A Phase I/II Open-label Study of Debio 0123 in Combination With Temozolomide in Adult Participants With Recurrent or Progressive Glioblastoma and of Debio 0123 in Combination With Temozolomide and Radiotherapy in Adult Participants With Newly Diagnosed Glioblastoma

Study Identifier:
Debio 0123-GBM-105
CT.gov Identifier:
NCT05765812
EudraCT Identifier:
202250000000
EU Trial (CTIS) Number:
2022-502156-31-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

Phase 1: To identify the dose-limiting toxicities (DLTs) of Debio 0123 combined with temozolomide (TMZ) (Arm A) and with TMZ and radiotherapy (RT) (Arms B and C) and to characterize the safety and tolerability of these combinations in adult participants with glioblastoma (GBM). Arm B which was previously added to the protocol, has been permanently halted per the safety monitoring committees' decision on the safety findings of this arm..

To evaluate Debio 0123 in combination with TMZ in patients (pts) with recurrent GBM isocitrate dehydrogenase (IDH)-wildtype (WT) or astrocytoma, IDH-mutant, Grade 3 (per WHO 2021 criteria) after first-line, TMZ-based chemoradiotherapy (CxRT) (Phase 1 Arm A) and Debio 0123 combined with TMZ-based CxRT in pts with newly diagnosed GBM IDH-WT (Phase 1 Arm B).

Phase 2 will comparing the efficacy (overall survival) of Debio 0123 combined with TMZ at the Phase 1 Arm A RP2D vs. standard of care in pts with recurrent GBM IDH-WT.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Brain
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Phase 1 (Dose Escalation): Arm A - Debio 0123 + Temozolomide
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  • Drug: In Arm A, pts will receive escalating doses of Debio 0123 with TMZ in 28-day cycles supported by a Bayesian logistic regression model (BLRM). Arm B is a Debio 0123 dose escalation with concomitant TMZ/RT for up to 6 weeks.
  • Drug: Drug: Temozolomide
  • Drug: Experimental: Phase 1 (Dose Escalation): Arm B - Debio 0123 + Temozolomide + Radiotherapy
  • Drug: Radiation: Radiotherapy
  • Drug: Experimental: Phase 1 (Dose Escalation): Arm C - Debio 0123 + Temozolomide + Radiotherapy
  • Drug: Experimental: Phase 1 (Dose Expansion): Debio 0123 + Temozolomide
  • Drug: Experimental: Phase 2: Debio 0123 RD + Temozolomide
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    Inclusion criteria
    • Screening Inclusion Criteria for Phase 1 and Phase 2:
    • Signed written informed consent approved before undertaking any study-specific procedures.
    • Age ≥18 years of age.
    • Willing to provide archived or fresh tumor sample, if available. Receipt of tumor sample is not required for the start of study treatment.
    • Adequate bone marrow, hepatic, and renal function.
    • Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
    • Willing to practice highly effective methods of contraception.
    • Life expectancy of at least 3 months in the best judgment of the Investigator.
    • Measurable or non-measurable disease as per RANO criteria by gadolinium (Gd)-based contrast-enhanced brain magnetic resonance imaging (MRI).
    • Participants receiving corticosteroids must be on a stable or decreasing dose of ≤4 mg daily dexamethasone (or ≤25 mg prednisone) for the 7 days prior to the start of study treatment.
    • Participants with seizures must be adequately controlled on a stable regimen of anti-epileptic drugs.
    • Additional specific inclusion criteria for Phase 1 and Phase 2:
    • • A maximum of 1 [for Phase 1 (Dose Expansion) and phase 2] or 2 (Phase 1 Arm A) prior treatment lines of which first-line must be treatment with TMZ-based chemoradiotherapy (TMZ concomitantly with RT).
    • Note: Only 1 prior line of systemic therapy is allowed; combination therapy with TMZ and RT with or without subsequent TMZ maintenance treatment is considered as 1 systemic line. Prior surgery, radiation, or localized delivery of therapeutic agents (i.e., carmustine-containing wafers [GLIADEL®]) for first recurrence is allowed.
    • Documented disease recurrence or progression by diagnostic biopsy or Gd-based contrast-enhanced brain MRI as per RANO criteria.
    • KPS ≥60.
    • Additional specific inclusion criteria for Phase 1 Arm A:
    • Participants must have one of the following histopathologically proven diagnoses (WHO 2021):
    • GBM Isocitrate dehydrogenase (IDH)-wildtype Grade 4 which may include secondary GBMs (i.e., those that progress from low-grade gliomas).
    • Astrocytoma, IDH-mutant, Grade 3
    • Additional specific inclusion criteria for Phase 1 Arm B and C:
    • Participants must have a new, histopathologically proven diagnosis of GBM, IDH-wildtype, Grade 4 (based on WHO 2021), which may include secondary GBMs (i.e., those that progress from low-grade gliomas) if the prior treatment included surgery only.
    • KPS ≥70.
    • Additional specific inclusion criteria for Phase 1 dose expansion and Phase 2:
    • • Participants must have a histopathologically proven diagnosis of GBM, IDH-wildtype Grade 4 WHO 2021
    • Additional specific exclusion criteria for Phase 1 Arm A • Prior treatment with more than 2 lines of therapy for GBM, IDH-wildtype, Grade 4, or for astrocytoma, IDH-mutant, Grade 3
    • Key inclusion/
    Exclusion criteria
    • recurrence or progression after 1st line with platinum-based chemotherapy CFI>45 (part 1) and CFI>90 (part 2), ECOG Performance Status 0-1, and measurable disease per RECIST 1.1. Prior 2nd line with lurbinectedin, and treated, stable brain metastasis are allowed.
    • Exclusion Criteria:
    • Additional specific exclusion criteria for Phase 1 and Phase 2
    • Known contraindication to undergoing for Gd-based, contrast-enhanced MRI.
    • Chemotherapy, monoclonal antibodies/biologics, investigational treatment, or RT with curative intent within 28 days prior to starting study treatment.
    • Exposure to high levels of ultraviolet (UV) light, for example occupational exposure to sunlight or sunbathing.
    • Hypersensitivity to Debio 0123, TMZ, dacarbazine, or any of the excipients found in the formulation for Debio 0123 or TMZ.
    • Prior exposure to any WEE1 inhibitor.
    • History of other malignancies requiring active treatment in the last 2 years prior to the first dose of study treatment except for superficial bladder cancers, adequately treated low-risk prostate cancer under active surveillance, ductal carcinoma in situ or other carcinomas in situ, and non-melanoma skin cancers (basal cell/squamous cell skin cancer) that have been treated with curative intent.
    • Left ventricular ejection fraction (LVEF) below 55%.
    • Additional specific exclusion criteria for Phase 1 Arm B and C:
    • Prior radiation, chemotherapy, biological therapy, interstitial brachytherapy, implanted chemotherapy, therapeutics delivered by local injection or convection-enhanced delivery for GBM.
    • Prior therapy that would result in an overlap of the radiation fields.
    • Additional specific exclusion criteria for Phase 1 dose expansion and Phase 2
    • Prior treatment with more than 1 line of systemic therapy for GBM, IDH-wildtype, Grade 4 (based on WHO 2021). Combination therapy with TMZ and RT with or without subsequent TMZ maintenance treatment is considered as 1 systemic line.
    • [Note: Other inclusion/exclusion criteria mentioned in the protocol may apply.]

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Victor Moreno Garcia
    Status
    Recruiting
    Condition(s) Treated at Site
    Brain