Taiho Pharmaceutical Co., Ltd. // Copyright © 2015 Elsevier Ltd. All rights reserved.
Lancet Oncol. 2015 Mar .
Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study.
Kawai A1, Araki N2, Sugiura H3, Ueda T4, Yonemoto T5, Takahashi M6, Morioka H7, Hiraga H8, Hiruma T9, Kunisada T10, Matsumine A11, Tanase T12, Hasegawa T13, Takahashi S14.
Author information1Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: akawai@ncc.go.jp.2Department of Orthopaedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.3Department of Orthopaedic Surgery, Aichi Cancer Center Hospital, Aichi, Japan.4Department of Orthopaedic Surgery, Osaka National Hospital, Osaka, Japan.5Division of Orthopaedic Surgery, Chiba Cancer Center, Chiba, Japan.6Division of Orthopaedic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.7Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.8Department of Orthopaedic Surgery, Hokkaido Cancer Center, Hokkaido, Japan.9Department of Musculoskeletal Tumor Surgery, Kanagawa Cancer Center, Kanagawa, Japan.10Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.11Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.12Department of Data Science, Taiho Parmaceutical Co., Ltd, Tokyo, Japan.13Department of Surgical Pathology, Sapporo Medical University School of Medicine, Hokkaido, Japan.14Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
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/m2 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.
FINDINGS:
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%).