| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with newly diagnosed glioblastoma with unmethylated MGMT promoter |
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| E.1.1.1 | Medical condition in easily understood language |
| Patient with newly diagnosed glioblastoma with special tumor characteristic (unmethylated MGMT promoter) |
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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 |
Phase I: Determination of safety and tolerability of the systemic molecularly defined therapy in conjunction with radiotherapy. The aim is to proof the proposed optimal monocompound dose also in conjunction with radiotherapy.
Phase IIa: The objective of Phase IIa part is the determination of efficacy of the systemic molecularly defined therapy in conjunction with radiotherapy. |
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| E.2.2 | Secondary objectives of the trial |
Phase I:
•Regimen-limiting toxicity (RLT), defined as any toxicity that meets the criteria of a DLT, but is observed after the end of the combination therapy in phase I or during phase IIa of the trial.
•Progression-free survival at six months (PFS-6) according to RANO or iRANO criteria
Phase IIa:
•Safety and tolerability (in particular RLTs, SAEs and AEs) of the systemic molecularly defined therapy,
•Progression-free survival (PFS),
•Overall survival (OS),
•Biomarker development, i.e. association of markers discovered in other preclinical or clinical studies with the outcome data of an N2M2subtrial; develop hypotheses on new prognostic or predictive markers from the molecular information obtained.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Subtrial A - APG101 Plus Radiotherapy for Patients with Newly Diagnosed MGMT-unmethylated Glioblastoma
Subtrial D - Atezolizumab plus radiotherapy for patients with newly diagnosed MGMT-unmethylated glioblastoma
Subtrial F - Palbociclib plus radiotherapy for patients with newly diagnosed MGMT-unmethylated glioblastoma and activity of the CDK4 or CDK6 and CDKN2A/B co-deletion |
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| E.3 | Principal inclusion criteria |
•Histologically confirmed, newly diagnosed glioblastoma (astrocytoma WHO grade IV) with unmethylated MGMT promoter and without mutation of the isocitrate dehydrogenase genes
•Open biopsy or resection
•Craniotomy or intracranial biopsy site must be adequately healed
•Informed consent
•Standard MRI ≤ 72 (+ 12 h) post-surgery according to the present national and international guidelines
•Availability of fresh-frozen tissue, FFPE tissue, and blood
•Patients eligible for RT at 60 Gy in 2 Gy fractions according to the local Standard of Care
•Age: ≥ 18 years
•KPS ≥70%
•Life expectancy > 6 months
•All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within 6 days prior to start of therapy. All female patients must be surgically sterile or must agree to use adequate contraception during the period of therapy and 6 months after the end of study treatment, or women must be postmenopausal for at least 2 years. Acceptable methods of contraception comprise barrier contraception combined with a medically accepted contraceptive method for the female patient or female partner (e.g. intra-uterine device with spermicide, hormonal contraceptive since at least 2 month). Female patients must agree not to donate lactation during treatment and until 6 months after end of treatment
•Male patients willing to use contraception (condoms with spermicidal jellies or cream) upon study entry and during the course of the study and 3 months after the end of the study, have undergone vasectomy, or are practicing total abstinence. Sperm donation is not permitted for the same time interval. |
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| E.4 | Principal exclusion criteria |
•Abnormal (≥ Grade 2 CTCAE) laboratory values for hematology (Hb, WBC, neutrophils, or platelets), liver (serum bilirubin, ALT, or AST) or renal function (serum creatinine).
•Active tuberculosis; HIV infection or active Hepatitis B or C infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease or pose a severe danger to site staff or lab personnel working on patients’ blood or tissue (e.g. rabies).
•Prior treatment with any of the questioned investigational medicinal products. Any prior anti-cancer therapy or co-administration of anti-cancer therapies other than those allowed in this study. History of low-grade glioma that did not require prior treatment with chemotherapy or radiotherapy is not an exclusion criterion.
•Immunosuppression, not related to prior treatment for malignancy.
•History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 5 years unless the patient has been disease-free for 5 years.
•Any clinically significant concomitant disease (including hereditary fructose intolerance) or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study.
•Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry.
•Pregnancy or breastfeeding.
•History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I part:
Primary safety endpoint is the Dose Limiting Toxicity (DLT), defined as all adverse events (AEs) coded using Medical Dictionary for Regulatory Activities (MedDRA) ≥ Grade 3 according to the National Cancer Institute Common Terminology Criteria for AE (CTCAE) that are definitely, probably, or possibly related to the administration of the investigational agents.
Phase IIa part:
Primary efficacy endpoint is the PFS-6 rate, defined as proportion of patients with progression-free survival 6 months after study entry. PFS-6 will be calculated from study entry (Day of Attribution) until clinical or radiographic progression or death, whichever comes first. Given that no drop-outs are anticipated, no censoring will have to be accounted for in the final analysis. In the interim analyses, censoring may occur due to patients recruited between the date of entry of the 15th and 25th patient (resp.) and the time point of analysis (“overrun”). The Kaplan-Meier estimate will be then used for making decisions on stopping for futility. Progression will be evaluated according to Response Assessment in Neurooncology (RANO) criteria (Wen et al. 2010) or iRANO (Okada et al. 2015) based on the central disease assessment by the Central Neuroradiology. Basis for the assessment of the disease progression will be MRI scans that were done ≤ 2 weeks before start of therapy (for RT planning). In case no such scan exists, basis for the disease assessment will be the 72 h-post-surgery MRI scan. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 month after treatment start |
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| E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints:
•Regimen-limiting toxicity (RLT), defined as any toxicity that meets the criteria of a DLT, but is observed after the end of the combination therapy in phase I or during phase IIa of the trial.
•Type, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]), seriousness, and relatedness of adverse events.
•Karnofsky Index (KPI)
•Vital signs (BP, HR, temperature, body weight/height)
•Clinical laboratory Parameters (hematology, chemistry, urinalysis), ECG
Secondary Efficacy Endpoints:
•PFS, defined as time from the study entry until the day of first documentation of clinical or radiographic tumor progression or death of any cause (whichever occurs first). Patients without a PFS event at the time of analysis will be censored at the last disease assessment showing no progression or at baseline if the patient has no post-baseline disease assessments. PFS analysis will be based on the central disease assessment by the Central Neuroradiology.
•OS, defined as the time from study entry until death due to any cause. Patients still alive or lost to follow-up at the time of the analysis will be censored at the last date they were known to be alive. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6 month after treatment start |
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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 | Yes |
| E.6.4 | Safety | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| 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 |
| partly randomised (randomised allocation for subtrial A, D, standard therapy) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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