First-in-Human Phase 1 Study of KHK2455 Monotherapy and in Combination With Mogamulizumab in Patients With Advanced Solid Tumors

Authors

Timothy A Yap
Olivier Rixe
Capucine Baldini
Ursa Brown-Glaberman
Sergey Efuni
David S Hong
Christophe Massard
Jameel Muzaffar
Andreea Varga
Emrullah Yilmaz
Yuta Ikawa
Lisa H Shiue
Yi Liu
Matthew W Hruska
Henry Zhao
Akihiro Tokunaga
Solmaz Sahebjam

Publication Date

7-1-2025

Journal

Cancer

DOI

10.1002/cncr.35939

PMID

40536766

PMCID

PMC12178318

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors.

Methods: Patients received oral KHK2455 at fixed doses of 0.3, 1, 3, 10, 30, and 100 mg once daily as run-in monotherapy for 28 days (cycle 0), and then in combination with 1 mg/kg intravenous mogamulizumab given weekly for cycle 1 and every 2 weeks from cycle 2 onward.

Results: Thirty-six patients were enrolled. One patient with an initial diagnosis of lower esophageal cancer (100-mg cohort) experienced grade 3 gastrointestinal necrosis, and did not receive mogamulizumab. Overall, KHK2455 + mogamulizumab was well tolerated, with manageable adverse events at all doses. KHK2455 + mogamulizumab demonstrated dose-dependent plasma concentration increases and suppression of IDO1 activity. One patient with advanced bevacizumab-resistant glioblastoma demonstrated a durable confirmed Response Evaluation Criteria in Solid Tumors, version 1.1, partial response, and nine patients achieved a durable disease stabilization of ≥6 months. On the basis of the preliminary antitumor response, the cohort expansion was not initiated.

Conclusions: KHK2455 + mogamulizumab was safe and well tolerated with manageable toxicities, and resulted in dose-dependent suppression of IDO1 activity; signals of antitumor activity were observed.

Keywords

Adult, Aged, Female, Humans, Male, Middle Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Neoplasms, indoleamine 2, 3‐dioxygenase 1 (IDO1) protein, mogamulizumab, pharmacodynamics, pharmacokinetics, phase 1 clinical trial, preclinical drug evaluation

Published Open-Access

yes

Recommended Citation

Yap, Timothy A; Rixe, Olivier; Baldini, Capucine; et al., "First-in-Human Phase 1 Study of KHK2455 Monotherapy and in Combination With Mogamulizumab in Patients With Advanced Solid Tumors" (2025). Faculty, Staff and Student Publications. 4488.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4488