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- Title
Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.
- 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 III, Howard A.
- Abstract
<bold>Background: </bold>This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.<bold>Clinical Trial Registration: </bold>ClinicalTrials.gov, NCT01058707.
- Subjects
RENAL cell carcinoma; BLADDER tumors; RESEARCH; DRUG dosage; CLINICAL trials; HETEROCYCLIC compounds; PROTEIN kinase inhibitors; RESEARCH methodology; ANTINEOPLASTIC agents; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; ENDOMETRIAL tumors; KIDNEY tumors; RESEARCH funding; TUMORS; DRUG toxicity
- Publication
British Journal of Cancer, 2020, Vol 123, Issue 11, p1590
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-01041-x