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Lancet Oncol. 2015 Apr;16(4):406-16. doi: 10.1016/S1470-2045(15)70098-7. Epub 2015 Mar 18.

Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study.

Author information

1
Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: akawai@ncc.go.jp.
2
Department of Orthopaedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
3
Department of Orthopaedic Surgery, Aichi Cancer Center Hospital, Aichi, Japan.
4
Department of Orthopaedic Surgery, Osaka National Hospital, Osaka, Japan.
5
Division of Orthopaedic Surgery, Chiba Cancer Center, Chiba, Japan.
6
Division of Orthopaedic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
7
Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
8
Department of Orthopaedic Surgery, Hokkaido Cancer Center, Hokkaido, Japan.
9
Department of Musculoskeletal Tumor Surgery, Kanagawa Cancer Center, Kanagawa, Japan.
10
Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
11
Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
12
Department of Data Science, Taiho Parmaceutical Co., Ltd, Tokyo, Japan.
13
Department of Surgical Pathology, Sapporo Medical University School of Medicine, Hokkaido, Japan.
14
Department 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/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.

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%]).

INTERPRETATION:

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.

FUNDING:

Taiho Pharmaceutical Co., Ltd.

PMID:
25795406
DOI:
10.1016/S1470-2045(15)70098-7
[Indexed for MEDLINE]

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