TY - JOUR
T1 - Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
AU - Voss, Martin H.
AU - Gordon, Michael S.
AU - Mita, Monica
AU - Rini, Brian
AU - Makker, Vicky
AU - Macarulla, Teresa
AU - Smith, David C.
AU - Cervantes, Andrés
AU - Puzanov, Igor
AU - Pili, Roberto
AU - Wang, Ding
AU - Jalal, Shadia
AU - Pant, Shubham
AU - Patel, Manish R.
AU - Neuwirth, Rachel l.
AU - Enke, Aaron
AU - Shou, Yaping
AU - Sedarati, Farhad
AU - Faller, Douglas V.
AU - Burris, Howard A.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/11/24
Y1 - 2020/11/24
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-020-01041-x
DO - 10.1038/s41416-020-01041-x
M3 - Article
C2 - 32913286
AN - SCOPUS:85090765850
SN - 0007-0920
VL - 123
SP - 1590
EP - 1598
JO - British journal of cancer
JF - British journal of cancer
IS - 11
ER -