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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 14
- 试验地点
- 2
- 主要终点
- Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞)
研究概览
简要总结
Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
排除标准
- •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
- •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
- •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.
研究组 & 干预措施
Sequence TR
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.
干预措施: Lurbinectedin alone (Drug)
Sequence TR
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.
干预措施: Lurbinectedin+Itraconazole co-administration (Drug)
Sequence RT
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)
干预措施: Lurbinectedin alone (Drug)
Sequence RT
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)
干预措施: Lurbinectedin+Itraconazole co-administration (Drug)
结局指标
主要结局
Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞)
时间窗: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
The primary parameter of interest for the statistical analysis will be plasma dose adjusted AUC(0-∞)
次要结局
- Pharmacokinetic Analysis: Dose-normalized AUC(0-t)(Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days))
- Pharmacokinetic Analysis: Dose-normalized Cmax(Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days))
- Pharmacokinetic Analysis: T1/2(Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days))
- Pharmacokinetic Analysis: Total Body Clearance (CL)(Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days))
- Pharmacokinetic Analysis: Volume of Distribution(Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days))