Continuing vs Intermittent Trabectedin in Patients With Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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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

Detailed Description
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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

Official Title
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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

Conditions
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Soft Tissue Sarcoma, Uterine Sarcoma

Intervention / Treatment
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* Drug: Trabectedin
* Other: Drug: holiday


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Continuation of Trabectedin<br>patient receives 6 cycles of trabectedin, then one dose 15 days after the 6th cycle, every 3 weeks until progression/ toxicity | Drug: Trabectedin<br>* Trabectedin will be administered without drug holiday in Arm A until unacceptable toxicity, progressive disease or patient decision. The treatment beyond disease progression and in case of intolerance will be decided according to investigator discretion. In case of progression after drug discontinuation by patient decision, a re-challenge of Trabectedin is possible.<br>* Other names: Yondelis;|
| Other: Drug holiday therapy<br>patient receives 6 cycles of trabectedin, then one dose 15 days after the 6th cycle and he stops the drug until progression and re-challenge | Other: Drug: holiday<br>* A drug-holiday will start after the 6th cycle until disease progression, and then Trabectedin will be re-challenged. Trabectedin will be administered until unacceptable toxicity, second evidence of progressive disease or patient decision.<br>* Other names: No drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS rate 24 weeks after randomization | In each arms among non progressive patients after the 6 first cycles of Trabectedin : occurrence of progression or death 24 weeks after the date of randomization. Intention to treat analysis. Centralised radiological review. | 24 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | stabilisation, complete and partial responses according to RECIST 1.1 | 6, 12 and 18 weeks after randomization | 
| Progression free survival rates | According to RECIST 1.1 | 12 and 54 weeks after randomization | 
| Survival rates |  | 12 and 24 months after randomization | 
| Median progression-free and median overall survivals |  | Up to 5 years after randomization | 
| Tolerability - safety | According to NCI-CTC V4.0 scale | Up to 30 days after the last study drg administration | 
| Clinical and biological predictive factors for non progression at the 6th cycle | Collected data at baseline : age, gender, comorbidity, disease history, previous treatment, tumor description, biological parameters | At baseline | 
| Post-randomization cost of care | Cost of care will be evaluated by macro-costing approach | For one year after randomization | 
| Self estimation of general health status | Evaluation every 6 weeks by 100-mm-long horizontal visual analog scale (VAS) that ranged from worst imaginable health (as bad as death, 0) to perfect health | For 1 year after randomization |