Efficacy Study on Trabectedin in Retroperitoneal Leiomyosarcoma and Well Differentiated/Dedifferentiated Liposarcoma

Study Overview
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Brief Summary
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This is an Italian, multicentre, single arm, phase II study, with an intra-patient comparison end point. This study aims at confirming the activity of the drug trabectedin as second/further line treatment in retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma expressed in terms of slowing down tumour growth. Another objective is to investigate this peculiar benefit of trabectedin in typical retroperitoneal sarcomas may be exploited to help multidisciplinary clinical decision-making in the management of retroperitoneal sarcomas

Detailed Description
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Retroperitoneal soft-tissue sarcomas (R-STSs) are rare neoplasms, accounting for 10% to 15% of Soft Tissue Sarcomas (STSs), which represent 1-3% of all cancers. They may show different histological types, but the predominant ones in the retroperitoneal region are: leiomyosarcoma, liposarcoma. The most commonly encountered in the retroperitoneum is the well differentiated/dedifferentiated liposarcoma. First-line chemotherapy usually consists of doxorubicin and/or ifosfamide. These two drugs are the most active agents in adult STSs, with a dose-response relationship and response rates between 20% and 50%. However, the sarcoma community is currently doubtful as to the activity of ifosfamide in the subgroup of leiomyosarcomas. Trabectedin has been found to be mainly active in leiomyosarcoma and liposarcoma and is approved by European Medicines Agency (EMA) as second-line chemotherapy for STSs. Although the response rate observed in pre-registration studies did not exceed 10%, trabectedin provided disease control, with progression arrest rates exceeding 50% and Progression Free Survival (PFS) rates exceeding 20% at 6 months. Since so far no phase II studies tested the activity of trabectedin in retroperitoneal sarcomas, this is the specific aim of this study. Target population: Patients with previously treated, histologically confirmed, retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma. Patients may be either unamenable to surgery or amenable but in whom the addition of medical treatment is considered clinically advisable. Translational studies will be performed, with the aim of characterising the tumour biological features associated with different response patterns to trabectedin. These assessments will be done in 15-20 patients who will undergo surgery after trabectedin, comparing tumour tissue specimens collected before and after treatment.

Official Title
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A Phase II Study on Trabectedin in Advanced Retroperitoneal Leiomyosarcoma and Well Differentiated/Dedifferentiated Liposarcoma

Conditions
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Liposarcoma, Leiomyosarcoma

Intervention / Treatment
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* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persistent or locally relapsed and/or metastatic disease (in case of local disease, surgery may be technically feasible or not, but the clinical judgment must be that medical therapy is indicated) Pathology specimens available for centralized review Age ≥ 18 years European Eastern Cooperative Oncology Group Personal Status (ECOG PS) ≤ 2 One or more previous systemic treatments employing anthracyclines and ifosfamide (unless one or both are clinically contraindicated) Measurable disease, as defined by Response Evaluation Criteria In Solid Tumors (RECIST) A minimum of 3 weeks since any previous medical therapy Recovery from toxic effects of prior therapies to National Cancer Institute Common Toxicity Criteria (NCI CTC) Grade 1 or lower Adequate haematological, renal and liver functions Ability and willingness to provide informed consent Exclusion Criteria: Pregnant or breast-feeding women Prior exposure to trabectedin Peripheral neuropathy, Grade 2 or higher History of other malignancies (except for basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission for 5 years or more and judged of negligible potential of relapse Known central nervous system (CNS) metastases Active viral hepatitis or chronic liver disease Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within one year before enrolment, uncontrolled arterial hypertension or arrhythmias Active major infection Other serious concomitant illnesses

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>Trabectedin will be administered intravenously at a dose of 1.5 mg/m2 or 1.3 mg/m2 (at investigator's discretion, with a top-dose of 2.6 total mg per cycle) as a 24-hour infusion once every 3 weeks (cycle day 1). Since trabectedin has no cumulative toxicities, treatment can be continued until progressive disease, major toxicity, patient's intolerance or unwillingness to continue treatment or medical decision by the responsible physician. In the subgroup of patients amenable to surgery, treatment will be reasonably continued until the best dimensional response. | Drug: Trabectedin<br>* Trabectedin administered at a dose of 1.5 mg/m2 - 1.3 mg/m2 (at investigator's discretion, with a top-dose of 2.6 total mg per cycle) as a 24-hour continuous infusion via a central venous access until progressive disease, major toxicity, patient's intolerance, unwillingness to continue treatment, or medical decision by the responsible physician<br>* Other names: Yondelis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth Modulation Rate | The primary end point of the study will be the proportion of responders to trabectedin, based on the ratio, in each single patient, between PFS under trabectedin (PFS) and time to progression after previous chemotherapy treatment (TTP1). | From date of randomization until progressive disease, assessed up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response (OR) in the overall sample |  | From date of randomization until progressive disease, assessed up to 48 months | 
| Pathological tumour response in the two eligible histological types, in patients undergoing surgery after treatment |  | From date of randomization until the best tumour dimensional response, assessed up to 48 months | 
| PFS and OR in the two eligible histological types |  | From date of randomization until progressive disease, assessed up to 48 months | 
| PFS in patients who undergo surgery after, or during, medical therapy and those who do not |  | From date of randomization until progressive disease, assessed up to 48 months | 
| Number of patients with grade>=3 adverse drug reactions, number of serious adverse events related to study drug and number of patients who will experience at least one serious adverse event |  | From date of randomization until progressive disease, assessed up to 48 months | 
| Efficacy of trabectedin in reducing cancer related pain | All patients will be administered a standardized questionnaire evaluating cancer related pain and use of antalgic medication. | From date of randomization until progressive disease, assessed up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STS, leiomyosarcoma, liposarcoma, trabectedin