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 )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
ALK-activated Tumors	Drug: Ceritinib	Phase 1

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 (Clinical Trial)
• Actual Enrollment: 83 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: August 28, 2013
• Actual Primary Completion Date: April 26, 2019
• Actual Study Completion Date: April 26, 2019

Arms and Interventions

Arm

Intervention/treatment

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

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

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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
7. 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
8. 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

9. 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
10. 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.
11. 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

12. 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
13. 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
14. 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

15. 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

Eligibility Criteria

• Ages Eligible for Study: 12 Months to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Massachusetts

Dana Farber Cancer Institute Dept of Onc

Boston, Massachusetts, United States, 02215

United States, New York

Memorial Sloan Kettering SC - 7

New York, New York, United States, 10017

United States, Ohio

Cincinnati Children s Hospital Medical Center Dept of Oncology

Cincinnati, Ohio, United States, 45229-3039

United States, Tennessee

St Jude s Childrens Research Hospital Dept of Oncology

Memphis, Tennessee, United States, 38105-2794

United States, Texas

Texas Children's Hospital Dept of Oncology

Houston, Texas, United States, 77030

Australia, New South Wales

Novartis Investigative Site

Randwick, New South Wales, Australia, 2130

Australia, Victoria

Novartis Investigative Site

Parkville, Victoria, Australia, 3052

Canada, Ontario

Novartis Investigative Site

Toronto, Ontario, Canada, M5G 1X8

France

Novartis Investigative Site

Paris, France, 75231

Novartis Investigative Site

Villejuif Cedex, France, 94805

Germany

Novartis Investigative Site

Koeln, Nordrhein-Westfalen, Germany, 50937

Novartis Investigative Site

Berlin, Germany, 13353

Novartis Investigative Site

Essen, Germany, 45147

Italy

Novartis Investigative Site

Milano, MI, Italy, 20133

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Netherlands

Novartis Investigative Site

Utrecht, CS, Netherlands, 3584

Novartis Investigative Site

Amsterdam, Netherlands, 1105 AZ

Novartis Investigative Site

Rotterdam, Netherlands, 3015 CN

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Valencia, Comunidad Valenciana, Spain, 46026

Novartis Investigative Site

Madrid, Spain, 28009

United Kingdom

Novartis Investigative Site

West Midlands, Birmingham, United Kingdom, B4 6NH

Novartis Investigative Site

Sutton, Surrey, United Kingdom, SM2 5PT

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] May 18, 2018

Statistical Analysis Plan  [PDF] May 30, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01742286
• Other Study ID Numbers: CLDK378X2103; 2012-002074-31 ( EudraCT Number )
• First Posted: December 5, 2012
• Results First Posted: June 9, 2020
• Last Update Posted: June 9, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Lymphoma; Neoplasms; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Ceritinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents