A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the potential effects of rifampin on blood levels of trabectedin after administration to patients with advanced malignancies.

Detailed Description
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This is an open-label study (patients will know the names of the study drugs they receive), randomized (patients will be assigned 1 of 2 treatment sequences by chance) that is designed to examine the pharmacokinetics (blood levels) and to assess survival and safety of trabectedin when coadministered with rifampin in patients with advanced malignancies. Study drugs include trabectedin and rifampin. Trabectedin is a drug being developed to treat patients with cancer that will be administered intravenously (i.v.) through a catheter (tube) into a central vein over a period of 3 hours once every 28 days with and without rifampin. Rifampin is an antibiotic that may interfere with the action of trabectedin that will be taken orally (by mouth) as capsules. In addition, dexamethasone, a drug used to prevent nausea and vomiting in chemotherapy patients that may have protective effects on the liver, will be administered to patients before the administration of trabectedin. In the study, 3 patients will initially be randomized sequentially to Treatment Sequence 1 or Treatment Sequence 2 to evaluate safety. If the safety and pharmacokinetic data collected from these 3 patients is deemed acceptable, additional patients will be randomized to 1 of 2 treatment sequences. Patients who complete the treatment phase of the study or who are discontinued due to rifampin toxicity, and who in the opinion of the investigator would derive an overall clinical benefit from further treatment with trabectedin, will have the opportunity to continue treatment with trabectedin in the optional extension phase. The dose and schedule of trabectedin may be modified by the treating physician in the optional extension phase to be more appropriate for the type of malignancy being treated. Patients will receive 20 mg of i.v. dexamethasone (or its equivalent) prior to trabectedin administration in all cycles. Patients randomized to Sequence 1 will receive rifampin 600mg 1X daily(6 doses)+trabectedin 1.3 mg/m2 i.v. followed 28 days later by trabectedin 1.3 mg/m2 i.v. Patients randomized to Sequence 2 will receive trabectedin 1.3 mg/m2 i.v. followed 28 days later by rifampin 600mg 1X daily(6 doses)+trabectedin 1.3mg/m2 i.v. Dexamethasone 20 mg i.v., or equivalent will be administered 30 minutes prior to trabectedin administration.

Official Title
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An Open-Label, Multicenter Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Subjects With Advanced Malignancies

Conditions
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Neoplasm Metastases

Intervention / Treatment
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* Drug: Sequence 1
* Drug: Sequence 2
* Drug: Sequence 1
* Drug: Sequence 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with locally advanced or metastatic disease, any solid tumor except hepatocellular carcinoma, who have relapsed or had progressive disease following standard of care treatment with chemotherapy prior to enrollment, or intolerant to prior standard of care treatment with chemotherapy Patients with Eastern Cooperative Oncology Group (ECOG) score of <=2 Patients able to receive dexamethasone Patients with hepatic function variables: total bilirubin <=upper limit of normal (ULN), alkaline phosphatase (ALP) <=1.5 ULN and liver function test results (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) of <=2.5x ULN Exclusion Criteria: Patients with previous exposure to trabectedin Patients with cancer that has metastasized (spread) to the central nervous system Patients with known liver disease Patients who had a myocardial infarct (heart attack) within 6 months before enrollment or who have any other clinically significant or unstable medical condition as assessed by the Investigator Patients unable to have a central catheter

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 002<br>Sequence 2 Cycle 1: Trabectedin 1.3 mg/m2 i.v. on Day 1 followed by 2 rifampin 300 mg capsules once daily on Days 24-28 followed by Cycle 2 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 of Cycle 2. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle. | Drug: Sequence 1<br>* Cycle 1: 2 rifampin 300 mg capsules 1x daily for 5 days followed by 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 followed 28 days later by cycle 2 trabectedin 1.3 mg/m2 i.v. on Day 1. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.<br>Drug: Sequence 2<br>* Cycle 1: Trabectedin 1.3 mg/m2 i.v. on Day 1 followed by 2 rifampin 300 mg capsules once daily on Days 24-28 followed by Cycle 2, 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 of Cycle 2. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.<br>|
| Experimental: 001<br>Sequence 1 Cycle 1: 2 rifampin 300 mg capsules 1x daily for 5 days followed by 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 followed 28 days later by cycle 2 trabectedin 1.3 mg/m2 i.v. on Day 1. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle. | Drug: Sequence 2<br>* Cycle 1: Trabectedin 1.3 mg/m2 i.v. on Day 1 followed by 2 rifampin 300 mg capsules once daily on Days 24-28 followed by Cycle 2, 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 of Cycle 2. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.<br>Drug: Sequence 1<br>* Cycle 1: 2 rifampin 300 mg capsules 1x daily for 5 days followed by 2 rifampin capsules prior to trabectedin 1.3 mg/m2 i.v. on Day 1 followed 28 days later by cycle 2 trabectedin 1.3 mg/m2 i.v. on Day 1. Dexamethasone 20 mg i.v. administered prior to trabectedin in each cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of trabectedin |  | At protocol-specified time points up to 8 days during each 28-day cycle in Sequence 1 and up to 6 days during each 28-day cycle in Sequence 2 | 
| Pharmacokinetics of rifampin |  | 1 day during Sequence 1 and Sequence 2 after rifampin is coadministered with trabectedin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | Time from 1st dose of trabectedin up to 30 days after the last dose of trabectedin | 
| Findings from clinical laboratory evaluations |  | Time from 1st dose of trabectedin up to 30 days after the last dose of trabectedin | 
| Findings from vital signs measurements |  | Time from 1st dose of trabectedin up to 30 days after the last dose of trabectedin | 
| Findings from physical examinations |  | Time from 1st dose of trabectedin up to 30 days after the last dose of trabectedin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trabectedin, YONDELIS, Rifampin (RIFADIN), Antineoplastic Agents, Solid tumors, Locally advanced or metastatic disease, Chemotherapy, Pharmacokinetics