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

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.