1. Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors
- Author
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Manish R. Patel, Luna Musib, Paul Conkling, Andrés Cervantes, Premal Patel, Kedan Lin, Nicholas J. Vogelzang, Ari David Baron, Johanna C. Bendell, J-C. Soria, Maha Hussain, Daniel J. Maslyar, Wai Y. Chan, Josep Tabernero, N. Xu, Steven J. Isakoff, Guillem Argiles, L. R. Molife, Han Ma, Deepak Sampath, Steven Gendreau, Institut Català de la Salut, [Isakoff SJ] Department of Hematology/Oncology, Massachusetts General Hospital, Boston, USA. [Tabernero J, Argilés G] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Molife LR] Drug Development Unit, The Royal Marsden and Institute of Cancer Research, Sutton, UK. [Soria JC] Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, and Université Paris-Sud, Orsay, France. [Cervantes A] CIBERONC, Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain. [Vogelzang NJ] Division of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, USA, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Maximum Tolerated Dose ,medicine.medical_treatment ,Càncer - Quimioteràpia ,Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores] ,Gastroenterology ,AKT inhibitor ,Piperazines ,Medicaments antineoplàstics - Efectes secundaris ,neoplasias [ENFERMEDADES] ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Other subheadings::Other subheadings::/adverse effects [Other subheadings] ,medicine ,advanced cancer ,Humans ,Enzalutamide ,terapéutica::protocolos clínicos::protocolos antineoplásicos::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Adverse effect ,Chemotherapy ,business.industry ,Hematology ,phase I ,Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Oxaliplatin ,Neoplasms [DISEASES] ,Pyrimidines ,030104 developmental biology ,Oncology ,Docetaxel ,Tolerability ,Paclitaxel ,chemistry ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Inhibidor d'AKT; Càncer avançat; Fase I Inhibidor de AKT; Cáncer avanzado; Fase I AKT inhibitor; Advanced cancer; Phase I Background 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. Patients and methods 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. Results 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. Conclusions Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. This work was supported by Genentech, Inc., a member of the Roche Group, and F. Hoffmann-La Roche Ltd. (no grant number).
- Published
- 2020