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

NCT01742286 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: CLDK378X21032012-002074-31
• Study Type: interventional
• Target: 83
• Locations: 10 countries
• Sites: 23

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment

  30 months

• Duration of Response (DoR) Per Investigator Assessment

  30 months

• Progression Free Survival (PFS) Based on Investigator Assessment

  30 months

• 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

• 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

Study Arms (1)

LDK378

EXPERIMENTAL

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

Drug: Ceritinib

Interventions

Ceritinib DRUG

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.

Also known as: LDK378

LDK378

Eligibility Criteria

• Age: 12 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (23)

Dana Farber Cancer Institute Dept of Onc

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering SC - 7

New York, New York, 10017, United States

Location

Cincinnati Children s Hospital Medical Center Dept of Oncology

Cincinnati, Ohio, 45229-3039, United States

Location

St Jude s Childrens Research Hospital Dept of Oncology

Memphis, Tennessee, 38105-2794, United States

Location

Texas Children's Hospital Dept of Oncology

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Randwick, New South Wales, 2130, Australia

Location

Novartis Investigative Site

Parkville, Victoria, 3052, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

Location

Novartis Investigative Site

Paris, 75231, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Utrecht, CS, 3584, Netherlands

Location

Novartis Investigative Site

Amsterdam, 1105 AZ, Netherlands

Location

Novartis Investigative Site

Rotterdam, 3015 CN, Netherlands

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Valencia, Valencia, 46026, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

West Midlands, Birmingham, B4 6NH, United Kingdom

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 34780709 DERIVED

• 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.

  PMID: 30697903 DERIVED

MeSH Terms

Conditions

Neoplasms; Neuroblastoma; Rhabdomyosarcoma; Lymphoma, Large-Cell, Anaplastic; Granuloma, Plasma Cell

Interventions

ceritinib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Granuloma; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Study Director
• Organization: Study Director

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2012
• First Posted: December 5, 2012
• Study Start: August 28, 2013
• Primary Completion: April 26, 2019
• Study Completion: April 26, 2019
• Last Updated: June 9, 2020
• Results First Posted: June 9, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1); CA (1); US (5); FR (2); DE (3); NL (3); ES (3); IT (1); AU (2); GB (2)