Evaluating Lurbinectedin in Patients with Advanced Solid Tumors and Liver Issues

An Open-Label, Multicenter, Pharmacokinetic Study of Lurbinectedin in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment

This study is testing how a cancer drug called Lurbinectedin works and is safe for people with advanced tumors who also have liver problems.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: PharmaMar (industry)
• Locations: 6 sites (Málaga, Andalucía and 5 other locations)
• Trial ID: NCT05101265 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the pharmacokinetics and safety of Lurbinectedin in patients with advanced solid tumors who have varying degrees of hepatic impairment. The study is designed as a prospective, open-label, phase Ib trial, comparing patients with hepatic impairment to a control group with normal liver function. By adjusting the dosage of Lurbinectedin based on liver function, the trial aims to determine the optimal treatment approach for this patient population. The findings may inform future clinical studies and prescribing guidelines for Lurbinectedin.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with advanced solid tumors and varying degrees of hepatic impairment.

Not a fit: Patients with primary central nervous system tumors or those who do not meet the inclusion criteria will not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to safer and more effective dosing of Lurbinectedin for patients with liver impairment.

How similar studies have performed: While studies on Lurbinectedin have been conducted, this specific approach focusing on hepatic impairment is novel and has not been extensively tested.

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.

Where this trial is running

Málaga, Andalucía and 5 other locations

• Hospital Universitario Virgen de la Victoria — Málaga, Andalucía, Spain (RECRUITING)
• Hospital Universitari Vall d'Hebron — Barcelona, Cataluña, Spain (RECRUITING)
• Hospital General Universitario Gregorio Marañón — Madrid, Spain (RECRUITING)
• Hospital Universitario Ramón y Cajal — Madrid, Spain (ACTIVE_NOT_RECRUITING)
• Hospital Universitario Fundación Jimenez Diaz — Madrid, Spain (RECRUITING)
• Hospital Universitario HM Sanchinarro — Madrid, Spain (RECRUITING)

Study contacts

• Study coordinator: Sara Martínez González, MD

Conditions: Advanced Solid Tumor, Hepatic Impairment, Lurbinectedin