| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| recurrent glioblastoma multiform |
|
| E.1.1.1 | Medical condition in easily understood language |
| recurrent glioblastoma multiforme |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 Ib : To determine the MTD and/or RP2D of buparlisib + carboplatin in patients with recurrent GBM who have progressed after SoC (RT with TMZ in combination and adjuvant) regardless of PI3K pathway activation status. same objective with buparlisib + lomustine
phase II : To assess anti-tumor activity of buparlisib + carboplatin
combination in patients with recurrent GBM who have progressed after SoC regardless of PI3K pathway activation status.
To assess anti-tumor activity buparlisib + lomustine combination compared to lomustine + placebo in patients with recurrent GBM who have progressed after SoC regardless the PI3K pathway activation |
|
| E.2.2 | Secondary objectives of the trial |
phase Ib:To assess safety and tolerability of buparlisib + carboplatin combination. To assess preliminary anti-tumor
activity of buparlisib + carboplatin combination in patients with
recurrent GBM who have progressed after SoC regardless of PI3K pathway activation status; Same objective for buparlisib+lomustine.
Phase II : To assess safety and tolerability of buparlisib + carboplatin combination. To further assess anti-tumor
activity of buparlisib + carboplatin combination in patients with
recurrent GBM who have progressed after SoC regardless the PI3K pathway activation status.Assess safety and tolerability of
buparlisib + lomustine combination compared to lomustine + placebo. To assess anti-tumor activity of buparlisib + lomustine
combination compared to lomustine + placebo in patients
with recurrent GBM who have progressed after SoC regardless
the PI3K pathway activation status |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria: - Patient is an adult ≥ 18 years old at the time of informed consent. - Patient has histologically confirmed
diagnosis of GBM with documented recurrence after first line treatment including radiotherapy and TMZ (SoC), not suitable for curative surgery or reirradiation. Patient has at least one measurable and/or non-measurable lesion as per RANO criteria - Patient has recovered (to Grade ≤1) from all clinically significant toxicities related to prior antineoplastic therapies. - Patient has Karnofsky performance status (KPS) ≥70%. - Patient has adequate organ and bone marrow functions: • Absolute Neutrophils Count (ANC) ≥ 1.5 x 109/L • Platelets ≥ 100 x 109/L (in case of transfusion stable for ≥14 days prior to treatment start) • Hemoglobin ≥ 9.0 g/dL (in case of transfusion stable for ≥14 days prior to treatment start) • INR ≤ 1,5 • Serum Creatinine ≤ 1.5 x ULN, or Creatinine Clearance > 45mL/min • Potassium and calcium (corrected for albumin), sodium and magnesium within institutional normal limits • Serum Bilirubin ≤ ULN, AST and ALT ≤ ULN • HbA1c ≤ 8% • Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L - Patient has tumor tissues available (archival or fresh). |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria: - Patient has received previous treatment with lomustine or carboplatin. - Patient has received previous antineoplastic treatment for recurrent GBM (e.g. VEGF inhibitors,
cytotoxic agents). - Patient has received more than one line of cytotoxic chemotherapy - Patient has concurrent use of anti-neoplastic agents including investigational therapy - Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is
allowed. - Patient is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers
of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to randomization is allowed. - Patient is currently two weeks prior to starting study drug. Other protocol-defined Inclusion/exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib]
12 week Progression Free Survival (PFS) rate (Phase II Carboplatin
combination)
Progression Free Survival (PFS) [phase II lomustine combinations] |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cycle 1 (21 days carboplatin combination or 42 days lomustine
combination )
12 weeks
Randomization until date of the event (expected average 3 months). |
|
| E.5.2 | Secondary end point(s) |
1: Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms]
2: Overall Response Rate (ORR) as per Response Assessment in
Neuro-Oncology(RANO) [Phase Ib , both combinations]
3: Progression Free Survival (PFS) [Phase Ib- both combinations]
4:Overall response rate (ORR) [Phae II, carboplatin combination]
5:Progression Free Survival (PFS) [Phase II, carboplatin combination]
6:24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination)
7: Overall Survival (OS) (Phase II Carboplatin combination)
8:Overall Response Rate (ORR) (Phase II Lomustine combinations)
9:12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
10 : 24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
11 : Overall survival (OS) [Phase II lomustine combinations] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For endpoint 1: Until 30 days after treatment discontinuation
For endpoints 2&4:Baseline, every 6 weeks from treatment start until or until start of another antineoplastic treatment or death which ever occurs first
For endpoints 3&5:Time from treatment start to the date of
the event (expected average 3 months)
For endpoint 6& 10: 24 weeks
For endpoint 7 &11 : 12 months
For endpoint 8: Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic
treatment or death which ever occurs first
For endpoint 9: 12 weeks
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 |
|
| 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 | 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
Phase II End of Study will be declared at the latest occurrence of:
•at least 9 months have elapsed since the data cut-off dates for the primary analysis in each of the carboplatin and lomustine arms and all patients have completed the safety follow-up period (30 days after treatment discontinuation) or
•at least 75% of patients have died in each of the carboplatin and lomustine arms
for details see protocol. |
|
| 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 | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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