Continuing vs Intermittent Trabectedin in Patients With Advanced Soft Tissue Sarcoma

Phase II Randomized Trial to Evaluate Two Strategies: Continuing Versus Intermittent (Drug-holiday) Trabectedin-regimen in Patients With Advanced Soft Tissue Sarcoma Experiencing Response or Stable Disease After the Sixth Cycle

This randomization discontinuation trial will allow for concomitant evaluation of the following:

• Side effects and benefits of immediate continuation of Trabectedin after the sixth cycle
• Side effects and benefits of a drug holiday

Selection part (220 patients):

Trabectedin (depending on dose reductions : between 1.5 and 1 mg/m²/3 weeks; over 24 hour administration) until progression, intolerance or 6 cycles (according to the SPC of Trabectedin)

Randomized part (50 patients):

After the 6 first cycles, if there is not progression or unacceptable toxicity, the patients will be randomly assigned to continuous or "intermittent/holiday" therapy with CT-scan evaluation every 6 weeks in both arms

• Arm A Continuation of Trabectedin (between 1.5 and 1 mg/m²/3 weeks; over 24 hour administration) until progression or intolerance
• Arm B "Intermittent/holiday" therapy. Rechallenge of Trabectedin will be implemented in the event of progression; in this case administration of Trabectedin will occur until the second progression or intolerance

Inclusion Criteria (for the selection part):

• Inoperable or metastatic soft tissue sarcoma and/or uterine sarcoma
• Measurable lesions (RECIST 1.1)
• Performance status ≤ 2
• Age ≥ 18
• Normal hematological parameters (polynuclear neutrophils ≥ 1500, hemoglobin level ≥ 9 g/dl, platelets counts ≥ 100,000)
• Adequate biological parameters :
• Adequate hepatic function (bilirubin ≤ ULN , SGPT/ALT and SGOT/AST ≤ 2.5 x ULN)
• Alkaline phosphatases ≤ 2.5 x ULN, If Alkaline phosphatases ≥ 2.5 ULN, hepatic isoenzymes 5-nucleotidases or GGT tests must be performed; hepatic isoenzymes 5- nucleotidases and/or GGT must be within the normal range
• Albumin ≥ 25 g/L
• Adequate renal function : Serum creatinine ≤ 1.5 x ULN
• Creatine phosphokinase ≤ 2.5 x ULN
• Adequate central venous access
• Pregnant or lactating women or men of reproductive potential must use effective contraceptive methods
• Patient covered by government health insurance
• Information sheet given to the patient (Patient information sheet 1)

Exclusion Criteria (for the selection part):

• Patients that have received more than one regimen of chemotherapy for metastatic or inoperable soft tissue or uterine sarcoma, after the failure/intolerance of doxorubicin and ifosfamide. Maintenance treatment does not count as treatment line
• The following histological subtypes : GIST, rhabdomyosarcoma, aggressive fibromatosis, desmoïd tumour, PNET, carcinosarcoma, and all bone sarcomas
• Single tumour in an irradiated region
• Other malignant tumour over the past five years (except basal cell carcinoma or cervical carcinoma in situ adequately treated)
• Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] Version 4.02). Known HIV1, HIV2, hepatitis B or hepatitis C infections
• Presence of known leptomeningeal or brain metastasis
• Patients unable to receive corticotherapy
• Any circumstance that could jeopardise compliance or proper follow-up during the trial
• Pregnant or nursing women

Inclusion Criteria (for the randomized part):

• Patient registered in the selection part
• Stable tumour or objective response (CR + PR) after 6 Trabectedin (Yondelis®) cycles, according to local assessment
• Available copies of thoraco-abdominal and pelvic scan performed prior to the first cycle and after the sixth cycle
• Performance status ≤ 2
• Patients receiving at least 1 mg/m²/3 weeks of Trabectedin at the time of the sixth cycle
• Normal hematological parameters (polynuclear neutrophils ≥ 1500, hemoglobin level ≥ 9 g/dl, platelets counts ≥ 100,000)
• Adequate biological parameters :
• Adequate hepatic function (bilirubin ≤ ULN , SGPT/ALT and SGOT/AST ≤ 2.5 x ULN)
• Alkaline phosphatases ≤ 2.5 x ULN, If Alkaline phosphatases ≥ 2.5 ULN, hepatic isoenzymes 5-nucleotidases or GGT tests must be performed; hepatic isoenzymes 5- nucleotidases and/or GGT must be within the normal range
• Albumin ≥ 25 g/L
• Adequate renal function : Serum creatinine ≤ 1.5 x ULN
• Creatine phosphokinase (CPK) ≤ 2.5 x ULN
• Adequate central venous access
• Pregnant or lactating women or men of reproductive potential must use effective contraceptive methods
• Informed consent form signed by the patient or the patient's legal representative (patient information sheet 2 and informed consent)

Exclusion Criteria (for the randomized part):

• Tumour progression (according to RECIST 1.1) during the first six Yondelis cycles
• Non-availability of baseline scans prior to the first cycle and following the sixth cycle
• Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] Version 4.02). Known HIV1, HIV2, hepatitis B or hepatitis C infections
• Presence of known leptomeningeal or brain metastasis
• Creatinine clearance less than 30 ml/min
• Patients unable to receive corticotherapy
• Any circumstance that could jeopardise compliance or proper follow-up during the trial
• Pregnant or nursing women
• Hypersensitivity to Trabectedin or any excipient in prior cycles