1. CBTTC Investigator Meeting Washington DC, May 2017
PNOC003
A pilot trial testing the clinical benefit of using molecular profiling to determine an individualized treatment plan in children and young adults with newly diagnosed DIPG
CBTTC Investigator Meeting Washington DC, May 2017

2. Precision medicine trial for children with DIPG
PK and PD analysis in recurrent sample
Child with newly diagnosed DIPG NO
Candidate for biopsy / resection
YES
Patient is eligible
Patient is not eligible
Biopsy / clinical pathology
Evidence of progression / recurrence: Re-consent patient for repeat biopsy NO
Adequate sample: > 50% tumor
YES
Correlative Studies:
Xenograft models
Circulating tumor cells
Whole-genome sequencing
Clinical genomics (TGEN):
Gene expression profiling
Whole-exome sequencing
Predictive modeling
Off study
Report
Specialized tumor board issues treatment recommendation
Monitor patient for safety and clinical response

3. PNOC003 Milestones 8/4/2014: Initial Protocol sent to sites
9/16/2014: First patient enrolled
5/11/2016: Protocol v3 sent to sites (feasibility portion completed) – manuscript in preparation

4. Enrollment Summary Total 31 patients enrolled to date
Feasibility portion:
enrolled total of 17 subjects:
2 were not eligible due to non eligible tissue diagnosis (astrocytoma grade 1, ETANTR)
For one patient RNA seq analysis was unsuccessful
8/14 from feasibility portion followed treatment recommendation:
One patient recommendation was single agent panobinostat but this was started already during radiation therapy
One patient followed the therapy recommendation however was started late on therapy plan and therefore counted as not following therapy recommendation
Several families decided not to pursue any further therapy or enroll into other trials such as CED etc.
PNOC003 – astro grade 1
PNOC004 did not follow
PNOC005- followed but started late and no communication with PNOC and therefore decision was made to not count as following therapy

5. DNA and RNA Alterations

6. Treatment Recommended
DNA Level Alterations & Treatment Recommendations
Treatment Recommended
Etoposide, dasatinib
Cabozantinib, etoposide, mebendazole
AZD1775 (clinical trial), temozolomide, sertraline
Panobinostat, mebendazole (or cabozantinib)
Panobinostat, mebendazole
Erlotinib, propranolol, everolimus, etoposide
Panobinostat, everolimus, sertraline (mebendazole if well-tolerated)
Panobinostat, everolimus, mebendazole (or dasatinib)
Panobinostat
Vemurafenib/dabrafenib, trametinib, minocycline, panobinostat
Etoposide, metformin, mebendazole, sertraline
Panobinostat, everolimus, mebendazole/cabozantinib, valproic acid
Panobinostat, mebendazole, cabozantinib, valproic acid
Panobinostat, cabozantinib, valproic acid, mebendazole
Panobinostat, mebendazole, propranolol, valproic acid
Panobinostat, olaparib, irinotecan
Trametinib, everolimus, palbociclib, mebendazole
Panobinostat, everolimus, metformin, etoposide
Everolimus, trametinib, panobinostat, metformin
Panobinostat, mebendazole, etoposide, consider ALK inhibitor
Panobinostat, dasatinib, mebendazole
Panobinostat, everolimus, propranolol, mebendazole/metformin
Panobinostat, mebendazole, sorafenib
Panobinostat, everolimus, mebendazole, etoposide (or dasatinib)

7. Recurrent sample driven by EGFR activation

8. Correlative Biology
7 cell lines established: PNOC003-04, PNOC003-5,PNOC003-26, SF10423, 10438, 10693, 10864
PNOC003-5, 11 and 26 have been passaged two times. PNOC3-04, SF10693, and in vivo have been passaged at least 3x with up to 7 passages; PNOC003-23, PNOC003-29,SF10424,10438, 10475, 10493,10516 and passaged once. => possible 7-15 new DIPG model systems
Analysis of circulating tumor DNA at baseline and with MRI scans (Javad Nazarian)
Whole genome analysis and methylation studies of both human samples and associated cell lines/xenografts (Adam Resnick)

9. Acknowledgements Patient & Families PNOC PIs PNOC OP’s Funding
Adam Resnick
Javad Nazarian
Nalin Gupta
Michael Prados
Lindsay Kilburn
John Kuhn
Mike Berens
Winnie Liang
Sara Byron
Mitch Berger
Claudia Petritsch
Nathalene Truffeaux
Xiaodong Yang
John Crawford
Kellie Nazemi
Eugene Huang
Brian Hood
Suresh Magge
Roger Packer
Allison Ross
David Craig
Alison Roos
Patient & Families
PNOC PIs
PNOC OP’s
Jenna Weight
Lajhem Cambridge
Jordana Sandy
Annette Molinaro
Funding
NIH through Cancer Center Award
V Foundation
Pediatric Brain Tumor Foundation
Vs. Cancer Foundation
Department of Neurosurgery, UCSF