Glioblastoma IDH (Isocitrate Dehydrogenase) Wildtype, Astrocytoma, Grade III
Conditions
Keywords
WEE1 inhibitor, Glioblastoma, IDH-wildtype, Grade 4, World Health Organization (WHO) 2021, Astrocytoma, IDH-mutant, Grade 3, WHO 2021
Brief summary
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.
Interventions
DRUGDebio 0123
Administered as capsules.
DRUGTemozolomide
Administered as capsules.
RADIATIONRadiotherapy
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.
Sponsors
Debiopharm International SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 (Dose Escalation): Number of Participants Experiencing Dose-limiting Toxicities (DLTs) | 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) | 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 | 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 | Until disease progression or end of study (approximately 66 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 1 (Dose Expansion): Number of Participants With At Least One Treatment-emergent Adverse Event (TEAE) | 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 | 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 | 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) | Predose and 4 to 6 hours post dose on Day 10 of Cycle 1 (Cycle=28 days) | — |
| Phase 2: Overall Survival (OS) | From the start of study treatment until death from any cause or end of study (up to approximately 66 months) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 (Dose Expansion): OS | From the start of study treatment until death from any cause or end of study (up to approximately 66 months) | — |
| Phase 1 (Dose Escalation): Plasma Concentration of Temozolomide | 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 29 (Arm B and C) | The PK of temozolomide will be evaluated in plasma. |
| Phase 1 (Dose Expansion): Number of Participants With Clinically Significant Abnormalities In Laboratory, Vital Signs, ECG, and (ECHO Parameters) | Up to 30 days after the end of treatment (up to approximately 26 months) | — |
| Phase 1 (Dose Expansion): Number of Participants With At Least one TEAE | Up to 30 days after the end of treatment (up to approximately 26 months) | — |
| Phase 1 (Dose Expansion): Change From Baseline in KPS Score | Until disease progression or end of study (approximately 66 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: Change From Baseline in KPS Score | Until disease progression or end of study (approximately 66 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: 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: Number of Participants With At Least One TEAE | Up to 30 days after the end of treatment (up to approximately 26 months) | — |
| Phases 1 and 2: Plasma Concentration of Debio 0123 and its Metabolite | Phase1(Dose Escalation):Predose, multiple timepoints upto 8hours postdose upto Day 15 of Cycle 1(Arm A) and upto Day 29(Arms B and C);Phase1(Dose expansion)andPhase2: Predose, multiple timepoints upto 4hours postdose upto Day 15 of Cycle1(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 | From the start of study treatment until disease progression or end of study (up to approximately 66 months) | — |
| Phases 1 and 2: Percentage of Participants with Objective Response (OR) Assessed As Per RANO Criteria | Up to end of study (approximately 66 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 66 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 66 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 66 months) | — |
Countries
Spain, Switzerland, United States
Contacts
CONTACTDebiopharm International S.A
STUDY_DIRECTORStudy Director
Debiopharm International SA
Outcome results
None listed