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287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors
  1. Solmaz Sahebjam1,
  2. Jameel Muzaffar1,
  3. Timothy Yap2,
  4. David Hong2,
  5. Olivier Rixe3,
  6. Ursa Brown-Glaberman4,
  7. Andreea Varga5,
  8. Christophe Massard5,
  9. Capucine Baldini5,
  10. Sergey Efuni6,
  11. Barbara Kapelan6,
  12. Yi Liu6,
  13. Eniola Ogunmefun6,
  14. Tomonori Tayama6,
  15. Henry Zhao6,
  16. Denis Healy6,
  17. Robert Latek6,
  18. Daisuke Nakashima7 and
  19. Emrullah Yilmaz8
  1. 1H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
  2. 2University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
  3. 3Quantum Santa Fe, Albuquerque, NM, USA
  4. 4University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA
  5. 5Institut de Cancérologie Gustave Roussy, Villejuif, France
  6. 6Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA
  7. 7Kyowa Kirin Co. Ltd., Tokyo, Japan
  8. 8University of New Mexico Comprehensive Comprehensive Cancer Center, Albuquerque, NM, USA


Background IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.

Methods In this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.

Results Thirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).

Abstract 287 Table 1

Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)

Abstract 287 Table 2
Abstract 287 Figure 1

Study 2455-001: Overall Survival

Conclusions KHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.

Acknowledgements Medical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.

Trial Registration NCT02867007 (

Ethics Approval This study was approved by Ethics Committees at all participating study institutions.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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