Abstract CT238: An open-label, phase 1 study of IDO inhibitor KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma
Authors: Desai Pratibha , Rao Santosh , Ikawa Yuta , Kapelan Barbara , Efuni Sergey , Latek Robert , Sato Takashi , Healy Denis , Zakharia Yousef 
Published: September 2020

Abstract
Background: Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan to kynurenine, suppressing T cell effector activity and increasing T regulatory cell activity. IDO1 expression is induced in some cancer cells and has been associated with suppression of effector T cell responses toward tumors. In nonclinical studies, IDO1 inhibition combined with other clinically established immune modulating agents (eg, anti-CTLA-4 or anti-PD-1 antibodies) showed a significant improvement in tumor growth suppression. KHK2455 is a long acting and selective IDO1 inhibitor under development as a new approach to enhance anti-tumor immunity. KHK2455 is being combined with different anti-cancer therapies to explore its ability to enhance anti-tumor immunity and overcome tumor immune evasion. Avelumab is a PD-L1 checkpoint inhibitor approved for treatment of urothelial carcinoma. This study represents an opportunity to assess the complementary action of KHK2455 IDO1 inhibition and avelumab checkpoint inhibition in the treatment of urothelial carcinoma. Methods: Study 2455-002 is a two-part, multicenter, open-label Phase 1 study of KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma (including bladder, urethra, ureters, and renal pelvis), who are checkpoint inhibitor naїve and previously treated with platinum-based therapy. Part 1 (dose-escalation) has a 3+3 design to evaluate safety and tolerability and identify the maximum tolerated dose (MTD). Dose de-escalation based on dose limiting toxicities is permitted. Part 2 (cohort expansion) further explores the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity for the combination regimen at the MTD or highest tested dose. All subjects will receive oral KHK2455 at their assigned dose and avelumab IV. The primary study endpoints are safety and tolerability, and the secondary endpoints are efficacy (based on RECIST v1.1 criteria), pharmacokinetics, and immunogenicity. Exploratory endpoints include examination of pre and post treatment biopsies for intratumoral suppression of IDO1 activity to correlate peripheral and intratumoral suppression, along with pre and post treatment serum markers including, but not limited to, immune mediators and related cytokines. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for continuous variables and frequency distributions and percentages for discrete variables will be utilized. Approximately 44 subjects are planned for enrollment (12 subjects in Part 1 and 32 subjects in Part 2). Clinical trial information: NCT03915405 (sponsor: Kyowa Kirin Pharmaceutical Development, Inc.)
Citation Format: Pratibha Desai, Santosh Rao, Yuta Ikawa, Barbara Kapelan, Sergey Efuni, Robert Latek, Takashi Sato, Denis Healy, Yousef Zakharia. An open-label, phase 1 study of IDO inhibitor KHK2455 in combination with avelumab in adult subjects with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT238.