Solid Tumors
Conditions
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.
Interventions
Sponsors
PharmaMar
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Spain, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 39 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disease Progression | 2 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Group A - Lurbinectedin (PM01183) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants |
| Age, Continuous | 56 years |
| Region of Enrollment Spain | 25 Participants |
| Region of Enrollment United States | 14 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 39 |
| other Total, other adverse events | 35 / 39 |
| serious Total, serious adverse events | 9 / 39 |
Outcome results
Primary
Change in QTcF (QT Corrected According to Fridericia's Formula)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 5 min before EOI | 3.32 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 30 min after EOI | 1.76 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 1 hour after EOI | 1.84 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 3 hour after EOI | 1.32 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 24 hour after EOI | -8.24 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 72 hour after EOI | -12.4 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - Before start of infusion | -0.46 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - 5 min before EOI | 2.25 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - 30 min after EOI | 2.32 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - 1 hour after EOI | 2.73 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - 3 hour after EOI | 5.39 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 2 - 168 hour after EOI | -4.22 ms (Milliseconds) |
| Group A - Lurbinectedin (PM01183) | Change in QTcF (QT Corrected According to Fridericia's Formula) | Cycle 1 - 168 hour after EOI | -5.20 ms (Milliseconds) |
Secondary
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Intercept)
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - Lurbinectedin (PM01183) | Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Intercept) | -6.40 Unitless |
Secondary
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Plasma Concentration)
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)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A - Lurbinectedin (PM01183) | Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Plasma Concentration) | 2.06 Microgram/milliliter (μg/mL) |
Secondary
Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Predicted ΔQTcF)
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)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A - Lurbinectedin (PM01183) | Relationship Between ΔQTcF and Time-matched Lurbinectedin Plasma Concentrations (Predicted ΔQTcF) | 2.94 Milliseconds (ms) |