Clinical trial NCT01828112: LDK378 Versus Chemotherapy in ALK Rearranged (ALK Positive) Patients Previously Treated With Chemotherapy (Platinum Doublet) and Crizotinib
Official title: A Phase III, Multicenter, Randomized, Open-label Study of Oral LDK378 Versus Standard Chemotherapy in Adult Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer Who Have Been Treated Previously With Chemotherapy (Platinum Doublet) and Crizotinib
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer
ALK
LDK378
Non-small cell lung carcinoma (NSCLC)
treatment of lung cancer after first metastasis
lung cancer
lung adenocarcinoma
Non small cell lung carcinoma
Non small cell lung cancer
NSCLC
chemotherapy
ALK-positive
ALK-rearranged advanced non-small cell lung cancer
crizotinib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-04-10
Enrollment: 231
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the study was to compare the antitumor activity of LDK378 vs. chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Patients in the chemotherapy arm were given the option to switch to LDK378 after confirmed progressive disease (PD), while also had the choice to continue with pemetrexed treatment.

Detailed description: A total of 231 patients were randomized to one of the two treatment arms in a 1:1 ratio. Randomization was stratified by World Health Organization (WHO) performance status (0 versus 1-2) and whether the patient had brain metastases at screening. The study was planned to be ended once the final overall survival (OS) analysis was performed (at the earliest of approximately 196 deaths observed or statistical significance reached at earlier OS interim analysis).

Following an agreement between Novartis and European Medicines Agency (EMA) in May 2023 to terminate the trial earlier, this study was completed when the total number of deaths was 190. Patients who had Response Evaluation Criteria In Solid Tumors (RECIST)-defined disease progression as confirmed by the Blinded Independent Review Committee (BIRC), but who, in the opinion of the Investigator, had continued clinical benefit from study treatment on either the chemotherapy arm or the ceritinib arm, continued to receive treatment. These patients continued assessments in the treatment phase. In addition, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy (extension treatment \[ET\] phase) after BIRC-confirmed, RECIST-defined disease progression, and provided they met the eligibility requirements.

Eligibility criteria: Inclusion Criteria:

1. Patient has a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as assessed by the FDA approved Abbott FISH Test.
2. Patient has stage IIIB or IV diagnosis and must have received one or two prior regimens (including platinum- doublet) of cytotoxic chemotherapy for the treatment of locally advanced or metastatic NSCLC.
3. Patient has at least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation
4. Patients must have received previous treatment with crizotinib for the treatment of locally advanced or metastatic NSCLC.

Exclusion Criteria:

1. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
2. Patient with a history of severe hypersensitivity reaction to pemetrexed or docetaxel or any known excipients of these drugs.
3. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.

Primary outcomes:
measure: Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)
timeFrame: From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 114 months
measure: Progression Free Survival (PFS) Per Investigator Assessment
timeFrame: Up to approximately 84 months
measure: Overall Response Rate (ORR) Per BIRC
timeFrame: Up to approximately 54 months
measure: Overall Response Rate (ORR) Per Investigator Assessment
timeFrame: Up to approximately 93 months
measure: Duration of Response (DOR) Per BIRC
timeFrame: Up to approximately 54 months
measure: Duration of Response (DOR) Per Investigator Assessment
timeFrame: Up to approximately 93 months
measure: Disease Control Rate (DCR) Per BIRC
timeFrame: Up to approximately 54 months
measure: Disease Control Rate (DCR) Per Investigator Assessment
timeFrame: Up to approximately 93 months
measure: Time to Response (TTR) Per BIRC
timeFrame: Up to approximately 52 weeks
measure: Time to Response (TTR) Per Investigator Assessment
timeFrame: Up to approximately 45 weeks
measure: Overall Intracranial Response Rate (OIRR) Per BIRC
timeFrame: Up to approximately 18 months
measure: Intracranial Disease Control Rate (IDCR) Per BIRC
timeFrame: Up to approximately 18 months
measure: Duration of Intracranial Response (DOIR) Per BIRC
timeFrame: Up to approximately 18 months
measure: Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30)
timeFrame: Screening and treatment phase up to 92 months
measure: EORTC QLQ-LC13 Time to Definitive Deterioration
timeFrame: Screening and treatment phase up to 92 months
measure: Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)
timeFrame: Screening and treatment phase up to 92 months
measure: Least Squares Mean Scores on the EQ-5D-5L Index
timeFrame: Screening and treatment phase up to 92 months
measure: Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)
timeFrame: Screening and treatment phase up to 92 months
measure: Cmax for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: Tmax for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: Tlast for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: AUC0-24h for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: Mean Accumulation Ratio (Racc) for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: Clearance Rate at Steady State (CLss/F) for Ceritinib
timeFrame: Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.
measure: Post-Hoc: All Collected Deaths
timeFrame: Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years.
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Hollywood
country: United States
facility: Memorial Cancer Institute
state: Florida
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Miami
country: United States
facility: University Of Miami
state: Florida
city: Marywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa
country: United States
facility: Uni Of Iowa Hospitals And Clinics
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute
state: Oklahoma
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Sugar Land
country: United States
facility: Texas Oncology-Sugarland
state: Texas
city: Waco
country: United States
facility: Texas Oncology Cancer Care and Research Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Edegem
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: Marseille cedex 20
country: France
facility: Novartis Investigative Site
state: Bouches Du Rhone
city: Besancon cedex
country: France
facility: Novartis Investigative Site
city: Brest
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Le Mans
country: France
facility: Novartis Investigative Site
city: Mulhouse cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Suresnes
country: France
facility: Novartis Investigative Site
city: Bad Berka
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Esslingen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Limerick
country: Ireland
facility: Novartis Investigative Site
state: Co Limerick
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Kfar Saba
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Avellino
country: Italy
facility: Novartis Investigative Site
state: AV
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Aviano
country: Italy
facility: Novartis Investigative Site
state: PN
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
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: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Akashi
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Okayama-city
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: Hirakata-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Takatsuki
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Niigata
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Moscow Region Istra Village
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Luzern
country: Switzerland
facility: Novartis Investigative Site
city: St Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Pendik Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Cheltenham
country: United Kingdom
facility: Novartis Investigative Site
state: Gloucestershire
city: Aberdeen
country: United Kingdom
facility: Novartis Investigative Site
state: Grampian Region
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Kiura K, Imamura F, Kagamu H, Matsumoto S, Hida T, Nakagawa K, Satouchi M, Okamoto I, Takenoyama M, Fujisaka Y, Kurata T, Ito M, Tokushige K, Hatano B, Nishio M. Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset. Jpn J Clin Oncol. 2018 Apr 1;48(4):367-375. doi: 10.1093/jjco/hyy016.
citation: Shaw AT, Kim TM, Crino L, Gridelli C, Kiura K, Liu G, Novello S, Bearz A, Gautschi O, Mok T, Nishio M, Scagliotti G, Spigel DR, Deudon S, Zheng C, Pantano S, Urban P, Massacesi C, Viraswami-Appanna K, Felip E. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):874-886. doi: 10.1016/S1470-2045(17)30339-X. Epub 2017 Jun 9.