This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.
PRIMARY OBJECTIVE: I. To determine the progression-free survival with osimertinib (AZD9291) plus bevacizumab compared to osimertinib (AZD9291) alone. SECONDARY OBJECTIVES: I. To assess the safety and tolerability of the combination of osimertinib (AZD9291) and bevacizumab. II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib (AZD9291) plus bevacizumab versus single-agent osimertinib (AZD9291). III. To determine the overall response rate and the intracranial response rate to the combination versus single agent. IV. To assess the overall survival in patients receiving osimertinib (AZD9291) plus bevacizumab compared to osimertinib (AZD9291) alone. TRANSLATIONAL OBJECTIVES: I. To investigate mechanisms of sensitivity and resistance to combination osimertinib (AZD9291) plus bevacizumab versus osimertinib (AZD9291) by molecularly characterizing tumor samples including T790M status. II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as an indicator of sensitivity and resistance to treatment. III. To determine whether an angiogenic signature using a multiplex panel array is associated with benefit from the combination of osimertinib (AZD9291) plus bevacizumab. IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to determine biomarkers predictive of benefit from combination therapy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), tumor biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed up for a minimum of 4 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
7
Given IV
Undergo tumor biopsy
Undergo blood sample collection
Undergo CT scan
Undergo MRI
Given PO
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Keck Medical Center of USC Pasadena
Pasadena, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Moffitt Cancer Center-International Plaza
Tampa, Florida, United States
Moffitt Cancer Center
Tampa, Florida, United States
University of Kansas Clinical Research Center
Fairway, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, United States
...and 8 more locations
Progression free survival (PFS)
The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI) will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Time frame: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 5.5 years
Overall survival (OS)
The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Time frame: From start of treatment to death, assessed up to 5.5 years
Incidence of adverse events
Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.
Time frame: Up to 5.5 years
Overall response rate
Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Time frame: Up to 5.5 years
Intracranial response rate
Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Time frame: Up to 5.5 years
Time to intracranial progression
Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.
Time frame: Up to 5.5 years
Time to central nervous system (CNS) progression
Time frame: From start of treatment to time of progression in the CNS, assessed up to 5.5 years
Objective response defined as a complete or partial response
Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
Time frame: Up to 5.5 years
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