Clinical Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment
- Registration Number
- NCT05101265
- Lead Sponsor
- PharmaMar
- Brief Summary
Lurbinectedin is mainly eliminated by the liver. Thus, Hepatic Impairment (HI) may alter the plasma concentrations of lurbinectedin. This study is designed to examine the PK and safety of an adjusted dose of lurbinectedin when administered to patients with HI. The results of this study may be used to support future clinical studies in patients and prescribing information in future labeling.
- Detailed Description
This is a prospective, open-label, parallel, phase Ib, hepatic impairment study in patients with advanced solid tumors who either have Hepatic Impairment (HI) at varying degrees (mild, moderate or severe) or qualify for the control group (normal hepatic function) according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification criteria of HI.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 24
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Mild Hepatic impairment cohort Lurbinectedin Patients with Mild Hepatic impairment must meet the following additional criteria * Total bilirubin ≤ 1.0 x ULN and AST \> 1.0 x ULN, or * Total bilirubin \> 1.0 - ≤ 1.5 x ULN and any AST, and * Albumin ≥ 3.0 g/dL Normal Hepatic function cohort Lurbinectedin Patients in the control cohort must meet the following criteria: * Total bilirubin ≤ 1.0 x upper limit of normal (ULN) and no clinical (or histological) evidence of liver disease. * Aspartate aminotransferase (AST) ≤ 1.0 x ULN and alanine aminotransferase (ALT) ≤ 1.0 x ULN. * Albumin ≥ 3.5 g/dL. * The age, weight and CLcr should be within ±10 years, ±15 kg and ±20 mL/min of the mean of pooled HI cohort, respectively; and with a similar male/female ratio. Moderate Hepatic impairment cohort Lurbinectedin Patients with Moderate Hepatic impairment must meet the following additional criteria * Total bilirubin \>1.5 - ≤ 3.0 x ULN and any AST, and * Albumin ≥ 2.8 g/dL Severe Hepatic impairment cohort Lurbinectedin Patients with Severe Hepatic impairment must meet the following additional criteria: * Total bilirubin \>3.0 x ULN and any AST, and * Albumin ≥ 2.5 g/dL
- Primary Outcome Measures
Name Time Method Total plasma dose-normalized Cmax Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Total plasma dose-normalized Cmax of lurbinectedin will be compared between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts
Total plasma dose-normalized AUC0-48h Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Total plasma dose-normalized area under curve (AUC) 0-48h of lurbinectedin will be compared between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts
Total plasma dose-normalized AUC0-∞ Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Total plasma dose-normalized AUC0-∞ (if data do not permit so, AUC0-t will be used) of lurbinectedin will be compared between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts
- Secondary Outcome Measures
Name Time Method Clearance Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in Clearance (Cl) of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Total plasma dose-normalized AUC0-t Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in dose-normalized total AUC0-t of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Dose-normalized unbound AUCu,0-48h Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in dose-normalized unbound AUCu,0-48h of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Dose-normalized unbound AUCu,0-t Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in dose-normalized unbound AUCu,0-t of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
T1/2,u Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in T1/2,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Ratios AUC0-48h Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in ratios between total AUC0-48h of main lurbinectedin metabolites relative to parent drug between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Ratios AUC0-t Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in ratios between total AUC0-t of main lurbinectedin metabolites relative to parent drug between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Volume of Distribution at Steady State Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in Volume of Distribution at Steady State (Vss) of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Percentage of patients with serious adverse events From first infusion to the end-of-treatment visit which will be scheduled within 31 days (±10 days) after administration of the last dose of lurbinectedin Treatment safety (SAEs) will be graded according to the NCI-CTCAE v.5.
T1/2 Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in T1/2 of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Dose-normalized unbound AUCu,0-∞ Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in dose-normalized unbound AUCu,0-∞ of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Dose-normalized unbound Cu,max Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in dose-normalized unbound Cu,max of lurbinectedin between Control (normal hepatic function) cohort and each of the HI cohorts will be explored.
Unbound CLu Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in CLu of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Unbound Vss,u Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in Vss,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Ratios total AUC0-∞ Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in ratios between total AUC0-∞ of main lurbinectedin metabolites relative to parent drug between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Ratios Cmax Preinfusion, 5 minutes before end of infusion, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours, 336 hours, and 504 hours after end of infusion Change in ratios between total Cmax of main lurbinectedin metabolites relative to parent drug between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Percentage of patients with non-serious adverse events From first infusion to the end-of-treatment visit which will be scheduled within 31 days (±10 days) after administration of the last dose of lurbinectedin Treatment safety (AEs) will be graded according to the NCI-CTCAE v.5.
Percentage of patients with Laboratory abnormalities From first infusion to the end-of-treatment visit which will be scheduled within 31 days (±10 days) after administration of the last dose of lurbinectedin Laboratory abnormalities will be graded according to the NCI-CTCAE v.5.
Pharmacogenetics After first cycle (21 days) The presence or absence of PGt polymorphisms in genes relevant for lurbinectedin disposition (distribution, metabolism and excretion) from a single blood sample collected at any time during the trial (but preferably at the same time as the pre-treatments PK sample on Day 1 of Cycle 1), which will be stored to explain individual variability in main PK parameters in future analyses
Trial Locations
- Locations (6)
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Cataluña, Spain
Hospital General Universitario Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Universitario Virgen de la Victoria
🇪🇸Málaga, Andalucía, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, Spain
Hospital Universitario Fundación Jimenez Diaz
🇪🇸Madrid, Spain