Phase Ib/II Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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This is a multi-center, phase Ib/ II study (two parts) with patients that had recurrent glioblastoma multiforme. The first part (phase Ib) was to investigate the maximum tolerated dose/Recommended phase ll dose (MTD/RP2D) of once daily buparlisib in combination with every-three-week carboplatin or buparlisib once daily in combination with every-six-week lomustine (CCNU) using a Bayesian model. Once MTD/ RP2D is established in either of the 2 arms, the corresponding phase II portion of the study was to start. Phase II was to assess the treatment effect of buparlisib in combination with carboplatin in terms of Progression Free Survival (PFS) and was to compare the treatment effect of buparlisib with lomustine versus lomustine plus placebo in terms of PFS. A preliminary assessment for both combinations (buparlisib plus carboplatin or lomustine) demonstrated that there was not enough antitumor activity compared to historical data with single agent carboplatin or lomustine. Based on the overall safety profile, and preliminary anti-tumor activity observed in this study, Novartis decided that no additional patients would be enrolled into this study. As a consequence, the Phase II part of the study was not conducted.

Official Title
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Phase Ib/II Multicenter Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme

Conditions
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Recurrent Glioblastoma Multiforme

Intervention / Treatment
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* Drug: buparlisib
* Drug: carboplatin
* Drug: lomustine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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 re-irradiation. 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). Exclusion Criteria: Patient has received previous treatment with PI3K inhibitors, 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 receiving an enzyme-inducing anti-epileptic drug (EIAED). The patient must have discontinued EIAED therapy for at least two weeks prior to starting study drug. Other protocol-defined Inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lomustine+ buparlisib (Phase Ib)<br> | Drug: buparlisib<br>* Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.<br>Drug: lomustine<br>* Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.<br>|
| Experimental: carboplatin+ buparlisib (Phase Ib)<br> | Drug: buparlisib<br>* Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.<br>Drug: carboplatin<br>* Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).<br>|
| Experimental: lomustine+ buparlisib (Phase II)<br> | Drug: buparlisib<br>* Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.<br>Drug: lomustine<br>* Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.<br>|
| Placebo Comparator: lumustine + placebo (Phase II)<br> | Drug: lomustine<br>* Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.<br>Drug: placebo<br>* Placebo will be administered orally on a continuous QD dosing schedule for cycles of 42 days. Buparlisib matching placebo is manufactured as 10 mg and 50 mg hard gelatin capsules.<br>|
| Experimental: carboplatin+ buparlisib (Phase II)<br> | Drug: buparlisib<br>* Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.<br>Drug: carboplatin<br>* Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib] | Maximum Tolerated Dose (MTD) is defined as the highest BKM120 dosage that does not cause medically unacceptable Dose Limiting Toxicities (DLTs) in more than 35% of the treated patients during the first cycle of treatment. DLT is defined as treatment-related toxicity occurring during the phase Ib cycle 1 and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the MTD. | Cycle 1 (21 days carboplatin combination or 42 days lomustine combination ) | 
| 12 week Progression Free Survival (PFS) rate (Phase II- Carboplatin combination) | 12-week Progression Free Survival (PFS) is defined as the percentage of patients who are progression free 12 weeks after the date of the start of the treatment (success). Patients who progressed, died or discontinued within the 12 weeks of observation are counted as failure. | 12 weeks | 
| Progression Free Survival (PFS) [phase II lomustine combinations] | Progression Free Survival (PFS) is defined as the time from date of randomization to the date of the event, which is the first radiologically documented disease progression [per local investigator assessment according to Response Assessment in Neuro-Oncology (RANO) criteria] or death due to any cause. | Randomization until date of the event (expected average 3 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms] | The incidence of Adverse Events (AEs) summarized by system organ class and or preferred term, severity (based on Common Terminology Criteria for Adverse Events (CTCAE) grades version 4), type of AE, relation to study treatment. | Until 30 days after treatment discontinuation | 
| Overall Response Rate (ORR) as per Response Assessment in Neuro-Oncology (RANO) [Phase Ib , both combinations] | Overall response rate (ORR) is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on the investigator assessment as per Response Assessment in Neuro-Oncology (RANO) criteria. | Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year | 
| Progression Free Survival (PFS) [Phase Ib- both combinations] | Progression Free Survival (PFS) is defined as time from date of treatment start to the date of the event, which is the first radiologically documented disease progression or death due to any cause per local investigator assessment. | Time from treatment start to the date of the event (expected average 3 months) | 
| Overall response rate (ORR) [Phae II, carboplatin combination] | Overall response rate (ORR) is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on the investigator assessment as per Response Assessment in Neuro-Oncology (RANO) criteria. | Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year | 
| Progression Free Survival (PFS) [Phase II, carboplatin combination] | Progression Free Survival (PFS) is defined as time from date of treatment start to the date of the event, which is the first radiologically documented disease progression or death due to any cause per local investigator assessment. | Time from treatment start to the date of the event (Expected average: 3 months) | 
| 24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination) | 24 weeks Progression Free Survival (PFS) is defined as the percentage of patients who are progression free 24 weeks after the date of the start of the treatment (success). Patients who progressed, died or discontinued within the 24 weeks of observation are counted as failure. | 24 weeks | 
| Overall Survival (OS) (Phase II Carboplatin combination) | Overall survival (OS) is defined as the time from the date of randomization for buparlisib + lomustine / placebo + lomustine Phase II, or the time from the first study drug intake for buparlisib + carboplatin Phase II, to the date of death due to any cause. | 12 months | 
| Overall Response Rate (ORR) (Phase II Lomustine combinations) | Overall response rate (ORR) is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on the investigator assessment as per Response Assessment in Neuro-Oncology (RANO) criteria. | Baseline, every 6 weeks from treatment start until disease progression or until start of another antineoplastic treatment or death which ever occurs first up to 1 year | 
| 12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations) | 12-week Progression Free Survival (PFS) is defined as the percentage of patients who are progression free 12 weeks after the date of the start of the treatment (success). Patients who progressed, died or discontinued within the 12 weeks of observation are counted as failure. | 12 weeks | 
| 24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations) | 24 weeks Progression Free Survival (PFS) is defined as the percentage of patients who are progression free 24 weeks after the date of the start of the treatment (success). Patients who progressed, died or discontinued within the 24 weeks of observation are counted as failure. | 24 weeks | 
| Overall survival (OS) [Phase II lomustine combinations] | Overall survival (OS) is defined as the time from the date of randomization for buparlisib + lomustine / placebo + lomustine Phase II, or the time from the first study drug intake for buparlisib + carboplatin Phase II, to the date of death due to any cause. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BKM120, Recurrent glioblastoma multiforme, rGBM, buparlisib