Angela J Waanders, MD, MPH. NeuroOncology Program Children s Hospital of Philadelphia

Transcription

1 Angela J Waanders, MD, MPH NeuroOncology Program Children s Hospital of Philadelphia

2 2 Landscape of pediatric oncology clinical trials: focus on brain tumors

3 Clinical Trial design ( Phase 1 Trial Study participants: 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 3

4 Issues with current clinical trial management Time for protocol development Time intensive to enroll and follow patients (modern consent forms are pages long) Resources it takes to run a clinical trial Time from closing of trial to reporting results Disincentive to report negative results 4

5 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 5 STAT news Ross JS et al. JAMA Intern Med 2013.

6 Issues with current clinical trial management 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 6

7 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 7 Mandel et al. NeuroOncology 2017.

8 Landscape: Pediatric Oncology Clinical Trials - General oncology consortium - Disease specific consortium - Single Institution - Multi-Institution Industry Sponsored 8

9 Challenges: Pediatric Oncology Clinical Trials - Diverse diseases - Diverse patient ages (infant to AYA) - Diverse dosing (weight vs BSA) - Diverse medication formulations required (liquid versus capsules) - Long-term toxicities 9

10 Additional special considerations for pediatric neuro-oncology clinical trials - 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 10 Byer L et al. CNS Oncology 2016.

11 Additional special considerations for pediatric neuro-oncology clinical trials 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 11 Douis DN et al. Acta Neuropathol 2016.

12 Additional special considerations for pediatric neuro-oncology clinical trials 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 How do you use historical cohorts as controls? 12 Douis DN et al. Acta Neuropathol 2016.

13 CBTRUS 2016 report Estimate of new cases of primary brain tumors in the United States in , 270 cases overall 4,830 childhood cases 13 Ostrom QT et al. NeuroOncology

14 Children s Oncology Group (COG) 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 14

15 Children s Oncology Group (COG) 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 15

16 Children s Oncology Group (COG) Challenges Shear size and scope of the consortium Reliance on paper records Insufficient biological correlative studies Insufficient funding to incentivize 16

17 Children s Oncology Group (COG) 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 17

18 Children s Oncology Group: Brain tumors 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/ Closed to accrual 02/24/ Results yet to be reported - First COG CNS trial to require tumor tissue for study entry 18

19 PBTC: Pediatric Brain Tumor Consortium 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 MSKCC Overall has opened 48 trials 7 trials currently open 19

20 POETIC: Pediatric Oncology Experimental Therapeutic Investigator s Consortium - Founded in Dr Lia University of Colorado - Dr. Tanya MSKCC - Website lists 10 participating institutions - 2 active clinical trials- none for brain tumors 20

21 PNOC: Pacific Pediatric NeuroOncology Consortium Formed in 2012 Focus is to provide children with brain tumors access to innovative treatments Project co-leaders Dr. Sabine Mueller and Dr. Michael UCSF Philanthropic funded 18+ member institutions 7 active clinical trials 21

22 22 Case study: pediatric low-grade gliomas

23 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 Classic Cerebellar Astrocytoma Pilocytic Astrocytomas Hypothalamic astrocytoma Cerebellar pilocytic astrocytoma With spinal metastasis Thalamic astrocytoma Khatua et al., Childs Nerv Syst 2015 Sievert et al. J Child Neuro 2009

24 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

25 BRAF gene rearrangements signal differently than canonical BRAF V600E KIAA1549 -BRAF Wild-type BRAF BRAF (V600E) Fusion-3 Fusion-4 Co-immunoprecipitation anti-myc anti-gst Input: Anti-MYC G/M G/M - M - - G/M G G- GST-tag; M-Myc-tag Disrupt dimerization KIAA1549-BRAF R509H Flank xenograft Monomeric BRAF V600E signaling BRAF-fusions= unique signaling complexes Sievert AJ, Lang SS et al. PNAS 2013

26 Landscape of genomic alterations in sporadic pediatric low-grade gliomas: Zhang J. et al. Nature Gene0cs 2013 Jones DT. et al. Nature Gene0cs 2013 Ramkissoon LA. et al. PNAS 2013

27

28 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

29 CBTTC Leadership 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

30 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

31 Capturing longitudinal phenotypic data

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

33 FREE TEXT ENTRY...

34 Solution.. Creation of a Clinical Working Group 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)

35 CBTTC Portal: Open Access to Clinical and Specimen Data

36 CBTTC Statistics as of July 2017 > 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

37 37 PNOC and CBTTC collaboration to empower clinical trial discovery

38 Pediatric Oncology Clinical Trials 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 38

39 Thoughts to end: 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). 39

40 40

41 41