Clinical trial NCT01685138: LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer
Official title: A Phase II, Multicenter, Single-arm Study of Oral LDK378 in Crizotinib naïve Adult Patients With ALK-activated Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer
Non small cell lung carcinoma
NSCLC
ALK
LDK378
Ceritinib
crizotinib naïve adult patients
ALK-activated non-small cell lung cancer
treatment of lung cancer after first metastasis
lung cancer
lung adenocarcinoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-09-14
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A single-arm, open-label, two-stage multicenter, phase II study. Patients were pre-screened for ALK positive status. Treatment with LDK378 at 750 mg qd was continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anticancer therapy and/or died. LDK378 was 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. 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. Male and female patients aged 18 or over with ALK-rearranged non-small cell cancer (NSCLC) were screened for eligibility. Patients had to have received no prior crizotinib, and had to be chemotherapy-naïve or been pretreated with cytotoxic chemotherapy (up to three prior lines).


Eligibility criteria: Key Inclusion criteria:

* Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that carried an ALK rearrangement, as per the FDA-approved Vysis ALK break-apart FISH assay (Abbott Molecular Inc.)
* Age 18 years or older at the time of informed consent.
* Patients must have NSCLC that had progressed during or after the last chemotherapy regimen received prior to the first dose of LDK378, if chemotherapy was received
* Patients must have been chemotherapy-naive or had received 1-3 lines of cytotoxic chemotherapy to treat their locally advanced or metastatic NSCLC
* Patients must have had 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 were not allowed to participate in the study.

Key Exclusion criteria:

* Prior treatment with crizotinib, or any other ALK inhibitor investigational agent, for NSCLC
* Patients with known hypersensitivity to any of the excipients of LDK378.
* Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or had 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.

Primary outcomes:
measure: Overall Response Rate (ORR) by Investigator Assessment
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
Secondary outcomes:
measure: ORR by Blinded Independent Review Committee (BIRC)
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Duration of Response (DOR) as Per Investigator
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Duration of Response (DOR) as Per BIRC
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Disease Control Rate (DCR) as Per Investigator and BIRC
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Time to Response (TTR) as Per Investigator
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug
measure: Time to Response (TTR) as Per BIRC
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Overall Intracranial Response Rate (OIRR) as Per Investigator
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Overall Intracranial Response Rate (OIRR) as Per BIRC
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Progression-free Survival (PFS) Per Investigator and BIRC
timeFrame: every 8 weeks (i.e. every 2 cycles; cycle = 28 days), starting from the first day of treatment with LDK378 until permanent discontinuation of study drug up to 5 years
measure: Overall Survival (OS)
timeFrame: Time from the date of first dose of LDK378 to the date of death due to any cause up to 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Mass Gen 5
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine Washington University (16)
state: Missouri
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Drug Ship - 4
state: Tennessee
city: Dallas
country: United States
facility: U of TX Southwestern Medical Center - SimmonsCompCancerCtr Clinical Research Office
state: Texas
city: St Leonards
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Franston
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Genk
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Saskatoon
country: Canada
facility: Novartis Investigative Site
state: Saskatchewan
city: Saint Herblain cedex
country: France
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Avellino
country: Italy
facility: Novartis Investigative Site
state: AV
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Akashi
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Sunto Gun
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Auckland
country: New Zealand
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: St-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Colchester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Nishio M, Felip E, Orlov S, Park K, Yu CJ, Tsai CM, Cobo M, McKeage M, Su WC, Mok T, Scagliotti GV, Spigel DR, Viraswami-Appanna K, Chen Z, Passos VQ, Shaw AT. Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC. J Thorac Oncol. 2020 Apr;15(4):609-617. doi: 10.1016/j.jtho.2019.11.006. Epub 2019 Nov 25.
citation: Lin YT, Yu CJ, Yang JC, Shih JY. Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non-Small-Cell Lung Cancer: Analysis and Literature Review. Clin Lung Cancer. 2016 Sep;17(5):e77-e94. doi: 10.1016/j.cllc.2016.03.005. Epub 2016 Mar 30.