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

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

The purpose of this study is to evaluate the potential effects of ketoconazole on blood levels of trabectedin after administration to patients with advanced malignancies.

Study Overview

• Status: Completed
• Conditions: Neoplasm Metastases
• Intervention / Treatment: Drug: Trabectedin; Drug: Ketoconazole; Drug: Dexamethasone or equivalent steroid

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) of trabectedin when coadministered with ketoconazole in patients with advanced malignancies. Study drugs include trabectedin and ketoconazole. Trabectedin is a drug being developed to treat patients with cancer that will be administered intravenously (IV) through a catheter (tube) into a central vein over a period of 3 hours once every 21 days with and without ketoconazole. Ketoconazole is an antifungal agent taken as tablets orally (by mouth), that may interfere with the metabolism of trabectedin. In addition, dexamethasone or equivalent steroid, 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 each treatment cycle. This study will consist of 2 parts, Part A and B. In Part A, trabectedin+ketoconazole followed by trabectedin alone will be administered with ketoconazole to 4 patients to evaluate safety. If the safety and PK data collected in Part A is deemed acceptable, enrollment in Part B of the study will begin and patients will receive 1 of 2 treatment sequences of trabectedin and ketoconazole. Patients in Part A and Part B who complete the treatment phase of the study or who are discontinued due to ketoconazole 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 IV dexamethasone or equivalent steroid prior to trabectedin administration in all cycles. Part A consists of ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v. followed 21 days later by trabectedin 1.3mg/m2 i.v. Part B consists of Sequence 1 (ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v.followed 21 days later by trabectedin 1.3mg/m2 i.v.) and Sequence 2 (trabectedin 1.3mg/m2 i.v followed 21 days later by ketoconazole 200mg 2x daily+trabectedin 0.2mg/m2 i.v). Dexamethasone 20mg i.v. or equivalent, will be given 30 minutes before trabectedin in each cycle.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium
  • Wilrijk, Belgium

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 (cancer of the liver), who have been 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1; Patients will receive trabectedin+ketoconazole followed by trabectedin alone. Each cycle will be will be separated by 21 days. Patients will receive 6 total consecutive doses of ketoconazole. Dexamethasone or equivalent steroid will be administered before trabectedin in each cycle.	Drug: Trabectedin; Patients will receive trabectedin 1.3 mg/m2 when given alone and 0.2mg/m2 when given with ketoconazole, intravenously (into a vein) for 3-hour.; Drug: Ketoconazole; Patients will receive ketoconazole 1 X 200 mg tablet, two times a day, orally (by mouth); Drug: Dexamethasone or equivalent steroid; Patients will receive dexamethasone 20 mg or equivalent steroid intravenously, 30 minutes before trabectedin in each cycle.
EXPERIMENTAL: Part 2; Patients will receive 1 of 2 treatment sequences; Sequence 1: trabectedin+ketoconazole followed by trabectedin alone or Sequence 2: trabectedin alone followed by trabectedin+ketoconazole. Each cycle will be separated by 21 days. Patients will receive 15 total consecutive doses of ketoconazole. Dexamethasone or equivalent steroid will be administered before trabectedin in each cycle.	Drug: Trabectedin; Patients will receive trabectedin 1.3 mg/m2 when given alone and 0.2mg/m2 when given with ketoconazole, intravenously (into a vein) for 3-hour.; Drug: Ketoconazole; Patients will receive ketoconazole 1 X 200 mg tablet, two times a day, orally (by mouth); Drug: Dexamethasone or equivalent steroid; Patients will receive dexamethasone 20 mg or equivalent steroid intravenously, 30 minutes before trabectedin in each cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of trabectedin		At protocol-specified time points for up to 8 days during each 21-day cycle in Sequence 1 and Sequence 2
Pharmacokinetics of ketoconazole	This will be measured when ketoconazole will be administered.	1 day during Sequence 1 or Sequence 2 after ketoconazole 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
Evaluation of Survival data	At a time point to be determined by the sponsor at a later date

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: PharmaMar

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 Ketoconazole on the Pharmacokinetics of Trabectedin in Subjects with Advanced Malignancies

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: December 23, 2010
• First Submitted That Met QC Criteria: December 23, 2010
• First Posted (ESTIMATE): December 24, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 14, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Solid tumors; Pharmacokinetics; Chemotherapy; Antineoplastic Agents; Ketoconazole; Locally advanced or metastatic disease; Trabectedin (YONDELIS)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Dexamethasone; Ketoconazole; Trabectedin
• Other Study ID Numbers: CR017539; ET743OVC1003 (OTHER: Janssen Research & Development, LLC)