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

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.

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