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.

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.

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.