CTNI-84 - PNOC022: A Combination Therapy Trial using an Adaptive Platform Design for patients with Diffuse Midline Gliomas (DMGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

Sunday, November 19, 2023

10:15 AM – 10:25 AM PT

Location: Room 121-122

Author(s)

Cassie Kline

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Andrea T. Franson

University of Michigan
Ann Arbor, Michigan, United States
AB

Anu Banerjee

UCSF
San FRancisco, California, United States
AR

Alyssa T. Reddy

University of California, San Francisco
San Francisco, California, United States
SR

Shannon Raber

UCSF
San Francisco, California, United States
CH

Carly Hoffman

UCSF
San Francisco, California, United States
JM

Jane Minturn

Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Jasper van der Lugt

Princess Máxima Center for Pediatric Oncology
Utrecht, Utrecht, Netherlands
Ed

E. de Vos-Kerkhof

Princess Máxima Center for Pediatric Oncology
Utrecht, Netherlands
Dv

Dannis van Vuurden

Princess Maxima Center for Pediatric Oncology
Utrecht, Netherlands
NG

Nicolas Gerber

University Children's Hospital
Zurich, Switzerland
AG

Ana Guerreiro Stuecklin

Kispi
Zurich, Switzerland
Lindsay B. Kilburn

Children’s National Hospital
Washington, District of Columbia, United States
JE

Jennifer Elster

University of California, San Diego
San Diego, California, United States
NW

Nicholas Whipple

University of Utah
Salt Lake City, Utah, United States
Kenneth J. Cohen

John Hopkins University
Baltimore, Maryland, United States
MY

Michal Yalon Oren

Sheba Medical Center
Ramat Gan, Tel Aviv, Israel
Sharon L. Gardner

NYU
New York, New York, United States
AC

Andrew Cluster

St. Louis Children's Hospital
San Louis, Missouri, United States
Susan N. Chi

Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
Boston, Massachusetts, United States
Daniel B. Landi

Duke University
Durham, North Carolina, United States
GM

Geoffrey McCowage

Sydney Children’s Hospitals Network
Westmead, New South Wales, Australia
AR

Adam Resnick

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Joanna J. Phillips

University of California, San Francisco
San Francisco, California, United States
AB

Aashim Bhatia

Children's Hospital of Philadelphia
Philadelphia, United States
AV

Arastoo Vossough

Children's Hospital of Philadelphia
Philadelphia, United States
EG

Elizabeth George

University of California, San Francisco
San Francisco, United States
AN

Ali Nabavizadeh

University of Pennsylvania
Philadelphia, Pennsylvania, United States
SB

Steve E. Braunstein

University of California San Francisco
San Francisco, California, United States
NG

Nalin Gupta

University of California, San Francisco
San Francisco, California, United States
MP

Michael Prados

University of California, San Francisco
San Francisco, California, United States
Sebastian M. Waszak

École Polytechnique Fédérale de Lausanne (EPFL)
Lausanne, Vaud, Switzerland
JB

Janel Boyle-Lang

University of California, San Francisco (UCSF)
San Francisco, California, United States
Annette M. Molinaro

University of California, San Francisco
San Francisco, California, United States
Matthew D. Dun

University of Newcastle
Callaghan, New South Wales, Australia
Carl J. Koschmann

University of Michigan
Ann Arbor, Michigan, United States
Javad Nazarian

University Children’s Hospital Zurich
Zürich, District of Columbia, Switzerland

Oral Abstract Presenter(s)

Sabine Mueller

University of California, San Francisco
San Francisco, California, United States

Background: Subjects diagnosed with diffuse midline glioma (DMG) face extremely poor prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, multi-institutional, international trial that aims to investigate combination therapies for patients with DMG. Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2).

Methods: Children and young adults aged 2-39 years were enrolled 4-14 weeks post-radiation and received maintenance therapy with weekly ONC201 (weight-based adult equivalent of 625 mg) and daily paxalisib (27mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and circulating tumor DNA (ctDNA) were collected at multiple timepoints.

Results: Sixty-eight patients with biopsy-proven DMG enrolled between November 2021 and June 2023 (median age 9 years [range 3-37], n=41 female [60%]). Site-determined tumor location includes 47 pontine (69%), 16 thalamic (24%), 3 spinal cord (4%) and 2 cerebellar (2%) DMGs. Median overall survival (OS) from time of diagnosis is 16.5 months (lower 95% CI 11.6 months) with a median follow-up time of 9.9 months (95% CI: 8.5, 11.4). The H3K27M mutation was found in 91% (n=50) and 9% were classified as H3K27-altered (n=5). TP53 was mutant in 50% (22/44 available). Most common grade 3 and above treatment-related adverse events were neutrophil count decreased (n=4); mucositis (n=3); and, colitis, DRESS, lymphocyte count decreased, hyperglycemia, hypokalemia (n=2). PK and ctDNA analyses are being finalized.

Conclusions: The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.