Creating Metabolic Vulnerabilities in Patients with EGFR Activated Recurrent Glioblastoma by Inhibiting EGFR with Osimertinib
Overview
- Phase
- Phase 2
- Intervention
- Fludeoxyglucose F-18
- Conditions
- EGFR Gene Amplification
- Sponsor
- Jonsson Comprehensive Cancer Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Intrapatient variance of tumor fludeoxyglucose F-18 (FDG) uptake as determined by a double baseline FDG positron emission tomography (PET) prior to osimertinib exposure
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies how well fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and osimertinib works in evaluating glucose utilization in patients with EGFR activated glioblastoma. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 18F-FDG PET imaging may help to detect changes in tumor glucose utilization, which may allow investigators to obtain an early read out on the impact of osimertinib on recurrent glioblastoma patients whose tumors have EGFR activation.
Detailed Description
PRIMARY OBJECTIVES: I. Define the test - retest variance of tumor fludeoxyglucose (FDG) uptake using double baseline 18F-FDG PET imaging (18 to 54 hours apart) in patients with EGFR activated recurrent glioblastoma. II. After defining #1, evaluate whether osimertinib can create a statistically significant decrease in glucose utilization as determined using early, post dosing (24-72 hour) FDG-PET imaging in patients with EGFR activated recurrent glioblastoma. SECONDARY OBJECTIVES: I. Safety and tolerability of osimertinib in this patient population. II. Determine clinical effect of osimertinib in this patient population, as determined by 6 months progression-free survival. III. Correlated clinical effect of osimertinib with FDG-PET results in this patient population, to define by receiver operating characteristic (ROC) analysis a clinically meaningful decrease in glucose utilization, which correlates with the clinical effect. IV. Evaluate pharmacokinetic (PK) in this patient population using spot PK during imaging and at set time points during the study. OUTLINE: Within days -28 to -4, patients receive fludeoxyglucose F-18 intravenously (IV) and after 60 minutes undergo PET scan over 15 minutes. After 18-54 hours, patients undergo a second fludeoxyglucose F-18 PET scan. Patients then receive osimertinib orally (PO) once daily (QD) on days -3 to -1 and after 24-72 hours, undergo a third fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 2 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must be able to provide written informed consent
- •Patients must have histologically proven World Health Organization (WHO) grade IV glioblastoma who have supratentorial contrast enhancing progressive or recurrent tumor by MRI imaging following standard or experimental treatment.
- •Patients must have measurable contrast enhancing disease with a measurement of at least 1 x 1 x 1 cm using MRI contrast imaging
- •Patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible:
- •12 weeks from the completion of radiation
- •6 weeks from a nitrosourea chemotherapy
- •3 weeks from a non-nitrosourea chemotherapy
- •4 weeks from any Food and Drug Administration (FDA) approved agents
- •5 half-lives or 4 weeks, whichever is greater, from any investigational (not FDA-approved) agents
- •4 weeks from the last treatment with bevacizumab
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study
- •Previous enrollment in the present study or previous treatment with osimertinib
- •Prior exposure to EGFR targeted therapy
- •Currently receiving any other investigational agents
- •Currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior)
- •Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia and grade 2, prior platinum-therapy? related neuropathy
- •Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator?s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
- •Any of the following cardiac criteria:
- •Mean resting corrected QT interval (QTc) \> 470 msec obtained from an electrocardiogram (ECG), using the screening clinic ECG machine derived QTc value
Arms & Interventions
Treatment (18F-FDG PET, osimertinib)
Within days -28 to -4, patients receive fludeoxyglucose F-18 IV and after 60 minutes undergo PET scan over 15 minutes. After 18-54 hours, patients undergo a second fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days -3 to -1 and after 24-72 hours, undergo a third fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Fludeoxyglucose F-18
Treatment (18F-FDG PET, osimertinib)
Within days -28 to -4, patients receive fludeoxyglucose F-18 IV and after 60 minutes undergo PET scan over 15 minutes. After 18-54 hours, patients undergo a second fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days -3 to -1 and after 24-72 hours, undergo a third fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Osimertinib
Treatment (18F-FDG PET, osimertinib)
Within days -28 to -4, patients receive fludeoxyglucose F-18 IV and after 60 minutes undergo PET scan over 15 minutes. After 18-54 hours, patients undergo a second fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days -3 to -1 and after 24-72 hours, undergo a third fludeoxyglucose F-18 PET scan. Patients then receive osimertinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Positron Emission Tomography
Outcomes
Primary Outcomes
Intrapatient variance of tumor fludeoxyglucose F-18 (FDG) uptake as determined by a double baseline FDG positron emission tomography (PET) prior to osimertinib exposure
Time Frame: At baseline
Test-retest variances in FDG uptake will be estimated considering the variance of sample specific differences between first and second PET scans. This variance component will be estimated using a Bayesian conjugate analysis of Gaussian variates. Model adequacy diagnostics will compare predictive distributions to the observed data via posterior predictive assessment. Bayesian (95%) high posterior density intervals, and Bayesian posterior means will be used as the basis for statistical inference.
Change in FDG uptake in tumor after short course exposure to osimertinib
Time Frame: Baseline to day -1
In order to estimate the difference in FDG tumor uptake between pre and post exposure to osimertinib, a simple change model will be considered, comparing the mean baseline uptake with the mean uptake, after treatment. A formal test for difference in mean will be based on a paired T statistic for difference in mean. 95% confidence intervals will be used to quantify uncertainty in estimation.
Secondary Outcomes
- Incidence and severity of adverse events (AEs) assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03(Up to 2 years)
- Concentrations of osimertinib and metabolites AZ5104 and AZ7550 in post-dosing plasma samples.(At the end of Cycle 1 (each cycle is 28 days).)
- Percentage of participants surviving 6 months from the start of study treatment without progression of disease determined by progression free survival (PFS) according to Response Assessment in Neuro-oncology criteria(From the date of study treatment initiation to the date of the first documented progression or to death due to any cause, assessed up to 6 months)
- Correlation between the reduction in glucose uptake and 6 months PFS(Up to 2 years)