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

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)

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01742286

Enrollment

Registered

2012-12-05

Start date

2013-08-28

Completion date

2019-04-26

Last updated

2020-06-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

ALK-activated Tumors

Keywords

LDK378, Ceritinib, pediatric, malignancies, anaplastic lymphoma kinase, ALK, ALK-activated tumors, neuroblastoma, rhabdomyosarcoma, anaplastic large-cell lymphoma, inflammatory myofibroblastic tumor

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.

Interventions

DRUGCeritinib

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Months to 17 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	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

Measure	Time frame	Description
Duration of Response (DoR) Per Investigator Assessment	30 months	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.
Progression Free Survival (PFS) Based on Investigator Assessment	30 months	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.
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	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.
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	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.
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	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
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	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
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	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
Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment	30 months	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.
PK Parameter: Cmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-dose	Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug.
PK Parameter: Cmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-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
PK Parameter: Tmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-dose	Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration
PK Parameter: Tmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-dose	Characterize single and multiple-dose PK of LDK378 in pediatric patients. Tmax: The time to reach maximum plasma concentration
PK Parameter: Tmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-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
PK Parameter: Racc in Dose Escalation Phase Cycle 2 Day 1	0hr pre-dose, 2, 4, 6 & 24hrs post-dose	Characterize single and multiple-dose PK of LDK378 in pediatric patients. Racc: Accumulation ratio
PK Parameter: Cmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)	0hr pre-dose, 2, 4, 6 & 24hrs post-dose	Characterize single and multiple-dose PK of LDK378 in pediatric patients. Cmax: Maximum (peak) concentration of drug

Countries

Australia, Canada, France, Germany, Italy, Netherlands, South Korea, Spain, United Kingdom, United States

Participant flow

Recruitment details

Eighty-three patients were treated at different dose levels in both fasted and fed states dose escalation and expansion groups.

Pre-assignment details

At least 15 patients for the fasted dose escalation & 12 patients for the fed dose escalation were expected to be treated. During the expansion part, approximately 45 patients were planned to be treated on the preferred regimen, approximately 25 patients in group 1 on the preferred regimen, and approximately 20 patients in group 2.

Participants by arm

Arm	Count
Fasted: Ceritinib 300 mg/m2 Participants in the fasted group who took 300 mg of ceritinib	5
Fasted: Ceritinib 450 mg/m2 Participants in the fasted group who took 450 mg of ceritinib	12
Fasted: Ceritinib 510 mg/m2 Participants in the fasted group who took 510 mg of ceritinib	13
Fasted: Ceritinib 560 mg/m2 Participants in the fasted group who took 560 mg of ceritinib	2
Fed: Ceritinib 320 mg/m2 Participants in the fed group who took 320 mg of ceritinib	4
Fed: Ceritinib 400 mg/m2 Participants in the fed group who took 400 mg of ceritinib	5
Fed: Ceritinib 500 mg/m2 Participants in the fed group who took 500 mg of ceritinib	42
Total	83

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Escalation Phase	Administrative problems	1	1	0	0	0	0	2
Escalation Phase	Adverse Event	0	1	2	0	0	1	0
Escalation Phase	Death	0	0	0	0	0	1	0
Escalation Phase	Disease progression	3	7	4	1	4	3	2
Escalation Phase	Physician Decision	0	3	0	1	0	0	2
Escalation Phase	Subject/guardian decision	1	0	0	0	0	0	0
Expansion Phase	Administrative problems	0	0	0	0	0	0	5
Expansion Phase	Adverse Event	0	0	0	0	0	0	6
Expansion Phase	Disease progression	0	0	3	0	0	0	15
Expansion Phase	Physician Decision	0	0	4	0	0	0	9
Expansion Phase	Withdrawal by Subject	0	0	0	0	0	0	1

Baseline characteristics

Characteristic	Total	Fed: Ceritinib 500 mg/m2	Fasted: Ceritinib 300 mg/m2	Fed: Ceritinib 400 mg/m2	Fed: Ceritinib 320 mg/m2	Fasted: Ceritinib 560 mg/m2	Fasted: Ceritinib 510 mg/m2	Fasted: Ceritinib 450 mg/m2
Age, Continuous	8.5 years STANDARD_DEVIATION 4.97	7.3 years STANDARD_DEVIATION 4.73	11.6 years STANDARD_DEVIATION 5.27	9.2 years STANDARD_DEVIATION 4.02	8.8 years STANDARD_DEVIATION 4.99	9.0 years STANDARD_DEVIATION 9.9	9.2 years STANDARD_DEVIATION 5.34	10.0 years STANDARD_DEVIATION 4.94
Age, Customized 12 - < 18 yrs	30 Participants	11 Participants	2 Participants	2 Participants	2 Participants	1 Participants	6 Participants	6 Participants
Age, Customized 1 - < 7 yrs	37 Participants	21 Participants	1 Participants	2 Participants	2 Participants	1 Participants	6 Participants	4 Participants
Age, Customized 7 - < 12 yrs	16 Participants	10 Participants	2 Participants	1 Participants	0 Participants	0 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Asian	5 Participants	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Black	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Caucasian	65 Participants	33 Participants	5 Participants	3 Participants	4 Participants	2 Participants	11 Participants	7 Participants
Race/Ethnicity, Customized Native American	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	11 Participants	5 Participants	0 Participants	2 Participants	0 Participants	0 Participants	1 Participants	3 Participants
Sex: Female, Male Female	30 Participants	14 Participants	3 Participants	3 Participants	1 Participants	1 Participants	5 Participants	3 Participants
Sex: Female, Male Male	53 Participants	28 Participants	2 Participants	2 Participants	3 Participants	1 Participants	8 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	1 / 5	1 / 12	2 / 13	0 / 2	2 / 4	1 / 5	5 / 42	12 / 83
other Total, other adverse events	5 / 5	12 / 12	13 / 13	2 / 2	4 / 4	5 / 5	42 / 42	83 / 83
serious Total, serious adverse events	1 / 5	4 / 12	8 / 13	2 / 2	3 / 4	1 / 5	21 / 42	40 / 83

Outcome results

Primary

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.

Time frame: up to day 21 after the patient's first dose; cycle = within the first 21 days of patient's first dose

Population: The dose determining analysis set (DDS) consisted of all patients from the Safety set who either met the minimum exposure criterion and had sufficient safety evaluations or discontinued earlier due to DLT in the escalation phase.

Arm	Measure	Group	Value (NUMBER)
Fasted: Ceritinib 300 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants
Fasted: Ceritinib 300 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fasted: Ceritinib 300 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	0 Participants
Fasted: Ceritinib 300 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	0 Participants
Fasted: Ceritinib 450 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fasted: Ceritinib 450 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	0 Participants
Fasted: Ceritinib 450 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants
Fasted: Ceritinib 450 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	0 Participants
Fasted: Ceritinib 510 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	0 Participants
Fasted: Ceritinib 510 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fasted: Ceritinib 510 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants
Fasted: Ceritinib 510 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	0 Participants
Fasted: Ceritinib 560 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fasted: Ceritinib 560 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	1 Participants
Fasted: Ceritinib 560 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	1 Participants
Fasted: Ceritinib 560 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	2 Participants
Fed: Ceritinib 320 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fed: Ceritinib 320 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants
Fed: Ceritinib 320 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	0 Participants
Fed: Ceritinib 320 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	0 Participants
Fed: Ceritinib 400 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	1 Participants
Fed: Ceritinib 400 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	0 Participants
Fed: Ceritinib 400 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	1 Participants
Fed: Ceritinib 400 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants
Fed: Ceritinib 500 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Total DLTs	1 Participants
Fed: Ceritinib 500 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Investigations: Alanine aminotransferase incr.	0 Participants
Fed: Ceritinib 500 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: Influenza	1 Participants
Fed: Ceritinib 500 mg/m2	Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment	Gastrointestinal disorders: abdominal pain	0 Participants

Secondary

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.

Time frame: 30 months

Population: Full Analysis Set/MTD/RDE patients with confirmed CR or PR): Efficacy results are presented only for patients with confirmed CR or PR who received at least 1 dose of ceritinib in either of the 2 MTD/RDE groups \& were based on combining data from across the dose-escalation \& dose-expansion phases, \& summarized according to primary tumor diagnosis.

Arm	Measure	Value (MEDIAN)
Fasted: Ceritinib 300 mg/m2	Duration of Response (DoR) Per Investigator Assessment	15.0 months
Fasted: Ceritinib 450 mg/m2	Duration of Response (DoR) Per Investigator Assessment	NA months
Fasted: Ceritinib 510 mg/m2	Duration of Response (DoR) Per Investigator Assessment	NA months
Fasted: Ceritinib 560 mg/m2	Duration of Response (DoR) Per Investigator Assessment	NA months

Secondary

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