Clinical trial NCT01189253: Doxorubicin Hydrochloride or Trabectedin in Treating Patients With Previously Untreated Advanced or Metastatic Soft Tissue Sarcoma
Official title: TRUSTS: A Phase IIB/III Multicenter Study Comparing the Efficacy of TRabectedin Administered as a 3-Hour or 24-Hour Infusion to Doxorubicin in Patients With Advanced or Metastatic Untreated Soft Tissue Sarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Sarcoma
Keywords: stage III adult soft tissue sarcoma
stage IV adult soft tissue sarcoma
adult alveolar soft-part sarcoma
adult angiosarcoma
adult desmoplastic small round cell tumor
adult epithelioid sarcoma
adult extraskeletal chondrosarcoma
adult extraskeletal osteosarcoma
adult fibrosarcoma
adult leiomyosarcoma
adult malignant fibrous histiocytoma
adult malignant hemangiopericytoma
adult malignant mesenchymoma
adult neurofibrosarcoma
adult synovial sarcoma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Sarcoma Alliance for Research through Collaboration
First posted: 2010-08-26
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride and trabectedin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether trabectedin is more effective than doxorubicin hydrochloride in treating patients with advanced or metastatic soft tissue sarcoma.

PURPOSE: This randomized phase II/III trial is studying the safety of trabectedin compared with doxorubicin hydrochloride and to see how well they work in treating patients with advanced or metastatic soft tissue sarcoma.

Detailed description: OBJECTIVES:

* To evaluate whether trabectedin given as first-line chemotherapy for patients with previously untreated advanced or metastatic malignant soft tissue sarcoma prolongs progression-free survival as compared to doxorubicin hydrochloride.
* To identify and validate biomarkers (including, but not limited to, XPG, BRCA1, RAD51, BRCA2, ATM and CHK1) of sensitivity to trabectedin in order to allow the selection of patients that benefit most from trabectedin treatment. (Optional translational research)

OUTLINE: This is a multicenter, phase IIB study followed by a phase III study. Patients are stratified according to institution, age at registration (\< 60 years old vs ≥ 60 years old), and presence of liver metastases (yes vs no).

* Phase IIB (step 1): Patients are randomized to 1 of 3 treatment arms.

  * Arm I: Patients receive doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  * Arm II: Patients receive trabectedin IV over 3 hours on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
  * Arm III: Patients receive trabectedin IV continuously over 24 hours on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

At the end of step 1, the best regimen of trabectedin will be determined. Patients receiving the non-selected trabectedin regimen ("losing arm") are offered to cross over in order to receive the selected regimen of trabectedin.

* Phase III (step 2): Patients are randomized to 1 of 2 treatment arms.

  * Arm I: Patients receive trabectedin IV on day 1 using the preferred regimen determined in step 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
  * Arm II: Patients receive doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life questionnaire (EORTC QLQ-C30 version 3) at baseline, at 6, 12, 24, and 36 weeks during study, and at the end of study.

Tumor tissue block obtained at diagnosis may be analyzed to identify and validate biomarkers of sensitivity to trabectedin and for tissue microarrays.

After completion of study therapy, patients are followed up at 1 month, every 6 or 12 weeks until disease progression, and every 12 weeks thereafter.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed intermediate- or high-grade malignant soft tissue sarcoma

  * Advanced and/or metastatic disease
  * Previously untreated disease
* The following tumor types are not allowed:

  * Well-differentiated liposarcoma
  * Embryonal rhabdomyosarcoma
  * Chondrosarcoma (excluding extraskeletal myxoid chondrosarcoma)
  * Osteosarcoma (excluding extraskeletal osteosarcoma)
  * Ewing tumors/primitive neuroectodermal tumor (PNET)
  * Gastrointestinal stromal tumors (GIST)
  * Dermatofibrosarcoma protuberans
* Must have confirmed disease progression based on investigator's judgment prior to study enrollment
* Measurable disease according to RECIST v 1.1 criteria

  * Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion
* Formalin fixed paraffin embedded tumor blocks or representative hematoxylin/eosin slides (preferably both) available (local histopathological diagnosis will be accepted for trial entry)
* No prior anticancer therapy for this disease

  * No prior anthracycline
  * Non-anthracycline therapy for nonmetastatic disease is acceptable
* No known history of CNS metastases or leptomeningeal tumor spread

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Absolute neutrophil count ≥ 1.5 x 10\^9/L
* Hemoglobin ≥ 9 g/dL
* Platelet count ≥ 100 x 10\^9/L
* Bilirubin normal
* ALT/AST ≤ 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase ≤ 2.5 times ULN, (if alkaline phosphatase \> 2.5 times ULN, hepatic isoenzymes 5-nucleotidase and/or GGT must be within the normal range)
* Albumin \> 30 g/L
* Serum creatinine ≤ 1.5 times ULN
* Creatinine clearance ≥ 30 mL/min
* Creatine phosphokinase (CPK) ≤ 2.5 times ULN
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception (double barrier method for men) 2 weeks prior to, during, and for 3 months (women) or 5 months (men) after completion of study therapy
* LVEF normal by MUGA scan or ECHO
* 12-lead ECG normal (without clinically significant abnormalities)
* None of the following unstable cardiac conditions:

  * Congestive heart failure
  * Angina pectoris
  * Myocardial infarction within the past year
  * Uncontrolled arterial hypertension, defined as BP ≥ 150/100 mm Hg despite optimal medical therapy
  * Clinically significant arrhythmias
* No active or uncontrolled infections or serious illnesses or medical conditions, including a history of any of the following:

  * Chronic alcohol abuse
  * Hepatitis
  * HIV
  * Cirrhosis
* No history of malignancy within the past 5 years, except soft tissue sarcoma, basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason score ≤ 6 and postoperative PSA \< 0.5 ng/mL)

  * Patients with any history of malignancies who are disease-free for more than 5 years are eligible
* a history of malignancy and disease-free for more than 5 years
* No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
* No concurrent alcohol consumption

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 28 days since prior and no concurrent anticancer therapy including systemic therapy, radiotherapy, or surgery
* At least 28 days since prior and no other concurrent investigational agents
* No concurrent phenytoin, live attenuated vaccines, or yellow fever vaccine

Primary outcomes:
measure: Progression-free survival as assessed by RECIST v 1.1 criteria (phase IIB and phase III)
measure: Safety (phase IIB)
Secondary outcomes:
measure: Overall survival (phase III)
measure: Response rate and response duration (phase III)
measure: Safety profile (phase III)
measure: Quality of life (phase III)
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Boston
country: United States
facility: Dana Farber Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachussets General Hospital
state: Massachusetts
city: Omaha
country: United States
facility: Methodist Estabrook Cancer Center
state: Nebraska
city: Charlotte
country: United States
facility: Carolinas Hematology-Oncology Associates
state: North Carolina
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia
state: Pennsylvania
city: Vienna
country: Austria
facility: Medical University Vienna
city: Brussels
country: Belgium
facility: HôPITAUX UNIVERSITAIRES BORDET-ERASME - INSTITUT JULES BORDET
city: Brussels
country: Belgium
facility: Cliniques Universitaires St. Luc
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Herlev
country: Denmark
facility: Herlev Hospital - University Copenhagen
city: Bordeaux
country: France
facility: Institut Bergonie
city: Dijon
country: France
facility: Centre Georges-Francois-Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: ASSISTANCE PUBLIQUE - HôPITAUX DE MARSEILLE - HôPITAL DE LA TIMONE
city: Nantes - St. Herblain
country: France
facility: Institut de Cancerologie de L'Ouest (Ico) - Centre Rene Gauducheau
city: Paris
country: France
facility: Institut Curie
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus
city: Hamburg
country: Germany
facility: Universitaets-Krankenhaus Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Mannheim
country: Germany
facility: Universitaetsmedizin Mannheim
city: Muenchen
country: Germany
facility: Klinikum Grosshadern Ludwig-Maximilians Univ. Muenchen
city: Budapest
country: Hungary
facility: Military Hospital - State Health Centre
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus Mc - Daniel Den Hoed Cancer Center
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Centre
city: Bratislava
country: Slovakia
facility: National Cancer Institute
city: Barcelona
country: Spain
facility: Hospital General Vall D'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario San Carlos
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Glasgow
country: United Kingdom
facility: Nhs Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre
city: Manchester
country: United Kingdom
facility: Christie Nhs Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Nhs Trust - City Hospital Campus
Study officials:
affiliation: Institut Bergonié
name: Nguyen Binh Bui, MD
role: STUDY_CHAIR
affiliation: Dana-Farber Cancer Institute
name: James E. Butrynski, MD
role: PRINCIPAL_INVESTIGATOR
References: