ID #1019 Initial Results from a Phase 1/2 Trial of Selinexor and Radiation in Newly Diagnosed Pediatric High-Grade Glioma and Diffuse Midline Glioma: A Children’s Oncology Group Trial
Adam Green, Yimei Li, Yu Wang, Olga Militano, Nicholas Stence, Julia Glade Bender, Sarah Leary, Maryam Fouladi, Lindsay KilburnAbstract
Introduction
Selinexor is an FDA-approved, CNS penetrant, oral targeted chemotherapy that reversibly inhibits XPO1, a nuclear transporter of many key tumor suppressor proteins. It was previously evaluated in a phase 1 trial for recurrent pediatric brain/solid tumors, demonstrating stable disease in a subset of pediatric high-grade glioma (PHGG) patients. We report phase 1 and early phase 2 trial results studying selinexor and radiation (RT) followed by maintenance selinexor in newly diagnosed PHGG and diffuse midline glioma (DMG) (NCT05099003).
Methods
Selinexor was given weekly during RT and maintenance. Phase 1 followed a rolling six design with dose escalation. In phase 2, patients were divided into three strata: diffuse intrinsic pontine glioma (DIPG), non-pontine DMG, and H3K27-wild type PHGG. The primary endpoint for the non-pontine DMG and PHGG strata was event-free survival, and for stratum DIPG, overall survival (OS), each compared to respective historical control cohorts.
Results
In phase 1, three selinexor dose levels (DL) were tested: 35, 45, and 55 mg/m2/dose PO/NG/GT weekly. Two dose-limiting toxicities (DLTs) were observed: grade 3 tumor hemorrhage (DL1), and grade 3 pulmonary embolus (DL2). No DLTs were observed at DL3, which was declared the recommended phase 2 dose. Similar side effects were observed as in the prior trial (hematopoietic, gastrointestinal, and neurologic) without clear increased toxicity from combination with standard RT. In phase 2, on planned interim analysis after 10 events in stratum DIPG (n = 26 evaluable), 12-month OS was 16.8%, vs. 41.4% in a historical cohort (p = 0.9989 by one-sided log-rank). Based on these findings, the DIPG and non-pontine DMG strata were closed. A second interim analysis (n = 40) showed 12-month OS in stratum DIPG had increased to 40.9% (p = 0.93).
Conclusions
Selinexor can be safely combined with RT in PHGG, supporting further development of this combination, but it does not increase OS in DMG over historical data.