A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Abstract

// Jordi Rodon 1 , Giuseppe Curigliano 2 , Jean-Pierre Delord 3 , Wael Harb 4 , Analia Azaro 1 , Yu Han 5 , Celine Wilke 6 , Valerie Donnet 7 , Dalila Sellami 5 and Thaddeus Beck 8 1 Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d’Hebron University Hospital, Centro Cellex, 08035, Barcelona, Spain 2 Division of Early Drug Development for Innovative Therapies, Department of Hematology and Oncology, University of Milano, Istituto Europeo di Oncologia, 20141, Milan, Italy 3 Clinical Research Unit, Institut Claudius Regaud, 31052, Toulouse, France 4 Horizon Oncology Center, 47905, Lafayette, IN, USA 5 Novartis Pharmaceuticals Corporation, 07936, East Hanover, NJ, USA 6 Novartis Pharma AG, Postfach, CH-4002, Basel, Switzerland 7 Novartis Pharma S.A.S., 92506, Rueil-Malmaison, France 8 Highlands Oncology Group, 72703, Fayetteville, AR, USA Correspondence to: Jordi Rodon, email: jrodon@vhio.net Keywords: breast neoplasms; drug resistance; PIK3CA protein; human; chemotherapy Received: February 08, 2018     Accepted: July 12, 2018     Published: August 03, 2018 ABSTRACT Phosphatidylinositol 3-kinase (PI3K) pathway activation is associated with resistance to paclitaxel in solid tumors. We assessed the safety and activity of alpelisib, an oral, selective PI3K p110α inhibitor, plus paclitaxel in patients with advanced solid tumors. This Phase Ib, multicenter, open-label, dose-finding study, with a planned dose-expansion phase of alpelisib once daily (QD) plus fixed-dose paclitaxel, recruited patients with advanced solid tumors. For the dose-finding phase, the primary objective was determination of maximum tolerated and/or recommended Phase II dose of alpelisib plus paclitaxel, and the secondary objectives included the assessment of safety for this combination. From March 2014 to August 2016, 19 patients with advanced solid tumors were treated with alpelisib QD (300 mg, n=6; 250 mg, n=4; 150 mg, n=9) plus paclitaxel (80 mg/m 2 , per standard of care). During dose finding, five of 12 (41.7%) evaluable patients for MTD determination experienced dose-limiting toxicities: alpelisib 300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia (n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent all-grade AEs were diarrhea (73.7%; Grade 3/4 10.5%) and hyperglycemia (57.9%; Grade 3/4 31.6%). The planned dose-expansion phase was not initiated. Alpelisib plus paclitaxel has a challenging safety profile in patients with advanced solid tumors. This study was closed following the completion of the dose-finding phase. Clinical trial registration: ClinicalTrials.gov NCT02051751.