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.

ESMO Open
Kathleen N MooreManish R Patel

Abstract

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. 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. 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 fas...Continue Reading

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Citations

Jun 25, 2019·ESMO Open·Christoph C Zielinski
Feb 6, 2020·Pathology Oncology Research : POR·Ildiko KrenczAndras Khoor
Jan 11, 2020·Frontiers in Oncology·Karen Griselda de la Cruz LópezAlejandro García Carrancá
Jul 20, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dean C BottinoArijit Chakravarty
Jan 9, 2020·Molecular Cancer Therapeutics·Melanie A KrookSameek Roychowdhury
Jan 23, 2021·RSC Medicinal Chemistry·Daniel J Baillache, Asier Unciti-Broceta
Jan 19, 2020·Trends in Cancer·Shawn McGuirkJulie St-Pierre
Dec 12, 2020·Frontiers in Endocrinology·Sara ZaniniGiovanna Bermano
Apr 17, 2021·Breast Cancer Research and Treatment·Emre KocaJenny Chee Ning Chang
Apr 7, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bora LimJennifer R Diamond
Nov 6, 2021·Scientific Reports·Thanh-Trang VoDavid A Fruman

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Methods Mentioned

BETA
xenograft

Clinical Trials Mentioned

NCT02412722

Software Mentioned

GastroPlus ( Simulations Plus

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