Clinical trial NCT01742286: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-12-05
Enrollment: 83
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Incidence Rate of Dose Limiting Toxicities (DLTs) Occurring During First Cycle of Treatment
timeFrame: up to day 21 after the patient's first dose; cycle = within the first 21 days of patient's first dose
Secondary outcomes:
measure: Summary of Best Overall Response by Overall Response Rate (ORR) Per Investigator Assessment
timeFrame: 30 months
measure: Duration of Response (DoR) Per Investigator Assessment
timeFrame: 30 months
measure: Progression Free Survival (PFS) Based on Investigator Assessment
timeFrame: 30 months
measure: Plasma Concentration Time Profiles by Treatment Group in Escalation Phase
timeFrame: 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
measure: Plasma Concentration Time Profiles by Treatment Group in Expansion Phase
timeFrame: 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
measure: Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: Pharmacokinetics (PK) Parameters: AUC0 - 24h & AUClast in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Cmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Cmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Cmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Tmax in Cycle 1 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Tmax in Cycle 2 Day 1 - Dose Escalation Phase (Single Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Tmax in Cycle 2 Day 1 - Dose Expansion Phase (Multiple Dose)
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
measure: PK Parameter: Racc in Dose Escalation Phase Cycle 2 Day 1
timeFrame: 0hr pre-dose, 2, 4, 6 & 24hrs post-dose
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute Dept of Onc
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering SC - 7
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children s Hospital Medical Center Dept of Oncology
state: Ohio
city: Memphis
country: United States
facility: St Jude s Childrens Research Hospital Dept of Oncology
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital Dept of Oncology
state: Texas
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Paris
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
state: CS
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: West Midlands
country: United Kingdom
facility: Novartis Investigative Site
state: Birmingham
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.