Clinical trial NCT05101265: 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
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Hepatic Impairment
Keywords: Hepatic Impairment
Advanced Solid Tumor
Lurbinectedin
Lead sponsor: PharmaMar
Sponsor class: INDUSTRY
First posted: 2021-11-01
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Total plasma dose-normalized Cmax
timeFrame: 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
measure: Total plasma dose-normalized AUC0-48h
timeFrame: 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
measure: Total plasma dose-normalized AUC0-∞
timeFrame: 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 outcomes:
measure: Total plasma dose-normalized AUC0-t
timeFrame: 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
measure: Clearance
timeFrame: 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
measure: Volume of Distribution at Steady State
timeFrame: 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
measure: T1/2
timeFrame: 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
measure: Dose-normalized unbound AUCu,0-∞
timeFrame: 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
measure: Dose-normalized unbound AUCu,0-48h
timeFrame: 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
measure: Dose-normalized unbound AUCu,0-t
timeFrame: 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
measure: Dose-normalized unbound Cu,max
timeFrame: 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
measure: Unbound CLu
timeFrame: 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
measure: Unbound Vss,u
timeFrame: 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
measure: T1/2,u
timeFrame: 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
measure: Ratios total AUC0-∞
timeFrame: 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
measure: Ratios AUC0-48h
timeFrame: 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
measure: Ratios AUC0-t
timeFrame: 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
measure: Ratios Cmax
timeFrame: 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
measure: Percentage of patients with non-serious adverse events
timeFrame: 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
measure: Percentage of patients with serious adverse events
timeFrame: 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
measure: Percentage of patients with Laboratory abnormalities
timeFrame: 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
measure: Pharmacogenetics
timeFrame: After first cycle (21 days)
Other outcomes:
Locations:
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
state: Andalucía
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Cataluña
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
Study officials:
affiliation: PharmaMar
name: Rubin Lubomirov, MD, PhD
role: STUDY_DIRECTOR
affiliation: PharmaMar
name: Sara Martínez González, MD
role: STUDY_DIRECTOR
References: