Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma

Jean Yves Blay, Margaret Von Mehren, Brian L. Samuels, Michael P. Fanucchi, Isabelle Ray-Coquard, Brigid Buckley, Leen Gilles, Claudia Lebedinsky, Yusri A. Elsayed, Axel Le Cesne

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78 Scopus citations

Abstract

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 doxorubicin60mg/m 2 immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m 2 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/m 2 and doxorubicin 60 mg/m 2. 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/m 2 followed by trabectedin 1.1 mg/m 2 every 21 days is safe and active in patients with soft-tissue sarcoma.

Original languageEnglish
Pages (from-to)6656-6662
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number20
DOIs
StatePublished - Oct 15 2008

Keywords

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics
  • Dioxoles/administration & dosage
  • Disease-Free Survival
  • Doxorubicin/administration & dosage
  • Female
  • Granulocyte Colony-Stimulating Factor/administration & dosage
  • Humans
  • Leiomyosarcoma/blood
  • Liposarcoma/blood
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Prognosis
  • Sarcoma/blood
  • Survival Rate
  • Tetrahydroisoquinolines/administration & dosage
  • Trabectedin
  • Young Adult

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