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Clinical Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment

Primary Purpose

Advanced Solid Tumor, Hepatic Impairment

Status
Recruiting
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
Lurbinectedin
Lurbinectedin
Sponsored by
PharmaMar
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Solid Tumor focused on measuring Hepatic Impairment, Advanced Solid Tumor, Lurbinectedin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

All patients must fulfill the following inclusion criteria (1 - 9) to be enrolled in the study:

  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) ≤ 2.
  4. Life expectancy > 1 month.
  5. Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no standard therapy exists.
  6. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade ≤ 2, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v.5).
  7. Laboratory values within fourteen days prior to registration:

    1. Absolute neutrophil count (ANC) > 2.0 x 10^9/L, platelet count > 120 x 10^9/L and hemoglobin > 9.0 g/dL (patients may be transfused as clinically indicated prior to study entry).
    2. Creatinine clearance (CLcr) ≥ 30 mL/min (using Cockcroft and Gault's formula).
    3. Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x ULN if disease related).
  8. Evidence of non-childbearing status for women of childbearing potential
  9. History of alcohol abuse is permissible providing that the results of alcohol (in breath or blood) test are negative at screening.

    Patients in the control cohort (normal hepatic function) must meet the following additional inclusion criteria (10 - 13) to be enrolled in the study:

  10. Total bilirubin ≤ 1.0 x upper limit of normal (ULN) and no clinical (or histological) evidence of liver disease.
  11. Aspartate aminotransferase (AST) ≤ 1.0 x ULN and alanine aminotransferase (ALT) ≤ 1.0 x ULN.
  12. Albumin ≥ 3.5 g/dL.
  13. 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.

    Patients with HI must meet the following additional inclusion criteria (14 - 16):

  14. Patients with HI per cohort must meet:

    a) Mild HI cohort:

    i) Total bilirubin ≤ 1.0 x ULN and AST > 1.0 x ULN, or

    ii) Total bilirubin > 1.0 - ≤ 1.5 x ULN and any AST, and

    iii) Albumin ≥ 3.0 g/dL

    b) Moderate HI cohort:

    i) Total bilirubin >1.5 - ≤ 3.0 x ULN and any AST, and

    ii) Albumin ≥ 2.8 g/dL

    c) Severe HI cohort:

    i) Total bilirubin >3.0 x ULN and any AST, and

    ii) Albumin ≥ 2.5 g/dL

  15. Documented liver disease and/or hepatic metastases, with physical examination, liver biopsy or hepatic ultrasound, CT scan or MRI consistent with diagnosis.
  16. Stable HI, defined as no clinically significant change in the disease status within the last 14 days, as documented by the patient's recent medical history (e.g., no worsening clinical signs of HI, or no worsening of total bilirubin or prothrombin time by more than 50%).

Exclusion criteria

All patients who meet any of the following criteria (1 - 6) will be excluded from participating in the study:

  1. Concomitant diseases/conditions:

    1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year.
    2. Symptomatic arrhythmia or any uncontrolled arrhythmia.
    3. Active infection by hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as: for hepatitis B, positive test for quantitative Hepatitis B virus polymerase chain reaction (PCR or HBV-DNA+), regardless of the HBsAg; and for hepatitis C, positive test for quantitative Hepatitis C virus by PCR (or HCV-RNA+).
    4. Human immunodeficiency virus (HIV)-positive patients.
    5. History of Gilbert's syndrome diagnosis.
    6. History of biliary sepsis in the past 2 months.
    7. Patients with biliary obstruction for which a stent has been placed are eligible, provided the stent has been in place for at least 10 days prior to the first dose of lurbinectedin and the liver function has stabilized; two measurements at least 2 days apart that put the patient in the same hepatic dysfunction cohort will be accepted as evidence of stable hepatic function; there should be no evidence of biliary sepsis.
    8. Active coronavirus disease of 2019 (COVID-19) disease (this includes positive test for severe acute respiratory syndrome coronavirus 2 (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. Less than three weeks since the last systemic anticancer therapy (investigational or standard), or less than two weeks since last radiotherapy before starting treatment of Day 1 of Cycle 1. Treatment with any other investigational product within the 30 days before Day 1 of Cycle 1.
  5. Women who are pregnant or breast-feeding and fertile patients (men and women) who are not using an effective method of contraception.
  6. Psychiatric illness/social situations that would limit compliance with study requirements.

    Patients with HI (all cohorts) who meet any of the following additional criteria (7 - 9) will be excluded:

  7. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than one month prior to Day 1 of Cycle 1.
  8. Signs of significant hepatic encephalopathy (> grade II Portal Systemic Encephalopathy).
  9. Severe ascites and/or pleural effusion, except for patients at the severe HI cohort.

Sites / Locations

  • Hospital Universitario Virgen de la VictoriaRecruiting
  • Hospital Universitari Vall d'HebronRecruiting
  • Hospital General Universitario Gregorio MarañónRecruiting
  • Hospital Universitario Ramón y Cajal
  • Hospital Universitario Fundación Jimenez DiazRecruiting
  • Hospital Universitario HM SanchinarroRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Normal Hepatic function cohort

Mild Hepatic impairment cohort

Moderate Hepatic impairment cohort

Severe Hepatic impairment cohort

Arm Description

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.

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

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

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

Outcomes

Primary Outcome Measures

Total plasma dose-normalized Cmax
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
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-∞
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

Total plasma dose-normalized AUC0-t
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.
Clearance
Change in Clearance (Cl) of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Volume of Distribution at Steady State
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.
T1/2
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-∞
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 AUCu,0-48h
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
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.
Dose-normalized unbound Cu,max
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
Change in CLu of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Unbound Vss,u
Change in Vss,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
T1/2,u
Change in T1/2,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Ratios total AUC0-∞
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 AUC0-48h
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
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.
Ratios Cmax
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
Treatment safety (AEs) will be graded according to the NCI-CTCAE v.5.
Percentage of patients with serious adverse events
Treatment safety (SAEs) will be graded according to the NCI-CTCAE v.5.
Percentage of patients with Laboratory abnormalities
Laboratory abnormalities will be graded according to the NCI-CTCAE v.5.
Pharmacogenetics
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

Full Information

First Posted
September 29, 2021
Last Updated
October 19, 2021
Sponsor
PharmaMar
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1. Study Identification

Unique Protocol Identification Number
NCT05101265
Brief Title
Clinical Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment
Official Title
An Open-Label, Multicenter, Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Recruiting
Study Start Date
March 9, 2021 (Actual)
Primary Completion Date
June 1, 2025 (Anticipated)
Study Completion Date
June 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PharmaMar

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Solid Tumor, Hepatic Impairment
Keywords
Hepatic Impairment, Advanced Solid Tumor, Lurbinectedin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
This is a prospective, open-label, parallel, phase Ib, hepatic impairment study in patients with advanced solid tumors who either have 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.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Normal Hepatic function cohort
Arm Type
Experimental
Arm Description
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.
Arm Title
Mild Hepatic impairment cohort
Arm Type
Experimental
Arm Description
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
Arm Title
Moderate Hepatic impairment cohort
Arm Type
Experimental
Arm Description
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
Arm Title
Severe Hepatic impairment cohort
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Lurbinectedin
Other Intervention Name(s)
PM1183
Intervention Description
Patients will receive lurbinectedin as a 1-hour (-5/+20 min) i.v. infusion on Day 1 every three weeks (q3wk), over a minimum of 100 mL dilution on 5% glucose or 0.9% sodium chloride via a central line (or a minimum of 250 mL dilution if a peripheral line is used). Of note, Cycle 2 or subsequent will be administered every q3wk (+ 48 hours). Patients will receive a maximum of two cycles: a first mandatory cycle with all study assessments followed by a second optional cycle with lurbinectedin (this last optional for patients with clinical benefit as per Investigator's criteria). After completing Cycle 2, those patients waiting for the compassionate use approval will continue on the study receiving lurbinectedin herein after until disease progression, unacceptable toxicity, consent withdrawal or while it is considered to be in their best interest, or until starting treatment with lurbinectedin under a Compassionate Use Agreement outside this study. Lurbinectedin at a 3.2 mg/m² dose.
Intervention Type
Drug
Intervention Name(s)
Lurbinectedin
Other Intervention Name(s)
PM1183
Intervention Description
Patients will receive lurbinectedin as a 1-hour (-5/+20 min) i.v. infusion on Day 1 every three weeks (q3wk), over a minimum of 100 mL dilution on 5% glucose or 0.9% sodium chloride via a central line (or a minimum of 250 mL dilution if a peripheral line is used). Of note, Cycle 2 or subsequent will be administered every q3wk (+ 48 hours). Patients will receive a maximum of two cycles: a first mandatory cycle with all study assessments followed by a second optional cycle with lurbinectedin (this last optional for patients with clinical benefit as per Investigator's criteria). After completing Cycle 2, those patients waiting for the compassionate use approval will continue on the study receiving lurbinectedin herein after until disease progression, unacceptable toxicity, consent withdrawal or while it is considered to be in their best interest, or until starting treatment with lurbinectedin under a Compassionate Use Agreement outside this study. Lurbinectedin at a 1.6 mg/m² dose
Primary Outcome Measure Information:
Title
Total plasma dose-normalized Cmax
Description
Total plasma dose-normalized Cmax of lurbinectedin will be compared between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts
Time Frame
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
Title
Total plasma dose-normalized AUC0-48h
Description
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
Time Frame
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
Title
Total plasma dose-normalized AUC0-∞
Description
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
Time Frame
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
Secondary Outcome Measure Information:
Title
Total plasma dose-normalized AUC0-t
Description
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.
Time Frame
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
Title
Clearance
Description
Change in Clearance (Cl) of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Time Frame
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
Title
Volume of Distribution at Steady State
Description
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.
Time Frame
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
Title
T1/2
Description
Change in T1/2 of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Time Frame
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
Title
Dose-normalized unbound AUCu,0-∞
Description
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.
Time Frame
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
Title
Dose-normalized unbound AUCu,0-48h
Description
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.
Time Frame
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
Title
Dose-normalized unbound AUCu,0-t
Description
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.
Time Frame
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
Title
Dose-normalized unbound Cu,max
Description
Change in dose-normalized unbound Cu,max of lurbinectedin between Control (normal hepatic function) cohort and each of the HI cohorts will be explored.
Time Frame
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
Title
Unbound CLu
Description
Change in CLu of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Time Frame
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
Title
Unbound Vss,u
Description
Change in Vss,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Time Frame
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
Title
T1/2,u
Description
Change in T1/2,u of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
Time Frame
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
Title
Ratios total AUC0-∞
Description
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.
Time Frame
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
Title
Ratios AUC0-48h
Description
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.
Time Frame
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
Title
Ratios AUC0-t
Description
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.
Time Frame
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
Title
Ratios Cmax
Description
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.
Time Frame
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
Title
Percentage of patients with non-serious adverse events
Description
Treatment safety (AEs) will be graded according to the NCI-CTCAE v.5.
Time Frame
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
Title
Percentage of patients with serious adverse events
Description
Treatment safety (SAEs) will be graded according to the NCI-CTCAE v.5.
Time Frame
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
Title
Percentage of patients with Laboratory abnormalities
Description
Laboratory abnormalities will be graded according to the NCI-CTCAE v.5.
Time Frame
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
Title
Pharmacogenetics
Description
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
Time Frame
After first cycle (21 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria All patients must fulfill the following inclusion criteria (1 - 9) to be enrolled in the study: 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) ≤ 2. Life expectancy > 1 month. Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no standard therapy exists. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade ≤ 2, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v.5). Laboratory values within fourteen days prior to registration: Absolute neutrophil count (ANC) > 2.0 x 10^9/L, platelet count > 120 x 10^9/L and hemoglobin > 9.0 g/dL (patients may be transfused as clinically indicated prior to study entry). Creatinine clearance (CLcr) ≥ 30 mL/min (using Cockcroft and Gault's formula). Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x ULN if disease related). Evidence of non-childbearing status for women of childbearing potential History of alcohol abuse is permissible providing that the results of alcohol (in breath or blood) test are negative at screening. Patients in the control cohort (normal hepatic function) must meet the following additional inclusion criteria (10 - 13) to be enrolled in the study: 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. Patients with HI must meet the following additional inclusion criteria (14 - 16): Patients with HI per cohort must meet: a) Mild HI cohort: i) Total bilirubin ≤ 1.0 x ULN and AST > 1.0 x ULN, or ii) Total bilirubin > 1.0 - ≤ 1.5 x ULN and any AST, and iii) Albumin ≥ 3.0 g/dL b) Moderate HI cohort: i) Total bilirubin >1.5 - ≤ 3.0 x ULN and any AST, and ii) Albumin ≥ 2.8 g/dL c) Severe HI cohort: i) Total bilirubin >3.0 x ULN and any AST, and ii) Albumin ≥ 2.5 g/dL Documented liver disease and/or hepatic metastases, with physical examination, liver biopsy or hepatic ultrasound, CT scan or MRI consistent with diagnosis. Stable HI, defined as no clinically significant change in the disease status within the last 14 days, as documented by the patient's recent medical history (e.g., no worsening clinical signs of HI, or no worsening of total bilirubin or prothrombin time by more than 50%). Exclusion criteria All patients who meet any of the following criteria (1 - 6) will be excluded from participating in the study: Concomitant diseases/conditions: History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year. Symptomatic arrhythmia or any uncontrolled arrhythmia. Active infection by hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as: for hepatitis B, positive test for quantitative Hepatitis B virus polymerase chain reaction (PCR or HBV-DNA+), regardless of the HBsAg; and for hepatitis C, positive test for quantitative Hepatitis C virus by PCR (or HCV-RNA+). Human immunodeficiency virus (HIV)-positive patients. History of Gilbert's syndrome diagnosis. History of biliary sepsis in the past 2 months. Patients with biliary obstruction for which a stent has been placed are eligible, provided the stent has been in place for at least 10 days prior to the first dose of lurbinectedin and the liver function has stabilized; two measurements at least 2 days apart that put the patient in the same hepatic dysfunction cohort will be accepted as evidence of stable hepatic function; there should be no evidence of biliary sepsis. Active coronavirus disease of 2019 (COVID-19) disease (this includes positive test for severe acute respiratory syndrome coronavirus 2 (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. Less than three weeks since the last systemic anticancer therapy (investigational or standard), or less than two weeks since last radiotherapy before starting treatment of Day 1 of Cycle 1. Treatment with any other 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. Patients with HI (all cohorts) who meet any of the following additional criteria (7 - 9) will be excluded: History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than one month prior to Day 1 of Cycle 1. Signs of significant hepatic encephalopathy (> grade II Portal Systemic Encephalopathy). Severe ascites and/or pleural effusion, except for patients at the severe HI cohort.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sara Martínez González, MD
Phone
+3491 823 4647
Email
smgonzalez@pharmamar.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rubin Lubomirov, MD, PhD
Organizational Affiliation
PharmaMar
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Sara Martínez González, MD
Organizational Affiliation
PharmaMar
Official's Role
Study Director
Facility Information:
Facility Name
Hospital Universitario Virgen de la Victoria
City
Málaga
State/Province
Andalucía
ZIP/Postal Code
29010
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Begoña Jiménez, Dra.
Email
bego.jimenez@ibima.eu
Facility Name
Hospital Universitari Vall d'Hebron
City
Barcelona
State/Province
Cataluña
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Irene Braña Garcia, Dra
Email
ibrana@vhio.net
Facility Name
Hospital General Universitario Gregorio Marañón
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antonio Calles Blanco, Dr
Email
investigaoncomedica.hgugm@salud.madrid.org
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Individual Site Status
Active, not recruiting
Facility Name
Hospital Universitario Fundación Jimenez Diaz
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tatiana Hernandez Guerrero, Dra
Email
tatiana.hernandez@startmadrid.com
Facility Name
Hospital Universitario HM Sanchinarro
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emiliano Calvo Aller, Dr
Email
emiliano.calvo@startmadrid.com

12. IPD Sharing Statement

Learn more about this trial

Clinical Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment

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