title: Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study.
abstract: BACKGROUND
  Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma.
  
  
  METHODS
  We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1·2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850.
  
  
  RESULTS
  Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5·6 months (95% CI 4·1-7·5) and the best supportive care group was 0·9 months (0·7-1·0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0·07 (90% CI 0·03-0·14 and 95% CI 0·03-0·16) by a Cox proportional hazards model (p<0·0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]).
  
  
  CONCLUSIONS
  Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population.
  
  
  BACKGROUND
  Taiho Pharmaceutical Co., Ltd.
authors: Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: akawai@ncc.go.jp.
authors: Akira
authors: A
authors: Kawai
authors: Department of Orthopaedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Nobuhito
authors: N
authors: Araki
authors: Department of Orthopaedic Surgery, Aichi Cancer Center Hospital, Aichi, Japan.
authors: Hideshi
authors: H
authors: Sugiura
authors: Department of Orthopaedic Surgery, Osaka National Hospital, Osaka, Japan.
authors: Takafumi
authors: T
authors: Ueda
authors: Division of Orthopaedic Surgery, Chiba Cancer Center, Chiba, Japan.
authors: Tsukasa
authors: T
authors: Yonemoto
authors: Division of Orthopaedic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
authors: Mitsuru
authors: M
authors: Takahashi
authors: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors: Hideo
authors: H
authors: Morioka
authors: Department of Orthopaedic Surgery, Hokkaido Cancer Center, Hokkaido, Japan.
authors: Hiroaki
authors: H
authors: Hiraga
authors: Department of Musculoskeletal Tumor Surgery, Kanagawa Cancer Center, Kanagawa, Japan.
authors: Toru
authors: T
authors: Hiruma
authors: Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors: Toshiyuki
authors: T
authors: Kunisada
authors: Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
authors: Akihiko
authors: A
authors: Matsumine
authors: Department of Data Science, Taiho Parmaceutical Co., Ltd, Tokyo, Japan.
authors: Takanori
authors: T
authors: Tanase
authors: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Hokkaido, Japan.
authors: Tadashi
authors: T
authors: Hasegawa
authors: Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Shunji
authors: S
authors: Takahashi
mesh_terms: D000328:Adult; D003907:Dexamethasone / Q000008:administration & dosage; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077606:Trabectedin; D016896:Treatment Outcome
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003907:Dexamethasone; D000077606:Trabectedin