Clinical trial NCT01934361: Phase Ib/II Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
Official title: Phase Ib/II Multicenter Study of Buparlisib Plus Carboplatin or Lomustine in Patients With Recurrent Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Recurrent Glioblastoma Multiforme
Keywords: BKM120
Recurrent glioblastoma multiforme
rGBM
buparlisib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-09-04
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Total Dose-limiting Toxicity (DLT) during Dose Escalation part to determine Maximum Tolerated Dose (MTD) [Phase Ib]
timeFrame: Cycle 1 (21 days carboplatin combination or 42 days lomustine combination )
measure: 12 week Progression Free Survival (PFS) rate (Phase II- Carboplatin combination)
timeFrame: 12 weeks
measure: Progression Free Survival (PFS) [phase II lomustine combinations]
timeFrame: Randomization until date of the event (expected average 3 months).
Secondary outcomes:
measure: Frequency and severity of Adverse Events (AEs) [Phase Ib, Phase II, all treatment arms]
timeFrame: Until 30 days after treatment discontinuation
measure: Overall Response Rate (ORR) as per Response Assessment in Neuro-Oncology (RANO) [Phase Ib , both combinations]
timeFrame: 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
measure: Progression Free Survival (PFS) [Phase Ib- both combinations]
timeFrame: Time from treatment start to the date of the event (expected average 3 months)
measure: Overall response rate (ORR) [Phae II, carboplatin combination]
timeFrame: 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
measure: Progression Free Survival (PFS) [Phase II, carboplatin combination]
timeFrame: Time from treatment start to the date of the event (Expected average: 3 months)
measure: 24 week Progression Free Survival (PFS) rate (Phase II carboplatin combination)
timeFrame: 24 weeks
measure: Overall Survival (OS) (Phase II Carboplatin combination)
timeFrame: 12 months
measure: Overall Response Rate (ORR) (Phase II Lomustine combinations)
timeFrame: 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
measure: 12 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
timeFrame: 12 weeks
measure: 24 week Progression Free Survival (PFS) rate (Phase II- lomustine combinations)
timeFrame: 24 weeks
measure: Overall survival (OS) [Phase II lomustine combinations]
timeFrame: 12 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Insitute St. Joseph's Hospital
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Houston
country: United States
facility: MD Anderson Cancer Center/University of Texas
state: Texas
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Marseille Cedex 05
country: France
facility: Novartis Investigative Site
city: Paris Cedex 13
country: France
facility: Novartis Investigative Site
city: Saint Herblain cedex
country: France
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.