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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

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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


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01742286


Locations
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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
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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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01742286    
Other Study ID Numbers: CLDK378X2103
2012-002074-31 ( EudraCT Number )
First Posted: December 5, 2012    Key Record Dates
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

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