A Phase 1 Study of Sapanisertib (TAK-228) in East Asian Patients with Advanced Nonhematological Malignancies

Abstract

Background: Sapanisertib is an oral, highly selective inhibitor of mammalian target of rapamycin complexes 1 and 2.

Objective: The aim of this study was to assess the safety, tolerability, pharmacokinetics, preliminary efficacy, and to establish the recommended phase 2 dose (RP2D) of sapanisertib.

Patients and methods: In this dose-escalation and expansion study, East Asian patients with nonhematologic malignancies received increasing sapanisertib doses once-daily (QD; starting at 2 mg) or once-weekly (QW; starting at 20 mg) in 28-day cycles.

Results: Among 28 patients (QD dosing, n = 22; QW dosing, n = 6), three dose-limiting toxicities were reported (stomatitis [n = 2], gastrointestinal inflammation, gingivitis, and acute myocardial infarction [all n = 1]), all in the 4 mg QD cohort. The RP2D of sapanisertib was 3 mg QD. The most common adverse events were stomatitis (64%), nausea (50%), and decreased appetite (50%) in the QD arm, and nausea (100%), blood alkaline phosphatase increased (67%), and hyperglycemia (67%) in the QW arm. The Tmax of sapanisertib was ~ 0.5-2.6 h and the T1/2 was ~ 5.9-7.6 h. Three patients achieved stable disease for ≥ 6 months (1 each in 3 mg QD, 4 mg QD and 20 mg QW cohorts, respectively); the clinical benefit rate was 45% and 67% in the QD and QW arms, respectively.

Conclusions: The RP2D of sapanisertib in East Asian patients (3 mg QD) was lower than in Western patients (4 mg QD), but the pharmacokinetics and safety profiles were similar. Sapanisertib was well tolerated and showed moderate anti-tumor effects in heavily pretreated patients with nonhematologic malignancies.

Nct number: NCT03370302; Registered December 7, 2017.

Conflict of interest statement

Toshio Shimizu has received grants/grants pending from Takeda Pharmaceutical Company Limited, Novartis, Eli Lilly, Daiichi-Sankyo, Bristol-Myers Squibb, Eisai, AbbVie, AstraZeneca, Incyte, Pfizer, Chordia Therapeutics, 3D-Medicine, Symbio Pharmaceuticals, PharmaMar, and Five Prime outside the submitted work, and consulting fees or honorarium from Takeda Pharmaceutical Company Limited and Daiichi Sankyo. Yasutoshi Kuboki has received grants/grants pending from Amgen, Takeda Pharmaceutical Company Limited, AstraZeneca, Ono Pharmaceutical Company Limited, Taiho Pharmaceutical Company Limited, Boehringer Ingelheim GmbH, AbbVie, GSK, Chugai Company Limited, Daiichi-Sankyo, and Genmab K.K., consulting fees or honorarium from Takeda Pharmaceutical Company Limited, and payment for lectures including services on speakers bureau from Taiho, Sanofi, Bayer Yakuhin, and Ono Pharmaceutical Company Limited. Chia-Chi Lin has received consulting fees from Blueprint Medicines, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Novartis, honorarium from Eli Lilly, Novartis, and Roche, and travel support from BeiGene and Eli Lilly. Kan Yonemori has received consulting fees or honorarium from Takeda Pharmaceutical Company Limited, Eisai, Chugai, AstraZeneca, Elli Lilly, Pfizer, Novartis, and Ono Pharmaceutical Company Limited. Tomoko Yanai is employed by Takeda Pharmaceutical Company Limited. Douglas V. Faller is employed by Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. lwona Dobler is employed by Millennium Pharmaceuticals, Inc. and has stock/stock options with Takeda Pharmaceutical Company Limited. Neeraj Gupta is employed by Millennium Pharmaceuticals, Inc. Farhad Sedarati is employed by Millennium Pharmaceuticals, Inc. Kyu-pyo Kim has no conflict of interests to declare.

© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Figures

Fig. 1.

Mean plasma concentration–time profiles (semi-log plot) of sapanisertib in patients at cycle 1 day 1 after a single dose of a 2–4 mg QD or b 20–30 mg QW, and at cycle 1 day 15 after a single dose of c 2–4 mg QD or d 20–30 mg QW. Concentrations represented at 0 h are collected right before the dosing. The LLOQ for sapanisertib is 1 ng/mL. For the estimation of summary statistics BLQ values were replaced by zero. For the calculation of the mean concentrations at predose, plasma concentrations less than the BLQ are set to half of the lower limit of quantification. BLQ below the limit of quantification, LLOQ lower limit of quantification, QD once daily, QW once weekly