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

NCT05072106 | Completed Phase 1 Results FDA Drug

• 1 other identifier: PM1183-A-019-20
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

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.

Conditions

Advanced Solid Tumor

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (2)

Single agent lurbinectedin cycle

ACTIVE COMPARATOR

3.2 mg/m² as a 1-hour i.v. infusion on Day 1.

Drug: Lurbinectedin

Bosentan co-administration cycle

ACTIVE COMPARATOR

* 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; Drug: Bosentan

Interventions

Lurbinectedin DRUG

3.2 mg/m² as a 1-hour i.v. infusion on Day 1.

Also known as: PM01183

Bosentan co-administration cycle; Single agent lurbinectedin cycle

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).

Bosentan co-administration cycle

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• PharmaMar: lead

Study Sites (2)

Fundación Jiménez Diaz

Madrid, 28040, Spain

Location

Hospital de Sanchinarro

Madrid, 28050, Spain

Location

MeSH Terms

Interventions

PM 01183; Bosentan

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Clinical Developtment, Department of PharmaMar's Oncology, Business Unit,
• Organization: Pharma Mar S.A.

AEincoming@pharmamar.com

0034918466000

Study Officials

• Pharma Mar, S.A.

  PharmaMar

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2021
• First Posted: October 8, 2021
• Study Start: January 14, 2021
• Primary Completion: January 18, 2022
• Study Completion: January 18, 2022
• Last Updated: September 16, 2025
• Results First Posted: September 16, 2025

Record last verified: 2025-08

Locations

ES (2)