Abstract
BackgroundThis Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.MethodsEligible 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).ResultsMaximum 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.ConclusionsSapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.Clinical trial registrationClinicalTrials.gov, NCT01058707.
Highlights
This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1)/mTORC2, in advanced solid tumours
From March 2013 to April 2014, an additional 82 patients with renal cell carcinoma (RCC), endothelial or bladder cancer were enrolled in the expansion phase to receive sapanisertib 5 mg QD (n = 39), 40 mg QW (n = 26) or 30 mg QW (n = 17)
The maximum tolerated dose (MTD) was determined to be 6 mg for the QD schedule based on 4/ 10 patients reporting a dose-limiting toxicities (DLTs) in cycle 1 and 40 mg for the QW schedule based on 2/12 patients reporting a DLT, 9 mg for the QD × 3dQW schedule based on 1/6 evaluable patients reporting a DLT and 7 mg for the Treated patientsa, Evaluable n patientsb, n
Summary
This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Inhibition of mTOR may decrease protein translation and prevent abnormal cell proliferation and tumour angiogenesis.[3,4] rapamycin analogues (“rapalogs”), such as temsirolimus and everolimus, have been approved by the US Food and Drug Administration for the treatment of advanced renal cell cancer (RCC) and several other cancers.[1,5,6,7,8,9,10]. Rapalogs exert their effect mainly on mTORC1, with only a mild inhibitory effect on mTORC2.11 Inhibition of mTORC1, without
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