Doxorubicin Hydrochloride or Trabectedin in Treating Patients With Previously Untreated Advanced or Metastatic Soft Tissue Sarcoma

Sarcoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01189253
• Other study ID #: EORTC-62091
• Secondary ID: EORTC-620912009-
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: August 25, 2010
• Last updated: August 7, 2014
• Start date: May 2011
• Est. completion date: June 2015

Study information

• Verified date: August 2013
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health ProductsAustria: Agency for Health and Food SafetyGermany: Federal Institute for Drugs and Medical DevicesDenmark: Danish Medicines AgencySpain: Agencia Española de Medicamentos y Productos SanitariosFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)United Kingdom: Medicines and Healthcare Products Regulatory AgencyHungary: National Institute of PharmacyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Slovakia: State Institute for Drug ControlPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 133
• Est. completion date: June 2015
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sarcoma

Intervention

Drug:
• doxorubicin hydrochloride

• trabectedin

Other:
• laboratory biomarker analysis

Procedure:
• quality-of-life assessment

Locations

Country	Name	City	State
Austria	Medical University Vienna	Vienna
Belgium	Cliniques Universitaires St. Luc	Brussels
Belgium	HôPITAUX UNIVERSITAIRES BORDET-ERASME - INSTITUT JULES BORDET	Brussels
Belgium	U.Z. Gasthuisberg	Leuven
Denmark	Aarhus University Hospital	Aarhus
Denmark	Herlev Hospital - University Copenhagen	Herlev
France	Institut Bergonie	Bordeaux
France	Centre Georges-Francois-Leclerc	Dijon
France	Centre Oscar Lambret	Lille
France	Centre Leon Berard	Lyon
France	ASSISTANCE PUBLIQUE - HôPITAUX DE MARSEILLE - HôPITAL DE LA TIMONE	Marseille
France	Institut de Cancerologie de L'Ouest (Ico) - Centre Rene Gauducheau	Nantes - St. Herblain
France	Institut Curie	Paris
France	Institut Gustave Roussy	Villejuif
Germany	Helios Klinikum Bad Saarow	Bad Saarow
Germany	Universitaetsklinikum Carl Gustav Carus	Dresden
Germany	Universitaets-Krankenhaus Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitaetsklinikum Koeln	Koeln
Germany	Universitaetsmedizin Mannheim	Mannheim
Germany	Klinikum Grosshadern Ludwig-Maximilians Univ. Muenchen	Muenchen
Hungary	Military Hospital - State Health Centre	Budapest
Netherlands	The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Centre	Leiden
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen
Netherlands	Erasmus Mc - Daniel Den Hoed Cancer Center	Rotterdam
Poland	Maria Sklodowska-Curie Memorial Cancer Centre	Warsaw
Slovakia	National Cancer Institute	Bratislava
Spain	Hospital General Vall D'Hebron	Barcelona
Spain	Hospital Universitario San Carlos	Madrid
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
United Kingdom	Nhs Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Christie Nhs Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals Nhs Trust - City Hospital Campus	Nottingham
United States	Dana Farber Institute	Boston	Massachusetts
United States	Massachussets General Hospital	Boston	Massachusetts
United States	Carolinas Hematology-Oncology Associates	Charlotte	North Carolina
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia	Philadelphia	Pennsylvania
United States	Sarcoma Oncology Center	Santa Monica	California
United States	Stanford Hospital and Clinics	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Sarcoma Alliance for Research through Collaboration

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Denmark,  France,  Germany,  Hungary,  Netherlands,  Poland,  Slovakia,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival as assessed by RECIST v 1.1 criteria (phase IIB and phase III)			No
Primary	Safety (phase IIB)			Yes
Secondary	Overall survival (phase III)			No
Secondary	Response rate and response duration (phase III)			No
Secondary	Safety profile (phase III)			Yes
Secondary	Quality of life (phase III)			No