ± 5% 3 yr OS is 64 ±12% 3 yr OS: 64 ± 12%

  17. Progressive Disease High-risk, Unresectable < 10 years A9952 Non-NF1 Carboplatin VCR 6-thioguanine Procarbazine CCNU VCR Management of Low-Grade Glioma • New Studies • Carbo/VCR/TMZ pilot • ACNS0223 (protocol opened 7/04; recently opened groupwide - 32 pts) • Conformal RT pilot • ACNS0221 (recently open) NF1 N=250 randomized, 350 total

  18. 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. A A CCG-9941 Jennings et al. JCO, 2002

  19. 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)

  20. 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

  21. One year (GBM)

  22. Differences in MGMT Expression are Noted Among Childhood Malignant Gliomas and Correlate with Promoter Methylation 3 1 4 2

  23. Combined Chemoradiotherapy for Non-Brainstem High-Grade Glioma (ACNS0423) • Builds upon ADVL0011 (CCNU/temozolomide) (1CR, 1 near CR, 2 PR, 3 MR among 27 pts during induction • MTD 90 mg/m2 CCNU and 160 mg/m2 x 5 TMD q6wk • ACNS0423, opened 3/21/05 – has accrued 58 pts • A third study (ACNS0622) is under development (TMZ/irinotecan)

  24. Management of Germinomas(ACNS 0232) – Approved by CTEP/CIRB Biopsy Confirmation - Markers Chemotherapy (Carbo/etoposide) Std RT (45Gy) 21Gy Whole ventricular 24 Gy boost to 1o site (30Gy CSR/15Gy 1o for disseminated) < CR 40.5 Gy to 1o site (24 Gy CSR/16.5 Gy 1o for disseminated) CR 30 Gy to 1o site (21Gy CSR/9 Gy 1o for disseminated) Endpoints: EFS, QOL, Neuropsych

  25. Management Paradigm for NGGCTs (ACNS0122) Tissue Diagnosis (Open/Stereo Bx) + Markers Induction Chemo Carbo/VP alt with Ifos/VP x 3 < CR (40%) CR (60%) Second Look Surgery PBSC Harvest High Dose Chemo Thiotepa/VP16 RT 36 Gy CS Axis 54 Gy Tumor Bed Activation 1/04 46 pts accrued

  26. Ependymoma Management SchemaACNS0121 (Opened 8/25/03) 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, twice projected rate – 5/62/76/127)

  27. CCG-99703: Phase I/II Study of Intensive Consolidation Chemo with PBSC SupportInfant Brain Tumors Completed: Results Pending Surgery Induction Chemotherapy (9921 Regimen A) PBSC harvesting Consolidation CBDCA/Thio/VCR x 3 courses

  28. Event-Free Survival 99703 v 9921 01/16/06

  29. BIOLOGICAL STRATIFICATION OF INFANT TUMORS: AT/RTs are prognostically distinct from PNETs and warrant distinct therapy

  30. Molecular Evaluation (FISH and Mutation Analysis) Will Be Included for Stratification on All Infant Malignant Tumor Studies Histologic diagnosis: PNET INI1 mutation analysis: Single base pair change FISH: Deletion 22 Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002

  31. Management of M0 Infant Medulloblastomas (P9934) Separate studies for M+ medullo (ACNS0334 (in queue to open)) and AT/RT (ACNS0333 (Protocol to CTEP )) SPECIMEN SUBMISSION MANDATORY Resection Staging 8-36 months Second Surgery Induction Chemotherapy 4 4-wk cycles Focal conformal RT (Age & response-adjusted) Maintenance Chemotherapy Endpoints: Survival vs. P8633/9233 Neuropsych and endocrine outcome Safety of 2nd-look surgery

  32. 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

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