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Phase I Combination Study of Trabectedin and Doxorubicin in Patients with Soft-Tissue Sarcoma

Authors' Affiliations: ¹ CONTICANET and UJOMM Hôpital Edouard Herrot, ² Centre Léon Bérard, Lyon, France; ³ Fox Chase Cancer Center, Philadelphia, Pennsylvania; ⁴ North Idaho Cancer Center, Coeur d'Alene, Idaho; ⁵ St. Vincent's Comprehensive Cancer Center, Manhattan, New York; ⁶ Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey; ⁷ PharmaMar S.A.U., Madrid, Spain; and ⁸ Institute Gustave Roussy, Villejuif, France

Requests for reprints: Jean-Yves Blay, Medical Oncology, INSERM U590 and UJOMM Pav E and Centre Léon Bérard, 28, rue Laennec, Lyon, France. Phone: 33-607507064; Fax: 33-472117398; E-mail: BLAY{at}lyon.fnclcc.fr.

Purpose: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma.

Methods: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m² immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m² on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed.

Results: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m² and doxorubicin 60 mg/m². Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration.

Conclusion: The combination of doxorubicin 60 mg/m² followed by trabectedin 1.1 mg/m² every 21 days is safe and active in patients with soft-tissue sarcoma.

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