A Study to Assess the Potential Effects of a Single-Dose Administration of Trabectedin on the QT Intervals of the Electrocardiogram

Study Overview
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Brief Summary
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The purpose of this study is to assess the potential effects of trabectedin on the QT/QTc interval duration measured by electrocardiograms (ECGs) in participants with advanced solid tumor malignancies when administered at a therapeutic dose.

Detailed Description
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This is a single-blind (where the participant does not know the treatment he receives), multicenter (study conducted at multiple sites), placebo-controlled (an inactive substance that is compared with the study medication to test whether the study medication has a real effect in clinical study), sequential design (it is a design in a single group of Participants where one or more study medication is administered in a sequence) study to evaluate the potential effects of a single-dose administration of trabectedin on the QT intervals of the electrocardiogram (ECG). Initially, the study will consist of 2 phases: a screening phase (within 21 days before administration of the study medication), and a single-blind treatment phase (for 2 days). Participants who complete the single-blind treatment phase will be opted to take trabectedin in an open-label extension (for a minimum of 6 cycles), as long as they derive a clinical benefit (ie, until there is clear evidence of disease progression or unacceptable toxicity, as judged by the investigator). Participants will be assessed for ECG on predose before the single-blind treatment phase. During the single-blind treatment phase, a placebo control will be given on Day 1, and trabectedin (1.3 mg per square meter) will be administered on Day 2. Participants will be monitored until completion of the 24 hour pharmacokinetic blood sample collection. During the open-label extension (21 days after completion of the single-blind treatment phase), all Participants will receive trabectedin intravenously on Day 1 of each 17- to 49 day treatment cycle. The dose and schedule of trabectedin will be modified according to the type of malignancy being treated (ie, sarcoma, ovarian, or breast cancer). Safety evaluations will include assessment of adverse events, vital signs, physical examination, and clinical laboratory tests which will be performed throughout the study. The study duration for the open-label extension will vary by participant.

Official Title
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A Single-Blind, Multicenter, Placebo-Controlled, Sequential Design Study Evaluating the Potential Effects of a Single-Dose Administration of Trabectedin on the QT Intervals of the Electrocardiogram

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Trabectedin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with locally advanced or metastatic solid tumors who have received three or less prior lines of systemic chemotherapy Participants must 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 Normal cardiac conduction and function as documented on a 12-lead electrocardiogram Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 Adequate organ function as evidenced by laboratory tests Able to receive dexamethasone or its equivalent Agrees to protocol-defined use of effective contraception Exclusion Criteria: Participants treated with more than three prior chemotherapy regimens (including adjuvant therapy) Previous exposure to trabectedin Central nervous system (CNS) metastasis Known hypersensitivity to any of the components of the trabectedin intravenous formulation or dexamethasone Heart rhythm disturbances, unusual T wave and U wave (if present) morphology, blood pressure outside of normal range, a history of cardiac failure, myocardial infarction, or cardiomyopathy, or a history of additional risk factors for torsade de pointes (eg, heart failure, electrolyte abnormalities, family history of Long QT Syndrome) Participants who at screening are on medication that is known to prolong the QT interval or who is on CYP3A4 inhibitors or inducers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>3-hour placebo intravenous infusion on Day 1 and trabectedin 1.3 mg/m2 3-hour intravenous infusion on Day 2 (single-blind). Patients may continue treatment with trabectedin until clinical benefit or drug is commercially available (open-label). | Drug: Trabectedin<br>* Trabectedin will be administered as 1.3 mg/m2 3-hour intravenous infusion on Day 2.<br>Drug: Placebo<br>* Participants will receive 3-hour placebo intravenous infusion on Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Difference in the Change From Baseline (Predose on Day 1) in QTc Intervals Trabectedin Relative to Placebo at 24 Hour Post Dose by Fridericia Correction | QTc interval was measured by electrocardiograms to evaluate the potential effect of trabectedin on QTc interval duration. The Fridericia correction was used as the standard clinical correction for calculating the heart rate-corrected QT interval. | Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2) | 
| The Difference in the Change From Baseline (Predose on Day 1) in QTc Intervals Trabectedin Relative to Placebo at 24 Hour Post Dose by Bazett's Correction | QTc interval was measured by electrocardiograms to evaluate the potential effect of trabectedin on QTc interval duration. The Bazett's Correction was used as the standard clinical correction for calculating the heart rate-corrected QT interval. | Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration of Trabectedin (Cmax) |  | Baseline (predose on Day 2) to 24 hour post dose (Day 2 or Day 3). | 
| Time Taken to Acheive Maximum Plasma Concentration (Tmax) |  | Baseline (predose on Day 2) to 24 hour post dose (Day 2 or Day 3). | 
| Number of Participants With QTc Interval Increase From Baseline (Predose on Day 1) Greater Than 30 Milli Seconds | The Fridericia (QTcF) and Bazett's (QTcB) correction were used as the standard clinical correction for calculating the heart rate-corrected QT interval. | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With QTc Interval Increase From Baseline (Predose on Day 1) Greater Than 60 Milli Seconds | The Fridericia (QTcF) and Bazett's (QTcB) correction were used as the standard clinical correction for calculating the heart rate-corrected QT interval. | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With QTc Interval Greater Than 450 Milli Seconds | The Fridericia (QTcF) and Bazett's (QTcB) correction were used as the standard clinical correction for calculating the heart rate-corrected QT interval. | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With QTc Interval Greater Than 480 Milli Seconds | The Fridericia (QTcF) and Bazett's (QTcB) correction were used as the standard clinical correction for calculating the heart rate-corrected QTc interval. | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With QTc Interval Greater Than 500 Milli Seconds | The Fridericia (QTcF) and Bazett's (QTcB) correction were used as the standard clinical correction for calculating the heart rate-corrected QTc interval. | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With PR Interval Greater Than 200 Milli Seconds | PR interval is the portion of the electrocardiogram between the onset of the P wave (atrial depolarization) and the QRS complex (ventricular depolarization). | Baseline (predose) to approximately 24 hour post dose | 
| Number of Participants With QRS Interval Greater Than 120 Milli Seconds | QRS interval is the interval from the beginning of the Q wave to the termination of the S wave, representing the time for ventricular depolarization. | Baseline (predose) to approximately 24 hour post dose | 
| Mean Heart Rate (Beats Per Minute) Over 24 Hours Postdose |  | Baseline (predose on Day 1) to 24 hour post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Yondelis, Solid tumor, Advanced solid tumor, Malignant tumors, Sarcoma, Breast tumor, Ovarian tumor, QT interval, Trabectedin, Ecteinascidin 743, ET743