A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 8
- 主要终点
- Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration
研究概览
简要总结
The purpose of this study is to characterize the effects of 25 and 50 milligram per square meter (mg/m^2) pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).
详细描述
The drug being tested in this study is called pevonedistat. Pevonedistat in combination with standard of care will be used to treat participants who have advanced solid tumors. This study will assess the effects of pevonedistat on the QTc interval in participants with advanced solid tumors.
The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:
- Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2
- Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2
Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.
- Pevonedistat 25 mg/m^2 + Docetaxel
- Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 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
- •Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Expected survival longer than 3 months from enrollment in the study.
- •Recovered (that is, grade less than or equal to [<=] 1 toxicity) from the reversible effects of prior anticancer therapy.
- •Suitable venous access for the study-required blood sampling (including pharmacokinetic [PK] sampling).
排除标准
- •Treatment with strong cytochrome P3A (CYP3A) inducers within 14 days before the first dose of pevonedistat. Participants must have no history of amiodarone use within 6 months before the first dose of pevonedistat nor require the use of these medications during the study.
- •Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
- •History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
- •Implantable cardioverter defibrillator.
- •Cardiac pacemaker with heart rate (HR) set at a fixed rate and treatment with concomitant medication that may limit increase in HR in response to hypotension (example, high-dose beta blocker).
- •Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
- •Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
- •Entry Criteria for Continuation to Optional Part B:
- •After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:
- •ECOG performance status of 0 to
- •Absolute neutrophil count (ANC) greater than or equal to (>=) 1500 per cubic millimeter (/mm^3).
- •Platelet count >=100,000/mm^
- •Laboratory values for hemoglobin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum creatinine or calculated/measured creatinine clearance.
- •Diarrhea symptoms resolved to Grade 1 or better.
- •QTc interval <480 millisecond (msec).
- •Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.
研究组 & 干预措施
Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2
Pevonedistat 50 mg/m^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 25 mg/m^2, infusion, intravenously, once on Day 8 of Cycle 1.
干预措施: Pevonedistat (Drug)
Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2
Pevonedistat 25 mg/m^2, infusion, intravenously, once on Day 1 of Cycle 1, followed by pevonedistat 50 mg/m^2, infusion, intravenously, once on Day 8 of Cycle 1.
干预措施: Pevonedistat (Drug)
Part B: Pevonedistat
Pevonedistat 25 mg/m^2 in combination with docetaxel 75 mg/m^2 or pevonedistat 20 mg/m^2 in combination with carboplatin plus paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m^2 or 20 mg/m^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.
干预措施: Pevonedistat (Drug)
Part B: Pevonedistat
Pevonedistat 25 mg/m^2 in combination with docetaxel 75 mg/m^2 or pevonedistat 20 mg/m^2 in combination with carboplatin plus paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m^2 or 20 mg/m^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.
干预措施: Docetaxel (Drug)
Part B: Pevonedistat
Pevonedistat 25 mg/m^2 in combination with docetaxel 75 mg/m^2 or pevonedistat 20 mg/m^2 in combination with carboplatin plus paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m^2 or 20 mg/m^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.
干预措施: Carboplatin (Drug)
Part B: Pevonedistat
Pevonedistat 25 mg/m^2 in combination with docetaxel 75 mg/m^2 or pevonedistat 20 mg/m^2 in combination with carboplatin plus paclitaxel 175 mg/m^2, infusion, intravenously, once on Day 1 in each 21-day treatment cycle followed by pevonedistat 25 mg/m^2 or 20 mg/m^2 infusion, intravenously, once on Days 3 and 5 in each 21-day treatment cycle for up to 12 cycles or symptomatic deterioration or PD, treatment is discontinued for another reason, or until the study is stopped. The combination and dose of pevonedistat will be based on investigator discretion.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration
时间窗: Baseline up to Day 8
Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.
次要结局
- Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration(Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A)
- Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration(Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A)
- Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration(Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A)
- Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat(Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A)
- Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration(Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A)
- Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat(Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A)
- Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat(Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A)
- Part B: Overall Response Rate (ORR)(Up to Cycle 45 (end of treatment) (Cycle length=21 days))