Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

Martin H Voss, Michael S Gordon, Monica Mita, Brian Rini, Vicky Makker, Teresa Macarulla, David C Smith, Andrés Cervantes, Igor Puzanov, Roberto Pili, Ding Wang, Shadia Jalal, Shubham Pant, Manish R Patel, Rachel L Neuwirth, Aaron Enke, Yaping Shou, Farhad Sedarati, Douglas V Faller, Howard A Burris 3rd, Martin H Voss, Michael S Gordon, Monica Mita, Brian Rini, Vicky Makker, Teresa Macarulla, David C Smith, Andrés Cervantes, Igor Puzanov, Roberto Pili, Ding Wang, Shadia Jalal, Shubham Pant, Manish R Patel, Rachel L Neuwirth, Aaron Enke, Yaping Shou, Farhad Sedarati, Douglas V Faller, Howard A Burris 3rd

Abstract

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.

Conflict of interest statement

M.H.V. has received honoraria from Novartis and consultancy fees from Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Natera, Novartis, Ontarget therapeutics and Pfizer. He has received research funding from Bristol-Myers Squibb, Genentech and Pfizer, and travel grants from Takeda and Eisai. M.S.G. has ownership of stock/shares with Medelis, CARE Mission and Beckon Call, and received consulting fees from Agenus, Deciphera and Salarius. B.R. is an advisor for and has received consultancy fees and research funding from Pfizer, Merck, Bristol-Myers Squibb and Roche. He has also received researching funding from AstraZeneca and Peloton. V.M. is an advisor for Eisai, Merck and Karyopharm, and has received honoraria from Eisai and Merck. He has received research funding from Eisai, Merck, Lilly, Karyopharm, Bristol-Myers Squibb, AstraZeneca, Takeda and Genentech. T.M. is an advisor for Roche, Amgen, Novartis, Sanofi, Shire, Incyte, Celgene and Baxter, and is a speaker for Celgene, Shire, Sanofi, Amgen and Servier. She has received research funding from Beigene, Novartis and Celgene. D.C.S. has received research funding from Agensys, Bayer, Exelixis, Incyte, Lilly, MedImmune, Novartis, OncoMed, Seattle Genetics, Bristol-Myers Squibb/Medarex, Essa, Genentech, Medivation/Astellas, Merck, Astellas and Takeda. A.C. is an advisor for Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Pierre Fabre, Amgen and Foundation Medicine. He has received grants from Merck Serono and Roche, and research funding from Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, AstraZeneca, MedImmune, Bristol-Myers Squibb and MSD. I.P. is an advisor for and has received honoraria and consultancy fees from Amgen. He has received research funding from Nektar, Amgen, Rgenix and ADC. S.J. has received grants from AstraZeneca, Tesaro and Astex. S.P. has received honoraria from UD Pharma and Tyme Inc. R.I.N., A.E., Y.S., F.S. and D.V.F. are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Co. Ltd. H.B. is an advisor for Mersana, AstraZeneca, FORMA Therapeutics, Janssen, Novartis, Roche/Genentech, MedImmune, Bristol-Myers Squibb, Celgene, Incyte, Boehringer Ingelheim, Eisai and Tolero Pharmaceuticals. He has received research funding from Roche/Genentech, Bristol-Myers Squibb, Incyte, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Celgene, Agios, Jounce Therapeutics, Morderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, Immunocore, Takeda, BioMed Valley Discoveries, TG Therapeutics, Loxo, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicioMed, Harpoon Therapeutics, Jiangsu Hengrui Medicine, Arch, Kyocera, Arvinas and Revolution Medicines. He has provided expert testimony for Novartis. All remaining authors have declared no conflicts of interest.

Figures

Fig. 1. Sapanisertib pharmacokinetics are dose dependent…
Fig. 1. Sapanisertib pharmacokinetics are dose dependent without plasma accumulation over time.
Mean (SD) plasma concentration–time profiles of multiple-dose sapanisertib (cycle 2, day 1) on the a QD, b QW, c QD × 3dQW and d QD × 5dQW dosing schedules. Error bars indicate SD. QD once daily, QD × 3dQW QD for 3 days on/4 days off QW, QD × 5dQW QD for 5 days on/2 days off QW, QW once weekly, SD standard deviation.

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Source: PubMed

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