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

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

Sponsors

Lead Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Collaborator: Sarcoma Alliance for Research through Collaboration

Source European Organisation for Research and Treatment of Cancer - EORTC
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.

Overall Status Terminated
Start Date May 2011
Completion Date June 2015
Primary Completion Date June 2013
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Progression-free survival as assessed by RECIST v 1.1 criteria (phase IIB and phase III)
Safety (phase IIB)
Secondary Outcome
Measure Time Frame
Overall survival (phase III)
Response rate and response duration (phase III)
Safety profile (phase III)
Quality of life (phase III)
Enrollment 133
Condition
Intervention

Intervention Type: Drug

Intervention Name: doxorubicin hydrochloride

Arm Group Label: Doxorubicin 75 mg/m² every 3 weeks

Intervention Type: Drug

Intervention Name: trabectedin

Intervention Type: Other

Intervention Name: laboratory biomarker analysis

Intervention Type: Procedure

Intervention Name: quality-of-life assessment

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Location
Facility:
Sarcoma Oncology Center | Santa Monica, California, 90403, United States
Stanford Hospital and Clinics | Stanford, California, United States
Holden Comprehensive Cancer Center at University of Iowa | Iowa City, Iowa, 52242-1002, United States
Dana Farber Institute | Boston, Massachusetts, 02115, United States
Massachussets General Hospital | Boston, Massachusetts, United States
Methodist Estabrook Cancer Center | Omaha, Nebraska, 68114-4199, United States
Carolinas Hematology-Oncology Associates | Charlotte, North Carolina, 28203-4239, United States
Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia | Philadelphia, Pennsylvania, 19106, United States
Medical University Vienna | Vienna, 1090, Austria
HôPITAUX UNIVERSITAIRES BORDET-ERASME - INSTITUT JULES BORDET | Brussels, 1000, Belgium
Cliniques Universitaires St. Luc | Brussels, 1200, Belgium
U.Z. Gasthuisberg | Leuven, 3000, Belgium
Aarhus University Hospital | Aarhus, 8000, Denmark
Herlev Hospital - University Copenhagen | Herlev, 2730, Denmark
Institut Bergonie | Bordeaux, 33076, France
Centre Georges-Francois-Leclerc | Dijon, 77980, France
Centre Oscar Lambret | Lille, B.P. 307, France
Centre Leon Berard | Lyon, 69008, France
ASSISTANCE PUBLIQUE - HôPITAUX DE MARSEILLE - HôPITAL DE LA TIMONE | Marseille, 13385, France
Institut de Cancerologie de L'Ouest (Ico) - Centre Rene Gauducheau | Nantes - St. Herblain, 44805, France
Institut Curie | Paris, 75231, France
Institut Gustave Roussy | Villejuif, 94805, France
Helios Klinikum Bad Saarow | Bad Saarow, 15526, Germany
Universitaetsklinikum Carl Gustav Carus | Dresden, 01307, Germany
Universitaets-Krankenhaus Eppendorf | Hamburg, 20246, Germany
Medizinische Hochschule Hannover | Hannover, 30625, Germany
Universitaetsklinikum Koeln | Koeln, 50924, Germany
Universitaetsmedizin Mannheim | Mannheim, 68167, Germany
Klinikum Grosshadern Ludwig-Maximilians Univ. Muenchen | Muenchen, 81377, Germany
Military Hospital - State Health Centre | Budapest, 1063, Hungary
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis | Amsterdam, 1066, Netherlands
University Medical Center Groningen | Groningen, 9700, Netherlands
Leiden University Medical Centre | Leiden, 2300, Netherlands
Radboud University Nijmegen Medical Centre | Nijmegen, 6500, Netherlands
Erasmus Mc - Daniel Den Hoed Cancer Center | Rotterdam, 3008, Netherlands
Maria Sklodowska-Curie Memorial Cancer Centre | Warsaw, 02 781, Poland
National Cancer Institute | Bratislava, 83310, Slovakia
Hospital General Vall D'Hebron | Barcelona, 08035, Spain
Hospital Universitario San Carlos | Madrid, 28040, Spain
Centre Hospitalier Universitaire Vaudois | Lausanne, 1011, Switzerland
Nhs Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre | Glasgow, G12 0YN, United Kingdom
Christie Nhs Foundation Trust | Manchester, M20 4BX, United Kingdom
Nottingham University Hospitals Nhs Trust - City Hospital Campus | Nottingham, NG5 1PB, United Kingdom
Location Countries

Austria

Belgium

Denmark

France

Germany

Hungary

Netherlands

Poland

Slovakia

Spain

Switzerland

United Kingdom

United States

Verification Date

August 2013

Responsible Party

Type: Sponsor

Keywords
Condition Browse
Number Of Arms 3
Arm Group

Label: Doxorubicin 75 mg/m² every 3 weeks

Type: Active Comparator

Description: Doxorubicin administered on day 1 every 3 weeks for a maximum of 6 cycles

Label: Trabectedin IV 3 hours

Type: Experimental

Description: Trabectedin administered on day 1 every 3 weeks at the dose of 1.3 mg/m² until progression

Label: Trabectedin IV 24 hours every 3 weeks

Type: Experimental

Description: Trabectedin administered on day 1 every 3 weeks at the dose of 1.5 mg/m² over 24 hours until progression

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov