Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer Journal Article
| Authors: | Voss, M. H.; Gordon, M. S.; Mita, M.; Rini, B.; Makker, V.; Macarulla, T.; Smith, D. C.; Cervantes, A.; Puzanov, I.; Pili, R.; Wang, D.; Jalal, S.; Pant, S.; Patel, M. R.; Neuwirth, R.; Enke, A.; Shou, Y.; Sedarati, F.; Faller, D. V.; Burris, H. A. 3rd |
| Article 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 |
| Abstract: | 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. © 2020, The Author(s). |
| Journal Title: | British Journal of Cancer |
| Volume: | 123 |
| Issue: | 11 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-11-01 |
| Start Page: | 1590 |
| End Page: | 1598 |
| Language: | English |
| DOI: | 10.1038/s41416-020-01041-x |
| PUBMED: | 32913286 |
| PROVIDER: | scopus |
| PMCID: | PMC7686313 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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