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

Astrocytoma, Grade III Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05765812
• Other study ID #: Debio 0123-GBM-105
• Secondary ID: 2022-502156-31U1
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 15, 2023
• Est. completion date: September 2028

Study information

• Verified date: April 2024
• Source: Debiopharm International SA
• Contact: Debiopharm International S.A
• Phone: +41 21 321 01 11
• Email: clinicaltrials[@]debiopharm.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: September 2028
• Est. primary completion date: September 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.]

Related Conditions & MeSH terms

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

Intervention

Drug:
• Debio 0123
Administered as capsules.
• 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.

Locations

Country	Name	City	State
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Clinica Universidad de Navarra (CUN)	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	South Texas Accelerated Research Therapeutics (START)	Madrid
Spain	Clinica Universidad de Navarra (CUN)	Pamplona
Switzerland	Universitaetsspital Zuerich	Zuerich
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center	New York	New York
United States	South Texas Accelerated Research Therapeutics (START)	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Debiopharm International SA

Countries where clinical trial is conducted

United States,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)]
Secondary	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)
Secondary	Phases 1 and 2: Percentage of Participants With Objective Response (OR) Assessed As Per RANO Criteria		Up to end of study (approximately 54 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Phase 2: Number of Participants With At Least One TEAE		Up to 30 days after the end of treatment (up to approximately 26 months)
Secondary	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)
Secondary	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)