Published OnlineFirst August 27, 2019; DOI: 10.1158/1078-0432.CCR-19-1090 Clinical Trials: Immunotherapy Clinical Cancer Research 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 Toshihiko Doi1, Kei Muro2, Hiroshi Ishii3, Terufumi Kato4, Takahiro Tsushima5, Mitsuhiro Takenoyama6, Satoshi Oizumi7, Kazuto Gemmoto8, Hideaki Suna8, Kouki Enokitani9, Tetsuyoshi Kawakami9, Hiroyoshi Nishikawa10,11, and Noboru Yamamoto12 Abstract Purpose: Regulatory T cells (Tregs) expressing CC chemo- part and 90 in the expansion part. No dose-limiting kine receptor 4 (CCR4) can suppress antitumor immune toxicities were observed in the dose-escalation part. Grade responses and are associated with poor prognoses in several 3/4 treatment-related adverse events (TRAEs) occurred in cancers. We assessed the safety and efficacy of combined 29% of patients in the expansion part (no grade 5 TRAEs). mogamulizumab (anti-CCR4 antibody) and nivolumab The most frequent TRAEs were rash (39%), rash maculopap- [anti-programmed death-1 (PD-1) antibody] in immunother- ular (20%), diarrhea (13%), stomatitis (12%), and pruritus apy-na€ve patients with advanced/metastatic solid tumors. (11%). There were four (27%) confirmed tumor responses Patients and Methods: This study (NCT02476123) com- among 15 patients with hepatocellular carcinoma, and prised dose-escalation (3þ3 design) and expansion parts. one confirmed and two unconfirmed responses among 15 Patients received nivolumab (3.0 mg/kg) every 2 weeks, with patients with pancreatic adenocarcinoma. During treatment, þ À mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, populations of effector Tregs (CD4 CD45RA FoxP3high) þ 1.0 mg/kg in expansion) once weekly for 4 weeks, then every decreased and CD8 T cells in tumor-infiltrating lymphocytes 2 weeks, until progression or unacceptable toxicity. Primary increased. objective was safety; secondary objectives were antitumor Conclusions: Combining an anti–PD-1 antibody, nivo- effects, pharmacokinetics, and immunogenicity. Exploratory lumab, with a Treg-depleting anti-CCR4 antibody, moga- biomarker analyses were conducted. mulizumab, provides an acceptable safety profile, antitu- Results: Ninety-six patients were enrolled (July mor activity, and a potentially effective option in cancer 2015ÀNovember 2016): six patients in the dose-escalation immunotherapy. Introduction 1Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan. 2Clinical Oncology and Outpatient Treatment Center, Aichi The immune checkpoint programmed death-1 (PD-1) receptor Cancer Center Hospital, Nagoya, Japan. 3Clinical Research Center, National and its ligand PD-L1 suppress antitumor immunity. Nivolumab, a 4 Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. Division of human IgG4 anti–PD-1 mAb, has been shown in randomized 5 Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan. Division of GI controlled studies to provide clinical benefits in patients with Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 6Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, various tumors, and is associated with health-related quality-of- Japan. 7Department of Respiratory Medicine, National Hospital Organization life improvement in patients with advanced melanoma and Hokkaido Cancer Center, Sapporo, Japan. 8Oncology Clinical Development Unit, advanced renal cell carcinoma (1–3). However, it has recently Ono Pharmaceutical Co., Ltd., Osaka, Japan. 9R&D Division, Kyowa Kirin Co., Ltd., been reported that primary, adaptive, or acquired resistance to 10 Tokyo, Japan. Department of Immunology, Nagoya University Graduate anti–PD-1/PD-L1 therapy may be partially mediated by regula- 11 School of Medicine, Nagoya, Japan. Division of Cancer Immunology, Research tory T cells (Tregs; ref. 4), and that these Tregs inhibit immune Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), Nation- al Cancer Center, Tokyo, Japan. 12Department of Experimental Therapeutics, responses against tumors (5). National Cancer Center Hospital, Tokyo, Japan. Mogamulizumab is a humanized IgG1 mAb targeting the CC chemokine receptor 4 (CCR4) that has a defucosylated Fc region, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). which enhances the antibody-dependent cellular cytotoxicity (ADCC; ref. 6), and has been approved for T-cell lymphomas by Corresponding Author: Toshihiko Doi, National Cancer Center Hospital East, the Pharmaceuticals and Medical Devices Agency, Food and Drug 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba-ken 277-8577, Japan. Phone: 814-7133- 1111; Fax: 814-7131-9960; E-mail: [email protected] Administration, and European Medicines Agency. The tolerabil- ity, safety, and antitumor activity of mogamulizumab against Clin Cancer Res 2019;XX:XX–XX CCR4-expressing T-cell lymphomas accompanied by the rapid doi: 10.1158/1078-0432.CCR-19-1090 and long-lasting depletion of peripheral Tregs have been con- Ó2019 American Association for Cancer Research. firmed in multiple clinical trials (7–9). In anticipation of this www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst August 27, 2019; DOI: 10.1158/1078-0432.CCR-19-1090 Doi et al. confirmed solid tumors; had progressed, been intolerant to any Translational Relevance standard treatment regimen, or had refused standard therapy; It was widely known that PD-1/PD-L1 inhibitors have were at least 20 years old; had measurable disease based on the encouraging clinical activity in several cancers and that Tregs revised Response Evaluation Criteria In Solid Tumors (RECIST) are key cells that affect the immunosuppressive tumor micro- guidelines version 1.1; had Eastern Cooperative Oncology Group environment. Before this study, there was no clinical evidence performance status score of 0 or 1; had adequate hematologic, regarding the combination of Treg depletion and an anti–PD- renal, hepatic, and respiratory functions; and had a life expectancy 1/PD-L1 antibody in patients with solid tumors. To our of at least 3 months. Key exclusion criteria were previous treatment knowledge, this is the first clinical report to provide evidence with antibodies or drugs that target T-cell costimulation or check- for the mechanism of tumor immunity activation by Treg point pathways, or with mogamulizumab. Patients who were depletion in the tumor microenvironment. Combination pregnant or lactating, or who had uncontrolled central nervous therapy with mogamulizumab and nivolumab resulted in a system metastases or known carcinomatous meningitis, were not þ clear depletion of effector Tregs and the expansion of CD8 eligible. Patients with HCC were required to have Child-Pugh T cells in tumor-infiltrating lymphocytes. In addition, a man- scores of 5 or 6 (Child-Pugh A). Patients infected with hepatitis B ageable safety profile and several tumor responses were virus (HBV) (HBs antigen positive) were excluded because of a observed in patients with solid tumors. These results provide potential risk of HBV reactivation by mogamulizumab (16). clinical evidence for the safety and potential efficacy of moga- This study was conducted in accordance with the Declaration of mulizumab and nivolumab combination therapy, as well as Helsinki and the Good Clinical Practice guidelines (GCP) and is the potential role of biomarkers in mediating the antitumor registered at ClinicalTrials.gov (identifier NCT02476123). The effects. study protocol and amendments were approved by the institu- tional review board of each participating institute, and written informed consent was obtained from all patients before conduct- ing any study-related procedures. antitumor activity by the depletion of Tregs, a phase I study of mogamulizumab monotherapy in patients with solid cancers was Procedures performed and a reduction in peripheral Tregs was clearly Patients were enrolled in a 3þ3 design and received nivolumab observed (10). (3.0 mg/kg) intravenously every 2 weeks and mogamulizumab at High levels of tumor-infiltrating effector Tregs are associated 0.3 mg/kg (cohort 1) or 1.0 mg/kg (cohort 2) in the dose- with poor clinical prognoses in some solid tumors (11). More- escalation part and 1.0 mg/kg in the expansion part weekly during þ À over, effector Tregs, which are defined by CD4 CD45RA Fork- cycle 1 and subsequently every 2 weeks until disease progression head box protein P3 (FoxP3)high that highly expresses CCR4, have or unacceptable toxicity. Each cycle lasted 28 days, and the the highest suppressive effects on antitumor immune responses in duration of a cycle was extended in the case of dose delays (the peripheral blood and the tumor microenvironment (TME; criteria for dose delays are provided in the Supplementary Data). ref. 12). According to a previous clinical study, patients with Oral antihistamine and acetaminophen were administered as melanoma who progressed after treatment with nivolumab and premedication before each dose, and a systemic corticosteroid a multipeptide vaccine had increased Tregs in peripheral blood was administered intravenously prior to the first dose of moga- compared with those who did not have progressive disease (13). mulizumab to prevent infusion-related reactions. Patients were Interestingly, a recent preclinical study suggested