A Study to Compare the Efficacy and Safety of Entrectinib and Crizotinib in Participants With Advanced or Metastatic ROS1 Non-small Cell Lung Cancer (NSCLC) With and Without Central Nervous System (CNS) Metastases

Randomized, Open Label, Multicenter, Phase III Study of Entrectinib Versus Crizotinib in Patients With Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring ROS1 Gene Rearrangements With and Without Central Nervous System Metastases

The study will compare the efficacy and safety of entrectinib with crizotinib in participants with advanced or metastatic ROS1 non-small cell lung cancer (NSCLC). The participants will self-administer oral entrectinib or crizotinib as described in the protocol and local prescribing information. Treatments will continue until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Entrectinib; Drug: Crizotinib

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: MO41552 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. and Canada); Email: global-roche-genentech-trials@gene.com

Study Locations

• Brazil
  • BA
    • Salvador, BA, Brazil, 41253-190
      • Recruiting
      • Hospital Sao Rafael - HSR
  • DF
    • Brasilia, DF, Brazil, 70390-140
      • Active, not recruiting
      • Hospitais Integrados da Gavea S/A
  • RJ
    • Rio de Janeiro, RJ, Brazil, 22250-905
      • Active, not recruiting
      • Oncoclinicas Rio de Janeiro S.A.
  • SC
    • Florianopolis, SC, Brazil, 88020-210
      • Recruiting
      • YNOVA Pesquisa Clinica
  • SP
    • Barretos, SP, Brazil, 14784-400
      • Active, not recruiting
      • Hospital de Cancer de Barretos
    • Sao Paulo, SP, Brazil, 01246-000
      • Active, not recruiting
      • Instituto do Cancer do Estado de Sao Paulo - ICESP
• China
  • Beijing, China, 100730
    • Completed
    • Beijing Union Hospital
  • Changchun, China, 132013
    • Active, not recruiting
    • Jilin Cancer Hospital
  • Changsha, China, 410011
    • Active, not recruiting
    • The Second Xiangya Hospital of Central South University
  • Changsha CITY, China, 410013
    • Active, not recruiting
    • Hunan Cancer Hospital
  • Chengdu, China, 610041
    • Active, not recruiting
    • West China Hospital, Sichuan University
  • Chengdu, China, 610041
    • Withdrawn
    • Sichuan Provincial Cancer Hospital
  • Guangzhou, China, 510120
    • Active, not recruiting
    • The First Affiliated Hospital of Guangzhou Medical University
  • Harbin, China, 150081
    • Active, not recruiting
    • Harbin Medical University Cancer Hospital
  • Jining, China, 272029
    • Active, not recruiting
    • Affiliated hospital of Jining Medical University
  • Nanjing City, China, 210008
    • Completed
    • Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
  • Nanning City, China, 530021
    • Active, not recruiting
    • Guangxi Cancer Hospital of Guangxi Medical University
  • Shanghai, China, 200433
    • Active, not recruiting
    • Shanghai Pulmonary Hospital
  • Shiyan, China, 442000
    • Active, not recruiting
    • Taihe Hospital of Hubei University of Medicine
  • Wuhan City, China, 430023
    • Active, not recruiting
    • Union Hospital Tongji Medical College Huazhong University of science and Technology
• Croatia
  • Zagreb, Croatia, 10000
    • Recruiting
    • Clinical Hospital Centre Zagreb
• France
  • Bordeaux, France, 33076
    • Active, not recruiting
    • Institut Bergonie; Pneumology
  • Lille, France, 59037
    • Recruiting
    • CHRU Lille
  • Lyon, France, 69008
    • Recruiting
    • Centre Léon Bérard
  • Marseille, France, 13015
    • Active, not recruiting
    • Hopital Nord AP-HM
  • Rennes cedex 09, France, 35033
    • Recruiting
    • CHU Rennes - Hôpital Pontchaillou
  • Toulouse, France, 31059
    • Recruiting
    • Hopital Larrey; Pneumologie
  • Vantoux, France, 57070
    • Recruiting
    • Hopital Robert Schuman; Pneumologie
• Greece
  • Athens, Greece, 115 27
    • Recruiting
    • Uoa Sotiria Hospital; Oncology
  • Athens, Greece, 185 47
    • Recruiting
    • Metropolitan Hospital
  • Larissa, Greece, 411 10
    • Recruiting
    • University Hospital of Larissa;Department of Medical Oncology
  • Thessaloniki, Greece, 546 45
    • Recruiting
    • Euromedical General Clinic of Thessaloniki; Oncology Department
• India
  • Chandigarh, India, 160012
    • Withdrawn
    • Postgraduate Institute of Medical Education and Research
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500019
      • Withdrawn
      • American Oncology Institute
  • Delhi
    • New Delhi, Delhi, India, 110029
      • Recruiting
      • All India Institute of Medical Sciences (AIIMS)
  • Kerala
    • Kozhikode, Kerala, India, 673601
      • Active, not recruiting
      • MVR Cancer Centre and Research Institute
  • Maharashtra
    • Mumbai, Maharashtra, India, 400036
      • Active, not recruiting
      • MOC Cancer Care & Research Centre (Unit of Cellcure Cancer Centre Pvt Ltd)
    • Mumbai, Maharashtra, India, 400036
      • Withdrawn
      • MOC Cancer Care & Research Centre
  • Tamil NADU
    • Ranipet, Tamil NADU, India, 632513
      • Withdrawn
      • Christian Medical College
  • WEST Bengal
    • Kolkata, WEST Bengal, India, 700160
      • Recruiting
      • Tata Medical Center; Department of Medical Oncology
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Recruiting
      • Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale
  • Lazio
    • Roma, Lazio, Italy, 00152
      • Active, not recruiting
      • Azienda Ospedaliera San Camillo Forlanini; U.O.C. Pneumologia Ad Indirizzo Oncologico 1
    • Roma, Lazio, Italy, 00144
      • Active, not recruiting
      • IRCCS Istituto Regina Elena (IFO); Oncologia Medica B
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Recruiting
      • IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A
  • Lombardia
    • Milano, Lombardia, Italy, 20141
      • Withdrawn
      • Irccs Istituto Europeo di Oncologia (IEO); Divisione di Oncologia
    • Milano, Lombardia, Italy, 20162
      • Recruiting
      • Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
    • Monza, Lombardia, Italy, 20900
      • Recruiting
      • ASST DI MONZA; Oncologia Medica
  • Piemonte
    • Orbassano, Piemonte, Italy, 10043
      • Recruiting
      • Azienda Sanitaria Ospedaliera S Luigi Gonzaga; SSD Oncologia Polomonare (II PAD. IV PIANO)
  • Toscana
    • Pisa, Toscana, Italy, 56124
      • Recruiting
      • Azienda Ospedaliera Universitaria Pisana - Ospedale Cisanello; Dipartimento Cardio Toraco Vascolare
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Active, not recruiting
      • IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda
• Jordan
  • Amman, Jordan, 11941
    • Active, not recruiting
    • King Hussein Cancer Center
• Lebanon
  • Beirut, Lebanon
    • Recruiting
    • Hotel Dieu de France
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Recruiting
      • Hospital Civil De Guadalajara Fray Antonio Alcalde
  • Mexico CITY (federal District)
    • Cdmx, Mexico CITY (federal District), Mexico, 03100
      • Active, not recruiting
      • Health Pharma Professional Research
    • Ciudad de México, Mexico CITY (federal District), Mexico, 06760
      • Recruiting
      • Superare; Centro de Infusion
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64460
      • Recruiting
      • Hospital Universitario; Dr. Jose E. Gonzalez
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Active, not recruiting
    • NKI/AvL
  • Nijmegen, Netherlands, 6525 GA
    • Active, not recruiting
    • UMC St Radboud
  • Rotterdam, Netherlands, 3015 GD
    • Active, not recruiting
    • Erasmus MC
• Romania
  • Cluj County, Romania, 407280
    • Recruiting
    • Amethyst Cluj; Medical Oncology
  • Cluj Napoca, Romania, 400015
    • Recruiting
    • Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj Napoca; Oncologie Medicala
  • Craiova, Romania, 200347
    • Recruiting
    • Centrul de Oncologie Sfantul Nectarie
  • Iasi, Romania, 700483
    • Withdrawn
    • Institutul Regional de Oncologie Iasi
  • Ploiesti, Romania
    • Recruiting
    • Emergency County Clinical Hospital Ploiesti; Medical oncology
  • Timisoara, Romania, 300239
    • Recruiting
    • Centrul de Oncologie Oncohelp
• Russian Federation
  • Sankt Petersburg
    • Sait-Petersburg Sankt Petersburg, Sankt Petersburg, Russian Federation, 196006
      • Completed
      • AV Medical Ltd.
• Slovakia
  • Bratislava, Slovakia, 826 06
    • Active, not recruiting
    • Univerzitna nemocnica Bratislava; Oddelenie Klinickej Onkologie, Klinika Pneumologie A Ftizeologie
  • Kosice, Slovakia, 041 91
    • Withdrawn
    • Vychodoslovensky onkologicky ustav
• Spain
  • Barcelona, Spain, 08003
    • Active, not recruiting
    • Hospital del Mar; Servicio de Oncologia
  • Barcelona, Spain, 08908
    • Active, not recruiting
    • Institut Catala d Oncologia Hospital Duran i Reynals
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Ramon y Cajal; Servicio de Oncologia
  • Malaga, Spain, 29011
    • Active, not recruiting
    • Hospital Regional Universitario Carlos Haya; Servicio de Oncologia
  • LA Coruña
    • A Coruña, LA Coruña, Spain, 15006
      • Recruiting
      • Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Oncologia
• Sweden
  • Stockholm, Sweden, 171 76
    • Recruiting
    • Karolinska Universitetssjukhuset, Solna; Kliniska prövningsenheten Z:4:01
• Turkey
  • Adana, Turkey, 01230
    • Withdrawn
    • Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital; Medical Oncology
  • Ankara, Turkey, 06500
    • Active, not recruiting
    • Gazi University Medical Faculty, Oncology Hospital
  • Ankara, Turkey, 06680
    • Active, not recruiting
    • Liv Hospital Ankara; Medical Oncology
  • Izmir, Turkey, 35100
    • Withdrawn
    • Ege Uni Medical Faculty Hospital; Oncology Dept
  • Malatya, Turkey, 44280
    • Withdrawn
    • Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department
  • Sar?yer/?stanbul, Turkey, 34457
    • Withdrawn
    • Ac?badem Maslak Hastanesi Büyükdere

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement.
• No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
• Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization
• Measurable systemic disease according to RECIST v1.1
• Participants with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis
• Life expectancy of at least 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Adequate hematologic, renal, liver functions
• 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
• Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year during the treatment period and for up to 5 weeks after the last dose of entrectinib or for at least 90 days after the last dose of crizotinib
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.

Exclusion Criteria:

• Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
• NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study drug
• History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
• History of prolonged corrected QTc interval
• Peripheral sensory neuropathy ≥ Grade 2
• Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
• Previous malignancy within the past 3 years
• Incomplete recovery from any surgery prior to the start of study treatment
• Active GI disease (e.g., Crohn's disease, ulcerative colitis or short gut syndrome) or other malabsorption syndrome that would reasonably impact drug absorption
• History of prior therapy-induced pneumonitis
• Any condition (in the past 3 months) e.g., myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication
• Known active infections (bacterial, fungal or viral, including human immunodeficiency virus positive)
• History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
• Pregnant or lactating women
• Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Entrectinib; Participants will be enrolled to receive 600 mg entrectinib orally once daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.	Drug: Entrectinib; Entrectinib will be self-administered orally at a dose of 600 mg (three 200 mg capsules per day) once daily with or without food.
Active Comparator: Crizotinib; Participants will be enrolled to receive 250 mg crizotinib orally twice daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.	Drug: Crizotinib; Crizotinib will be self-administered orally at a dose of 250 mg twice daily with or without food.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) in participants with central nervous system (CNS) metastases at baseline	PFS is defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause whichever occurs first determined by a blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).	Up to 7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival in the Central Nervous System (CNS-PFS)	CNS-PFS is defined as the time from randomization to the first documented disease progression in the CNS or death from any cause, whichever occurs first, as determined by the BIRC using RECIST v1.1	Up to 7 Years
Overall response rate (ORR)	ORR is defined as the percentage of participants who attain Complete Response (CR) or Partial Response (PR) as assessed by the BIRC and the investigator per RECIST v1.1	Up to 7 Years
Duration of response (DOR)	DOR is defined as the time from when response (CR or PR) is first documented to disease progression or death, whichever occurs first, as assessed by the BIRC and the investigator per RECIST v1.1	Up to 7 Years
Progression-free survival (PFS)	PFS is defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by the BICR and investigator using RECIST v1.1	Up to 7 years
Overall survival (OS)	OS is defined as the time from randomization to death from any cause	Up to 7 Years
Percentage of participants with confirmed deterioration as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)		Up to 7 Years
Percentage of participants with impact on lung cancer-specific symptoms assessed by the EORTC QLQ-LC13		Up to 7 Years
Objective response rate in the CNS-ORR in participants with CNS metastases at baseline	CNS-ORR is defined as the percentage of participants who attain CR or PR for lesions in the CNS, as determined by the BIRC per RECIST v1.1	Up to 7 Years
Duration of response in the CNS (CNS-DOR) in participants with CNS metastases at baseline	CNS-DOR is defined as the time from when a CNS response (CR or PR) is first documented to disease progression in the CNS, as determined by the BIRC per RECIST v1.1	Up to 7 Years
Percentage of participants with Adverse Events and Serious Adverse Events and Adverse Events leading to dose modifications/interruptions, study drug withdrawal or death	Assessed by the investigator according to the NCI CTCAE v5.0	Up to 7 Years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the scores of EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L)	To evaluate health status utility scores of participants to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale (VAS) scores	Up to 7 Years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 27, 2020

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: ROS1 Non-small-cell lung
• 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; Tyrosine Kinase Inhibitors; Crizotinib; Entrectinib
• Other Study ID Numbers: MO41552; 2019-003859-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No