Clinical trial NCT02075840: A Study Comparing Alectinib With Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer Participants
Official title: Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-03-03
Enrollment: 303
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized, active controlled, multicenter phase III open-label study is designed to evaluate the efficacy and safety of alectinib compared with crizotinib treatment in participants with treatment-naive anaplastic lymphoma kinase-positive (ALK-positive) advanced non-small cell lung cancer (NSCLC). Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The study is expected to last approximately 144 months.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test
* Life expectancy of at least 12 weeks
* Eastern cooperative oncology group performance status (ECOG PS) of 0-2
* Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC
* Adequate renal, and hematologic function
* Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
* Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment
* Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline)
* Negative pregnancy test for all females of child bearing potential
* Use of highly effective contraception as defined by the study protocol

Exclusion Criteria:

* Participants with a previous malignancy within the past 3 years
* Any gastrointestinal (GI) disorder or liver disease
* National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia)
* History of organ transplant
* Co-administration of anti-cancer therapies other than those administered in this study
* Participants with baseline QTc greater than (\>) 470 milliseconds or symptomatic bradycardia
* Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment
* Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only
* History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation
* Pregnancy or lactation
* Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study
* Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry

Primary outcomes:
measure: Progression-Free Survival (PFS) by Investigator Assessment
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With PFS Event by Investigator Assessment
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
Secondary outcomes:
measure: PFS Independent Review Committee (IRC)-Assessed
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With PFS Event by IRC
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria
timeFrame: Randomization to CNS PD as first occurrence of disease progression (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria
timeFrame: Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Duration of Response (DOR) According to RECIST V1.1 Criteria as Assessed by the Investigators
timeFrame: First occurrence of objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Overall Survival (OS)
timeFrame: From randomization until death (up to 43 months)
measure: Percentage of Participants With OS Event
timeFrame: From randomization until death (up to 43 months)
measure: Percentage of Participants With CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 Criteria
timeFrame: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: CNS DOR IRC-assessed According to RECIST v1.1 Criteria
timeFrame: First occurrence of CNS objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to 28 months in the crizotinib arm and up to 30 months in the alectinib arm
measure: Area Under The Concentration-Time Curve (AUC) of Alectinib
timeFrame: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)
measure: Maximum Concentration (Cmax) of Alectinib
timeFrame: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
measure: Time to Reach Cmax (Tmax) of Alectinib
timeFrame: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
measure: AUC of Alectinib Metabolite
timeFrame: Pre-dose (within 2 hours before alectinib) (baseline), 1, 2, 4, 6, and 8 hours post-dose at Visit 0 (first dosing day) and Week 4; Pre-dose (within 2 hours) at Week 8, then every 8 weeks until disease progression or death/withdrawal (up to 33 months)
measure: Cmax of Alectinib Metabolite
timeFrame: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
measure: Tmax of Alectinib Metabolite
timeFrame: Pre-dose (within 2 hours before alectinib), 1, 2, 4, 6, and 8 hours post-dose at baseline and Week 4; Pre-dose (within 2 hours before alectinib) at Week 8, then every 8 weeks until disease progression or death/withdrawal from study (up to 33 months)
measure: Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30)
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: Percentage of Participants With Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30)
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: Percentage of Participants With Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13)
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder
timeFrame: Baseline, every 4 weeks until disease progression (up to 33 months)
Other outcomes:
Locations:
city: Northridge
country: United States
facility: North Valley Hem Onc Med Grp
state: California
city: Redondo Beach
country: United States
facility: TMPN/ Cancer Care Associates
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Deerfield Beach
country: United States
facility: University of Miami-Deerfield Beach
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Can Ins
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington Uni School of Medicine
state: Missouri
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
city: Darlinghurst
country: Australia
facility: Kinghorn Cancer Centre
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Adelaide
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Victoria
country: Australia
facility: Monash Health Translational Precinct
city: Sarajevo
country: Bosnia and Herzegovina
facility: University Clinical Center Sarajevo
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo - ICESP
state: São Paulo
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Santiago
country: Chile
facility: Centro Internacional de Estudios Clínicos (CIEC)
city: Guangzhou
country: China
facility: Sun Yet-sen University Cancer Center
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
city: San Jose
country: Costa Rica
facility: Clinica CIMCA
city: Cairo
country: Egypt
facility: Kasr Eieny Uni Hospital
city: Grenoble
country: France
facility: Chu Grenoble - Hopital Albert Michallon
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Centre Leon Berard
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Guatemala City
country: Guatemala
facility: Grupo Angeles
city: Hong Kong
country: Hong Kong
facility: Tuen Mun Hospital
city: Hong Kong
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hosp
city: Hong Kong
country: Hong Kong
facility: Princess Margaret Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Parma
country: Italy
facility: A.O. Universitaria Di Parma
state: Emilia-Romagna
city: Ravenna
country: Italy
facility: Ospedale Provinciale Santa Maria Delle Croci
state: Emilia-Romagna
city: Roma
country: Italy
facility: Policlinico Umberto i di Roma
state: Lazio
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int)
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Europeo Di Oncologia (IEO)
state: Lombardia
city: Bari
country: Italy
facility: Irccs Ist. Tumori Giovanni Paolo Ii
state: Puglia
city: Catania
country: Italy
facility: Az Ospedaliera Nuovo Garibaldi Quartiere Nesima
state: Sicilia
city: Perugia
country: Italy
facility: Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia
state: Umbria
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Ciudad de México
country: Mexico
facility: Instituto Nacional De Enfermedades Respiratorias
state: Mexico CITY (federal District)
city: Auckland
country: New Zealand
facility: Uni of Auckland
city: Gda?sk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lublin
country: Poland
facility: Ms Clinsearch Specjalistyczny Niepubliczny Zaklad Opieki Zdrowotnej
city: Olsztyn
country: Poland
facility: Warminsko-Mazurskie Centrum Chorób P?uc w Olsztynie
city: Otwock
country: Poland
facility: Mazowieckie Centrum Leczenia Chorob Pluc I Gruzlicy
city: Warszawa
country: Poland
facility: Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie
city: Coimbra
country: Portugal
facility: CHUC - Unidade de Pneumologia Oncológica
city: Lisboa
country: Portugal
facility: IPO de Lisboa
city: Porto
country: Portugal
facility: IPO do Porto
city: Moscovskaya Oblast
country: Russian Federation
facility: Moscow City Oncology Hospital #62
state: Moskovskaja Oblast
city: Sankt-peterburg
country: Russian Federation
facility: SPb City Clin Onc Dsp
state: Sankt Petersburg
city: St. Petersburg
country: Russian Federation
facility: Scientific Research Oncology Institute named after N.N. Petrov
state: Sankt Petersburg
city: Moscow
country: Russian Federation
facility: N.N.Burdenko Main Military Clinical Hospital
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Sremska Kamenica
country: Serbia
facility: Institute for pulmonary diseases of Vojvodina
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Alicante
country: Spain
facility: Hospital General Univ. de Alicante
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology (VHIO), Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Basel
country: Switzerland
facility: Universitaetsspital Basel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Lausanne
country: Switzerland
facility: CHUV
city: Zürich
country: Switzerland
facility: UniversitätsSpital Zürich
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung Univ Hosp
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Bangkok
country: Thailand
facility: National Cancer Inst.
city: Chiang Rai
country: Thailand
facility: Chiang Rai Prachanukroh Hospital
city: Khonkaen
country: Thailand
facility: Khonkaen Hospital
city: Patumwan
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Songkla
country: Thailand
facility: Songklanagarind Hospital
city: Adana
country: Turkey
facility: Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital
city: Ankara
country: Turkey
facility: Ankara University Medical Faculty
city: Edirne
country: Turkey
facility: Trakya University Medical Faculty Research And Practice Hospital Medical Oncology Department
city: Malatya
country: Turkey
facility: Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department
city: Kyiv
country: Ukraine
facility: Kyiv Regional Oncological Dispensary
city: Lviv
country: Ukraine
facility: Lviv State Oncology Regional Treatment and Diagnostic Centre
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Guys & St Thomas Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Dziadziuszko R, Peters S, Mok T, Camidge DR, Gadgeel SM, Ou SI, Konopa K, Noe J, Nowicka M, Bordogna W, Morcos PN, Smoljanovic V, Shaw AT. Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial. Clin Cancer Res. 2022 May 2;28(9):1800-1808. doi: 10.1158/1078-0432.CCR-21-2840.
citation: Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim DW, Perol M, Ou SI, Ahn JS, Shaw AT, Bordogna W, Smoljanovic V, Hilton M, Ruf T, Noe J, Peters S. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020 Aug;31(8):1056-1064. doi: 10.1016/j.annonc.2020.04.478. Epub 2020 May 11.
citation: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Perol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nuesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. doi: 10.1093/annonc/mdy405.
citation: Burudpakdee C, Wong W, Seetasith A, Corvino FA, Yeh W, Gubens M. Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer. Lung Cancer. 2018 May;119:103-111. doi: 10.1016/j.lungcan.2018.03.008. Epub 2018 Mar 9.
citation: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Perol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. doi: 10.1056/NEJMoa1704795. Epub 2017 Jun 6.
citation: Gainor JF, Shaw AT. J-ALEX: alectinib versus crizotinib in ALK-positive lung cancer. Lancet. 2017 Jul 1;390(10089):3-4. doi: 10.1016/S0140-6736(17)31074-7. Epub 2017 May 10. No abstract available.