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Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
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Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
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Journal Article
Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
2020
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult
/ Aged
/ Antineoplastic Agents - administration & dosage
/ Antineoplastic Agents - adverse effects
/ Antineoplastic Agents - pharmacokinetics
/ Asthenia
/ Biomedical and Life Sciences
/ Carcinoma, Renal Cell - drug therapy
/ Dosage
/ Endometrial Neoplasms - drug therapy
/ Female
/ Humans
/ Kidney Neoplasms - drug therapy
/ Male
/ Oncology
/ Patients
/ Protein Kinase Inhibitors - administration & dosage
/ Protein Kinase Inhibitors - adverse effects
/ Protein Kinase Inhibitors - pharmacokinetics
/ Pyrazoles - administration & dosage
/ Pyrazoles - pharmacokinetics
/ Pyrimidines - administration & dosage
/ Pyrimidines - adverse effects
/ Pyrimidines - pharmacokinetics
/ TOR Serine-Threonine Kinases - antagonists & inhibitors
/ Tumors
