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)
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 83
- Locations
- 6
- Primary Endpoint
- Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment
Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 12 Months to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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)
Exclusion Criteria
- Not provided
Arms & Interventions
LDK378
All participants were administered a single-agent LDK378 (Ceritinib) orally, once daily, continuously in fasted or fed conditions.
Intervention: Ceritinib (Drug)
Outcomes
Primary Outcomes
Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment
Time Frame: 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.
Secondary Outcomes
- 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)