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Randomized Trials in Development

Session: Poster Session

RTID-07 - A randomized window of opportunity trial with dose escalation to evaluate fluoxetine and temozolomide in glioma

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

    Author(s)

  • Kirit Singh

    Duke Brain Tumor Immunotherapy Program
    Durham, North Carolina, United States

    • Poster Presenter(s)

  • Chelsea Railton

    Duke Brain Tumor Immunotherapy Program
    Durham, United States

    • Author(s)

  • Kelly M. Hotchkiss

    Duke University
    Durham, North Carolina, United States

  • JH

    James E. Herndon, II

    Duke Cancer Institute, Department of Biostatistics
    Durham, North Carolina, United States

  • Katherine B. Peters

    Duke University Medical Center
    Durham, North Carolina, United States

  • HF

    Henry S. Friedman

    The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
    Durham, North Carolina, United States

  • Annick Desjardins

    Duke University
    Durham, North Carolina, United States

  • David M. Ashley

    The Preston Robert Tisch Brain Tumor Center
    Durham, North Carolina, United States

  • Margaret O. O. Johnson

    Duke University School of Medicine, The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery
    Durham, North Carolina, United States

  • AP

    Anoop Patel

    Department of Neurosurgery, Duke University
    Durham, North Carolina, United States

  • AF

    Allan H. Friedman

    Department of Neurosurgery, Duke University
    Durham, North Carolina, United States

  • Michael Lim

    Stanford University School of Medicine
    Stanford, California, United States

  • Peter E. Fecci

    Duke University Department of Neurosurgery
    Durham, North Carolina, United States

  • DP

    David Piccioni, MD, PhD

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

  • Tresa McGranahan

    Scripps Cancer Center
    Seattle, Washington, United States

  • Seema Nagpal

    Division of Neuro-oncology, Stanford University
    Stanford, California, United States

  • Erik P. Sulman

    New York University Grossman School of Medicine, Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
    New York, New York, United States

  • PM

    Paul S. Mischel

    Stanford University
    Stanford, California, United States

  • Mustafa Khasraw

    Duke Cancer Institute
    Durham, North Carolina, United States

The blood brain barrier limits the efficacy of many drugs in brain tumors. Fluoxetine (Prozac) is FDA-approved and brain penetrant. Preclinical studies show synergy between fluoxetine and temozolomide (TMZ), resulting in lysosomal stress and enhanced DNA damage in human-derived glioma in vitro and in vivo. We present our randomized surgical window of opportunity trial (NCT05634707) in patients with recurrent IDH wild type glioma. The primary objective is to evaluate if fluoxetine induces tumoral lysosomal stress while exploratory objectives will determine if combination therapy enhances tumor DNA damage. We will randomize 30 patients, ≥ 24yo, with recurrent glioma and who are eligible for re-treatment with TMZ (MGMT methylated, progression >6 months post TMZ). Following informed consent, patients will be randomized 1:2 to control or experimental arms. Control patients will receive 50 mg/m2 TMZ for 7 days pre-resection. The experimental arm will receive 20 mg/day fluoxetine for 5 days before escalating to 40 mg/day. If < 3/10 participants receiving 40mg/day experience dose-limiting toxicity (DLT), subsequent experimental arm patients will escalate to 60 mg/day. All experimental arm participants will receive 50 mg/m2 TMZ for 7 days after starting fluoxetine, starting 21 days pre-resection. The regimen of 50 mg/m2 TMZ for 7 days is based on a similar pre-surgical trial combining TMZ with experimental therapy (NCT05188508). This reduced dose was chosen to limit potential synergistic toxicities like thrombocytopenia or neutropenia. Following resection, patients will continue TMZ, initially at reduced dose for the first post-op cycle, before reverting to standard doses of 150-200mg/m2 (up to 12 cycles or progression). All patients (control and experimental) will be offered fluoxetine post-operatively. The primary study outcome will be quantification of tumoral lysosomal stress via Lysosomal-associated membrane protein 1 (LAMP1) expression while DNA damage will be assessed via γH2A histone family member X (γH2AX) using immunohistochemistry.