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

• ClinicalTrials.gov Identifier: NCT05765812
• Recruitment Status: Recruiting
• First Posted: March 13, 2023
• Last Update Posted: April 24, 2024
• Sponsor: Debiopharm International SA
• Information provided by (Responsible Party): Debiopharm International SA

Tracking Information

• First Submitted Date: February 15, 2023
• First Posted Date: March 13, 2023
• Last Update Posted Date: April 24, 2024
• Actual Study Start Date: May 15, 2023
• Estimated Primary Completion Date: September 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2023)

• Phase 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Until disease progression or end of study (approximately 54 months) ]
  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.
• Phase 2: Overall Survival (OS) [ Time Frame: From the start of study treatment until death from any cause or end of study (up to approximately 54 months) ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 9, 2023)

• Phases 1 and 2: Plasma Concentration of Debio 0123 and its Metabolite [ Time Frame: 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)] ]
  The pharmacokinetics (PK) of Debio-0123 and its metabolite will be evaluated in plasma.
• Phases 1 and 2: Percentage of Participants With Best Overall Response (BOR) Assessed As Per Response Assessment in Neuro-oncology (RANO) Criteria [ Time Frame: 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 [ Time Frame: Up to end of study (approximately 54 months) ]
• Phases 1 and 2: Percentage of Participants With Disease Control (DC) Assessed As Per RANO Criteria [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) ]
  The PK of temozolomide will be evaluated in plasma.
• Phase 2: Number of Participants With At Least One TEAE [ Time Frame: 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 [ Time Frame: Up to 30 days after the end of treatment (up to approximately 26 months) ]
• Phase 2: Change From Baseline in KPS Score [ Time Frame: Until disease progression or end of study (approximately 54 months) ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

Brief 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment

Condition

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

Intervention

• 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.

Study 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.
  Interventions:

  • Drug: Debio 0123
  • Drug: Temozolomide
• 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.
  Interventions:

  • Drug: Debio 0123
  • Drug: Temozolomide
  • Radiation: Radiotherapy
• 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
  • Drug: Temozolomide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 29, 2024): 120
• Original Estimated Enrollment (submitted: March 9, 2023): 89
• Estimated Study Completion Date: September 2028
• Estimated Primary Completion Date: September 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.]

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Debiopharm International S.A; +41 21 321 01 11; clinicaltrials@debiopharm.com

• Listed Location Countries: Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT05765812
• Other Study ID Numbers: Debio 0123-GBM-105; 2022-502156-31 ( EudraCT Number ); U1111-1283-6423 ( Other Identifier: UTN Number (World Health Organization) )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Debiopharm International SA
• Original Responsible Party: Same as current
• Current Study Sponsor: Debiopharm International SA
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Debiopharm International SA

• PRS Account: Debiopharm International SA
• Verification Date: April 2024