Clinical Trial

. 2020 Nov;123(11):1590-1598.

doi: 10.1038/s41416-020-01041-x. Epub 2020 Sep 11.

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 Voss¹, Michael S Gordon², Monica Mita³, Brian Rini⁴, Vicky Makker⁵, Teresa Macarulla⁶, David C Smith⁷, Andrés Cervantes⁸, Igor Puzanov^{9

10}, Roberto Pili¹¹, Ding Wang¹², Shadia Jalal¹³, Shubham Pant¹⁴, Manish R Patel¹⁵, Rachel L Neuwirth¹⁶, Aaron Enke^{17

10}, Yaping Shou^{17

18}, Farhad Sedarati¹⁷, Douglas V Faller¹⁷, Howard A Burris 3rd¹⁹

Affiliations

¹ Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. vossm@mskcc.org.
² Oncology Research, HonorHealth Research Institute, 10510 N 92nd St Suite 200, Scottsdale, AZ, 85258, USA.
³ Department of Hematology and Oncology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd North Tower, Los Angeles, CA, 90048, USA.
⁴ Cleveland Clinic Foundation, Department of Solid Tumor Oncology, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
⁵ Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶ Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Passeig de la Vall d'Hebron, 119, 129, 08035, Barcelona, Spain.
⁷ University of Michigan, Department of Internal Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.
⁸ CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Avda. Menéndez Pelayo 4 acc., 46010, Valencia, Spain.
⁹ Vanderbilt University Medical Center, Department of Medicine, Division of Hematology/Oncology, 1161 21st Ave S, Nashville, TN, 37232, USA.
¹⁰ Clovis Oncology, San Francisco, CA, USA.
¹¹ Indiana University-Simon Cancer Center, Department of Medicine, Division of Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA.
¹² Henry Ford Health System, Hematology/Oncology, 1 Ford Pl, Detroit, MI, 48202, USA.
¹³ Indiana University Melvin and Bren Simon Cancer Center, Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA.
¹⁴ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
¹⁵ Florida Cancer Specialists/SCRI, Drug Development Unit, 600 N Cattlemen Rd #200, Sarasota, FL, 34232, USA.
¹⁶ Biostatistics, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
¹⁷ Oncology Clinical Research, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
¹⁸ Trillium Therapeutics Inc., Cambridge, MA, USA.
¹⁹ Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.

PMID: 32913286
PMCID: PMC7686313
DOI: 10.1038/s41416-020-01041-x

Clinical Trial

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 et al. Br J Cancer. 2020 Nov.

. 2020 Nov;123(11):1590-1598.

doi: 10.1038/s41416-020-01041-x. Epub 2020 Sep 11.

Authors

Affiliations

¹ Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. vossm@mskcc.org.
² Oncology Research, HonorHealth Research Institute, 10510 N 92nd St Suite 200, Scottsdale, AZ, 85258, USA.
³ Department of Hematology and Oncology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd North Tower, Los Angeles, CA, 90048, USA.
⁴ Cleveland Clinic Foundation, Department of Solid Tumor Oncology, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
⁵ Department of Medicine, 300 East 66th Street, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶ Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Passeig de la Vall d'Hebron, 119, 129, 08035, Barcelona, Spain.
⁷ University of Michigan, Department of Internal Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.
⁸ CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Avda. Menéndez Pelayo 4 acc., 46010, Valencia, Spain.
⁹ Vanderbilt University Medical Center, Department of Medicine, Division of Hematology/Oncology, 1161 21st Ave S, Nashville, TN, 37232, USA.
¹⁰ Clovis Oncology, San Francisco, CA, USA.
¹¹ Indiana University-Simon Cancer Center, Department of Medicine, Division of Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA.
¹² Henry Ford Health System, Hematology/Oncology, 1 Ford Pl, Detroit, MI, 48202, USA.
¹³ Indiana University Melvin and Bren Simon Cancer Center, Hematology/Oncology, 535 Barnhill Drive, Indianapolis, IN, 46202, USA.
¹⁴ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
¹⁵ Florida Cancer Specialists/SCRI, Drug Development Unit, 600 N Cattlemen Rd #200, Sarasota, FL, 34232, USA.
¹⁶ Biostatistics, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
¹⁷ Oncology Clinical Research, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
¹⁸ Trillium Therapeutics Inc., Cambridge, MA, USA.
¹⁹ Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.

PMID: 32913286
PMCID: PMC7686313
DOI: 10.1038/s41416-020-01041-x

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.

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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 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.

See this image and copyright information in PMC

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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

Affiliations

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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Abstract

Conflict of interest statement

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