Study on Debio 0123 with Temozolomide for Recurrent or New Glioblastoma in Adults

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

Additional specific exclusion criteria for Phase 1 and Phase 2

• Known contraindication to undergoing for Gd-based, contrast-enhanced MRI.
• Any anticancer treatment, monoclonal antibodies/biologics, investigational treatment, or RT with curative intent within 28 days prior to starting study treatment.
• 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.]