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

Inclusion Criteria:

• Patients must be able to provide written informed consent

• Patients must have histologically proven World Health Organization (WHO) grade IVglioblastoma who have supratentorial contrast enhancing progressive or recurrenttumor by MRI imaging following standard or experimental treatment.

• Patients must have measurable contrast enhancing disease with a measurement of atleast 1 x 1 x 1 cm using MRI contrast imaging

• Patients must have recovered from severe toxicity of prior therapy. The followingintervals 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 (notFDA-approved) agents

• 4 weeks from the last treatment with bevacizumab

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

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

• Patient tumor sample must not have p53 mutation

• Note: Patients will be enrolled based on the documented EGFR/p53 status fromthe previous assays completed locally. If post enrollment evaluation of thearchival tissue revealed that neither EGFR amplification nor EGFR mutationswere present by using FISH or next generation sequencing, or mutant p53 by exonsequencing, the patients may continue their participation in the study. Theinvestigator should discuss with patients regarding their willingness ofcontinuation 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 tostudy entry. Women of childbearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while participating in this study, she shouldinform her treating physician immediately.

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

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

• Women under 50 years old would be considered postmenopausal if they havebeen amenorrheic for 12 months or more following cessation of exogenoushormonal treatments and with luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels in the post-menopausal range for theinstitution

• 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 adequatecontraception prior to the study, for the duration of study participation, and for 4months 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 ofstudy treatment) medications or herbal supplements known to be potent inducers ofCYP3A4 (at least 3 weeks prior)

• Any unresolved toxicities from prior therapy greater than Common TerminologyCriteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment,with the exception of alopecia and grade 2, prior platinum-therapy? relatedneuropathy

• Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses, which in the investigator?s opinionmakes it undesirable for the patient to participate in the trial or which wouldjeopardize 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 toswallow the formulated product or previous significant bowel resection that wouldpreclude adequate absorption of osimertinib

• Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) > 470 msec obtained from anelectrocardiogram (ECG), using the screening clinic ECG machine derived QTcvalue

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG e.g. complete left bundle branch block, third degree heart blockand second degree heart block

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, familyhistory of long QT syndrome or unexplained sudden death under 40 years of agein first degree relatives or any concomitant medication known to prolong the QTinterval

• 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 demonstrableliver 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 thepresence of documented Gilbert?s syndrome (unconjugated hyperbilirubinemia) or livermetastases

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

• History of hypersensitivity active or inactive excipients of osimertinib or drugswith a similar chemical structure or class to osimertinib

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

• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements