Ctni-53. Establishing a Phase I and Randomized Phase Ii Trial of Selinexor and Temozolomide in Glioblastoma
Year: 2023
Type: article
Abstract: BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).
Source: Neuro-Oncology
Authors: Frances Chow, Michael Berens, Sharon Tamir, Yosef Landesman, Christopher Walker, Joycelynne Palmer, Alyx Porter, David Piccioni, Douglas Ney, Macarena de la Fuente, Sani H Kizilbash, Kimberly Bojanowski-Hoang, Lindsay Lipinski, Roy Strowd, Pierre Giglio, Maya Hrachova, Megan Mantica, David Schiff, Steven Gore, Jana Portnow
Institutions: USC Norris Comprehensive Cancer Center, Translational Genomics Research Institute, Karyopharm Therapeutics (United States), City Of Hope National Medical Center, City of Hope, Mayo Clinic in Arizona, University of California San Diego, University of Colorado Denver, Sylvester Comprehensive Cancer Center, Mayo Clinic, Emory University Hospital, Roswell Park Comprehensive Cancer Center, Wake Forest University, The Ohio State University Wexner Medical Center, University of Oklahoma, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, University of Virginia, National Cancer Institute, Beckman Research Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4388588741