Clinical Trials /

18F-FDG PET and Osimertinib in Evaluating Glucose Utilization in Patients With EGFR Activated Recurrent Glioblastoma

NCT03732352

Description:

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.

Related Conditions:
  • Glioblastoma
  • Malignant Supratentorial Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 18F-FDG PET and Osimertinib in Evaluating Glucose Utilization in Patients With EGFR Activated Recurrent Glioblastoma
  • Official Title: Creating Metabolic Vulnerabilities in Patients With EGFR Activated Recurrent Glioblastoma by Inhibiting EGFR With Osimertinib

Clinical Trial IDs

  • ORG STUDY ID: 18-001000
  • SECONDARY ID: NCI-2018-02010
  • SECONDARY ID: 18-001000
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT03732352

Conditions

  • EGFR Gene Amplification
  • EGFR Gene Mutation
  • Glioblastoma
  • Recurrent Glioblastoma
  • Supratentorial Glioblastoma
  • TP53 wt Allele

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (18F-FDG PET, osimertinib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (18F-FDG PET, osimertinib)ExperimentalWithin 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.
  • Osimertinib

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

               -  2 weeks from administration of a non-cytotoxic, FDA-approved agent other than
                  bevacizumab (e.g., hydroxychloroquine, etc.)

          -  Patient tumor sample must have evidence of EGFR activation as determined by EGFR
             amplification and/or EGFR mutations by fluorescent in situ hybridization (FISH) or
             sequencing approaches

          -  Patient tumor sample must not have p53 mutation

               -  Note: Patients will be enrolled based on the documented EGFR/p53 status from the
                  previous assays completed locally. If post enrollment evaluation of the archival
                  tissue revealed that neither EGFR amplification nor EGFR mutations were present
                  by using FISH or next generation sequencing, or mutant p53 by exon sequencing,
                  the patients may continue their participation in the study. The investigator
                  should discuss with patients regarding their willingness of continuation of
                  participation in the study

          -  Patients must have a Karnofsky performance status (KPS) >= 60

          -  Patients must have a life expectancy >= 12 weeks

          -  Patients must be able to swallow medication by mouth

          -  Women of childbearing potential must have a negative serum pregnancy test prior to
             study entry. Women of childbearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation. Should a woman become pregnant or
             suspect she is pregnant while participating in this study, she should inform her
             treating physician immediately.

               -  Female subjects should be using highly effective contraceptive measures, and must
                  have a negative pregnancy test and not be breast-feeding prior to start of dosing
                  if of child-bearing potential or must have evidence of non-child-bearing
                  potential by fulfilling one of the following criteria at screening:

                    -  Post-menopausal defined as aged more than 50 years and amenorrheic for at
                       least 12 months following cessation of all exogenous hormonal treatments

                    -  Women under 50 years old would be considered postmenopausal if they have
                       been amenorrheic for 12 months or more following cessation of exogenous
                       hormonal treatments and with luteinizing hormone (LH) and follicle
                       stimulating hormone (FSH) levels in the post-menopausal range for the
                       institution

                    -  Documentation of irreversible surgical sterilization by hysterectomy,
                       bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

          -  Men treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and for 4 months after
             completion of osimertinib administration

          -  Provision of informed consent for genetic research

        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

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG e.g. complete left bundle branch block, third degree heart block and
                  second degree heart block

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age in
                  first degree relatives or any concomitant medication known to prolong the QT
                  interval

          -  Absolute neutrophil count < 1.5 x 10^9/L

          -  Platelet count < 100 x 10^9/L

          -  Hemoglobin < 90 g/L

          -  Alanine aminotransferase > 2.5 times upper limit of normal (ULN) if no demonstrable
             liver metastases or > 5 times ULN in the presence of liver metastases

          -  Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5
             times ULN in the presence of liver metastases

          -  Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the
             presence of documented Gilbert?s syndrome (unconjugated hyperbilirubinemia) or liver
             metastases

          -  Serum creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min
             (measured or calculated by Cockcroft and Gault equation)?confirmation of creatinine
             clearance is only required when creatinine is > 1.5 times ULN

          -  History of hypersensitivity active or inactive excipients of osimertinib or drugs with
             a similar chemical structure or class to osimertinib

          -  Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis which required steroid treatment, or any evidence of
             clinically active interstitial lung disease

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence and severity of adverse events (AEs) assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:Up to 2 years
Safety Issue:
Description:All events will be recorded from the time a subject has signed the Informed Consent Form. AE analyses will include only treatment emergent adverse events. Specifically, following quantities will be estimated: incidence (number [no.] of patients) and frequency (no. of events) overall and broken down by System Organ Classification and incidence (no. of patients) and frequency (no. of events) broken down by severity.
Measure: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
Time Frame: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
Safety Issue:
Description:Will be based on the sampling distribution of a simple binomial proportion. Additionally, descriptive data will be provided for the duration of PFS as a Kaplan-Meier curve.
Measure:Correlation between the reduction in glucose uptake and 6 months PFS
Time Frame:Up to 2 years
Safety Issue:
Description:Reduction in glucose uptake will be correlated with clinical outcome-- 6 months PFS, receiver operating characteristic curve (ROC) analyses of simple thresholding strategies will be performed using leave one out cross validation.
Measure:Concentrations of osimertinib and metabolites AZ5104 and AZ7550 in post-dosing plasma samples.
Time Frame:At the end of Cycle 1 (each cycle is 28 days).
Safety Issue:
Description:PK concentration data will be summarized using appropriate summary statistics

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

November 8, 2019