Pharmacometabolomic of Trabectedin in Soft Tissue Patients

Study Overview
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Brief Summary
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This perspective, mono institutional study is addressed to find potential serum and urine biomarkers predictive of the pharmacokinetic and pharmacodynamic profile of soft tissue sarcomas patients treated with trabectedin.

Detailed Description
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This investigation enrolled patients with unresectable and/or metastatic soft tissue sarcoma not responsive to the first-line treatment based on anthracycline/ifosfamide. Patients underwent trabectedin monotherapy that was administered intravenously at the dose of 1.3 mg/m2 every 21 days. Single overnight fasting urine and blood samples were collected on day-1 of the first trabectedin administration. Plasma pharmacokinetics was performed during cycle 1. Blood samples, drawn from a site separate from the drug infusion site, were obtained prior to the infusion (basal) at 2, 8, 24 (end of infusion) and 0.5, 1.0, 4.0, 8.0, 24.0 after the end of the infusion. Plasma concentrations of trabectedin were measured by liquid chromatography, tandem mass spectrometry assay (LC-MS/MS) and the pharmacokinetic parameters (Cmax, Clearance, AUC and T1/2) were calculated from the concentration-time curve using a non-compartmental model. Metabolomics profiles were explored by LC-MS/MS in predose urine and serum and encompassed a total of 192: a) 45 amino acid derivatives, virtually involved in a wide set of biochemical pathways; b) 40 different acylcarnitines, principally involved in the cellular energy metabolism; c) 15 lysophosphatidylcholine metabolites, 77 phosphatidylcholine derivatives, and 15 sphingomyelins, involved in fatty acid metabolism and cellular signaling. The identification of predictive metabolomics biomarkers is performed using univariate and multivariate statistical analyses.

Official Title
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Research of Serum and Urine Metabolomic Biomarkers Predictive Pharmacokinetic Parameters of Trabectidin in Patients With Soft Tissues Sarcomas

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: Trabectedin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced Soft Tissues Sarcoma STSs (unresectable and/or metastatic disease). One previous systemic treatment with ananthracycline ± ifosfamide. Measurable disease, as defined by RECIST criteria. ECOG PS ≤2. Age ≥18 years. A minimum of 3 weeks since prior tumor directed therapy Recovery from toxic effects of prior therapies to NCI CTC Grade 1 or lower. Adequate haematological, renal liver function. Ability and willingness to provide informed consent Exclusion Criteria: Pregnant or breast-feeding women Prior exposure to Trabectedin. Peripheral neuropathy, Grade 2 or higher. Known 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Trabectedin|1.3 mg/m2 with a top-dose of 2.6 mg per cycle, via a central venous catheter as a 24-hour infusion every 21 days.All patients received premedication with dexamethasone 20 mg i.v. 30 min before administration of trabectedin.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) | Pharmacokinetics profile of Trabectedin for 24 hours intravenous infusion | 0-48 hours | 
| Cmax | Maximum plasma concentration of Trabectedin | 0-48 hours | 
| Metabolomics profile | Predose metabolomic profile in serum and urine | 0 hours ( pre-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | From the first day of treatment to progression or death due to any cause | 2 years | 
| Overall survival | The time from the first course of trabectedin to death from any cause or to the last follow-up | 2 years | 
| Treatment Toxicity | Hematologic and non-hematologic toxicity according to WHO | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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soft tissues sarcoma