Clinical Trial of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors

Detailed Description
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Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors. The study will include a pre-treatment (screening) phase (within 14 days before the first lurbinectedin or itraconazole administration) followed by a treatment phase consisting of two lurbinectedin cycles, one cycle in combination with itraconazole and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles, and then follow-up of adverse events if any.

Official Title
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An Open-Label, Multicenter Study to Assess the Potential Effects of Itraconazole (a Strong CYP3A4 Inhibitor) on the Pharmacokinetics of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Lurbinectedin alone
* Drug: Lurbinectedin+Itraconazole co-administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary signed and dated written informed consent prior to any specific study procedure. Male or female with age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (App. 1). Life expectancy > 3 months. Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no standard therapy exists. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and grade 1/2 asthenia or fatigue, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v.5). Laboratory values within fourteen days prior to Day 1 of Cycle 1 Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-gated acquisition (MUGA) within normal range (according to institutional standards). Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six months after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in App. 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose. Exclusion Criteria: Concomitant diseases/conditions: History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For hepatitis B, this includes positive test for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or HVB-DNA+). For hepatitis C, this includes positive test for both Hepatitis C antibody and quantitative Hepatitis C by PCR (or HVC-RNA+). History of obstructive cholestatic liver disease (suitable for stenting procedure) or biliary sepsis in the past 2 months. Known of active COVID-19 disease (this includes positive test for SARS-CoV- 2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR). 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. Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1. Use of CYP3A4 substrates such as HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin for which concomitant administration with strong CYP3A4 inhibitor is contraindicated (App 3). Treatment with any investigational product within the 30 days before Day 1 of Cycle 1. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception (see App 2). Psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence TR<br>Sequence 1 (TR) Cycle 1: Itraconazole + lurbinectedin 0.8 mg/m² Cycle 2: Lurbinectedin alone 3.2 mg/m² Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional) PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional). PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. | Drug: Lurbinectedin alone<br>* The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.<br>Drug: Lurbinectedin+Itraconazole co-administration<br>* The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A.<br>|
| Active Comparator: Sequence RT<br>Sequence 2 (RT): Cycle 1: Lurbinectedin alone 3.2 mg/m² Cycle 2: Itraconazole + lurbinectedin 0.8 mg/m² Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional) | Drug: Lurbinectedin alone<br>* The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.<br>Drug: Lurbinectedin+Itraconazole co-administration<br>* The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Analysis: AUC(0-∞) | The primary parameter of interest for the statistical analysis will be plasma doseadjusted AUC(0-∞) | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Analysis: AUC(0-t) | The area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 
| Pharmacokinetic Analysis: Cmax | The maximum plasma concentration (Cmax) will be obtained directly from the experimental data. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 
| Pharmacokinetic Analysis: T1/2 | Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 
| Pharmacokinetic Analysis: Total body clearance | Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 
| Pharmacokinetic Analysis: Volume of distribution | Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) | 
| Pharmacogenetics | A genotype evaluation in genes relevant for lurbinectedin metabolism and transport will be investigated and reported in an independent report in order to determine whether the observed differences between patients in PK parameters are related to these genetic features. | Before treatment start along with PK sample on Day 1 of Cycle 1 (each cycle is 21 days) |