This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.
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).
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.
Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.
British journal of cancer. 2020 Sep 11 [Epub ahead of print]
Martin H Voss, Michael S Gordon, Monica Mita, Brian Rini, Vicky Makker, Teresa Macarulla, David C Smith, Andrés Cervantes, Igor Puzanov, Roberto Pili, Ding Wang, Shadia Jalal, Shubham Pant, Manish R Patel, Rachel L Neuwirth, Aaron Enke, Yaping Shou, Farhad Sedarati, Douglas V Faller, Howard A Burris
Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. ., Oncology Research, HonorHealth Research Institute, 10510 N 92nd St Suite 200, Scottsdale, AZ, 85258, USA., Department of Hematology and Oncology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd North Tower, Los Angeles, CA, 90048, USA., Cleveland Clinic Foundation, Department of Solid Tumor Oncology, 9500 Euclid Avenue, Cleveland, OH, 44195, USA., Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Passeig de la Vall d'Hebron, 119, 129, 08035, Barcelona, Spain., University of Michigan, Department of Internal Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA., CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Avda. Menéndez Pelayo 4 acc., 46010, Valencia, Spain., Vanderbilt University Medical Center, Department of Medicine, Division of Hematology/Oncology, 1161 21st Ave S, Nashville, TN, 37232, USA., Indiana University-Simon Cancer Center, Department of Medicine, Division of Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA., Henry Ford Health System, Hematology/Oncology, 1 Ford Pl, Detroit, MI, 48202, USA., Indiana University Melvin and Bren Simon Cancer Center, Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA., Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Florida Cancer Specialists/SCRI, Drug Development Unit, 600 N Cattlemen Rd #200, Sarasota, FL, 34232, USA., Biostatistics, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA., Oncology Clinical Research, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA., Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.