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.
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Phase 1 (Dose Escalation): Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
Timeframe: Phase 1: Arm A: Cycle 1 (Cycle=28 days); Arms B and C: Up to approximately 1.8 months
Phase 1 (Dose Escalation): Number of Participants With At Least One Treatment-emergent Adverse Event (TEAE)
Timeframe: Up to 30 days after the end of treatment (Arm A: Up to approximately 26 months and Arms B and C: Up to approximately 3.5 months)
Phase 1 (Dose Escalation): Number of Participants With Clinically Significant Abnormalities in Laboratory, Vital Signs, Electrocardiogram (ECG), and Echocardiogram (ECHO) Parameters
Timeframe: Up to 30 days after the end of treatment (Arm A: Up to approximately 26 months and Arms B and C: Up to approximately 3.5 months)
Phase 1 (Dose Escalation): Change From Baseline in Karnofsky Performance Status (KPS) Score
Timeframe: Until disease progression or end of study (approximately 66 months)
Phase 1 (Dose Expansion): Number of Participants With At Least One Treatment-emergent Adverse Event (TEAE)
Timeframe: Up to approximately 26 months
Phase 1 (Dose Expansion): Change from Baseline in Tumor Size Assessed by Objective Response (OR) as per Response Assessment in Neuro-oncology (RANO) Criteria
Timeframe: From the start of study treatment until disease progression or end of study (up to approximately 66 months)
Phase 1 (Dose Expansion): Plasma Concentration of Debio 0123 and its Metabolite
Timeframe: Predose and at multiple timepoints up to 6 hours post dose up to Day 15 of Cycle 1 (Cycle=28 days)
Phase 1 (Dose Expansion): Pharmacodynamic(s) PDy, Change from baseline in Phosphorylated Cell Division Cycle (pCDC2)
Timeframe: Predose and 4 to 6 hours post dose on Day 10 of Cycle 1 (Cycle=28 days)
Phase 2: Overall Survival (OS)
Timeframe: From the start of study treatment until death from any cause or end of study (up to approximately 66 months)