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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01934361
Registration number
NCT01934361
Ethics application status
Date submitted
20/08/2013
Date registered
4/09/2013
Titles & IDs
Public title
Phase Ib/II Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
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Scientific title
Phase Ib/II Multicenter Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
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Secondary ID [1]
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2013-003129-27
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Secondary ID [2]
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CBKM120E2102
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Recurrent Glioblastoma Multiforme
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Condition category
Condition code
Cancer
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Brain
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - buparlisib
Treatment: Drugs - carboplatin
Treatment: Drugs - lomustine
Treatment: Drugs - placebo
Experimental: Lomustine+ buparlisib (Phase Ib) -
Experimental: carboplatin+ buparlisib (Phase Ib) -
Experimental: lomustine+ buparlisib (Phase II) -
Placebo comparator: lumustine + placebo (Phase II) -
Experimental: carboplatin+ buparlisib (Phase II) -
Treatment: Drugs: buparlisib
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.
Treatment: Drugs: carboplatin
Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).
Treatment: Drugs: lomustine
Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.
Treatment: Drugs: placebo
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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib]
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Assessment method [1]
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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.
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Timepoint [1]
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Cycle 1 (21 days carboplatin combination or 42 days lomustine combination )
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Primary outcome [2]
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12 week Progression Free Survival (PFS) rate (Phase II- Carboplatin combination)
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Assessment method [2]
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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".
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Timepoint [2]
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12 weeks
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Primary outcome [3]
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Progression Free Survival (PFS) [phase II lomustine combinations]
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Assessment method [3]
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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.
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Timepoint [3]
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Randomization until date of the event (expected average 3 months).
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Secondary outcome [1]
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Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms]
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Assessment method [1]
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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.
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Timepoint [1]
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Until 30 days after treatment discontinuation
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Secondary outcome [2]
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Overall Response Rate (ORR) as per Response Assessment in Neuro-Oncology (RANO) [Phase Ib , both combinations]
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Secondary outcome [3]
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Progression Free Survival (PFS) [Phase Ib- both combinations]
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Assessment method [3]
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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.
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Timepoint [3]
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Time from treatment start to the date of the event (expected average 3 months)
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Secondary outcome [4]
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Overall response rate (ORR) [Phae II, carboplatin combination]
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Assessment method [4]
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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.
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Timepoint [4]
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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
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Secondary outcome [5]
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Progression Free Survival (PFS) [Phase II, carboplatin combination]
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Assessment method [5]
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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.
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Timepoint [5]
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Time from treatment start to the date of the event (Expected average: 3 months)
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Secondary outcome [6]
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24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination)
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Assessment method [6]
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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".
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Timepoint [6]
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24 weeks
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Secondary outcome [7]
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Overall Survival (OS) (Phase II Carboplatin combination)
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Assessment method [7]
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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.
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Timepoint [7]
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12 months
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Secondary outcome [8]
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Overall Response Rate (ORR) (Phase II Lomustine combinations)
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Assessment method [8]
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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.
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Timepoint [8]
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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
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Secondary outcome [9]
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12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
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Assessment method [9]
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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".
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Timepoint [9]
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12 weeks
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Secondary outcome [10]
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24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
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Assessment method [10]
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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".
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Timepoint [10]
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24 weeks
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Secondary outcome [11]
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Overall survival (OS) [Phase II lomustine combinations]
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Assessment method [11]
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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.
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Timepoint [11]
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12 months
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Eligibility
Key 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).
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
28/02/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
7/07/2016
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Sample size
Target
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Accrual to date
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Final
35
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Heidelberg
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Recruitment hospital [2]
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Novartis Investigative Site - Parkville
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Recruitment postcode(s) [1]
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3084 - Heidelberg
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Recruitment postcode(s) [2]
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3050 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Arizona
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Country [2]
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United States of America
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State/province [2]
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Arkansas
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Country [3]
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United States of America
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State/province [3]
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Illinois
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Country [4]
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United States of America
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State/province [4]
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Massachusetts
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Country [5]
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United States of America
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State/province [5]
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Texas
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Country [6]
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Belgium
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State/province [6]
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Leuven
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Country [7]
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Canada
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State/province [7]
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Ontario
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Country [8]
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France
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State/province [8]
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Marseille Cedex 05
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Country [9]
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France
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State/province [9]
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Paris Cedex 13
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Country [10]
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France
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State/province [10]
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Saint Herblain cedex
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Country [11]
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Spain
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State/province [11]
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Catalunya
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT01934361
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Trial related presentations / publications
Rosenthal M, Clement PM, Campone M, Gil-Gil MJ, DeGroot J, Chinot O, Idbaih A, Gan H, Raizer J, Wen PY, Pineda E, Donnet V, Mills D, El-Hashimy M, Mason W. Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study. ESMO Open. 2020 Jul;5(4):e000672. doi: 10.1136/esmoopen-2020-000672.
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT01934361