Clinical Trial Finder

Screening Inclusion Criteria for Phase 1 Arm A 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 Arm A and Phase 2:

• - A maximum of 1 (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).

• - 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: - GBM Isocitrate dehydrogenase (IDH)-wildtype Grade 4 (based on WHO 2021), which may include secondary GBMs (i.e., those that progress from low-grade gliomas).

• - Astrocytoma, IDH-mutant, Grade 3 (based on WHO 2021).

Additional specific inclusion criteria for Phase 1 Arm B:

• - 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).

• - KPS ≥70.

Additional specific inclusion criteria for Phase 2:

• - Participants must have a histopathologically proven diagnosis of GBM, IDH-wildtype Grade 4 (based on WHO 2021).

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 based on WHO 2021.

Exclusion Criteria for Phases 1 and 2:

• - Known contraindication 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%.

Specific exclusion criteria for Phase 1 Arm A and Phase 2:

• - Prior treatment with bevacizumab or with other vascular endothelial growth factor (VEGF) inhibitors or VEGF-receptor signaling inhibitors.

• - Prior TMZ-related hematological event leading to discontinuation of TMZ during the concurrent chemoradiotherapy.

Specific exclusion criteria for Phase 1 Arm B:

• - 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.

Exclusion criteria for 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 line. [Note: Other inclusion/exclusion criteria mentioned in the protocol may apply.]

Arms

Experimental: Phase 1: Arm A - Debio 0123 + Temozolomide

Participants will receive Debio 0123, escalating doses along with temozolomide (TMZ) in each 28-day cycle for up to 2 years.

Experimental: Phase 1: Arm B - Debio 0123 + Temozolomide + Radiotherapy

Participants will receive Debio 0123, escalating doses along with TMZ and concomitant administration of radiotherapy (RT) for up to 6 weeks.

Experimental: Phase 2: Debio 0123 RP2D + Temozolomide

Participants will receive Debio 0123 RP2D along with TMZ in each 28-day cycle for up to 2 years.

Interventions

Drug: - Debio 0123

Administered as capsules.

Drug: - Temozolomide

Administered as capsules.

Radiation: - Radiotherapy

Administered in accordance with the local clinical practice and applicable Radiation Therapy Oncology Group (RTOG) or the European Organization for Research and Treatment of Cancer (EORTC) guidelines.