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Clinical trials: Non-immunologic

Session: Poster Session

CTNI-53 - Establishing a phase I and randomized phase II trial of selinexor and temozolomide in glioblastoma

Friday, November 17, 2023
7:30 PM – 9:30 PM PT
Location: Exhibit Hall A/B
Non-CME

    Poster Presenter(s)

  • Frances Chow

    University of Southern California, Norris Comprehensive Cancer Center
    Los Angeles, California, United States

    • Author(s)

  • MB

    Michael Berens

    Translational Genomics Research Institute
    Phoenix, Arizona, United States

  • Sharon Tamir

    Karyopharm
    Newton, Massachusetts, United States

  • YL

    Yosef Landesman

    Karyopharm
    Newton, Massachusetts, United States

  • CW

    Christopher Walker

    Karyopharm
    Newton, Massachusetts, United States

  • JP

    Joycelynne Palmer

    City of Hope Comprehensive Cancer Center
    Duarte, California, United States

  • Alyx B. Porter

    Mayo Clinic Arizona
    Phoenix, Arizona, United States

  • DP

    David Piccioni, MD, PhD

    University of California San Diego Health
    La Jolla, California, United States

  • DN

    Douglas Ney

    University of Colorado
    Aurora, Colorado, United States

  • Macarena I. de la Fuente

    Sylvester Comprehensive Cancer Center
    Miami, Florida, United States

  • Sani H. Kizilbash

    Mayo Clinic (Rochester)
    Rochester, Minnesota, United States

  • KB

    Kimberly Bojanowski-Hoang

    Emory University Hospital
    Atlanta, Georgia, United States

  • Lindsay Lipinski

    Roswell Park Cancer Institute
    Buffalo, New York, United States

  • Roy E. Strowd

    Wake Forest University School of Medicine
    Winston Salem, North Carolina, United States

  • PG

    Pierre Giglio

    The Ohio State University Wexner Medical Center
    Columbus, Ohio, United States

  • MH

    Maya Hrachova

    University of Oklahoma
    Oklahoma City, United States

  • MM

    Megan M. Mantica

    University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center
    Pittsburgh, United States

  • David Schiff

    University of Virginia School of Medicine
    Charlottesville,, Virginia, United States

  • SG

    Steven Gore

    National Cancer Institute
    Bethesda, Maryland, United States

  • JP

    Jana L. Portnow

    Department of Medical Oncology, City of Hope Beckman Research Institute
    Duarte, California, United States


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).