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

• Sponsor: PharmaMar (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02451007
• Collaborator: (none)
• Enrollment: 39
• Locations: 16
• Arm: 1
• Actual Duration (Months): 12.3
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Study to assess the potential effects of lurbinectedin (PM01183) at a therapeutic dose on the duration of the QTc interval, measured by electrocardiograms (ECGs), to characterize the PM01183 plasma concentration/QTc relationship, and to explore related ECG parameters in patients with selected solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors	Drug: lurbinectedin (PM01183)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Evaluation of the Effect of Lurbinectedin (PM01183) on Cardiac Repolarization (QTc Duration) in Patients With Selected Solid Tumors
• Actual Study Start Date: Aug 12, 2015
• Actual Primary Completion Date: Aug 19, 2016
• Actual Study Completion Date: Aug 19, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A (lurbinectedin) lurbinectedin (PM01183) 4 mg vials of powder for concentrate for solution for infusion	Drug: lurbinectedin (PM01183)

Outcome Measures

Primary Outcome Measures

1. Change in QTcF (QT Corrected According to Fridericia's Formula) [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.]

   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

Secondary Outcome Measures

1. Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Plasma Concentration) [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.

2. Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Predicted ΔQTcF) [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.

3. Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Intercept) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Voluntarily signed and dated informed consent

• Normal cardiac conduction and function (centrally read)

• Blood pressure between 90 and 150 mmHg systolic, inclusive, and not higher than 90 mmHg diastolic.

• Specific serum electrolyte levels

Exclusion Criteria:

• Age > 65 years

• Performance status = 2 [Eastern Cooperative Oncology Group (ECOG)]

• Heart rhythm disturbances

• Significant ischemic coronary disease, heart failure, myocardial infarction, or unstable angina within the last six months.

• Prior exposure to anthracyclines at a cumulative dose of doxorubicin (or equivalent) > 450 mg/m²

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarcoma Oncology Research Center	Santa Monica	California	United States	90403
2	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
3	Dana Farber Cancer lnstitute	Boston	Massachusetts	United States	02215
4	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Cancer Therapy & Research Center	San Antonio	Texas	United States	78229
6	Hospital Universitari Vall D'Hebron	Barcelona		Spain	08035
7	Complejo Hospitalario Regional Reina Sofía	Córdoba		Spain	14004
8	Hospital Universitario 12 de Octubre	Madrid		Spain	280035
9	Hospital Ramón Y Cajal	Madrid		Spain	28034
10	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
11	Hospital Universitario Madrid Sanchinarro	Madrid		Spain	28050
12	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda		Spain	28222
13	Complejo Hospitalario de Especialidades Virgen de La Victoria	Málaga		Spain	29010
14	Complexo Hospitalario Universitario de Santiago	Santiago De Compostela		Spain	15706
15	Hospital Universitari I Politècnic La Fe	Valencia		Spain	46026
16	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009

Sponsors and Collaborators

• PharmaMar

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT02451007
• Other Study ID Numbers: PM1183-B-005-14-QT
• First Posted: May 21, 2015
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Neoplasms

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	39
COMPLETED	32
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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 Participants	39
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	37 94.9%
>=65 years	2 5.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	22 56.4%
Male	17 43.6%
Region of Enrollment (Count of Participants)
United States	14 35.9%
Spain	25 64.1%

Outcome Measures

1. Primary Outcome

Title	Change in QTcF (QT Corrected According to Fridericia's Formula)
Description	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
Time Frame	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 Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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.
Measure Participants	39
Cycle 1 - 5 min before EOI	3.32
Cycle 1 - 30 min after EOI	1.76
Cycle 1 - 1 hour after EOI	1.84
Cycle 1 - 3 hour after EOI	1.32
Cycle 1 - 24 hour after EOI	-8.24
Cycle 1 - 72 hour after EOI	-12.4
Cycle 1 - 168 hour after EOI	-5.20
Cycle 2 - Before start of infusion	-0.46
Cycle 2 - 5 min before EOI	2.25
Cycle 2 - 30 min after EOI	2.32
Cycle 2 - 1 hour after EOI	2.73
Cycle 2 - 3 hour after EOI	5.39
Cycle 2 - 168 hour after EOI	-4.22

2. Secondary Outcome

Title	Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Plasma Concentration)
Description	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.
Time Frame	Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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.
Measure Participants	39
Mean (90% Confidence Interval) [Microgram/milliliter (μg/mL)]	2.06

3. Secondary Outcome

Title	Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Predicted ΔQTcF)
Description	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.
Time Frame	Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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.
Measure Participants	39
Mean (90% Confidence Interval) [Milliseconds (ms)]	2.94

4. Secondary Outcome

Title	Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Intercept)
Description	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.
Time Frame	Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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.
Measure Participants	39
Number (90% Confidence Interval) [Unitless]	-6.40

Adverse Events

Time Frame	Through study completion, each patient had to be followed for 2 cycles (1 cycle =3 weeks)
Arm/Group Title	Group A - Lurbinectedin (PM01183)
Arm/Group Description	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).
All Cause Mortality
	Group A - Lurbinectedin (PM01183)
	Affected / at Risk (%)	# Events
Total	13/39 (33.3%)
Serious Adverse Events
	Group A - Lurbinectedin (PM01183)
	Affected / at Risk (%)	# Events
Total	9/39 (23.1%)
Blood and lymphatic system disorders
Febrile neutropenia	1/39 (2.6%)
Gastrointestinal disorders
Abdominal pain	3/39 (7.7%)
Small intestinal obstruction	1/39 (2.6%)
General disorders
General physical health deterioration	1/39 (2.6%)
Hepatobiliary disorders
Cholangitis	1/39 (2.6%)
Infections and infestations
Device related infection	1/39 (2.6%)
Skin infection	1/39 (2.6%)
Investigations
Blood calcium decreased	1/39 (2.6%)
Blood phosphorus decreased	1/39 (2.6%)
Nervous system disorders
Facial paralysis	1/39 (2.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/39 (2.6%)
Aspiration	1/39 (2.6%)
Other (Not Including Serious) Adverse Events
	Group A - Lurbinectedin (PM01183)
	Affected / at Risk (%)	# Events
Total	35/39 (89.7%)
Blood and lymphatic system disorders
Anaemia	3/39 (7.7%)
Neutropenia	6/39 (15.4%)
Gastrointestinal disorders
Abdominal pain	6/39 (15.4%)
Abdominal pain upper	3/39 (7.7%)
Constipation	8/39 (20.5%)
Nausea	19/39 (48.7%)
Vomiting	7/39 (17.9%)
General disorders
Fatigue	15/39 (38.5%)
Pyrexia	4/39 (10.3%)
Metabolism and nutrition disorders
Decreased appetite	4/39 (10.3%)
Hyponatraemia	2/39 (5.1%)
Musculoskeletal and connective tissue disorders
Back pain	3/39 (7.7%)
Nervous system disorders
Dysgeusia	2/39 (5.1%)
Headache	4/39 (10.3%)
Psychiatric disorders
Insomnia	3/39 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.