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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

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ClinicalTrials.gov Identifier: NCT04603807
Recruitment Status : Recruiting
First Posted : October 27, 2020
Last Update Posted : May 16, 2023
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: Entrectinib Drug: Crizotinib Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 30, 2021
Estimated Primary Completion Date : December 1, 2027
Estimated Study Completion Date : December 1, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free survival (PFS) in participants with central nervous system (CNS) metastases at baseline [ Time Frame: Up to 7 years ]
    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).


Secondary Outcome Measures :
  1. Progression-free survival in the Central Nervous System (CNS-PFS) [ Time Frame: Up to 7 Years ]
    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

  2. Overall response rate (ORR) [ Time Frame: Up to 7 Years ]
    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

  3. Duration of response (DOR) [ Time Frame: Up to 7 Years ]
    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

  4. Progression-free survival (PFS) [ Time Frame: Up to 7 years ]
    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

  5. Overall survival (OS) [ Time Frame: Up to 7 Years ]
    OS is defined as the time from randomization to death from any cause

  6. 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) [ Time Frame: Up to 7 Years ]
  7. Percentage of participants with impact on lung cancer-specific symptoms assessed by the EORTC QLQ-LC13 [ Time Frame: Up to 7 Years ]
  8. Objective response rate in the CNS-ORR in participants with CNS metastases at baseline [ Time Frame: Up to 7 Years ]
    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

  9. Duration of response in the CNS (CNS-DOR) in participants with CNS metastases at baseline [ Time Frame: Up to 7 Years ]
    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

  10. Percentage of participants with Adverse Events and Serious Adverse Events and Adverse Events leading to dose modifications/interruptions, study drug withdrawal or death [ Time Frame: Up to 7 Years ]
    Assessed by the investigator according to the NCI CTCAE v5.0


Other Outcome Measures:
  1. Change in the scores of EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L) [ Time Frame: Up to 7 Years ]
    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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04603807


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

Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04603807    
Other Study ID Numbers: MO41552
2019-003859-11 ( EudraCT Number )
First Posted: October 27, 2020    Key Record Dates
Last Update Posted: May 16, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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).
Supporting Materials: Study Protocol

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hoffmann-La Roche:
ROS1 Non-small-cell lung
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
 Lung Diseases
Respiratory Tract Diseases
Crizotinib
Entrectinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action