Phase I Study of LDK378 in Pediatric, Malignancies With a Genetic Alteration in Anaplastic Lymphoma Kinase (ALK)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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ALK-activated Tumors

Intervention / Treatment
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* Drug: Ceritinib


Participation Criteria
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Eligibility Criteria
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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) 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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDK378<br>All participants were administered a single-agent LDK378 (Ceritinib) orally, once daily, continuously in fasted or fed conditions. | Drug: Ceritinib<br>* LDK378 is a capsule taken by mouth, contents can be mixed with food for pediatric patients or mixed with water and given via nasogastric/gastric (NG/G) tube. For patients in fasted group: 1-2 tablespoons (15-30 mL) of an appropriate food such as apple sauce or non-fat yogurt and a glass of water were allowed. For patients in the fed cohort: LDK378 was taken with, or within 30 minutes after finishing a low-fat light snack containing 100-300 calories and 1.5-2 grams of fat.<br>* Other names: LDK378;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment | 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. | up to day 21 after the patient's first dose; cycle = within the first 21 days of patient's first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: Tmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Racc in Dose Escalation Phase Cycle 2 Day 1 | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Racc: Accumulation ratio | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment | ORR is the percentage of participants with a best overall response of complete response (CR) or partial response (PR). ORR was assessed per Investigator as per RECIST 1.1 in participants with neuroblastoma and other solid tumors, and by International Working Group (IWG) criteria in patients with lymphoma. Per RECIST 1.1 (for neuroblastoma & other solid tumors): CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesion, taking as reference the baseline sum diameters. Per IWG criteria (for patients with lymphoma): CR: normalization of all index nodal lesions or complete disappearance of all index extranodal lesions. PR: at least 50% decrease from baseline in the sum of diameters of all index lesions. | 30 months | 
| Duration of Response (DoR) Per Investigator Assessment | DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression (PD) or death due to any cause. DOR was assessed per Investigator as per RECIST 1.1 in participants with neuroblastoma and other solid tumors, and by International Working Group (IWG) criteria in patients with lymphoma. Per RECIST 1.1 (for neuroblastoma & other solid tumors): CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesion, taking as reference the baseline sum diameters. Per IWG criteria (for patients with lymphoma): CR: normalization of all index nodal lesions or complete disappearance of all index extranodal lesions. PR: at least 50% decrease from baseline in the sum of diameters of all index lesions. | 30 months | 
| Progression Free Survival (PFS) Based on Investigator Assessment | PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS was assessed per Investigator as per RECIST 1.1 in participants with neuroblastoma and other solid tumors, and by International Working Group (IWG) criteria in patients with lymphoma. Per RECIST 1.1 (for neuroblastoma & other solid tumors): CR: disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameter of all target lesion, taking as reference the baseline sum diameters. Per IWG criteria (for patients with lymphoma): CR: normalization of all index nodal lesions or complete disappearance of all index extranodal lesions. PR: at least 50% decrease from baseline in the sum of diameters of all index lesions. | 30 months | 
| Plasma Concentration Time Profiles by Treatment Group in Escalation Phase | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Only PK plasma concentrations with non-missing sampling date and time, and for which the last dose date and time prior to the PK sample draw are non-missing, were included in the PK analysis. | 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 | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Only PK plasma concentrations with non-missing sampling date and time, and for which the last dose date and time prior to the PK sample draw are non-missing, were included in the PK analysis. | 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 | 
| Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the concentration-time curve from time zero to the last measureable concentration time AUC0-24h: Area under the plasma concentration-time curve t=0-24 h | 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) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the concentration-time curve from time zero to the last measureable concentration time; AUC0-24h: Area under the plasma concentration-time curve t=0-24 h | 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) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. AUC: Area under the plasma (serum, or blood) concentration versus time curve AUClast: Area under the plasma (serum, or blood) concentration versus time curverea under the concentration-time curve from time zero to the last measureable concentration time AUC0-24h: Area under the plasma concentration-time curve t=0-24 h | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Cmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Cmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug. | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Cmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. In this phase ceritinib was expanded at 500mg/m2 fed and 510mg/m2 fasted administered orally once daily and was assessed only at steady state, Cycle 2 Day 1. Cmax: Maximum (peak) concentration of drug | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Tmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 
| PK Parameter: Tmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose) | Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration | 0hr pre-dose, 2, 4, 6 & 24hrs post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LDK378, Ceritinib, pediatric, malignancies, anaplastic lymphoma kinase, ALK, ALK-activated tumors, neuroblastoma, rhabdomyosarcoma, anaplastic large-cell lymphoma, inflammatory myofibroblastic tumor