E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Oncology - Glioblastoma (GBM) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018336 |
E.1.2 | Term | Glioblastoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To identify experimental therapies that improve overall survival (OS) for GBM patients in the Screening stage (Stage 1), determining if predefined patient subtypes or associated biomarkers uniquely benefit from the treatment.
• To confirm identified efficacious experimental therapies and associated biomarker signatures in an expansion stage (Stage 2) designed to support a new drug application.
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E.2.2 | Secondary objectives of the trial |
• To evaluate Progression Free Survival (PFS), duration of response, and tumour response by each biomarker/therapeutic combination. • To evaluate OS by each biomarker/therapeutic combination. • To determine short- and long-term safety signals and quality of life (QOL) measures of an experimental Arm in GBM patients versus standard of care.
Exploratory Objectives: • To generate general prognostic and predictive biomarker hypotheses. • To build and validate a longitudinal endpoint model of OS comprised of early assessments (eg, performance status, disease progression) that are associated with OS.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main Inclusion Criteria - Newly Diagnosed: • Age ≥ 18 years. • Histologically confirmed Grade IV GBM/gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. • - An MRI scan performed within 21 days prior to randomization preferably. • Use of no more than 4mg of dexamethasone per day within 5 days prior to randomization. • Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization. • Availability of tumor tissue representative of GBM from definitive surgery or biopsy.
Main Inclusion Criteria - Recurrent: • Age ≥ 18 years. • Histologically confirmed GBM/gliosarcoma (WHO criteria; non-IDH R132H mutant) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum Radiation Therapy (RT). • Evidence of recurrent disease (RD) demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria. • Use of no more than 4mg of dexamethasone per day within 5 days prior to randomization. • Baseline MRI performed within 14 days prior to randomization. • Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization. • Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.
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E.4 | Principal exclusion criteria |
Main Exclusion Criteria - Newly Diagnosed: • Any prior treatment for glioma including: prior prolifeprospan 20 with carmustine wafer; prior intracerebral agent; prior radiation treatment for GBM or lower-grade glioma; prior chemotherapy or immunotherapy for GBM or lower-grade glioma. • Receiving additional, concurrent, active therapy for GBM outside of the trial • Extensive leptomeningeal disease. • QTc > 450 msec if male and QTc > 470 msec if female. • History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. • Laboratory results that meet exclusionary parameters.
Main Exclusion Criteria - Recurrent Exclusion Criteria: • Early disease progression prior to 3 months (12 weeks) from the completion of RT. • More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of Temozolomide (TMZ) with an experimental agent is considered one line of chemotherapy.). • Any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other VEG)- or VEGF receptor-mediated targeted agent. • Any prior treatment with prolifeprospan 20 with carmustine wafer. • Any prior treatment with an intracerebral agent. • Receiving additional, concurrent, active therapy for GBM outside of the trial. • Extensive leptomeningeal disease. • QTc > 450 msec if male and QTc > 470 msec if female. • History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Participant with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. • Laboratory results that meet exclusionary parameters.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Overall Survival: - defined from the time of randomization to death from any cause.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Defined from the time of randomization to death from any cause.
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E.5.2 | Secondary end point(s) |
• Progression-Free Survival: - defined as the time from randomization to clinically determined progression or death from any cause. •Tumor Response: - complete response, partial response, progressive disease, stable disease. • Duration of Response: - Complete Response + Partial Response - defined as time from date of response to date of clinically determined disease progression or death from any cause.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Progression-Free Survival: - defined as the time from randomization to clinically determined progression or death from any cause. • Tumor Response: - complete response, partial response, progressive disease, stable disease. • Duration of Response: - Complete Response + Partial Response - defined as time from date of response to date of clinically determined disease progression or death from any cause. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Response Adaptive Randomization Platform Trial |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
China |
United States |
Austria |
France |
Germany |
Italy |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last patient, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |