title: Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial.
abstract: BACKGROUND
  Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival.
  
  
  METHODS
  Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480.
  
  
  RESULTS
  Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]).
  
  
  CONCLUSIONS
  Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care.
  
  
  BACKGROUND
  Pharmamar and Amgen.
authors: Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. Electronic address: patricia.pautier@gustaveroussy.fr.
authors: Patricia
authors: P
authors: Pautier
authors: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors: Anne
authors: A
authors: Floquet
authors: Department of Medical Oncology, Institut Claudius-Regaud, Toulouse, France.
authors: Christine
authors: C
authors: Chevreau
authors: Department of Medical Oncology, Centre Oscar-Lambret, Lille, France.
authors: Nicolas
authors: N
authors: Penel
authors: Department of Medical Oncology, Centre Henri-Becquerel, Rouen, France.
authors: Cécile
authors: C
authors: Guillemet
authors: Department of Medical Oncology, Centre François-Baclesse, Caen, France.
authors: Corinne
authors: C
authors: Delcambre
authors: Department of Medical Oncology, Centre Val d'Aurelle, Montpellier, France.
authors: Didier
authors: D
authors: Cupissol
authors: Department of Medical Oncology, Hôpital Tenon, Paris, France.
authors: Frédéric
authors: F
authors: Selle
authors: Department of Medical Oncology, Centre GF Leclerc, Dijon, France.
authors: Nicolas
authors: N
authors: Isambert
authors: Department of Medical Oncology, Institut Curie, Paris, France.
authors: Sophie
authors: S
authors: Piperno-Neumann
authors: Department of Medical Oncology Centre Antoine Lacassagne, Nice, France.
authors: Antoine
authors: A
authors: Thyss
authors: Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors: François
authors: F
authors: Bertucci
authors: Department of Medical Oncology, Centre René Gauducheau, Saint Herblain, France.
authors: Emmanuelle
authors: E
authors: Bompas
authors: Department of Medical Oncology, Hôpital Cochin, Paris, France.
authors: Jerôme
authors: J
authors: Alexandre
authors: Department of Medical Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez, France.
authors: Olivier
authors: O
authors: Collard
authors: Department of Medical Oncology, Centre Hospitalo-Universitaire Dupuytren, Limoges, France.
authors: Sandrine
authors: S
authors: Lavau-Denes
authors: Department of Medical Oncology, Centre Paul Papin, Angers, France.
authors: Patrick
authors: P
authors: Soulié
authors: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors: Maud
authors: M
authors: Toulmonde
authors: Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors: Axel
authors: A
authors: Le Cesne
authors: Department of Biostatistics, Institut Gustave Roussy, Villejuif, France.
authors: Benjamin
authors: B
authors: Lacas
authors: Department of Medical Oncology, La Timone University Hospital, Marseille, France.
authors: Florence
authors: F
authors: Duffaud
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D004149:Dioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077606:Trabectedin; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D000077606:Trabectedin