A 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 Overview
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Brief Summary
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The primary purpose of Phase 1 (dose escalation) of this study is to identify the recommended Phase 2 dose (RP2D) of Debio 0123 in combination with temozolomide (TMZ) (Arm A) and in combination with TMZ and radiotherapy (RT) (Arm B) and to characterize the safety and tolerability of these combinations in adult participants with glioblastoma (GBM). The primary purpose of Phase 2 of this study is to assess the efficacy of Debio 0123 at the RP2D in combination with TMZ, compared to standard of care (SOC) in adult participants with GBM.

Official Title
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A Phase 1/2 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

Conditions
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Glioblastoma IDH (Isocitrate Dehydrogenase) Wildtype, Astrocytoma, Grade III

Intervention / Treatment
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* Drug: Debio 0123
* Drug: Temozolomide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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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.]

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment applies to the arm groups within Phase 1 of the study. Sequential assignment will apply to Phases 1 and 2 of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Arm A - Debio 0123 + Temozolomide<br>Participants will receive Debio 0123, escalating doses along with temozolomide (TMZ) in each 28-day cycle for up to 2 years. | Drug: Debio 0123<br>* Administered as capsules.<br>Drug: Temozolomide<br>* Administered as capsules.<br>|
| Experimental: Phase 1: Arm B - Debio 0123 + Temozolomide + Radiotherapy<br>Participants will receive Debio 0123, escalating doses along with TMZ and concomitant administration of radiotherapy (RT) for up to 6 weeks. | Drug: Debio 0123<br>* Administered as capsules.<br>Drug: Temozolomide<br>* Administered as capsules.<br>Radiation: Radiotherapy<br>* 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.<br>|
| Experimental: Phase 2: Debio 0123 RP2D + Temozolomide<br>Participants will receive Debio 0123 RP2D along with TMZ in each 28-day cycle for up to 2 years. | Drug: Debio 0123<br>* Administered as capsules.<br>Drug: Temozolomide<br>* Administered as capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) |  | Phase 1: Arm A: Cycle 1 (Cycle=28 days); Arm B: Up to approximately 1.9 months | 
| Phase 1: Number of Participants With At Least One Treatment-emergent Adverse Event (TEAE) |  | Up to 30 days after the end of treatment (Arm A: Up to approximately 26 months and Arm B: Up to approximately 3.5 months) | 
| Phase 1: Number of Participants With Clinically Significant Abnormalities in Laboratory, Vital Signs, and Electrocardiogram (ECG) Parameters |  | Up to 30 days after the end of treatment (Arm A: Up to approximately 26 months and Arm B: Up to approximately 3.5 months) | 
| Phase 1: Change From Baseline in Karnofsky Performance Status (KPS) Score | KPS is an assessment tool for functional impairment. It is a standard way of measuring the ability of participants with cancer to perform ordinary tasks. The KPS scores range from 0 (death) to 100 (no evidence of disease). A higher score means the participant is better able to carry out daily activities. | Until disease progression or end of study (approximately 54 months) | 
| Phase 2: Overall Survival (OS) |  | From the start of study treatment until death from any cause or end of study (up to approximately 54 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phases 1 and 2: Plasma Concentration of Debio 0123 and its Metabolite | The pharmacokinetics (PK) of Debio-0123 and its metabolite will be evaluated in plasma. | Phase 1: Predose and at multiple timepoints up to 8 hours post dose up to Day 15 of Cycle 1 (Arm A) and up to Day 37 (Arm B); Phase 2: Predose and at multiple timepoints up to 4 hours post dose up to Day 15 of Cycle 1 (Cycle=28 days)] | 
| Phases 1 and 2: Percentage of Participants With Best Overall Response (BOR) Assessed As Per Response Assessment in Neuro-oncology (RANO) Criteria |  | From the start of study treatment until disease progression or end of study (up to approximately 54 months) | 
| Phases 1 and 2: Percentage of Participants With Objective Response (OR) Assessed As Per RANO Criteria |  | Up to end of study (approximately 54 months) | 
| Phases 1 and 2: Percentage of Participants With Disease Control (DC) Assessed As Per RANO Criteria |  | From the start of study treatment until disease progression or end of study (up to approximately 54 months) | 
| Phases 1 and 2: Duration of Response (DOR) Assessed As Per RANO Criteria |  | Up to disease progression or end of study (up to approximately 54 months) | 
| Phases 1 and 2: Progression Free Survival (PFS) Assessed As Per RANO Criteria |  | From the start of study treatment until disease progression or death or end of study (up to approximately 54 months) | 
| Phase 1: Plasma Concentration of Temozolomide | The PK of temozolomide will be evaluated in plasma. | Phase 1: Predose and at multiple timepoints up to 7 hours post dose up to Day 5 of Cycle 1 (Arm A) and up to Day 37 (Arm B) | 
| Phase 2: Number of Participants With At Least One TEAE |  | Up to 30 days after the end of treatment (up to approximately 26 months) | 
| Phase 2: Number of Participants With Clinically Significant Abnormalities in Laboratory, Vital Signs, and ECG Parameters |  | Up to 30 days after the end of treatment (up to approximately 26 months) | 
| Phase 2: Change From Baseline in KPS Score | KPS is an assessment tool for functional impairment. It is a standard way of measuring the ability of participants with cancer to perform ordinary tasks. The KPS scores range from 0 (death) to 100 (no evidence of disease). A higher score means the participant is better able to carry out daily activities. | Until disease progression or end of study (approximately 54 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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WEE1 inhibitor, Glioblastoma, IDH-wildtype, Grade 4, World Health Organization (WHO) 2021, Astrocytoma, IDH-mutant, Grade 3, WHO 2021