Overview

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.

Eligibility

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.