Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

医学 耐受性 药理学 临床试验 髓系白血病 组蛋白脱乙酰酶抑制剂 临床终点 神经毒性 肿瘤科 毒性 内科学 不利影响 组蛋白脱乙酰基酶 组蛋白 化学 基因 生物化学
作者
Timothy A. Yap,Naval Daver,Mikhila Mahendra,Jixiang Zhang,Carlos Kamiya-Matsuoka,Funda Meric‐Bernstam,Hagop M. Kantarjian,Farhad Ravandi,Meghan Collins,Maria Emilia Di Francesco,Ecaterina E. Dumbrava,Siqing Fu,Sisi Gao,Jason Gay,Sonal Gera,Jing Han,David S. Hong,Elias Jabbour,Zhenlin Ju,Daniel D. Karp,Alessia Lodi,Jennifer R. Molina,Natalia Baran,Aung Naing,Maro Ohanian,Shubham Pant,Naveen Pemmaraju,Prithviraj Bose,Sarina A. Piha‐Paul,Jordi Rodón,Carolina Salguero,Koji Sasaki,Anand Kumar Singh,Vivek Subbiah,Apostolia M. Tsimberidou,Quanyun A. Xu,Musa Yılmaz,Qi Zhang,Yuan Li,Christopher A. Bristow,Meenakshi B. Bhattacharjee,Stefano Tiziani,Timothy P. Heffernan,Christopher P. Vellano,Philip Jones,Cobi J. Heijnen,Annemieke Kavelaars,Joseph R. Marszalek,Marina Konopleva
出处
期刊:Nature Medicine [Springer Nature]
卷期号:29 (1): 115-126 被引量:145
标识
DOI:10.1038/s41591-022-02103-8
摘要

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.
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