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

Conditions

Solid Tumor

Keywords

Solid tumor, Advanced solid tumor, Malignant tumors, Sarcoma, Breast tumor, Ovarian tumor, QT interval, Trabectedin, Yondelis, Ecteinascidin 743, ET743

Brief summary

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

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.

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Interventions

DRUGTrabectedin

Trabectedin will be administered as 1.3 mg/m2 3-hour intravenous infusion on Day 2.

DRUGPlacebo

Participants will receive 3-hour placebo intravenous infusion on Day 1.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame	Description
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	Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2)	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.
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	Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2)	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.

Secondary

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

Countries

Belgium, France, India, Russia, South Korea, Spain, United States

Participant flow

Recruitment details

This study was conducted in 7 countries: Belgium (3 sites), France (2 sites), India (2 sites), Republic of Korea (4 sites), Russia (4 sites), Spain (1 site), and the United States (4 sites). Total 75 participants were enrolled in this study.

Pre-assignment details

All enrolled participants (ie, 75 participants) received study medication. 26 participants completed the study.

Participants by arm

Arm	Count
Trabectedin 1.3 mg/m2 of trabectedin was administered as a 3-hour intravenous infusion on Day 2	75
Total	75

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	6
Overall Study	Death	4
Overall Study	Physician Decision	4
Overall Study	Progressive disease	31
Overall Study	Withdrawal by Subject	4

Baseline characteristics

Characteristic	Trabectedin
Age, Continuous	50.2 years STANDARD_DEVIATION 11.04
Race/Ethnicity, Customized Asian	23 participants
Race/Ethnicity, Customized Other	1 participants
Race/Ethnicity, Customized White	51 participants
Region of Enrollment Belgium	17 participants
Region of Enrollment France	3 participants
Region of Enrollment India	8 participants
Region of Enrollment Republic Of Korea	15 participants
Region of Enrollment Russia	17 participants
Region of Enrollment Spain	4 participants
Region of Enrollment United States Of America	11 participants
Sex: Female, Male Female	51 Participants
Sex: Female, Male Male	24 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	70 / 75
serious Total, serious adverse events	31 / 75

Outcome results

Primary

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.

Time frame: Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2)

Population: All evaluable participants set: All participants who received placebo on Day 1 and trabectedin on Day 2 with atleast 1 paired predose and 1 paired postdose assessments. One participant who received study medication in reverse order (trabectedin and placebo were given on Days 1 and 2, respectively) was excluded from evaluations.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	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	0.1 milli seconds	Standard Deviation 10.15
Trabectedin	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	-1.5 milli seconds	Standard Deviation 13.61

Primary

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.

Time frame: Baseline (predose on Day 1) to 24 hour post dose (Day 1 or Day 2)

Population: All evaluable participants set: All participants who received placebo on Day 1 and trabectedin on Day 2 with atleast 1 paired predose and 1 paired postdose assessments. One participant who received study medication in reverse order (trabectedin and placebo were given on Days 1 and 2, respectively) was excluded from evaluations.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	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	3.6 milli seconds	Standard Deviation 10.08
Trabectedin	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	-6.2 milli seconds	Standard Deviation 10.65

Secondary

Maximum Plasma Concentration of Trabectedin (Cmax)

Time frame: Baseline (predose on Day 2) to 24 hour post dose (Day 2 or Day 3).

Population: All evaluable participants set: All participants who received placebo on Day 1 and trabectedin on Day 2 with atleast 1 paired predose and 1 paired postdose assessments. One participant who received study medication in reverse order (trabectedin and placebo were given on Days 1 and 2, respectively) was excluded from evaluations.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Maximum Plasma Concentration of Trabectedin (Cmax)	9.24 nanogram per milliliter	Standard Deviation 3.75

Secondary

Mean Heart Rate (Beats Per Minute) Over 24 Hours Postdose

Time frame: Baseline (predose on Day 1) to 24 hour post dose

Population: All evaluable participants set: All participants who received placebo on Day 1 and trabectedin on Day 2 with atleast 1 paired predose and 1 paired postdose assessments. One participant who received study medication in reverse order was excluded from evaluations. 73 participants analyzed in trabectedin group to derive the mean.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Mean Heart Rate (Beats Per Minute) Over 24 Hours Postdose	76.9 beats per minute	Standard Deviation 10.51
Trabectedin	Mean Heart Rate (Beats Per Minute) Over 24 Hours Postdose	82.6 beats per minute	Standard Deviation 11.13

Secondary

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).