Patients who have advanced or metastatic NSCLC harboring ROS1 gene rearrangements with and without CNS metastases NSCLC
Conditions
Interventions
Study MO41552 is a randomized, open-label, multicenter, Phase III trial. The general purpose of the study is to compare the efficacy and
safety of entrectinib compared with crizotinib in patients wh
at a dose of 600 mg once daily with or without food, e.g. three 200-mg capsules per day
oral crizotinib as described in local prescribing information, e.g., 250 mg twice-daily per os taken with or without food
Entrectinib
Crizotinib
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: Patients must meet the following criteria for study entry: - Signed Informed Consent Form - Age = 18 years at time of signing the Informed Consent Form - 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 For a patient to be considered for this study, documented positivity for ROS1 gene rearrangements must have been determined locally at CLIA-certified or equivalently accredited diagnostic laboratories using nucleic acid-based testing methods that rely on direct assessment of ROS1 gene rearrangements in tumor tissue. Examples of acceptable methods include next-generation sequencing (NGS), Sanger sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR), NanoString and EdgeSeq. Fluorescence in situ hybridization (FISH) is also an acceptable method, with ROS1positivity defined as the detection of at least 15% of neoplastic nuclei with ROS1 gene rearrangements among a minimum of 50 total neoplastic nuclei. Immunohistochemistry (IHC) is not an acceptable method - 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. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment - Measurable systemic disease according to RECIST v1.1 - Patients with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis, are eligible, provided that the patient is neurologically stable for at least 1 week prior to the first dose of study treatment Patients who are receiving corticosteroids must be on a stable or decreasing corticosteroid dose within 7 days prior to start of treatment. The use of seizure prophylaxis is allowed so long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs) (Appendix 6). If patients were previously on EIAEDs (Appendix 6) and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment NOTE: Previously irradiated CNS lesions cannot be selected as target (measurable) lesions. - Life expectancy of at least 12 weeks - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (see Appendix 4 in attached protocol) - Adequate hematologic function: Platelet count = 75 x 109/L Absolute neutrophil count (ANC) = 1000 cells/µL Hemoglobin = 8.0 g/dL - Adequate renal function: An estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease equation of at least 45 mL/min/1.73 m2 (see Appendix 9 in attached protocol) - Adequate liver function: Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) = 3.0 × upper limit of normal (ULN); = 5.0 × ULN if liver metastases are present Total serum bilirubin = 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible - Patients
Exclusion criteria
Exclusion criteria: - Current participation in another therapeutic clinical trial - 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 medication - 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 QTc interval (e.g., repeated demonstration of a QTcF interval > 450 milliseconds from ECGs performed at least 24 hours apart) (see Appendix 10) - History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome) - Peripheral sensory neuropathy = Grade 2 - Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis Note: Radiation-induced lung disorders are not included in this exclusion criterion - Previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC) - Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy - 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) that would interfere with the determination of safety or efficacy of study treatments, 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 that would interfere with the assessment of safety or efficacy of study treatments (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 or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient 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 patient before trial entry
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline;Timepoints: End of Study;Measure: · Progression-free survival (PFS), 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 a blinded independent review committee (BIRC) using RECIST v1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC in the whole study population (ITT);Timepoints: End of Study;Measure: · Progression-free survival in the CNS (CNS-PFS), 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 · Overall response rate (ORR), defined as the percentage of patients who attain CR or PR, as assessed by the BIRC and the investigator per RECIST v1.1 · Duration of response (DOR), 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 · Progression-free survival (PFS), 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 · Overall survival (OS), defined as the time from randomization to death from any cause · Impact on functioning, including health related quality of life, using the Global Health Status/Quality of Life (GHS/QoL), the Physical Functioning (PF) and Role Function (RF) scores, as assessed by the EORTC QLQ-C30 and analyzed as a time to first and confirmed clinically meaningful deterioration · Impact on lung cancer-specific symptoms, as assessed by the EORTC QLQ-LC13;Name: To evaluate the efficacy of entrectinib compared with crizotinib in patients who have ROS1 rearrangement-positive NSCLC with CNS metastases at baseline;Timepoints: End of Study;Measure: · Objective response rate in the CNS (CNS-ORR), defined as the percentage of patients who attain CR or PR for lesions in the CNS, as determined by the BIRC per RECIST v1.1 · Duration of response in the CNS (C | — |
Countries
Brazil, China, Croatia, France, Germany, Greece, India, Italy, Jordan, Lebanon, Mexico, Netherlands, Romania, Slovakia, Spain, Sweden, Thailand, Turkey
Contacts
Public ContactFadi Karak
Oncologist - Hotel- Dieu De France
Outcome results
None listed