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

• ClinicalTrials.gov Identifier: NCT01742286
• Recruitment Status: Completed
• First Posted: December 5, 2012
• Results First Posted: June 9, 2020
• Last Update Posted: June 9, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 30, 2012
• First Posted Date: December 5, 2012
• Results First Submitted Date: October 24, 2019
• Results First Posted Date: June 9, 2020
• Last Update Posted Date: June 9, 2020
• Actual Study Start Date: August 28, 2013
• Actual Primary Completion Date: April 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 27, 2020)

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.

Original Primary Outcome Measures (submitted: December 3, 2012)

Incidence rate of Dose Limiting Toxicities (DLT) [ Time Frame: up to day 21 after the patient's first dose ]

cycle = within the first 21 days of patient's first dose

Current Secondary Outcome Measures (submitted: May 27, 2020)

• Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment [ Time Frame: 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.
• Duration of Response (DoR) Per Investigator Assessment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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
• PK Parameter: Cmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose) [ Time Frame: 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 Escalation Phase (Single Dose) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients. Racc: Accumulation ratio

Original Secondary Outcome Measures (submitted: December 3, 2012)

• Number of patients with Adverse events [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Changes in laboratory values [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Assessments of physical examinations [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Assessments of vital signs and electrocardiograms [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Plasma concentration time profiles [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Overall response rate (ORR) [ Time Frame: 30 months ]
  Assess the anti-tumor activity of LDK378
• Duration of response (DoR) [ Time Frame: 30 months ]
  Assess the anti-tumor activity of LDK378
• Progression free survival (PFS) [ Time Frame: 30 months ]
  Assess the anti-tumor activity of LDK378 as per RECIST 1.1
• Changes in disease burden in patients with lymphoma [ Time Frame: 30 months ]
  Assess the anti-tumor activity of LDK378 as per International Working Group (IWG) criteria
• Number of patients with serious adverse events [ Time Frame: 30 months ]
  Characterize the safety and tolerability of LDK378 in the pediatric patients
• Pharmacokinetics (PK) parameter: AUClast [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: AUCtau [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: Cmin [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: Cmax [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: Tmax [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: Racc [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: t1/2 [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients
• PK parameter: acc [ Time Frame: 30 months ]
  Characterize single and multiple-dose PK of LDK378 in pediatric patients

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I Study of LDK378 in Pediatric, Malignancies With a Genetic Alteration in Anaplastic Lymphoma Kinase (ALK)
• Official Title: 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)
• 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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: ALK-activated Tumors

Intervention

Drug: Ceritinib

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.

Other Name: LDK378

Study Arms

Experimental: LDK378

All participants were administered a single-agent LDK378 (Ceritinib) orally, once daily, continuously in fasted or fed conditions.

Intervention: Drug: Ceritinib

Publications *

• Fischer M, Moreno L, Ziegler DS, Marshall LV, Zwaan CM, Irwin MS, Casanova M, Sabado C, Wulff B, Stegert M, Wang L, Hurtado FK, Branle F, Geoerger B, Schulte JH. Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study. Lancet Oncol. 2021 Dec;22(12):1764-1776. doi: 10.1016/S1470-2045(21)00536-2. Epub 2021 Nov 12.
• Brivio E, Zwaan CM. ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: Efficacy and side effects. Pediatr Blood Cancer. 2019 May;66(5):e27645. doi: 10.1002/pbc.27645. Epub 2019 Jan 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 23, 2019): 83
• Original Estimated Enrollment (submitted: December 3, 2012): 80
• Actual Study Completion Date: April 26, 2019
• Actual Primary Completion Date: April 26, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Italy, Korea, Republic of, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01742286
• Other Study ID Numbers: CLDK378X2103; 2012-002074-31 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: May 2020