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

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.

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