title: Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.
abstract: OBJECTIVE
  Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients.
  
  
  METHODS
  Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity.
  
  
  RESULTS
  All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities.
  
  
  CONCLUSIONS
  IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamazaki
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Uhara
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Uchi
authors.affiliation: Department of Dermatology, Yamanashi University Hospital, Yamanashi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shibagaki
authors.affiliation: Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kiyohara
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tsutsumida
authors.affiliation: Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Namikawa
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Okuyama
authors.affiliation: Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Otsuka
authors.affiliation: Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. takuto0806@gmail.com.
authors.forename: T
authors.initials: T
authors.lastname: Tokudome
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D004700:Endocrine System Diseases / Q000139:chemically induced; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D000074324:Ipilimumab; D007564:Japan; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D000074324:Ipilimumab; D009363:Neoplasm Proteins; D003606:Dacarbazine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Dacarbazine; Immune-checkpoint inhibitor; Ipilimumab; Japanese patients; Melanoma; Phase 2 study