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oai:recercat.cat:11351/65032025-09-30T02:07:34Zcom_2072_378070com_2072_378040col_2072_378092

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer Voss, Martin H. Gordon, Michael S. Mita, Monica Rini, Brian Makker, Vicky Macarulla Mercadé, Teresa Institut Català de la Salut [Voss MH, Makker V] Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. [Gordon MS] Oncology Research, HonorHealth Research Institute, 10510 N 92nd St Suite 200, Scottsdale, AZ 85258, USA. [Mita M] Department of Hematology and Oncology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd North Tower, Los Angeles, CA 90048, USA. [Rini B] Cleveland Clinic Foundation, Department of Solid Tumor Oncology, 9500 Euclid Avenue, Cleveland, OH 44195, USA. [Macarulla T] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Càncer - Tractament Medicaments - Administració DISEASES::Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose ENFERMEDADES::neoplasias Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada Teràpia del càncer; Càncer ginecològic; Càncer urològic Terapia del cáncer; Cáncer ginecológico; Cáncer urológico Cancer therapy; Gynaecological cancer; Urological cancer Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. This study was supported by Millennium Pharmaceuticals Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. NIH/NCI Cancer Center Support Grant (Memorial Sloan Kettering Cancer Center, P30 CA008748). 2021-11-05T06:58:39Z 2021-11-05T06:58:39Z 2020-11 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Voss MH, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, et al. Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Br J Cancer. 2020 Nov;123:1590–8. 1532-1827 https://hdl.handle.net/11351/6503 10.1038/s41416-020-01041-x 32913286 000568843200001 eng British Journal of Cancer;123 https://doi.org/10.1038/s41416-020-01041-x Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Springer Nature Scientia