1. Pediatric Brain Tumors: The Need for “Pristine” Biologic and Clinical Data
Roger J. Packer, MD Senior Vice-President Neuroscience and Behavioral Medicine Director, Brain Tumor Institute Children’s National Health System Washington, DC

2. Welcome to CBTTC CNHS honored to be a member
Leaders of efforts at CNHS
Brian Rood, MD
Javad Nazarian, PhD
Efforts like CBTTC of critical importance
We are clearly in the molecular era
Great opportunities
Molecular/Genetic/Biologic advances leaped over clinical advance data past decade; clinical has not kept up
Early biologic assumptions not as clear cut as regards therapeutic/prognostic implications (clinical data not as “clean”)
Transition from retrospective to prospective studies, role of CBTTC critical

4. 100% 90% 80% Percent Event-Free 70% 60% 50% 1 2 3 4 5 6 7 Time (years)
A9961 Event-Free Survival from Study Entry
RegA
RegB
100%
90%
85 +/- 3%
80%
Percent Event-Free
83 +/- 3%
70%
60%
p=0.65
50% 1 2 3 4 5 6 7
Time (years)

6. Medulloblastoma: Trial Design
Present cooperative group trials 10+ years to complete
Not taken advantage of biologic insights
Reduction or dosing fraction changes of RT not going to get where we need to go
Accelerated Hyperfractionation
Reduced dose CSRT
Proton beam
Need studies that can accrue in months with outcome measure within 3-5 years of initiation (closer to 36 months, the better)

7. Medulloblastoma: Consensus and Controversies
Taylor MD et al,
Acta Neuropathol

8. Northcott. J Clin Oncol

10. SHH Subgroup Therapeutically 2 subgroups Mutation-driven
For “upstream” (infants, adults) mutations
How do we measure benefit of a SHH inhibitor (survival as good as “average-risk”)
For downstream mutations
Presently there are not effective molecularly-targeted agents

11. Clinical prognostication of patients with SHH medulloblastoma.
Clinical prognostication of patients with SHH medulloblastoma. (A) Risk stratification of SHH medulloblastomas by molecular and clinical prognostic markers. Decision tree, with events plot depicting status of molecular and clinical markers across risk groups below. (B) Overall survival curves for SHH risk groups. (C) Average time-dependent areas under the curve (AUCs) for risk groups stratified using only clinical or molecular markers or both. Risk stratification regimens applied to SHH and non-SHH medulloblastomas. ***P < .001 by Friedman rank sum tests. (D) Survival curves for SHH risk groups in validation cohort. Survival differences evaluated by log-rank tests; hazard ratio estimates derived from Cox proportional hazards analyses.
Shih D J et al. JCO 2014;32:
©2014 by American Society of Clinical Oncology

14. Current Medulloblastoma Subclassification
Ramaswamy et al, Acta Neuropathologica2014

15. Proposed model to “move-up” novel agents for high-risk medulloblastoma: children > 3 or 4
DIAGNOSIS
Risk Stratification
Targeted
Induction chemotherapy plus novel agent
Evaluation of Response/MRD
Radiation Therapy (consolidation)
Evaluation of Response/MRD
Maintenance plus novel agents
?Targeted
?non-targeted
PFS/OS

17. DIPG and Non-BS HGG

19. Molecular Subgroups of Pediatric HGG

20. PNOC’s Pediatric HGG/DIPG Approach
H3.3 K27 M positiveMidline Gliomas
DIPG
Not eligible for 007
HGG & DIPG
No Biopsy required
Biopsy required
Genomic Based Precision Medicine Approach
PNOC007:
H3.3K27M peptide Vaccine trial
CED of nanoliposomalCPT11 for DIPG
PD1 + XRT
Immunotherapy
Targeted CNS delivery + liposomal technology
Immunotherapy
Genomic Based Precision Medicine Approach

21. PA – a single pathway disease
Zhang et al. Nature Genetics 2013
 Time for clinical prime-time!
Jones et al. Nature Genetics 2013

22. Relevant Pathways for LGG

23. Selumetinib: Response

24. Largest Percentage Reduction in Tumor Volume from Baseline by BRAF Aberration (Min Tumor Vol/Baseline Vol)