A multicenter, multinational, pharmacokinetic, safety, and efficacy study with IV NEPA (fosnetupitant/palonosetron) for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients undergoing highly emetogenic chemotherapy (HEC). A 2-part study with Phase 2, open-label, randomized, single-dose IV NEPA vs fosaprepitant/ondansetron in single-day HEC and repeated-dose IV NEPA in multi-day HEC (Part I, single cycle) and with Phase 3, double-blind, randomized, repeated-dose IV NEPA vs aprepitant/ondansetron in multi-day HEC (Part II, repeated cycles).
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 80
- 试验地点
- 12
- 主要终点
- Part I: Cohort 1: Netupitant exposure parameters maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUClast) and to infinity (AUCinf).
研究概览
简要总结
Part I: Cohort 1: To confirm by netupitant PK assessment that a single dose of 3.13 mg/kg IV fosnetupitant (for patients aged ≥3 months up to <18 years - to a maximum of 235 mg fosnetupitant for patients weighing ≥75 kg) or 1.88 mg/kg IV fosnetupitant (for patients <3 months) as IV NEPA provides the expected netupitant exposure observed in previous single-dose oral NEPA studies in paediatric cancer patients receiving 4 mg/kg or 2.4 mg/kg oral netupitant, respectively, with single-day chemotherapy and in adult population following 300 mg oral netupitant (oral NEPA).
Part I: Cohort 2: To assess the safety and tolerability of IV NEPA infusion after repeated administration (Days 1, 3 and Days 1, 3, 5).
Part II: To demonstrate the non-inferiority of IV NEPA (fosnetupitant + palonosetron) in Cycle 1 versus IV fosaprepitant + IV ondansetron in the prevention of CINV in the delayed (>24-120 h) phase of emesis in paediatric cancer patients aged between ≥6 months and <18 years receiving multi-day HEC.
研究设计
- 分配方式
- Randomized
- 主要目的
- Part II (phase 3)
- 盲法
- Double (Investigator, Monitor, Subject, Carer)
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •Part I: Cohort 1: Patient < 6 months weighing at least 4 kg or patient ≥ 6 months weighing at least 6 kg. Cohort 2: Patient weighing at least 4 kg.
- •Part I and Part II: Patient with non-clinically significant abnormal laboratory values or with clinically relevant abnormal laboratory values may be enrolled if in the Investigator’s opinion the patient’s safety is not expected to be jeopardized.
- •Part I: Cohort 1: Patient scheduled and eligible to receive at least 1 cycle of single-day HEC. Cohort 2: Patient scheduled and eligible to receive at least 1 cycle of multi-day HEC.
- •Part II: Patient weight at least 6 kg.
- •Part II: Patient scheduled and eligible to receive repeated cycles of multi-day HEC.
- •Part I and Part II: Patient with a predicted life expectancy ≥3 months according to Investigator’s opinion.
- •Part I and Part II: For patients aged ≥10 years: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤
- •Part I and Part II: For patient with known hepatic impairment: the patient may be enrolled provided the serum ALT and AST are ≤2.5 ULN, the total bilirubin is ≤1.5 ULN, and in the Investigator’s opinion the impairment is not expected to jeopardize the patient’s safety during the study.
- •Part I and Part II: For patient with known renal impairment: the patient may be enrolled provided the estimated glomerular filtration rate (eGFR) is ≥70 mL/min/1.73m2 (≥50 mL/min/1.73m2 for children <3 months old) (the eGFR should be calculated using the modified Schwartz equation) and in the Investigator’s opinion the impairment is not expected to jeopardize the patient’s safety during the study.
- •Part I and Part II: For patient with known history or predisposition to cardiac abnormalities: as per the Investigator’s opinion, the history/predisposition should not jeopardize patient’s safety during the study.
排除标准
- •Part I and Part II: Patient has received or is scheduled to receive total body irradiation; total nodal irradiation; upper abdomen radiotherapy; half or upper body irradiation; or radiotherapy of the cranium, craniospinal regions, head and neck, lower thorax region, or the pelvis within 1 week prior to study entry (Day 1) or within 120 h after last study drug administration.
- •Part I and Part II: Any illness or condition that, in the opinion of the Investigator, may pose unwarranted risks in administering the investigational product to the patient.
- •Part I and Part II: Uncontrolled medical condition (e.g., uncontrolled insulin-dependent diabetes mellitus).
- •Part I and Part II: Patient experiencing ongoing vomiting from any organic aetiology (including patients with history of gastric outlet obstruction or intestinal obstruction due to adhesions or volvulus), or patient with hydrocephalus.
- •Part I and Part II: Use of any drugs or substances known to interfere with CYP3A4 or CYP2D6 enzymes within 1 week prior to Day 1
- •Part I and Part II: Marked baseline prolongation of QTc interval (QTcF>460 millisecond [msec]). At the discretion of the investigator, criterion may be based on automatic interpretation of results.
- •Part II: Patient planned to receive multi-day HEC with cycle duration of less than 20 days (less than 20 days between 2 consecutive cycles’ Days 1).
结局指标
主要结局
Part I: Cohort 1: Netupitant exposure parameters maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUClast) and to infinity (AUCinf).
Part I: Cohort 1: Netupitant exposure parameters maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUClast) and to infinity (AUCinf).
Part I: Cohort 2: Safety parameters (monitoring of AEs, physical examination, vital signs, clinical laboratory tests [haematology, serum chemistry and urinalysis], and 12-lead ECG) following repeated IV NEPA administration (Days 1, 3 and Days 1, 3, 5) to paediatric cancer patients receiving multi-day HEC treatment.
Part I: Cohort 2: Safety parameters (monitoring of AEs, physical examination, vital signs, clinical laboratory tests [haematology, serum chemistry and urinalysis], and 12-lead ECG) following repeated IV NEPA administration (Days 1, 3 and Days 1, 3, 5) to paediatric cancer patients receiving multi-day HEC treatment.
Part II: Proportion of patients with CR (i.e., no emetic episodes and no rescue medication) during the delayed (>24-120 h) phase of emesis after start of chemotherapy administration in Cycle 1.
Part II: Proportion of patients with CR (i.e., no emetic episodes and no rescue medication) during the delayed (>24-120 h) phase of emesis after start of chemotherapy administration in Cycle 1.
次要结局
- Part I: Cohort 1: Physical examination, vital signs, clinical laboratory tests (haematology, serum chemistry and urinalysis), 12-lead ECG, and AEs.
- Part I: Cohort I: - Other PK parameters for netupitant: tmax, (λz, t1/2, AUC0-48), AUC0-120 SD, CL/F, and Vz/F. PK parameters for netupitant metabolites M1, M2, and M3: Cmax, tmax, AUClast, AUC0-48, AUC0-120 SD, AUCinf, λz, t1/2, CL/F, and Vz/F. - PK parameters for fosnetupitant and palonosetron: Cmax, tmax, AUClast, AUC0-48, AUCinf, λz, t1/2, CL, and Vz.
- Part I: Cohort 1 and Cohort 2: Population PK analysis using samples of patients from both Cohorts and all Age Groups to characterise PK values for fosnetupitant, netupitant, netupitant metabolites M1, M2, and M3, and palonosetron in paediatric patients upon single and multiple IV NEPA administration.
- Part I: Cohort 1 and Cohort 2: PK/PD correlations between netupitant and palonosetron exposure parameters and antiemetic efficacy parameters (CR).
- Part I: Cohort 1 and Cohort 2: Efficacy parameters, such as Proportion of patients with CR, Proportion of patients with no emetic episodes, Proportion of patients with no rescue medication, and Time to treatment failure
- Part II: in Cycle 1 and repeated Cycles: Efficacy parameters, such as Proportion of patients with CR during the acute delayed and overall phase of emesis, Proportion of patients with no emetic episodes, Proportion of patients with no vomiting, Proportion of patients with no rescue medication, Proportion of patients with no nausea and no use of rescue medication, and Time to treatment failure
- Part II: in Cycle 1 and repeated Cycles: Population PK for fosnetupitant, netupitant, netupitant metabolites, and palonosetron will be evaluated using pooled plasma concentration-time data from Study Part I and Part II.
- Part II: in Cycle 1 and repeated Cycles: Physical examination, vital signs, clinical laboratory tests (haematology, serum chemistry and urinalysis), 12-lead ECG, and AEs.
研究者
Head of Clinical Affairs
Scientific
Helsinn Healthcare S.A.