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

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ClinicalTrials.gov Identifier: NCT01934361
Recruitment Status : Completed
First Posted : September 4, 2013
Last Update Posted : August 3, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.


Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Multiforme Drug: buparlisib Drug: carboplatin Drug: lomustine Drug: placebo Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Multicenter Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
Actual Study Start Date : February 28, 2014
Actual Primary Completion Date : July 7, 2016
Actual Study Completion Date : July 7, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lomustine+ buparlisib (Phase Ib) Drug: buparlisib
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.

Drug: lomustine
Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.

Experimental: carboplatin+ buparlisib (Phase Ib) Drug: buparlisib
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.

Drug: carboplatin
Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).

Experimental: lomustine+ buparlisib (Phase II) Drug: buparlisib
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.

Drug: lomustine
Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.

Placebo Comparator: lumustine + placebo (Phase II) Drug: lomustine
Lomustine will be administered as a single oral dose of 100 mg/m² every 6 weeks in a 42 day cycles.

Drug: 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.

Experimental: carboplatin+ buparlisib (Phase II) Drug: buparlisib
Buparlisib administered orally on a continuous daily schedule. Buparlisib is manufactured as 10mg and 50mg hard gelatin capsules.

Drug: carboplatin
Carboplatin intravenous infusion will be administered at a dose of AUC 5 in a 21 day cycle (every 3 weeks).




Primary Outcome Measures :
  1. Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib] [ Time Frame: Cycle 1 (21 days carboplatin combination or 42 days lomustine combination ) ]
    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.

  2. 12 week Progression Free Survival (PFS) rate (Phase II- Carboplatin combination) [ Time Frame: 12 weeks ]
    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".

  3. Progression Free Survival (PFS) [phase II lomustine combinations] [ Time Frame: Randomization until date of the event (expected average 3 months). ]
    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.


Secondary Outcome Measures :
  1. Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms] [ Time Frame: Until 30 days after treatment discontinuation ]
    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.

  2. Overall Response Rate (ORR) as per Response Assessment in Neuro-Oncology (RANO) [Phase Ib , both combinations] [ 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 ]
    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.

  3. Progression Free Survival (PFS) [Phase Ib- both combinations] [ Time Frame: Time from treatment start to the date of the event (expected average 3 months) ]
    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.

  4. Overall response rate (ORR) [Phae II, carboplatin combination] [ 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 ]
    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.

  5. Progression Free Survival (PFS) [Phase II, carboplatin combination] [ Time Frame: Time from treatment start to the date of the event (Expected average: 3 months) ]
    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.

  6. 24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination) [ Time Frame: 24 weeks ]
    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".

  7. Overall Survival (OS) (Phase II Carboplatin combination) [ Time Frame: 12 months ]
    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.

  8. Overall Response Rate (ORR) (Phase II Lomustine combinations) [ 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 ]
    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.

  9. 12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations) [ Time Frame: 12 weeks ]
    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".

  10. 24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations) [ Time Frame: 24 weeks ]
    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".

  11. Overall survival (OS) [Phase II lomustine combinations] [ Time Frame: 12 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01934361


Locations
United States, Arizona
Barrow Neurological Insitute St. Joseph's Hospital
Phoenix, Arizona, United States, 85013
United States, Arkansas
Highlands Oncology Group
Fayetteville, Arkansas, United States, 72703
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Texas
MD Anderson Cancer Center/University of Texas
Houston, Texas, United States, 77030
Australia, Victoria
Novartis Investigative Site
Heidelberg, Victoria, Australia, 3084
Novartis Investigative Site
Parkville, Victoria, Australia, 3050
Belgium
Novartis Investigative Site
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 1Z6
France
Novartis Investigative Site
Marseille Cedex 05, France, 13885
Novartis Investigative Site
Paris Cedex 13, France, 75651
Novartis Investigative Site
Saint Herblain cedex, France, 44805
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Hospitalet de LLobregat, Catalunya, Spain, 08907
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Additional Information:
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01934361     History of Changes
Other Study ID Numbers: CBKM120E2102
2013-003129-27 ( EudraCT Number )
First Posted: September 4, 2013    Key Record Dates
Last Update Posted: August 3, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
BKM120
Recurrent glioblastoma multiforme
rGBM
buparlisib

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Carboplatin
Lomustine
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action