Angela J Waanders, MD, MPH NeuroOncology Program

Children’s Hospital of Philadelphia

Landscape of pediatric oncology clinical trials:

focus on brain tumors

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Clinical Trial design (www.fda.gov) Phase 1 Trial •  Study participants: 20-100 healthy volunteers or people with the

disease/condition •  Length of study: several months •  Purpose: Dose finding, Safety •  Approximately 70% od drugs move to the next phase Phase 2 Trial •  Study participants: Up to ”several hundred” people with the

disease/condition •  Length of study: several months to 2 years •  Purpose: Efficacy and side effects •  Approximately 33% of drugs move to the next phase Phase 3 Trial •  Study participants: 300 to 3,000 volunteers who have the disease

or condition (usually newly diagnosed) •  Length of Study: 1 to 4 years •  Purpose: Efficacy and monitoring of adverse reactions •  Approximately 25-30% of drugs move to the next phase

Issues with current clinical trial management

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•  Time for protocol development •  Time intensive to enroll and follow patients

(modern “consent forms” are 15-20 pages long) •  Resources it takes to run a clinical trial •  Time from closing of trial to reporting results •  Disincentive to report “negative” results

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Top academic institutions and industry fail to report clinical trial results to clinicaltrials.gov 25-50% of clinical trials are never published. On average takes more than 2 years from study completion to publication, regardless of source of funding STAT news Ross JS et al. JAMA Intern Med 2013.

Issues with current clinical trial management

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We need high quality, verified clinical trial data to make decisions on what to move forward. We need to not just look at PFS and OS but ask why did a given patient respond or not respond (mine the outlier data) Lack of infrastructure to share clinical trial data across academic and industry

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Inability of positive Phase II clinical trials to predict positive Phase III clinical trials in adult glioblastoma

-  Methods: PubMed search to identify interventional Phase III trials in past 25 years

-  7 Phase III trials – newly diagnosed pts -  4 Phase III trials – recurrent pts -  Studies used 6 month PFS as primary endpoint -  Only 1 study documented improvement in

overall survival

Mandel et al. NeuroOncology 2017.

Landscape: Pediatric Oncology Clinical Trials

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-  General oncology consortium -  Disease specific consortium -  Single Institution -  Multi-Institution Industry Sponsored

Challenges: Pediatric Oncology Clinical Trials

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-  Diverse diseases -  Diverse patient ages (infant to AYA) -  Diverse dosing (weight vs BSA) -  Diverse medication formulations

required (liquid versus capsules) -  Long-term toxicities

Additional special considerations for pediatric neuro-oncology clinical trials

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-  In the USA, number of adult survivors of childhood brain tumors steadily increasing

-  Average 5-year survival rate for all-comers of childhood brain cancers has risen to ~73%

-  Surgery, cytoxic chemotherapy, and radiation therapy remain mainstay of treatment

-  Need to reconsider endpoint measurements -  Need to improve survival for tumors with dismal outcomes -  Need to improve QoL for brain tumor survivors

Byer L et al. CNS Oncology 2016.

Additional special considerations for pediatric neuro-oncology clinical trials

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2016 CNS WHO Classification •  Incorporate molecular information •  Major restructuring of gliomas •  Addition of new classification of astrocytomas •  Major restructuring of medulloblastomas •  Removal of “primitive neuroectodermal tumor (PNET)” •  Incorporation of a genetically defined ependymoma variant

Douis DN et al. Acta Neuropathol 2016.

Additional special considerations for pediatric neuro-oncology clinical trials

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2016 CNS WHO Classification •  Incorporate molecular information •  Major restructuring of gliomas •  Addition of new classification of astrocytomas •  Major restructuring of medulloblastomas •  Removal of “primitive neuroectodermal tumor (PNET)” •  Incorporation of a genetically defined ependymoma variant

Douis DN et al. Acta Neuropathol 2016.

How do you use historical cohorts as controls?

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CBTRUS 2016 report

Estimate of new cases of primary brain tumors in the United States in 2017 •  79, 270 cases overall •  4,830 childhood cases

Ostrom QT et al. NeuroOncology 2016. .

Children’s Oncology Group (COG)

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•  History: In 2000, 4 pediatric cooperative cancer groups voluntarily merged to form COG

•  Primarily funded by NCI •  Supplemental Industry support for specific trials •  Member of the NCI National clinical Trials Network

Children’s Oncology Group (COG)

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•  Strength is in Phase III trials •  Expanding early phase clinical trials with

Developmental Therapeutics COG consortium (supporting 21 COG institutions with early phase clinical trials)

•  New campaigns include NCI-COG Pediatric MATCH trial, and Project: Every Child

Children’s Oncology Group (COG)

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Challenges •  Shear size and scope of the consortium •  Reliance on paper records •  Insufficient biological correlative studies •  Insufficient funding to “incentivize”

Children’s Oncology Group (COG)

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Neuro-Oncology Trials as of 10/22/17 •  17 currently open open •  4 are general registry and/or biobanking studies •  2 are neurocognitive focused •  4 are brain tumor specific interventional trials •  Remaining are non-brain tumor DVL trials

Children’s Oncology Group: Brain tumors

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ACNS0333: Treatment of Atypical Teratoid/Rhabdoid Tumors of the Central Nervous System with Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation -  Opened for entry 12/8/2008 -  Closed to accrual 02/24/2014 -  Results yet to be reported -  First COG CNS trial to require tumor tissue for study entry

PBTC: Pediatric Brain Tumor Consortium

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•  Formed in 1999 by National Cancer Institute •  Focus on early phase clinical trials (Phase i/II to

feed into COG) •  Participants: 11 academic and children’s

hospitals across the US, competitively selected •  Chair: Dr. Ira Dunkel @ MSKCC •  Overall has opened 48 trials •  7 trials currently open

POETIC: Pediatric Oncology Experimental Therapeutic Investigator’s Consortium

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-  Founded in 2003 -  Dr Lia Gore @ University of Colorado -  Dr. Tanya Trippett @ MSKCC -  Website lists 10 participating institutions -  2 active clinical trials- none for brain tumors

PNOC: Pacific Pediatric NeuroOncology Consortium

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•  Formed in 2012 •  Focus is to provide children with brain tumors

access to innovative treatments •  Project co-leaders Dr. Sabine Mueller and Dr.

Michael Prados @ UCSF •  Philanthropic funded •  18+ member institutions •  7 active clinical trials

Case study: pediatric low-grade gliomas

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Pediatric low-grade gliomas • Most common brain tumor in children, ~30% of all CNS primary tumors.

• Incidence of 2.1/100,000 (1500 children diagnosed every year)

• A heterogeneous group of histologies • WHO grade I and II classification • Pilocytic Astrocytoma • Diffuse Fibrillary Astrocytoma • Angiocentric Glioma • Pleomorphic Xanthoastrocytoma • Pilomixoid astrocytoma

Khatua et al., Childs Nerv Syst 2015 Sievert et al. J Child Neuro 2009

Classic Cerebellar Astrocytoma

Hypothalamic astrocytoma

Thalamic astrocytoma

Cerebellar pilocytic astrocytoma With spinal metastasis

Pilocytic Astrocytomas

Lessons learned: therapeutic targeting

•  KIAA1549-BRAF fusion reported in 2008 •  Phase II clinical trial for Sorafenib (BRAF inhibitor) stopped

early due to unexpected tumor progression on treatment

Accelerated tumor growth with Sorafenib

Karajannis et al, Neuro-Oncology 2014

BRAF gene rearrangements signal differently than canonical BRAF V600E

Disrupt dimerization KIAA1549-BRAF R509H

Co-immunoprecipitation

G- GST-tag; M-Myc-tag

KIA

A15

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-B

RA

F

Dimerization

anti-MYC

anti-GST

Input: Anti-MYC

Wild-type BRAFBRAF (V600E)Fusion-3Fusion-4

G/M M M M - - - - - G - - G/M - - - - - G - - G/M - M - - - G - - G/M G

Dimerization

anti-MYC

anti-GST

Input: Anti-MYC

Wild-type BRAFBRAF (V600E)Fusion-3Fusion-4

G/M M M M - - - - - G - - G/M - - - - - G - - G/M - M - - - G - - G/M G

BRAF-fusions= unique signaling complexes Monomeric BRAF

V600E signaling

Sievert AJ, Lang SS et al. PNAS 2013

Flank xenograft

Landscape of genomic alterations in sporadic pediatric low-grade gliomas:

ZhangJ.etal.NatureGene0cs2013JonesDT.etal.NatureGene0cs2013RamkissoonLA.etal.PNAS2013

www.cbttc.org cbttcadmin@email.chop.edu

www.CBTTC.org

Children’s Brain Tumor Tissue Consortium

•  The CBTTC is dedicated to find new innovative treatments for all types of pediatric brain tumors.

•  Open-source data sharing, pooling of biospecimens,

and real-time global research collaboration capabilities to fast track and boost bench-to-bedside innovations in the field of pediatric brain cancer.

•  Leading pediatric brain cancer clinicians, researchers and

institutions partnered for cutting edge scientific innovation and collaboration.

3rd Annual CBTTC Investigator Meeting Highlight Video

Executive Committee Executive Chair – Rishi R. Lulla, MD, MS, Ann & Robert H. Lurie Children’s Hospital of Chicago Scientific Committee Co-chair – Adam Resnick, PhD, Children’s Hospital of Philadelphia Co-chair – Javad Nazarian, PhD, MSC, Children’s National Health System Operations* Director of Operations – Angela Waanders, MD, MPH, Children’s Hospital of Philadelphia Operations Manager – Jennifer Mason, Children’s Hospital of Philadelphia *The operations center of the CBTTC is located at Children’s Hospital of Philadelphia

CBTTC "One Word" Video

CBTTC Leadership

4 Members to now 15 Member Institutions Today ●  Children’s Hospital of Philadelphia (CHOP) ●  Children’s Hospital of Pittsburgh of UPMC ●  Seattle Children’s Hospital ●  Ann & Robert H. Lurie Children’s Hospital of Chicago ●  Meyer Children’s Hospital (Florence, Italy) ●  UCSF Benioff Children’s Hospital ●  Lucile Packard Children’s Hospital Stanford Bristol-Meyers

Squibb Children’s Hospital at Robert Wood Johnson University Hospital

●  Children’s National Health System ●  Weill Cornell Pediatric Brain & Spine Center ●  Joseph M. Sanzari Children’s Hospital at Hackensack University

Medical Center ●  Children’s Hospital of Orange County: CHOC Children’s ●  University of California Santa Cruz: Treehouse Childhood Cancer

Initiative ●  The Beijing Tiantan Hospital Neurosurgery Center (Beijing,

China) ●  Genebank (Beijing Genomics Institute – Shenzhen, China)

PHILANTHROPIC FUNDING SUPPORT

Capturing longitudinal phenotypic data

In 2011, as I joined CBTTC this was the status of CRF’s…........

FREE TEXT ENTRY…..........

•  Queried all of the CBTTC investigators- what data is important to capture?

•  Data capture- discrete options and eliminate most of free text

•  Data dictionary

•  Resources for clinical data capture (training, ongoing quality control)

Solution….. Creation of a “Clinical Working Group”

CBTTC Portal: Open Access to Clinical and Specimen Data

•  > 20 Scientific Projects

•  > 2,055 Subjects Enrolled • Clinical Data: + 30 brain tumor

types /+ 30 clinical data points with 15 year follow up

• Molecular Data: WGS, RNAseq, Proteomics (Atlas)

•  > 12,000 Biospecimens Aliquots • Tissue; flash frozen, freezing

media • Blood, CSF, Saliva, Cell lines

CBTTC Statistics as of July 2017

PNOC and CBTTC collaboration to empower clinical trial discovery

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Pediatric Oncology Clinical Trials

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•  Adaptive study design? •  Accelerate/Rethink Phase 1 trials? •  Improve design of Phase 2 trials •  Standardize endpoints for cross comparison •  Empower discovery through biological

correlatives •  Accelerate translational findings by maximizing

data generation and analysis

Thoughts to end:

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“Dark Remedy: The impact of thalidomide and it’s revival as a vital medicine” Our job as disciplined scientists is ”to find the right questions to ask, the right tests to perform, and then eliminate from interpretation of the data any expectations, assumptions, biases, or hopes that we may have in order to see the significance of the results with objective clarity. The clarity can make the difference between finding a cure for an incurable disease and raising false hopes…” (Stephens & Brynner, 2001).

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