A Phase I, Open-label, Dose Escalation Study of LDK378 in Pediatric Patients With Malignancies That Have a Genetic Alteration in Anaplastic Lymphoma Kinase (ALK)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 83
- 试验地点
- 6
- 主要终点
- Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment
研究概览
简要总结
The purpose of this study was to estimate the maximum tolerated dose and/or recommended dose for expansion of LDK378 as a single agent, assess safety, tolerability and anti-tumor activity and characterize single and multiple-dose pharmacokinetics when administered orally to pediatric patients with ALK-activated tumors, with and without food.
详细描述
LDK378 is a novel inhibitor of ALK that is active in a broad range of ALK-activated tumor models, including models driven by mutated versions of ALK known to be resistant to crizotinib, and by ALK gene amplification.
The primary purpose of this study was to determine the maximum tolerated dose and/or recommended dose for expansion in pediatric patients, and to delineate a clinical dose to be used in any future pediatric studies, with and without food. This study also assessed the safety, tolerability, PK and preliminary evidence of antitumor activity of LDK378 in pediatric patients with neuroblastoma, and other ALK-activated tumors.
Fasted cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken at least 2 hours after last meal & subjects did not eat until 1 hour after LDK378 was taken. Each daily dose of LDK378 was taken with 1-2 tablespoons (15-30 mL) of an appropriate food (such as applesauce or non-fat yogurt) & a glass of water
Fed cohort: each daily dose of LDK378 (including days which involved PK blood sampling) was taken with, or within 30 minutes after finishing a low-fat light snack containing 100-300 calories & 1.5-2 grams of fat.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed with a locally advanced or metastatic malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists
- •Age ≥ 12 months and < 18 years
- •The tumor must carry a genetic alteration of ALK
- •Patients must have evaluable or measurable disease.
- •Karnofsky performance status score ≥ 60% for patients > 12 years of age; Lansky score ≥ 50% for patients ≤ 12 years of age.
- •Exclusion criteria:
- •Symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS disease
- •Inadequate end organ function as defined by specified laboratory values
- •Body surface area (BSA) < 0.35 m2
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LDK378 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
- •Use of medications that are known to be strong inhibitors or inducers of CYP3A4/5 that cannot be discontinued at least 1 week prior to start of treatment with LDK378 and for the duration of the study
- •Use of medications that are mainly metabolized by CYP3A4/5 or CYP2C9 that cannot be discontinued at least 1 week prior to start of treatment with LDK378 and for the duration of the study
- •History of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
- •History of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease.
- •Medications with a known risk of prolongation of QT interval
排除标准
- 未提供
研究组 & 干预措施
LDK378
All participants were administered a single-agent LDK378 (Ceritinib) orally, once daily, continuously in fasted or fed conditions.
干预措施: Ceritinib (Drug)
结局指标
主要结局
Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment
时间窗: up to day 21 after the patient's first dose; cycle = within the first 21 days of patient's first dose
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 21 days of treatment with LDK378 and meets a specified defined criteria. A participant with multiple occurrences of DLTs under one treatment is counted only once in the Adverse Event category for that treatment. A participant with multiple DLTs within a primary system organ class is counted only once in the total row.
次要结局
- Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment(30 months)
- Progression Free Survival (PFS) Based on Investigator Assessment(30 months)
- Plasma Concentration Time Profiles by Treatment Group in Escalation Phase(0hr pre-dose, 2hrs post-dose, 4hrs post-dose, 6hrs post-dose & 24hrs post-dose in Cycle1 Day1 & Cycle 2 day 1; 0hr pre-dose in Cycle 1 Day 15, Cycle 2 Day1, Cycle 2 Day 2, Cycle 3 day 1 & Cycle 4 Day 1)
- Plasma Concentration Time Profiles by Treatment Group in Expansion Phase(0hr pre-dose Cycle 1 Day 1, cycle 1 Day 15; 0hr pre-dose, 2hrs post-dose, 4hrs post-dose, 6hrs post-dose & 24hrs post-dose in Cycle2 Day1; 0hr pre-dose in Cycle2 Day2, Cycle 3 Day 1 & Cycle 4 Day 1)
- Duration of Response (DoR) Per Investigator Assessment(30 months)
- Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Cmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Cmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Cmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Tmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Tmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Tmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)
- PK Parameter: Racc in Dose Escalation Phase Cycle 2 Day 1(0hr pre-dose, 2, 4, 6 & 24hrs post-dose)