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

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasm Metastases
• Intervention / Treatment: Drug: Sequence 1; Drug: Sequence 2

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • Utah
    • Salt Lake City, Utah, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 002; 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; 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; 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.
Experimental: 001; 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 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Machiels JP, Staddon A, Herremans C, Keung C, Bernard A, Phelps C, Khokhar NZ, Knoblauch R, Parekh TV, Dirix L, Sharma S. Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies. Cancer Chemother Pharmacol. 2014 Oct;74(4):729-37. doi: 10.1007/s00280-014-2554-1. Epub 2014 Aug 7.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: December 23, 2010
• First Submitted That Met QC Criteria: January 7, 2011
• First Posted (Estimate): January 10, 2011

Study Record Updates

• Last Update Posted (Estimate): November 25, 2014
• Last Update Submitted That Met QC Criteria: November 24, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Solid tumors; Pharmacokinetics; Chemotherapy; Antineoplastic Agents; Trabectedin, YONDELIS; Locally advanced or metastatic disease; Rifampin (RIFADIN)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis
• Other Study ID Numbers: CR017536; ET743OVC1002 (Other Identifier: Janssen Research & Development, LLC)