LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib

A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Adult Patients With ALK-activated Non-small Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib

A single-arm, open-label, multicenter, phase II study. Treatment with LDK378 750 mg qd continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anti-cancer therapy and/or died. LDK378 could be continued beyond RECIST-defined progressive disease (PD) as assessed by the investigator if, in the judgment of the investigator, there was evidence of clinical benefit. In these patients tumor assessment would continue as per the schedule of assessments until treatment with LDK378 was permanently discontinued. Patients who discontinued the study medication in the absence of progression continued to be followed for tumor assessment until the time of PD as assessed by the investigator

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: LDK378

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Oshawa, Ontario, Canada, L1G 2B9
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• France
  • Marseille cedex 20, France, 13915
    • Novartis Investigative Site
  • Paris, France, 75970
    • Novartis Investigative Site
• Germany
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Italy
  • AV
    • Avellino, AV, Italy, 83100
      • Novartis Investigative Site
  • LI
    • Livorno, LI, Italy, 57124
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06129
      • Novartis Investigative Site
  • PR
    • Parma, PR, Italy, 43100
      • Novartis Investigative Site
• Japan
  • Fukuoka, Japan, 811-1395
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Novartis Investigative Site
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Novartis Investigative Site
  • Okayama
    • Okayama-city, Okayama, Japan, 700-8558
      • Novartis Investigative Site
  • Osaka
    • OsakaSayama, Osaka, Japan, 589-8511
      • Novartis Investigative Site
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 411-8777
      • Novartis Investigative Site
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Novartis Investigative Site
    • Koto, Tokyo, Japan, 135-8550
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03080
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03722
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Maastricht, Netherlands, 5800
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Galicia
    • La Coruna, Galicia, Spain, 15006
      • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group Dept of Highlands Oncology Grp
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center Dept of Oncology 2
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Reg-5
    • San Diego, California, United States, 92103
      • University of California at San Diego, Moores Cancer Ctr SC
    • Stanford, California, United States, 94304
      • Stanford University Medical Center Stanford Cancer Center(2)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital SC
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine/Winship Cancer Institute Dept of Oncology
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center SC
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center DeptofUofKansas CancerCenter-2
    • Wichita, Kansas, United States, 67214-3728
      • Cancer Center of Kansas Dept of CCK
  • Maryland
    • Rockville, Maryland, United States, 20850
      • Maryland Oncology Hematology, P.A. SC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Mass General
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Cancer Institute SC 1
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Drug Ship - 4
  • Texas
    • Dallas, Texas, United States, 75390
      • U of TX Southwestern Medical Center - SimmonsCompCancerCtr Clinical Research Office
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance SC-1
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Univ Wisc 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion critieria:

• Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carries an ALK rearrangement, as per the FDA-approved FISH assay (Abbott Molecular Inc.).
• Age 18 years or older at the time of informed consent.
• Patients must have NSCLC that has progressed during therapy with crizotinib or within 30 days of the last dose
• Patients must have received 1-3 lines of cytotoxic chemotherapy (of which 1 must have been a platinum doublet) to treat their locally advanced or metastatic NSCLC
• Patients must have a tumor tissue sample available, collected either at the time of diagnosis of NSCLC or any time since.
• Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 2, except for patients with grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not be allowed to participate in the study.

Exclusion criteria:

• Patients with known hypersensitivity to any of the excipients of LDK378.
• Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
• History of carcinomatous meningitis.
• Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years.
• Clinically significant, uncontrolled heart disease
• Systemic anti-cancer therapy given after the last dose of crizotinib and prior to starting study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LDK378; Patients treated with ceritinib/LDK378 750 mg once-daily, fasted	Drug: LDK378; Ceritinib/LDK378 was supplied as 150 mg hard gelatin capsules and were administered orally, once-daily at a dose of 750 mg on a continuous dosing schedule (5 x 150 mg capsules).; Other Names: Ceritinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) to LDK378 Per Investigator Assessment	ORR per RECIST 1.1 calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+PR) as assessed by investigator. 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	6 cycles of 28 days up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR Per Blinded Independent Review Committee (BIRC) Assessment	ORR (CR+PR) by BIRC is calculated as the percentage of patients with a best overall confirmed response defined as complete response or partial response (CR+PR) as assessed by BIRC. 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	6 cycles of 28 days up to 24 weeks
Duration of Response (DOR) by Investigator	DOR, calculated as the time from the date of the first confirmed CR or PR to the first documented progression or death due to any cause, by investigator. 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	6 cycles of 28 days up to 24 weeks
Duration of Response (DOR) by BIRC	DOR, calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer, by BIRC (Blinded Imaging Review Committee). 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	6 cycles of 28 days up to 24 weeks
Disease Control Rate (DCR)	DCR was calculated as the percentage of patients with best overall response of CR, PR, SD, or non-CR non-PD (NCRNPD), per RECIST 1.1 by investigator. 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 1. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Non-CR/Non-PD (NCRNPD): refers to best overall responses that are neither CR nor PD per RECIST 1.1 criteria for patients with non-measurable disease only at baseline.	6 cycles of 28 days up to 24 weeks
Time to Response (TTR) Per Investigator	TTR is the time from date of start of treatment to the first CR or PR observed which were confirmed afterwards.	6 cycles of 28 days up to 24 weeks
Time to Response (TTR) Per BIRC	TTR is the time from date of start of treatment to the first CR or PR observed which are confirmed afterwards.	6 cycles of 28 days up to 24 weeks
Progression-free Survival (PFS) Per Investigator	PFS, defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had no event or when the patient received any further anticancer therapy in the absence of disease progression, progression-free survival was censored at the date of last adequate tumor assessment.	6 cycles of 28 days up to 24 weeks
Progression-free Survival (PFS) Per BIRC	PFS, defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had no event or when the patient received any further anticancer therapy in the absence of disease progression, progression-free survival was censored at the date of last adequate tumor assessment.	6 cycles of 28 days up to 24 weeks
Overall Intracranial Response Rate (OIRR) Per Investigator	OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who had measureable disease in the brain at baseline.	6 cycles of 28 days up to 24 weeks
Overall Intracranial Response Rate (OIRR) Per BIRC	OIRR calculated as the ORR (CR+PR) of lesions in the brain for patients who had measureable disease in the brain at baseline.	6 cycles of 28 days up to 24 weeks
Overall Survival (OS)	OS, defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive.	6 cycles of 28 days up to 24 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Hida T, Satouchi M, Nakagawa K, Seto T, Matsumoto S, Kiura K, Nokihara H, Murakami H, Tokushige K, Hatano B, Nishio M. Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset. Jpn J Clin Oncol. 2017 Jul 1;47(7):618-624. doi: 10.1093/jjco/hyx045.
• Crino L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, Mok T, Spigel D, Felip E, Nishio M, Scagliotti G, Branle F, Emeremni C, Quadrigli M, Zhang J, Shaw AT. Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol. 2016 Aug 20;34(24):2866-73. doi: 10.1200/JCO.2015.65.5936. Epub 2016 Jul 18.

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2012
• Primary Completion (Actual): March 29, 2016
• Study Completion (Actual): March 29, 2016

Study Registration Dates

• First Submitted: September 4, 2012
• First Submitted That Met QC Criteria: September 12, 2012
• First Posted (Estimate): September 13, 2012

Study Record Updates

• Last Update Posted (Actual): June 19, 2017
• Last Update Submitted That Met QC Criteria: May 25, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: NSCLC; Non-Small Cell Lung Cancer; ALK; LDK378; Ceritinib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ceritinib
• Other Study ID Numbers: CLDK378A2201; 2012-003432-24 (EudraCT Number)