Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours

Abstract

Background: Sapanisertib (TAK-228) is an investigational, orally available, potent and highly selective mTORC1/2 inhibitor demonstrating promise in numerous malignancies. This phase I study (NCT02412722) evaluated the safety, tolerability, pharmacokinetics and antitumour activity of single-agent TAK-228 (milled capsules), administered daily (QD) or weekly (QW) and in combination with paclitaxel in patients with advanced solid tumours. Pharmacokinetic comparisons of milled versus unmilled TAK-228 and the impact of food were also investigated.

Methods: Patients were enrolled to receive: TAK-228 QD, TAK-228 3 days/week plus paclitaxel 80 mg/m2 days 1, 8, 15 (TAK-228+P) or TAK-228 QW (all 28-day cycles); starting TAK‑228 doses were 4, 6 and 20 mg, respectively.

Results: Sixty-one adults were enrolled. Maximum tolerated doses for milled TAK-228 were 3 mg (TAK-228 QD), 6 mg (TAK-228+P) and 30 mg (TAK-228 QW). Most patients reported ≥1 adverse event (AE); there were no meaningful differences in drug-related AEs across regimens or doses. Three on-study deaths occurred, all considered unrelated to study drugs. TAK-228 pharmacokinetics did not differ between unmilled/milled capsules or with/without paclitaxel. However, TAK-228 Cmax decreased by ~40% in fed versus fasted patients. Objective response rates were 12% (TAK-228 QD), 18% (TAK-228+P) and 0% (TAK-228 QW). One patient receiving TAK-228+P had a complete response; three patients receiving TAK-228+P and two patients receiving TAK-228 QD had partial responses.

Conclusions: Milled TAK-228 was well tolerated with signs of antitumour activity; administration did not reduce overall exposure (area under the plasma concentration-time curve) but reduced Cmax, which is expected when dosed in the fed state. These promising findings warrant further investigation.

Trial registration number: NCT02412722.

Keywords: Medical Oncology; Mtor Protein; Pharmacokinetics; Safety; Tak-228.

Conflict of interest statement

Competing interests: KNM reports honoraria for advisory board work from Astra Zeneca, Advaxis, Clovis, Tesaro, Genentech/Roche, Immunogen, VBL Therapeutics, outside the submitted work. GSF reports research funding from Millennnium for the work under consideration for publication and outside the submitted work. SC, RN, CP, AE and FZ are paid, full-time employees of Takeda Oncology, the sponsor of the clinical trial on which this manuscript is based. TMB and MRP have nothing to disclose.

Figures

Figure 1

Plasma concentration–time profile, relative bioavailability and pharmacokinetic (PK) parameters of 4 mg TAK-228 in the single-agent QD PK run-in period, according to manufacturing process and dosing conditions. *Geometric mean; †Median; ‡Arithmetic mean. –, not available/not applicable; AUC, area under the plasma concentration–time curve; CL/F, apparent oral clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; t½, plasma half-life; TAK-228+P, TAK-228 once daily 3 days/week+paclitaxel 80 mg/m2 on days 1, 8 and 15; Tmax, time of maximum plasma concentration; QW, once weekly; Vz/F, apparent terminal phase volume of distribution.