Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors.

This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules.

The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels.

In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure.

Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors.

NCT01362374.

Annals of oncology : official journal of the European Society for Medical Oncology. 2020 Feb 20 [Epub ahead of print]

S J Isakoff, J Tabernero, L R Molife, J-C Soria, A Cervantes, N J Vogelzang, M R Patel, M Hussain, A Baron, G Argilés, P R Conkling, D Sampath, D Maslyar, P Patel, W Chan, S Gendreau, L Musib, N Xu, H Ma, K Lin, J Bendell

Department of Hematology/Oncology, Massachusetts General Hospital, Boston, USA. Electronic address: ., Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain., Drug Development Unit, The Royal Marsden and Institute of Cancer Research, Sutton, UK., Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, and Université Paris-Sud, Orsay, France., CIBERONC, Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain., Division of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, USA., Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, USA., Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA., Department of Medicine, California Pacific Medical Center, San Francisco, USA., Virginia Oncology Associates, US Oncology Research, Norfolk, USA., Genentech, Inc., South San Francisco, USA., Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA.