Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder 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 pa...

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Bibliographic Details
Published in:	British journal of cancer Vol. 123; no. 11; pp. 1590 - 1598
Main Authors:	Voss, Martin H., Gordon, Michael S., Mita, Monica, Rini, Brian, Makker, Vicky, Macarulla, Teresa, Smith, David C., Cervantes, Andrés, Puzanov, Igor, Pili, Roberto, Wang, Ding, Jalal, Shadia, Pant, Shubham, Patel, Manish R., Neuwirth, Rachel l., Enke, Aaron, Shou, Yaping, Sedarati, Farhad, Faller, Douglas V., Burris, Howard A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 24-11-2020 Nature Publishing Group
Subjects:	692/4028/67/1059 692/4028/67/1517 692/4028/67/589 Adult Aged Aged, 80 and over Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Asthenia Biomedical and Life Sciences Biomedicine Bladder cancer Cancer Research Carcinoma, Renal Cell - drug therapy Dosage Drug Resistance Endometrial cancer Endometrial Neoplasms - drug therapy Endometrium Epidemiology Female Humans Hyperglycemia Kidney cancer Kidney Neoplasms - drug therapy Male Maximum Tolerated Dose Middle Aged Molecular Medicine Neoplasms - drug therapy Oncology Patients Pharmacodynamics Pharmacokinetics Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - pharmacokinetics Pyrazoles - administration & dosage Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Pyrimidines - administration & dosage Pyrimidines - adverse effects Pyrimidines - pharmacokinetics Renal cell carcinoma Solid tumors Stomatitis TOR Serine-Threonine Kinases - antagonists & inhibitors Tumors Urinary Bladder Neoplasms - drug therapy
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Summary:	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. Clinical trial registration ClinicalTrials.gov, NCT01058707.
ISSN:	0007-0920 1532-1827
DOI:	10.1038/s41416-020-01041-x