Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.
Клиническое исследование I фазыСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Yap Timothy A, Daver Naval, Mahendra Mikhila, Zhang Jixiang, Kamiya-Matsuoka Carlos, Meric-Bernstam Funda, Kantarjian Hagop M, Ravandi Farhad, Collins Meghan E, Francesco Maria Emilia Di, Dumbrava Ecaterina E, Fu Siqing, Gao Sisi, Gay Jason P, Gera Sonal, Han Jing, Hong David S, Jabbour Elias J, Ju Zhenlin, Karp Daniel D, Lodi Alessia, Molina Jennifer R, Baran Natalia, Naing Aung, Ohanian Maro, Pant Shubham, Pemmaraju Naveen, Bose Prithviraj, Piha-Paul Sarina A, Rodon Jordi, Salguero Carolina, Sasaki Koji, Singh Anand K, Subbiah Vivek, Tsimberidou Apostolia M, Xu Quanyun A, Yilmaz Musa, Zhang Qi, Li Yuan, Bristow Christopher A, Bhattacharjee Meenakshi B, Tiziani Stefano, Heffernan Timothy P, Vellano Christopher P, Jones Philip, Heijnen Cobi J, Kavelaars Annemieke, Marszalek Joseph R, Konopleva Marina
Аннотация
Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.