Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study

Abstract

Background: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models.

Methods: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine.

Results: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model.

Conclusion: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine.

Trial registration number: NCT01934361.

Keywords: BKM120; buparlisib; rGBM; recurrent glioblastoma.

Conflict of interest statement

Competing interests: PMC reports grants from AstraZeneca and personal fees from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Leo Pharma, Merck, MSD and Vifor, outside the submitted work. MC acted in an advisory role for Novartis, Sanofi, Pierre Fabre, Lilly and AstraZeneca, outside the submitted work. MJG-G has received honoraria from Novartis, Pfizer and Roche and acted in an advisory role for Daiichi Sankyo, Novartis and Pfizer. OC reports grants from Roche, personal fees and non-financial support from Roche and AbbVie, personal fees from Ipsen and Celdex, and non-financial support from Servier, outside the submitted work. AI reports grants and travel funding from Carthera (September 2019), research grants from Transgene, Sanofi and Air Liquide, and travel funding from Leo Pharma, outside the submitted work. HG reports grants from AbbVie, personal fees and non-financial support from AbbVie and Ignyta, personal fees from BMS, MSD, Eisai and Merck Serono, outside the submitted work. JR reports grants from Novartis during the conduct of the study. PYW reports research support from Agios, AstraZeneca, BeiGene, Eli Lilly, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi Aventis and VBI Vaccines, participated on advisory boards for AbbVie, Agios, AstraZeneca, Blue Earth Diagnostics, Eli Lilly, Genentech/Roche, Karyopharm, Kiyatec, Puma, Vascular Biogenics, Taiho, Deciphera, VBI Vaccines and Tocagen, and speaker for Merck and Prime Oncology. EP reports scientific consultancy role for Celgene. VD is an employee of Novartis Pharma SAS and holds Novartis stock options. DM is an employee of Novartis Pharma and holds Novartis stock options. ME-H is an employee of Novartis Pharmaceuticals Corporation and holds Novartis stock options.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1

Study design. MTD, maximum tolerated dose; qd, once daily; q3w, once every 3 weeks; q6w, once every 6 weeks; RP2D, recommended phase II dose.