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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Terminated

CT.gov ID

NCT01189253

Collaborator

Sarcoma Alliance for Research through Collaboration (Other)

133

Enrollment

Locations

Arms

Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Drug: doxorubicin hydrochloride Drug: trabectedin Other: laboratory biomarker analysis Procedure: quality-of-life assessment	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

133 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2011

Actual Primary Completion Date :

Jun 1, 2013

Anticipated Study Completion Date :

Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Doxorubicin 75 mg/m² every 3 weeks Doxorubicin administered on day 1 every 3 weeks for a maximum of 6 cycles	Drug: doxorubicin hydrochloride Other: laboratory biomarker analysis Procedure: quality-of-life assessment
Experimental: Trabectedin IV 3 hours Trabectedin administered on day 1 every 3 weeks at the dose of 1.3 mg/m² until progression	Drug: trabectedin Other: laboratory biomarker analysis Procedure: quality-of-life assessment
Experimental: Trabectedin IV 24 hours every 3 weeks Trabectedin administered on day 1 every 3 weeks at the dose of 1.5 mg/m² over 24 hours until progression	Drug: trabectedin Other: laboratory biomarker analysis Procedure: quality-of-life assessment

Arm

Intervention/Treatment

Active Comparator: Doxorubicin 75 mg/m² every 3 weeks

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

Drug: doxorubicin hydrochloride

Other: laboratory biomarker analysis

Procedure: quality-of-life assessment

Experimental: Trabectedin IV 3 hours

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

Drug: trabectedin

Other: laboratory biomarker analysis

Procedure: quality-of-life assessment

Experimental: Trabectedin IV 24 hours every 3 weeks

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

Drug: trabectedin

Other: laboratory biomarker analysis

Procedure: quality-of-life assessment

Outcome Measures

Primary Outcome Measures

Progression-free survival as assessed by RECIST v 1.1 criteria (phase IIB and phase III) []
Safety (phase IIB) []

Secondary Outcome Measures

Overall survival (phase III) []
Response rate and response duration (phase III) []
Safety profile (phase III) []
Quality of life (phase III) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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