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Trials in Progress and Late Breaking Clinical Trials

(P 442) TRIAL IN PROGRESS: A SINGLE-ARM, OPEN-LABEL PHASE 4 TRIAL OF NIROGACESTAT IN ADULT PREMENOPAUSAL FEMALES WITH DESMOID TUMORS

    Author(s)

  • Winette T.A. T.A van der Graaf, MD, PhD

    Professor of Medical Oncology at NKI and ErasmusMC; Head of Department of Medical Oncology at NKI; Groupleader AYA and Sarcoma Research at NKI
    Netherlands Cancer Institute
    Amsterdam, Noord-Holland, Netherlands

    • Co-Author(s)

  • Alessandro Gronchi, MD (he/him/his)

    Surgical Oncologist
    Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan
    Milano, Lombardia, Italy

  • LM

    Laurie J. McKenzie, M.D.

    Associate Professor
    University of Texas MD Anderson Cancer Center
    Houston, Texas, United States

  • RC

    Rachel Cohen, PhD

    Associate Director, Clinical Development
    SpringWorks Therapeutics
    Stamford, Connecticut, United States

  • Ana B. Oton, MD

    Vice President Medical Strategy
    SpringWorks Therapeutics
    Centennial, Colorado, United States

  • Bernd Kasper, MD, PhD (he/him/his)

    Medical Director Mannheim Cancer Center (MCC)
    Mannheim University Medical Center, University of Heidelberg
    Mannheim, Baden-Wurttemberg, Germany

Objective: Nirogacestat (niro) is an oral, targeted, gamma secretase inhibitor (GSI) and the only FDA-approved treatment for adults with progressing desmoid tumors (DT) who require systemic treatment. In the DeFi trial, niro had clinically significant improvement vs placebo in progression-free survival, objective response rate, and patient-reported outcomes with a manageable safety profile. Also, 75% (27/36) of females of reproductive potential (FORP) on niro had ovarian toxicity (OT) events vs none for 37 FORP on placebo. OT was identified by investigators per abnormal reproductive hormone values, perimenopausal symptoms, or both. Off-treatment resolution of OT was reported by investigators in all (100%; 11/11) FORP who discontinued niro for any reason. Due to OT incidence with niro as a novel GSI drug class, this trial aims to further characterize the incidence and recovery rate of OT events in FORP with DT treated with niro.

Methods: In this single-arm, phase 4 clinical trial, eligible patients (pts) will be female, aged 18–40 years, and premenopausal (estradiol >30 pg/mL, follicle-stimulating hormone [FSH] < 40 IU/L, and regular menses for ≥3 menstrual cycles) at baseline, with histologically confirmed, symptomatic/progressive DT requiring systemic treatment and Eastern Cooperative Oncology Group performance status ≤2 at screening. Pts will receive niro, starting at 150 mg BID, for ≥12 to ≤24 cycles (28-day cycle). After last dose, pts reporting an OT event will be followed until OT resolution, new DT treatment is initiated, or ≤2 years, whichever occurs first. Primary endpoint is percentage of pts reporting an OT event who achieve ovarian function recovery, including recovery after niro discontinuation. OT is defined as new onset amenorrhea lasting ≥3 consecutive menstrual periods, FSH ≥30 mIU/mL, and a negative serum β-human chorionic gonadotropic hormone pregnancy test. Ovarian function recovery is defined as resumption of menses and normalization of hormone values or a positive pregnancy test. Secondary endpoints include OT incidence, time to ovarian function recovery, and safety/tolerability.

Results: ~50 eligible pts with progressing DT will be enrolled. Trial is planned for Belgium, Germany, Italy, Netherlands, Spain, and the UK. EudraCT number: 2024-515215-21-00.

Conclusion: N/A