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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
35
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.
Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).
Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.
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.
Barrow Neurological Insitute St. Joseph's Hospital
Phoenix, Arizona, United States
Highlands Oncology Group
Fayetteville, Arkansas, United States
Northwestern University
Chicago, Illinois, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
MD Anderson Cancer Center/University of Texas
Houston, Texas, United States
Novartis Investigative Site
Heidelberg, Victoria, Australia
Novartis Investigative Site
Parkville, Victoria, Australia
Novartis Investigative Site
Leuven, Belgium
Novartis Investigative Site
Toronto, Ontario, Canada
Novartis Investigative Site
Marseille, France
...and 4 more locations
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.
Time frame: 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".
Time frame: 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.
Time frame: Randomization until date of the event (expected average 3 months).
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.
Time frame: 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.
Time frame: 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 frame: 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.
Time frame: 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 frame: 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".
Time frame: 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.
Time frame: 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.
Time frame: 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".
Time frame: 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".
Time frame: 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.
Time frame: 12 months
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