Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study
David Mills,
Hui Gan,
Jeffrey Raizer,
Patrick Yung Wen,
Warren Mason,
John DeGroot,
Valerie Donnet,
Mona El-Hashimy,
Mark Rosenthal,
Paul M Clement,
Mario Campone,
Miguel J Gil-Gil,
Olivier Chinot,
Ahmed Idbaih,
Estela Pineda
Affiliations
David Mills
1 Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
Hui Gan
Aff551 grid.414094.c0000000101627225Austin Hospital Melbourne Victoria Australia
Jeffrey Raizer
Aff3 grid.16753.360000000122993507Department of Neurology and Division of Hematology and Oncology Northwestern University 60611 Chicago IL USA
Patrick Yung Wen
Neuro-oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
Warren Mason
Radiation-Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
John DeGroot
Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Valerie Donnet
Novartis Pharma SAS, Paris, France
Mona El-Hashimy
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
Mark Rosenthal
Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Paul M Clement
Department of Oncology, Leuven Cancer Institute, Leuven, Belgium
Mario Campone
Institut de Cancérologie de l’Ouest, Centre René Gauducheau, Saint Herblain, Pays de la Loire, France
Miguel J Gil-Gil
Institut Català d'Oncologia, Barcelona, Spain
Olivier Chinot
Department of Neuro-Oncology, Assistance Publique - Hôpitaux de Marseille Office Central des Bibliothèques, Marseille, Provence-Alpes-Côte d'Azur, France
Ahmed Idbaih
Department of Neuro-Oncology, Sorbonne Université, Paris, Île-de-France, France
Estela Pineda
Medical Oncology, University of Barcelona Faculty of Medicine and Health Sciences, Barcelona, Catalunya, Spain
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.
