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

• ClinicalTrials.gov Identifier: NCT05101265
• Recruitment Status: Recruiting
• First Posted: November 1, 2021
• Last Update Posted: November 27, 2023
• Sponsor: PharmaMar
• Information provided by (Responsible Party): PharmaMar

Tracking Information

• First Submitted Date: September 29, 2021
• First Posted Date: November 1, 2021
• Last Update Posted Date: November 27, 2023
• Actual Study Start Date: March 9, 2021
• Estimated Primary Completion Date: June 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2021)

• Total plasma dose-normalized Cmax [ 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 ]
  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 [ 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 ]
  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-∞ [ 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 ]
  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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 19, 2021)

• Total plasma dose-normalized AUC0-t [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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-∞ [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  Change in CLu of lurbinectedin between Control (normal hepatic function) cohort and each of the Hepatic impairment cohorts will be explored.
• Unbound Vss,u [ 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 ]
  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 [ 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 ]
  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-∞ [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  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 [ 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 ]
  Treatment safety (AEs) will be graded according to the NCI-CTCAE v.5.
• Percentage of patients with serious adverse events [ 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 ]
  Treatment safety (SAEs) will be graded according to the NCI-CTCAE v.5.
• Percentage of patients with Laboratory abnormalities [ 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 ]
  Laboratory abnormalities will be graded according to the NCI-CTCAE v.5.
• Pharmacogenetics [ Time Frame: 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment

Condition

• Advanced Solid Tumor
• Hepatic Impairment

Intervention

• Drug: Lurbinectedin

  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.

  Other Name: PM1183
• Drug: Lurbinectedin

  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

  Other Name: PM1183

Study Arms

• Experimental: Normal Hepatic function cohort

  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.
  Intervention: Drug: Lurbinectedin
• Experimental: Mild Hepatic impairment cohort

  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
  Intervention: Drug: Lurbinectedin
• Experimental: Moderate Hepatic impairment cohort

  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
  Intervention: Drug: Lurbinectedin
• Experimental: Severe Hepatic impairment cohort

  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: Drug: Lurbinectedin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 19, 2021): 24
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 1, 2025
• Estimated Primary Completion Date: June 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sara Martínez González, MD; +3491 823 4647; smgonzalez@pharmamar.com

• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT05101265
• Other Study ID Numbers: PM1183-A-017-20; 2020-002789-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: PharmaMar
• Original Responsible Party: Same as current
• Current Study Sponsor: PharmaMar
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Rubin Lubomirov, MD, PhD; PharmaMar
• Study Director: Sara Martínez González, MD; PharmaMar

• PRS Account: PharmaMar
• Verification Date: November 2023