Advanced Solid Tumor
Conditions
Brief summary
Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors. The study consisting of two lurbinectedin cycles, one cycle in combination with bosentan and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles.
Detailed description
All patients will receive a maximum of three cycles: two consecutive cycles of lurbinectedin, one cycle with and one cycle without bosentan co-administration (in different order depending on the study Sequence 1 or Sequence 2 of treatment), followed by a third cycle with lurbinectedin alone (this last optional for patients with clinical benefit). Lurbinectedin will be administered as a 1-hour intravenous (i.v.) infusion every three weeks (q3wk) via a central or peripheral vein. The dose of lurbinectedin will be 3.2 mg/m² for all patients when administered with and without bosentan. If toxicity occurs, the appropriate intra-patient dose level (DL) reductions will be implemented in the subsequent cycle. Patients will be randomized in a 1:1 ratio to Sequence 1 (TR: Test-Reference; lurbinectedin + bosentan in Cycle 1) or Sequence 2 (RT: reference-Test; lurbinectedin + bosentan in Cycle 2). Patients will receive lurbinectedin until disease progression, unacceptable toxicity, consent withdrawal or while it is considered to be in their best interest. Treatment with lurbinectedin outside this study could be continued under a Compassionate Use Agreement after the completion of the optional third study cycle.
Interventions
DRUGLurbinectedin
3.2 mg/m² as a 1-hour i.v. infusion on Day 1.
DRUGBosentan
Bosentan: 125 mg (one film-coated tablet of 125 mg) orally (p.o.) twice daily in the morning and in the evening during the prior five consecutive days before the day of lurbinectedin infusion (Day 1), and once daily on Day 1 (before lurbinectedin infusion).
Sponsors
PharmaMar
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary signed and dated written informed consent prior to any specific study procedure. 2. Male or female with age ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. 4. Life expectancy \> 3 months. 5. Pathologically confirmed diagnosis of advanced solid tumors \[except for primary central nervous system (CNS) tumors\], for which no approved therapy exists. 6. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and grade ≤2 asthenia or fatigue, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5). 7. Laboratory values within fourteen days prior to registration: a) Absolute neutrophil count (ANC) \> 2.0 x 109/L, platelet count \> 120 x 109/L and hemoglobin \> 9.0 g/dL (patients may be transfused as clinically indicated prior to study entry). b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN). c) Serum total bilirubin ≤ 1.0 x ULN. If total bilirubin is \> 1.0 x ULN, but ≤ 1.5 x ULN, direct bilirubin must be ≤ 1.0 x ULN. d) Albumin ≥ 3.5 g/dL. e) Creatinine clearance (CLcr) \>= 30 mL/min (using Cockcroft and Gault's formula). f) Creatine phosphokinase (CPK) ≤ 2.5 x ULN. 8. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-gated acquisition (MUGA) within normal range (according to institutional standards). 9. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six months after treatment discontinuation. As bosentan may render hormonal contraceptives ineffective, and taking into account the teratogenic effects observed in animals, hormonal contraceptives cannot be the sole method of contraception during treatment with bosentan. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
Exclusion criteria
1. Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For hepatitis B, this includes positive test for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or HVB-DNA+). For hepatitis C, this includes positive test for both Hepatitis C antibody and quantitative Hepatitis C by PCR (or HVCRNA+). d) History of obstructive cholestatic liver disease (suitable for stenting procedure) or biliary sepsis in the past 2 months. e) Active COVID-19 disease (this includes positive test for SARS-CoV-2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR). 2. Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Patients with asymptomatic documented stable brain metastases not requiring corticosteroids during the last four weeks are allowed. 3. Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1. 4. Use of CYP3A4 substrates for which concomitant administration with moderate CYP3A4 inductor is contraindicated. 5. Treatment with any investigational product within the 30 days before Day 1 of Cycle 1. 6. Women who are pregnant or breast-feeding and fertile patients (men and women) who are not using an effective method of contraception. 7. Psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin: Alone and in Combination With Bosentan. | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Total Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Volume of Distribution at Steady-state (Vss) of Total Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Terminal Elimination Half-life (t1/2) in Plasma of Total Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Unbound Plasma Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Plasma Clearance (CL) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Terminal Elimination Half-life (t1/2) in Plasma of Unbound Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Plasma Volume of Distribution at Steady-state (Vss) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
| Plasma Clearance (CL) of Total Lurbinectedin: Alone and in Combination With Bosentan | Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days) | Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary. |
Countries
Spain
Participant flow
Recruitment details
11 patients were included/treated at 2 sites: 7 in Sequence 1 (TR: Test-Reference; bosentan+lurbinectedin in Cycle 1) and 4 in Sequence 2 (RT: Reference-Test; bosentan+lurbinectedin in Cycle 2). Patients participated between 14 Jan 2021 and 22 Dec 2021. The 1st dose of the 1st cycle was given on 25 Jan 2021 and the last dose of the last cycle on 25 Nov 2021
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 (TR: Test-Reference) Patients received two consecutive cycles of lurbinectedin, the first one with bosentan co-administration and the second one lurbinectedin alone, followed by a third cycle with lurbinectedin alone (this last was optional for patients with clinical benefit). | 7 |
| Sequence 2 (RT: Refence-Test) Patients received two consecutive cycles of lurbinectedin, the first one lurbinectedin alone and the second one with bosentan co-administration, followed by a third cycle with lurbinectedin alone (this last was optional for patients with clinical benefit) | 4 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Compassionate use | 3 | 1 |
| Overall Study | Progressive disease | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Sequence 2 (RT: Refence-Test) | Sequence 1 (TR: Test-Reference) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 63 years | 60 years | 67 years |
| Body Surface Area | 1.7 square metre | 1.9 square metre | 1.7 square metre |
| ECOG PS PS 0 | 6 Participants | 2 Participants | 4 Participants |
| ECOG PS PS 1 | 5 Participants | 2 Participants | 3 Participants |
| Height | 168 cm | 174.5 cm | 163 cm |
| Number of disease sites at baseline | 3 sites | 6 sites | 3 sites |
| Number of prior Anticancer Therapy lines | 4 lines | 2.5 lines | 5 lines |
| Number of prior chemotherapy lines | 3 lines | 2.5 lines | 3 lines |
| Primary tumor site Breast | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor site Cervical | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor site Colon | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor site Gall bladder | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor site Lung | 3 Participants | 2 Participants | 1 Participants |
| Primary tumor site Mesothelioma | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor site Neuroendocrine tumor | 1 Participants | 1 Participants | 0 Participants |
| Primary tumor site Ovarian | 2 Participants | 1 Participants | 1 Participants |
| Prior radiotherapy | 8 Participants | 4 Participants | 4 Participants |
| Prior surgery | 9 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 3 Participants |
| Stage at diagnosis Early | 5 Participants | 1 Participants | 4 Participants |
| Stage at diagnosis Locally advanced | 3 Participants | 1 Participants | 2 Participants |
| Stage at diagnosis Metastatic | 3 Participants | 2 Participants | 1 Participants |
| Time from diagnosis to first infusion | 47.3 months | 13.7 months | 47.7 months |
| Weight | 66.4 kg | 72.4 kg | 66.4 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 11 | 0 / 8 |
| other Total, other adverse events | 7 / 11 | 5 / 8 |
| serious Total, serious adverse events | 3 / 11 | 1 / 8 |
Outcome results
Primary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Total Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Total Lurbinectedin: Alone and in Combination With Bosentan | 58.83 μg·h/L/mg | Geometric Coefficient of Variation 75.83 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Total Lurbinectedin: Alone and in Combination With Bosentan | 73.71 μg·h/L/mg | Geometric Coefficient of Variation 86.93 |
90% CI: [64.78, 98.32]
Primary
Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin: Alone and in Combination With Bosentan.
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for Pharmacokinetic (PK) assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin: Alone and in Combination With Bosentan. | 20.71 μg/L/mg | Geometric Coefficient of Variation 54.81 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin: Alone and in Combination With Bosentan. | 21.39 μg/L/mg | Geometric Coefficient of Variation 49.56 |
90% CI: [81.09, 115.62]
Secondary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Unbound Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 0.095 μg·h/L/mg | Geometric Coefficient of Variation 73.04 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Extrapolated Infinity (AUC0-∞) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 0.114 μg·h/L/mg | Geometric Coefficient of Variation 61.09 |
90% CI: [54.8, 119.96]
Secondary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin: Alone and in Combination With Bosentan | 56.33 μg·h/L/mg | Geometric Coefficient of Variation 76.47 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin: Alone and in Combination With Bosentan | 71.13 μg·h/L/mg | Geometric Coefficient of Variation 84.97 |
90% CI: [64.12, 97.82]
Secondary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2. For 1 patient all PK samples for M1 in lurbinectedin alone cycle were below the limit of quantification
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | 0.728 μg·h/L/mg | Geometric Coefficient of Variation 236.22 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | 0.6916 μg·h/L/mg | Geometric Coefficient of Variation 114.55 |
Comparison: PK parameter used was the log-transformed metabolite/parent ratio (MPR) of M1 dose-normalized AUC0-t.90% CI: [133.4, 451.65]
Secondary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | 0.9962 μg·h/L/mg | Geometric Coefficient of Variation 267.9 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | 1.382 μg·h/L/mg | Geometric Coefficient of Variation 390.96 |
Comparison: PK parameter used was the log-transformed metabolite/parent ratio (MPR) of M4 dose-normalized AUC0-t.90% CI: [71.39, 116.04]
Secondary
Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Unbound Plasma Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Unbound Plasma Lurbinectedin: Alone and in Combination With Bosentan | 0.0907 μg·h/L/mg | Geometric Coefficient of Variation 72.73 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Area Under the Plasma Concentration-time Profile From Time Zero to Last Quantifiable Concentration (AUC0-t) of Unbound Plasma Lurbinectedin: Alone and in Combination With Bosentan | 0.1099 μg·h/L/mg | Geometric Coefficient of Variation 58.24 |
90% CI: [54.26, 118.72]
Secondary
Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2. For 1 patient all PK samples for M1 in lurbinectedin alone cycle were below the limit of quantification
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | 0.3849 μg/L/mg | Geometric Coefficient of Variation 92.13 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan | 0.268 μg/L/mg | Geometric Coefficient of Variation 78.43 |
Comparison: PK parameter used was the log-transformed metabolite/parent ratio (MPR) of M1 dose-normalized Cmax.90% CI: [132.93, 266.26]
Secondary
Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7 and 25 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | 0.5617 μg/L/mg | Geometric Coefficient of Variation 103.28 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan | 0.5528 μg/L/mg | Geometric Coefficient of Variation 101.15 |
Comparison: PK parameter used was the log-transformed metabolite/parent ratio (MPR) of M4 dose-normalized Cmax.90% CI: [94.07, 117.05]
Secondary
Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Unbound Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 0.0324 μg/L/mg | Geometric Coefficient of Variation 51.77 |
| Single Agent Lurbinectedin Cycle | Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 0.0332 μg/L/mg | Geometric Coefficient of Variation 19.18 |
90% CI: [65.62, 119.19]
Secondary
Plasma Clearance (CL) of Total Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Plasma Clearance (CL) of Total Lurbinectedin: Alone and in Combination With Bosentan | 17.00 L/h | Geometric Coefficient of Variation 75.83 |
| Single Agent Lurbinectedin Cycle | Plasma Clearance (CL) of Total Lurbinectedin: Alone and in Combination With Bosentan | 13.57 L/h | Geometric Coefficient of Variation 86.93 |
90% CI: [101.71, 154.36]
Secondary
Plasma Clearance (CL) of Unbound Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Plasma Clearance (CL) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 10530.93 L/h | Geometric Coefficient of Variation 73.04 |
| Single Agent Lurbinectedin Cycle | Plasma Clearance (CL) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 8773.36 L/h | Geometric Coefficient of Variation 61.09 |
90% CI: [83.36, 182.49]
Secondary
Plasma Volume of Distribution at Steady-state (Vss) of Total Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Plasma Volume of Distribution at Steady-state (Vss) of Total Lurbinectedin: Alone and in Combination With Bosentan | 412.94 L | Geometric Coefficient of Variation 78.11 |
| Single Agent Lurbinectedin Cycle | Plasma Volume of Distribution at Steady-state (Vss) of Total Lurbinectedin: Alone and in Combination With Bosentan | 386.69 L | Geometric Coefficient of Variation 65.5 |
90% CI: [74.63, 152.8]
Secondary
Plasma Volume of Distribution at Steady-state (Vss) of Unbound Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Plasma Volume of Distribution at Steady-state (Vss) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 266905.87 L | Geometric Coefficient of Variation 73.09 |
| Single Agent Lurbinectedin Cycle | Plasma Volume of Distribution at Steady-state (Vss) of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 241282.16 L | Geometric Coefficient of Variation 23.18 |
90% CI: [64.79, 224.13]
Secondary
Terminal Elimination Half-life (t1/2) in Plasma of Total Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Terminal Elimination Half-life (t1/2) in Plasma of Total Lurbinectedin: Alone and in Combination With Bosentan | 35.51 h | Geometric Coefficient of Variation 61.54 |
| Single Agent Lurbinectedin Cycle | Terminal Elimination Half-life (t1/2) in Plasma of Total Lurbinectedin: Alone and in Combination With Bosentan | 33.84 h | Geometric Coefficient of Variation 35.26 |
90% CI: [69.49, 158.44]
Secondary
Terminal Elimination Half-life (t1/2) in Plasma of Unbound Lurbinectedin: Alone and in Combination With Bosentan
Pharmacokinetic analyses will be evaluated in plasma by standard non-compartmental methods, or population methods, if necessary.
Time frame: Preinfusion, 0.917, 1.5, 2, 3, 5, 7, 25, 49, 97 and 169 hours post lurbinectedin infusion start on Day 1 of Cycle 1 or Cycle 2 (each cycle is 21 days)
Population: Three treated patients were not evaluable for PK assessments due to lack of treatment at Cycle 2 and two patients were excluded due to extremely high unbound fraction values
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosentan Co-administration Cycle | Terminal Elimination Half-life (t1/2) in Plasma of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 37.41 h | Geometric Coefficient of Variation 73.98 |
| Single Agent Lurbinectedin Cycle | Terminal Elimination Half-life (t1/2) in Plasma of Unbound Lurbinectedin: Alone and in Combination With Bosentan | 32.33 h | Geometric Coefficient of Variation 39.36 |
90% CI: [64.79, 224.13]