Roger J Packer MD Senior VicePresident Neuroscience and Behavioral Medicine Director Brain Tumor Institute Childrens National Health System Washington DC Welcome to CBTTC CNHS honored to be a member ID: 798341
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Slide1
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
Slide2Welcome 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
Slide3Slide4A9961 Event-Free Survival from Study Entry
50%
60%
70%
80%
90%
100%
0
1
2
3
4
5
6
7
Time (years)
Percent Event-Free
RegA
RegB
p=0.65
85 +/- 3%
83 +/- 3%
Slide5Slide6Medulloblastoma: 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 18-36 months with outcome measure within 3-5 years of initiation (closer to 36 months, the better)
6
Slide7Medulloblastoma: Consensus and Controversies
Taylor MD et al,
Acta Neuropathol. 2012
Slide8Northcott.
J Clin Oncol 28. 2010
Slide9Slide10Therapeutically 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
SHH Subgroup
Slide11Clinical prognostication of patients with SHH medulloblastoma.
Shih D J et al. JCO 2014;32:886-896
©2014 by American Society of Clinical Oncology
Slide12Slide13Slide14Current Medulloblastoma Subclassification
Ramaswamy et al,
Acta
Neuropathologica2014
Slide15Proposed model to “move-up” novel agents for high-risk medulloblastoma
: children > 3 or 4
15
DIAGNOSIS
Induction chemotherapy plus novel
a
gent
Risk Stratification
Radiation Therapy (consolidation)
Evaluation of Response/MRD
Maintenance plus novel
a
gents
Evaluation of Response/MRD
PFS/OS
Targeted
?Targeted
?non-targeted
Slide16Slide17DIPG and Non-BS HGG
Slide18Slide19Molecular Subgroups of Pediatric HGG
Slide20PNOC’s Pediatric HGG/DIPG Approach
H3.3 K27 M
positiveMidline
Gliomas
PNOC007:
H3.3K27M peptide Vaccine trial
Genomic Based Precision Medicine Approach
CED of nanoliposomalCPT11 for DIPG
HGG
&
DIPG
DIPG
Not eligible for 007
Biopsy required
No Biopsy required
PD1 + XRT
Targeted CNS delivery + liposomal technology
Immunotherapy
Immunotherapy
Genomic Based Precision Medicine Approach
Slide21PA – a single
pathway
disease
Jones et al.
Nature
Genetics
2013
Zhang et al.
Nature Genetics 2013
Time
for
clinical
prime-time!
Slide22Relevant Pathways for LGG
Slide23Selumetinib: Response
Slide24Largest Percentage Reduction in Tumor Volume from Baseline by BRAF Aberration (Min Tumor Vol/Baseline Vol)