Study to Evaluate the Effect of Bosentan on the Pharmacokinetics of Lurbinectedin in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label, Multicenter Study to Assess the Potential Effects of Bosentan (a Moderate CYP3A4 Inducer) on the Pharmacokinetics of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Lurbinectedin
* Drug: Bosentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary signed and dated written informed consent prior to any specific study procedure. Male or female with age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. Life expectancy > 3 months. Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no approved therapy exists. 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). 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. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-gated acquisition (MUGA) within normal range (according to institutional standards). 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: 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). 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. Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1. Use of CYP3A4 substrates for which concomitant administration with moderate CYP3A4 inductor is contraindicated. Treatment with any investigational product within the 30 days before Day 1 of Cycle 1. Women who are pregnant or breast-feeding and fertile patients (men and women) who are not using an effective method of contraception. Psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single agent lurbinectedin cycle<br>3.2 mg/m² as a 1-hour i.v. infusion on Day 1. | Drug: Lurbinectedin<br>* 3.2 mg/m² as a 1-hour i.v. infusion on Day 1.<br>* Other names: PM01183;|
| Active Comparator: Bosentan co-administration cycle<br>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). Lurbinectedin: 3.2 mg/m² as a 1-hour i.v. infusion on Day 1 in first three patients. Dose for remaining five patients will depend on PK and safety outcomes in first three patients. | Drug: Lurbinectedin<br>* 3.2 mg/m² as a 1-hour i.v. infusion on Day 1.<br>* Other names: PM01183;Drug: Bosentan<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| Dose-normalized maximum observed plasma concentration (Cu,max) 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. | 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) | 
| Dose-normalized area under the plasma concentration-time profile from time zero to extrapolated infinity (AUCu,0-∞) 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. | 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) | 
| Plasma clearance (CLu) 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. | 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) | 
| Plasma volume of distribution at steady-state (Vss,u) 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. | 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) | 
| Terminal elimination half-life (t1/2,u) 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. | 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) | 
| 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. | 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) | 
| Dose-normalized area under the plasma concentration-time profile from time zero to extrapolated infinity (AUC0-∞) 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| Dose-normalized area under the plasma concentration-time profile from time zero to extrapolated infinity (AUC0-∞) 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. | 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) | 
| 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. | 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) | 
| Number of patients with Treatment Emergent Adverse Events (AEs) | Graded according to the NCI-CTCAE v.5. | Baseline up to end of study (up to 83 days) | 
| Number of patients with Serious Adverse Events (SAEs) | Graded according to the NCI-CTCAE v.5. | Baseline up to end of study (up to 83 days) | 
| Number of patients with Abnormalities in Laboratory Parameters | Graded according to the NCI-CTCAE v.5. | Baseline up to end of study (up to 83 days) | 
| The presence or absence of germinal genetic polymorphisms in genes relevant for lurbinectedin disposition | Lurbinectedin disposition (distribution, metabolism and excretion) from a single blood sample | Day 1 of Cycle 1 (each cycle is 21 days) |