Originally published as JCO Early Release 10.1200/JCO.2008.21.0088 on August 3 2009

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Efficacy and Safety of Trabectedin in Patients With Advanced or Metastatic Liposarcoma or Leiomyosarcoma After Failure of Prior Anthracyclines and Ifosfamide: Results of a Randomized Phase II Study of Two Different Schedules

From the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Sarcoma Oncology Center, Santa Monica, CA; Fox Chase Cancer Center, Philadelphia, PA; Medical College of Wisconsin, Milwaukee, WI; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, MI; Vanderbilt-Ingram Cancer Center, Nashville, TN; Columbia Presbyterian Medical Center, NY; North Idaho Cancer Center, Coeur d'Alene, ID; Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ; Centre Léon Bérard, Lyon, France; PharmaMar Clinical R&D, Colmenar Viejo, Madrid, Spain; and the Institut Gustave Roussy, Villejuif, France.

Corresponding author: George D. Demetri, MD, Center for Sarcoma and Bone Oncology and Ludwig Center of Dana-Farber/Harvard Cancer Center; Dana-Farber Cancer Institute, D1212; 44 Binney St, Boston, MA 02115; e-mail: gdemetri{at}partners.org.

Purpose To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide.

Patients and Methods Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m² 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m² 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images.

Results Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted.

Conclusion Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.

Supported in part by funding from PharmaMar SAU, as well as with philanthropic support (G.D.D.) from the following sources: The Virginia and Daniel K. Ludwig Trust for Cancer Research, the Rubenstein Foundation, the Katz Foundation, the Quick Family Fund for Cancer Research, the Ronald O. Perelman Fund for Cancer Research at Dana-Farber, Leslie's Links, and the Fasseus and Close Family Funds for Liposarcoma Research.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology 2007.

Written on behalf of the Trabectedin Global Sarcoma Study Group.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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