title: Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).
abstract: BACKGROUND
  Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest.
  
  
  METHODS
  We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose.
  
  
  RESULTS
  Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing.
  
  
  CONCLUSIONS
  The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.
authors.affiliation: University of Heidelberg, Mannheim University Medical Center, Interdisciplinary Tumor Center Mannheim, Sarcoma Unit, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. bernd.kasper@umm.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kasper
authors.affiliation: HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Schwanebecker Chaussee 50, D-13125 Berlin, Germany. peter.reichardt@helios-kliniken.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.affiliation: HELIOS Klinikum Bad Saarow, Pieskower Straße 33, D-15526 Bad Saarow, Germany. daniel.pink@helios-kliniken.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pink
authors.affiliation: University of Heidelberg, Mannheim University Medical Center, Interdisciplinary Tumor Center Mannheim, Sarcoma Unit, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. michaela.sommer@umm.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Sommer
authors.affiliation: University of Heidelberg, Mannheim University Medical Center, Interdisciplinary Tumor Center Mannheim, Sarcoma Unit, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. monika.mathew@umm.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Mathew
authors.affiliation: University of Heidelberg, Institute of Medical Biometry and Informatics, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. rauch@imbi.uni-heidelberg.de.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rauch
authors.affiliation: University of Heidelberg, Mannheim University Medical Center, Interdisciplinary Tumor Center Mannheim, Sarcoma Unit, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. peter.hohenberger@umm.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenberger
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy; D008080:Liposarcoma / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D000077606:Trabectedin; D000637:Transaminases / Q000097:blood; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003841:Deoxycytidine; D000637:Transaminases; D000077606:Trabectedin; D000093542:Gemcitabine