Trial Outcomes & Findings for Evaluation of the Effect of Lurbinectedin (PM01183) on Cardiac Repolarization in Patients With Selected Solid Tumors (NCT NCT02451007)

Last Updated: 2019-11-19

Results Overview

ΔQTCF (Change in QTcF); EOI (end of infusion); LSM (Least Square Means); PK (Pharmacokinetic(s)). On Day 1 (D1) of Cycle 1 (C1), LSM ΔQTcF should have low difference values, without any clear trend to change with time. Therefore, the upper bound (UB) of the (two-sided) 90%Confidence Interval (CI) at all time points had to be less than the protocol-specified cut-off of 20 ms at each time point. If so, non-inferiority of any ECG time point to baseline with respect of QTc prolongation could be concluded

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

39 participants

Primary outcome timeframe

Scheduled post-baseline ECG time points were taken 5-10 min before their time-matched PK samples: i.e., 5 min before EOI, 30 min, 1, 3, 24, 72 and 168 hours after EOI of Cycle 1, and 5 min before EOI, 30 min, 1, 3 and 168 hours after EOI of Cycle 2.

Results posted on

2019-11-19

Participant Flow

This study was nested into a multicenter clinical trial with a competitive recruitment. From August 2015 to June 2016, a total of 39 evaluable patients at 12 sites in USA and Spain were included in this QT evaluation study with baseline and one or more postbaseline Electrocardiogram (ECG) assessments available.

Participant milestones

Participant milestones
Measure	Group A - Lurbinectedin (PM01183) lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Overall Study STARTED	39
Overall Study COMPLETED	32
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Group A - Lurbinectedin (PM01183) lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Overall Study Withdrawal by Subject	4
Overall Study Adverse Event	1
Overall Study Disease Progression	2

Baseline Characteristics

Evaluation of the Effect of Lurbinectedin (PM01183) on Cardiac Repolarization in Patients With Selected Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group A - Lurbinectedin (PM01183) n=39 Participants lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Age, Categorical <=18 years	0 Participants n=99 Participants
Age, Categorical Between 18 and 65 years	37 Participants n=99 Participants
Age, Categorical >=65 years	2 Participants n=99 Participants
Age, Continuous	56 years n=99 Participants
Sex: Female, Male Female	22 Participants n=99 Participants
Sex: Female, Male Male	17 Participants n=99 Participants
Region of Enrollment United States	14 Participants n=99 Participants
Region of Enrollment Spain	25 Participants n=99 Participants

PRIMARY outcome

Timeframe: Scheduled post-baseline ECG time points were taken 5-10 min before their time-matched PK samples: i.e., 5 min before EOI, 30 min, 1, 3, 24, 72 and 168 hours after EOI of Cycle 1, and 5 min before EOI, 30 min, 1, 3 and 168 hours after EOI of Cycle 2.

Outcome measures

Outcome measures
Measure	Group A - Lurbinectedin (PM01183) n=39 Participants lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 5 min before EOI	3.32 ms (Milliseconds) Interval 1.12 to 5.51
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 30 min after EOI	1.76 ms (Milliseconds) Interval -0.41 to 3.93
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 1 hour after EOI	1.84 ms (Milliseconds) Interval -1.02 to 4.69
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 3 hour after EOI	1.32 ms (Milliseconds) Interval -1.4 to 4.05
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 24 hour after EOI	-8.24 ms (Milliseconds) Interval -11.2 to -5.26
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 72 hour after EOI	-12.4 ms (Milliseconds) Interval -15.4 to -9.39
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 1 - 168 hour after EOI	-5.20 ms (Milliseconds) Interval -7.98 to -2.41
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - Before start of infusion	-0.46 ms (Milliseconds) Interval -3.27 to 2.35
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - 5 min before EOI	2.25 ms (Milliseconds) Interval -1.18 to 5.68
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - 30 min after EOI	2.32 ms (Milliseconds) Interval -1.02 to 5.66
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - 1 hour after EOI	2.73 ms (Milliseconds) Interval -1.08 to 6.54
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - 3 hour after EOI	5.39 ms (Milliseconds) Interval 1.17 to 9.6
Change in QTcF (QT Corrected According to Fridericia's Formula) Cycle 2 - 168 hour after EOI	-4.22 ms (Milliseconds) Interval -7.36 to -1.08

SECONDARY outcome

Timeframe: Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

ΔQTcF (Change from Baseline in QT Corrected According to Fridericia's Formula); CI (Confidence Interval); Cmax (Maximum Plasma Concentration). Table below details the results of the linear mixed effects model to quantify the relationship between the lurbinectedin plasma concentrations and ΔQTcF and Predicted ΔQTcF and 90% CI at mean lurbinectedin Cmax.

Outcome measures

Outcome measures
Measure	Group A - Lurbinectedin (PM01183) n=39 Participants lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Plasma Concentration)	2.06 Microgram/milliliter (μg/mL) Interval 1.42 to 2.71

SECONDARY outcome

Timeframe: Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Outcome measures

Outcome measures
Measure	Group A - Lurbinectedin (PM01183) n=39 Participants lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Predicted ΔQTcF)	2.94 Milliseconds (ms) Interval 0.79 to 5.1

SECONDARY outcome

Timeframe: Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Outcome measures

Outcome measures
Measure	Group A - Lurbinectedin (PM01183) n=39 Participants lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle). QTc interval duration was assessed when the patient was treated with lurbinectedin for the first time.
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Intercept)	-6.40 Unitless Interval -8.44 to -4.35

Adverse Events

Group A - Lurbinectedin (PM01183)

Serious events: 9 serious events

Other events: 35 other events

Deaths: 13 deaths

Serious adverse events

Serious adverse events
Measure	Group A - Lurbinectedin (PM01183) n=39 participants at risk lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle).
Investigations Blood calcium decreased	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Investigations Blood phosphorus decreased	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Respiratory, thoracic and mediastinal disorders Aspiration	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Blood and lymphatic system disorders Febrile neutropenia	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Nervous system disorders Facial paralysis	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
General disorders General physical health deterioration	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Abdominal pain	7.7% 3/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Small intestinal obstruction	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Hepatobiliary disorders Cholangitis	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Infections and infestations Device related infection	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Infections and infestations Skin infection	2.6% 1/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Other adverse events

Other adverse events
Measure	Group A - Lurbinectedin (PM01183) n=39 participants at risk lurbinectedin (PM01183) is presented as a lyophilized powder for concentrate for solution for infusion with strength of 4 mg / vial. Lurbinectedin was administered at a dose of 3.2 mg/m² given as a 1-hour i.v. every three weeks (q3wk) (three weeks = one treatment cycle).
Blood and lymphatic system disorders Anaemia	7.7% 3/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Blood and lymphatic system disorders Neutropenia	15.4% 6/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Nervous system disorders Dysgeusia	5.1% 2/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Nervous system disorders Headache	10.3% 4/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
General disorders Fatigue	38.5% 15/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
General disorders Pyrexia	10.3% 4/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Psychiatric disorders Insomnia	7.7% 3/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Abdominal pain	15.4% 6/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Abdominal pain upper	7.7% 3/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Constipation	20.5% 8/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Nausea	48.7% 19/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Gastrointestinal disorders Vomiting	17.9% 7/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Metabolism and nutrition disorders Decreased appetite	10.3% 4/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Metabolism and nutrition disorders Hyponatraemia	5.1% 2/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Musculoskeletal and connective tissue disorders Back pain	7.7% 3/39 • Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Additional Information

Clinical Development Department of PharmaMar's Oncology Business Unit

Pharma Mar, S.A.

Phone: +34 91 846 60 00

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60