A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.

Abstract

PURPOSE:

Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-naïve patients with advanced/metastatic solid tumors.

PATIENTS AND METHODS:

This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.

RESULTS:

Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.

CONCLUSIONS:

Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.

• Authors: Toshihiko Doi, Kei Muro, Hiroshi Ishii, Terufumi Kato, Takahiro Tsushima, Mitsuhiro Takenoyama, Satoshi Oizumi, Kazuto Gemmoto, Hideaki Suna, Kouki Enokitani, Tetsuyoshi Kawakami, Hiroyoshi Nishikawa, Noboru Yamamoto
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 22 Pg. 6614-6622 (11 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31455681 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• Receptors, CCR4
• Nivolumab
• mogamulizumab

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers, Tumor
• Combined Modality Therapy
• Female
• Gene Expression
• Humans
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms (drug therapy, metabolism, mortality, pathology)
• Nivolumab (administration & dosage)
• Receptors, CCR4 (antagonists & inhibitors)
• Retreatment
• T-Lymphocyte Subsets (drug effects, immunology, metabolism)
• Treatment Outcome
• Tumor Microenvironment (immunology)