Clinical trial NCT01828099: LDK378 Versus Chemotherapy in Previously Untreated Patients With ALK Rearranged Non-small Cell Lung Cancer
Official title: A Phase III Multicenter, Randomized Study of Oral LDK378 Versus Standard Chemotherapy in Previously Untreated Adult Patients With ALK Rearranged (ALK-positive), Stage IIIB or IV, Non-squamous Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer
NSCLC
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
non-squamous non-small cell lung cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-04-10
Enrollment: 376
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: To compare the efficacy and safety of ceritinib with standard first-line chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with stage IIIB (not candidates for definitive multimodality therapy) or stage IV, non-squamous non-small cell lung cancer (NSCLC) harboring a confirmed anaplastic lymphoma kinase (ALK) rearrangement, using the Ventana immunohistochemistry (IHC) test.

Detailed description: This was an open-label, randomized, global, Phase III study that compared the efficacy and safety of ceritinib to standard first-line chemotherapy in patients with advanced (NSCLC) harboring ALK rearrangement. The confirmation of ALK rearrangement was done using the ICH test by a Novartis designated central laboratory. Prior to the study, patients had not received any previous systemic, anti-cancer therapy, including ALK inhibitors, for newly diagnosed advanced non-squamous NSCLC.

The patients were randomized in a 1:1 ratio to either receive ceritinib (750 mg once daily, fasted) or chemotherapy. The chemotherapy regimen consisted of a platinum-based doublet with pemetrexed followed by pemetrexed maintenance in patients without progressive disease after 4 cycles.

Treatment was continued until the blinded independent review committee (BIRC) confirmed disease progression based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), occurrence of unacceptable toxicity, or meeting other discontinuation criteria. Patients in either arm were permitted to continue the assigned study treatment beyond BIRC-confirmed disease progression in case of continued clinical benefit, as determined by the Investigator.

All patients who discontinued treatment during the treatment phase for reasons other than death, lost to follow-up, pregnancy or disease progression entered the post-treatment follow-up period until disease progression, withdrawal of consent or death.

In the chemotherapy arm, patients were allowed to switch and receive ceritinib after BIRC-confirmed disease progression (extension-treatment period).

Eligibility criteria: Key Inclusion Criteria:

1. The patient had a histologically or cytologically confirmed diagnosis of non-squamous Non-small cell lung cancer (NSCLC) that was Anaplastic lymphoma kinase (ALK) positive as assessed by the Ventana Immunohistochemistry (IHC) test. The test was performed at Novartis designated central laboratories.
2. The patient had a newly diagnosed stage IIIB (who was not a candidate for definitive multimodality therapy) or stage IV NSCLC or relapsed locally advanced or metastatic NSCLC not previously treated with any systemic anti-cancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not), with the exception of neo-adjuvant or adjuvant therapy.
3. The patient had at least one measurable lesion as defined by RECIST 1.1.

Key Exclusion Criteria:

1. The patient had known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate).
2. The patient had a history of severe hypersensitivity reaction to platinum-containing drugs, pemetrexed, or any known excipients of these drugs.
3. The patient had symptomatic central nervous system (CNS) metastases and was neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.

Primary outcomes:
measure: Progression Free Survival (PFS) by 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 34 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization to date of death due to any cause, up to approximately 120 months
measure: Overall Response Rate (ORR) by BIRC Assessment
timeFrame: Up to approximately 34 months
measure: Overall Response Rate (ORR) by Investigator Assessment
timeFrame: Up to approximately 120 months
measure: Duration of Response (DOR) by BIRC Assessment
timeFrame: From first documented response to first documented disease progression or death, assessed up to approximately 34 months
measure: Duration of Response (DOR) by Investigator Assessment
timeFrame: From first documented response to first documented disease progression or death, assessed up to approximately 120 months
measure: Disease Control Rate (DCR) by BIRC Assessment
timeFrame: Up to approximately 34 months
measure: Disease Control Rate (DCR) by Investigator Assessment
timeFrame: Up to approximately 120 months
measure: Time to Response (TTR) by BIRC Assessment
timeFrame: From randomization to date of first documented response, up to approximately 34 months
measure: Time to Response (TTR) by Investigator Assessment
timeFrame: From randomization to date of first documented response, up to approximately 120 months
measure: PFS by Investigator Assessment
timeFrame: From the date of randomization to the date of first radiologically documented disease progression or death due to any cause, up to approximately 120 months
measure: Overall Intracranial Response Rate (OIRR)
timeFrame: Up to approximately 34 months
measure: Intracranial Disease Control Rate (IDCR)
timeFrame: Up to approximately 34 months
measure: Duration of Intracranial Response (DOIR)
timeFrame: From first documented response to first documented disease progression in the brain or death, assessed up to approximately 34 months
measure: Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS)
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Least Squares Mean Scores on the EORTC-QLQ C30
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Least Squares Mean Scores on the EORTC QLQ- LC13
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Least Squares Mean Scores on the EQ-5D-5L Index
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS)
timeFrame: Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months
measure: Cmax of LDK378
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
measure: Tmax of LDK378
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
measure: Tlast of LDK378
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
measure: AUC0-24 of LDK378
timeFrame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: La Rioja
country: Argentina
facility: Novartis Investigative Site
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Auckland
country: Australia
facility: Novartis Investigative Site
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Recife
country: Brazil
facility: Novartis Investigative Site
state: PE
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Rio De Janiero
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: RN
city: Itajai
country: Brazil
facility: Novartis Investigative Site
state: SC
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Chang Chun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Changchun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: XI An
country: China
facility: Novartis Investigative Site
state: Shanxi
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Chongqing
country: China
facility: Novartis Investigative Site
city: Chongqing
country: China
facility: Novartis Investigative Site
city: Guang Dong Province
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Herlev
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Limoges
country: France
facility: Novartis Investigative Site
state: Haute Vienne
city: Toulon Cedex 9
country: France
facility: Novartis Investigative Site
state: Val De Marne
city: Caen
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Coswig
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Gottingen
country: Germany
facility: Novartis Investigative Site
city: Grosshansdorf
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Oldenburg
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Wiesbaden
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Heraklion Crete
country: Greece
facility: Novartis Investigative Site
city: Zalaegerszeg
country: Hungary
facility: Novartis Investigative Site
state: Zala
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Nyiregyhaza
country: Hungary
facility: Novartis Investigative Site
city: Veszprem
country: Hungary
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Kochi
country: India
facility: Novartis Investigative Site
state: Kerala
city: Nashik
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Jaipur
country: India
facility: Novartis Investigative Site
state: Rajasthan
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Madurai
country: India
facility: Novartis Investigative Site
state: TamilNadu
city: Kolkata
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Delhi
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
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: Parma
country: Italy
facility: Novartis Investigative Site
state: PR
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Udine
country: Italy
facility: Novartis Investigative Site
state: UD
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Akashi
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Hirakata-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Osaka-city
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: Bundang Gu
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Gyeonggi do
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
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: Saida
country: Lebanon
facility: Novartis Investigative Site
city: Guadalajara
country: Mexico
facility: Novartis Investigative Site
state: Jalisco
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Amersfroort
country: Netherlands
facility: Novartis Investigative Site
city: Enschede
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Zoetermeer
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Szczecin
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
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: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Lerida
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Mataro
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Reus
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Badajoz
country: Spain
facility: Novartis Investigative Site
state: Extremadura
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Lugo
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Palma De Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: La Laguna
country: Spain
facility: Novartis Investigative Site
state: Santa Cruz De Tenerife
city: Barcelona
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: Madrid
country: Spain
facility: Novartis Investigative Site
city: Linkoping
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Exeter
country: United Kingdom
facility: Novartis Investigative Site
state: Devon
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
state: West Yorkshire
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G Jr. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X. Epub 2017 Jan 24.
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.