The primary purpose of the Phase 1 (Dose Escalation) of this study is 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.

The primary purpose of Phase 1 (Dose expansion) of the study is to assess the doses studied under Phase 1 (Dose Escalation) Arm A and identify the recommended dose (RD) for further development.

The Phase 2 will start once the RD Phase 1 has been defined. The primary objective of Phase 2 is to assess the efficacy of Debio 0123 at the RD for further development in combination with TMZ, compared to the standard of care (SOC) in adult participants with GBM.

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.]