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Purpose: Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S. Experimental Design: The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose–escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks. Results: Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed. Conclusion: IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted. Clin Cancer Res; 22(21); 5204–10. ©2016 AACR.

Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.Kyowa Kirin.

3040Background: 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. Unlike other ...

TPS8622 Background: The receptor for macrophage derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC) CC chemokine receptor 4 (CCR4) is over expressed in several T-cell mali...

Introduction: Cutaneous T- cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Patients with CTCL suffer reduced quality of life from intractable itching and recurrent infections. Advanced stages have a poor prognosis. Mogamulizumab (Moga) is a monoclonal antibody directed against chemokine receptor 4 (CCR4), which is overexpressed on malignant T-cells. In a Phase I-II study in CTCL, Moga demonstrated a tolerable safety profile with a 37% overall response rate (ORR). Based on these results, MAVORIC [NCT01728805], an open-label, multinational, randomized, Phase III study, was initiated to compare Moga to vorinostat (Vor) in previously treated CTCL. This study is the largest randomized trial and the first pivotal trial to use progression-free survival (PFS) as a primary endpoint in CTCL. Methods: Adult patients with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 systemic therapy were enrolled, stratified by disease type (MF or SS) and stage (IB/II or III/IV), and randomized 1:1 to Moga 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or Vor (400 mg daily). Patients randomized to Vor could crossover to Moga upon progression or intolerable toxicity. The primary endpoint was investigator-assessed PFS in the randomized population using the global composite response (based on skin, blood, nodes and viscera) according to the ISCL/EORTC consensus guidelines. Sample size was calculated to provide 90% power to detect a 50% improvement in PFS. Key secondary endpoints included ORR, duration of response (DOR) and quality of life (QoL). Results: A total of 372 patients were randomized (Intent-to-Treat population) and had the following characteristics (Moga vs Vor): median age 63.5 yrs (25-101) vs 65.0 yrs (25-89); ECOG-PS 0-1, 184 (99%) vs 186 (100%); ECOG-PS 2, 2 (1%) vs 0; stage IB/IIA, 36 (19.4%) vs 49 (26.3%); stage IIB, 32 (17.2%) vs 23 (12.4%); stage III/IV, 118 (63.4%) vs 114 (61.3%); MF, 105 (56.5%) vs 99 (53.2%); SS, 81 (43.5%) vs 87 (46.8%). The median number of prior systemic treatments for both the Moga and Vor arms was 3. According to investigator assessment, treatment with Moga resulted in a significant improvement in PFS compared to Vor (HR 0.53 [95% CI: 0.41, 0.69], p20%) that were more frequent (>15% difference) in the Moga vs Vor arm included infusion-related reactions (33.2% vs 0.5%, respectively) and skin eruptions due to drug (23.9% vs 0.5%, respectively). The majority of TEAEs with Moga were mild to moderate in severity (grade I/II, 54.9%; grade III/IV/V, 42.4%). Common TEAEs reported more often with Vor vs Moga included diarrhea (61.8% vs 23.4%), nausea (42.5% vs 15.2%), thrombocytopenia (30.6% vs 11.4%), dysgeusia (29.0% vs 3.3%), and increased blood creatinine (28.0% vs 3.3%). Conclusions: In this first report of a randomized Phase III study evaluating PFS as primary endpoint in CTCL, Moga, a novel CCR4-targeting antibody therapy, demonstrated significantly superior PFS, ORR, and QoL compared to Vor in patients with previously treated CTCL. The safety profile was consistent with previous reports. This study supports Moga as a valuable new therapeutic option in patients with CTCL. Disclosures Kim: Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bagot: Innate Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees. Horwitz: Kyowa-Hakka-Kirin: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron Therapeutics: Research Funding. Whittaker: Celgene: Honoraria; Galderma: Research Funding. Vermeer: Innate Pharma safety board for IPH4102-101: Membership on an entity's Board of Directors or advisory committees. Zinzani: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sokol: Spectrum Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Kim: Kyowa Kirin Pharmaceutical Development, Inc.: Other: Clinical trials investigator; Solgenix: Other: Clinical trials investigator; Actelion: Consultancy; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; US Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy. Ortiz-Romero: ACTELION: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding. Eradat: Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Scarisbrick: 4SC: Consultancy; Takeda: Consultancy; Mallinckrodt: Consultancy; Innate Pharma: Consultancy; Actelion: Consultancy. Elmets: NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Assn: Research Funding; Solegenix: Research Funding; Idera: Research Funding; Elorac: Research Funding; Ferndale Labs: Consultancy, Research Funding; Astellas Pharma: Research Funding. Dalle: Kyowa Hakko Kirin Pharmaceutical: Research Funding. Fisher: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Halwani: Amgen: Research Funding; Pharmacyclics: Research Funding; Takeda: Research Funding; Genetech Inc.: Research Funding; Roche/Genentech Inc.: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; Kyowa Hikko Kirin: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Poligone: Actelion Pharmaceutical: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding. Khot: Celgene: Consultancy; Janssen: Consultancy; Amgen: Other: Travel Grant. Moskowitz: Incyte: Research Funding; Takeda: Honoraria; Bristol Myers-Squibb: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding. Dwyer: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Moriya: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Humphrey: KYOWA KYRIN PHARMACEUTICAL DEVELOPMENT: Employment. Hudgens: Clinical Outcomes Solutions: Consultancy, Research Funding. Grebennik: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Tobinai: AbbVie: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding. Duvic: MDACC: Other: Safety Oversight Committee, Research Funding.