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

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.

• Lurbinectedin (Drug), also known as PM01183: 3.2 mg/m² as a 1-hour i.v. infusion on Day 1.
• Bosentan (Drug): 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).

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin: Alone and in Combination With Bosentan. (Primary), Geometric mean, μg/L/mg: Bosentan Co-administration Cycle 20.71 +/- 54.81; Single Agent Lurbinectedin Cycle 21.39 +/- 49.56
• 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 (Primary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 58.83 +/- 75.83; Single Agent Lurbinectedin Cycle 73.71 +/- 86.93
• 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 (Secondary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 56.33 +/- 76.47; Single Agent Lurbinectedin Cycle 71.13 +/- 84.97
• Plasma Clearance (CL) of Total Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, L/h: Bosentan Co-administration Cycle 17.00 +/- 75.83; Single Agent Lurbinectedin Cycle 13.57 +/- 86.93
• Plasma Volume of Distribution at Steady-state (Vss) of Total Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, L: Bosentan Co-administration Cycle 412.94 +/- 78.11; Single Agent Lurbinectedin Cycle 386.69 +/- 65.5
• Terminal Elimination Half-life (t1/2) in Plasma of Total Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, h: Bosentan Co-administration Cycle 35.51 +/- 61.54; Single Agent Lurbinectedin Cycle 33.84 +/- 35.26
• Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Unbound Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, μg/L/mg: Bosentan Co-administration Cycle 0.0324 +/- 51.77; Single Agent Lurbinectedin Cycle 0.0332 +/- 19.18
• 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 (Secondary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 0.095 +/- 73.04; Single Agent Lurbinectedin Cycle 0.114 +/- 61.09
• 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 (Secondary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 0.0907 +/- 72.73; Single Agent Lurbinectedin Cycle 0.1099 +/- 58.24
• Plasma Clearance (CL) of Unbound Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, L/h: Bosentan Co-administration Cycle 10530.93 +/- 73.04; Single Agent Lurbinectedin Cycle 8773.36 +/- 61.09
• Plasma Volume of Distribution at Steady-state (Vss) of Unbound Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, L: Bosentan Co-administration Cycle 266905.87 +/- 73.09; Single Agent Lurbinectedin Cycle 241282.16 +/- 23.18
• Terminal Elimination Half-life (t1/2) in Plasma of Unbound Lurbinectedin: Alone and in Combination With Bosentan (Secondary), Geometric mean, h: Bosentan Co-administration Cycle 37.41 +/- 73.98; Single Agent Lurbinectedin Cycle 32.33 +/- 39.36
• Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M1: Alone and in Combination With Bosentan (Secondary), Geometric mean, μg/L/mg: Bosentan Co-administration Cycle 0.3849 +/- 92.13; Single Agent Lurbinectedin Cycle 0.268 +/- 78.43
• 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 (Secondary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 0.728 +/- 236.22; Single Agent Lurbinectedin Cycle 0.6916 +/- 114.55
• Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Total Lurbinectedin Metabolite M4: Alone and in Combination With Bosentan (Secondary), Geometric mean, μg/L/mg: Bosentan Co-administration Cycle 0.5617 +/- 103.28; Single Agent Lurbinectedin Cycle 0.5528 +/- 101.15
• 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 (Secondary), Geometric mean, μg·h/L/mg: Bosentan Co-administration Cycle 0.9962 +/- 267.9; Single Agent Lurbinectedin Cycle 1.382 +/- 390.96

Adverse events

Time frame: From 14 January 2021 to 18 January 2022 (1 year). Adverse events will be monitored from first administration date to the end of the follow-up period which corresponds to the visit of the end of treatment (EOT), calculated as 31 days (±10 days) after the last lurbinectedin infusion or until the patient starts a new antitumor therapy or until the date of death, whichever occurs first

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2021-03-15)
• Statistical Analysis Plan (PDF, 2022-03-18)

• Pharma Mar, S.A., Study director, PharmaMar