Osimertinib In EGFR Mutant Lung Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.

This research study is studying a targeted therapy as a possible treatment for Non-Small Cell
Lung Cancer (NSCLC) with an EGFR (epidermal growth factor receptor) genetic mutation. The
EGFR gene produces a protein that helps cells divide. Specific changes or a mutation in the
genetic information causes abnormal cell division and can lead to lung cancer. Patients who
have NSCLC with an EGFR gene mutation can be treated by drugs called EGFR tyrosine kinase
inhibitors (EGFR TKIs). They may stop (or "inhibit") the effect of the mutation in the EGFR
gene.

- Osimertinib has been approved by the FDA (the U.S. Food and Drug Administration) for this
disease.

Inclusion Criteria:

- Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition)
from time of initial diagnosis with either the L858R or exon 19 deletion activating
EGFR mutation as identified in a CLIA-approved laboratory from tumor tissue.

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

- Participants must be aged ≥ 18 years

- Participants must have an ECOG performance status of 0-1 (Appendix A)

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin >9.0 g/dL

- total bilirubin < 1.5 times the ULN if no liver metastases or < 3 times the ULN
in the presence of documented Gilbert's syndrome (unconjugated
hyperbilirubinemia) or liver metastases

- AST(SGOT)/ALT(SGPT) <2.5 × institutional upper limit of normal or <5 times the
ULN in the presence of liver metastases

- creatinine ≤ 1.5 x institutional upper limit of normal

--- OR

- creatinine clearance ≥50 mL/min as determined by the Cockcroft-Gault formula.

- Participants must have biopsy tissue at time of diagnosis available and sufficient for
targeted next-generation sequencing. The testing does not have to be completed prior
to study enrollment. If the specimen is insufficient a repeat biopsy will need to be
performed.

- Participants must be willing to undergo a repeat tumor biopsy at the time of disease
progression.

- Participants must be ≥2 weeks since any major surgery (excluding vascular access
placement, mediastinoscopy, or biopsies performed by an interventional service)

- Male patients: Willing to use adequate contraception (barrier or abstinence) while on
treatment with study drug and for 3 months after finishing treatment.

- Female patients: Willing to use adequate contraception (barrier or abstinence) at
least 2 weeks before receiving any study medication, while on treatment with study
drug, and for 3 months after finishing treatment.

- Female patients: Must not be pregnant or breast-feeding. Women of child-bearing
potential must have a negative pregnancy test (urine or serum) prior to start of
dosing or must have evidence of non-child-bearing potential by fulfilling one of the
following criteria at screening:

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

- b) Women under 50 years are considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and FSH levels in the post-menopausal range for the
institution.

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

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Subjects should not enter the study if any of the following exclusion criteria are
fulfilled:

- Prior or ongoing treatment with any of the following:

- EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting
the ERBB family

- Any cytotoxic chemotherapy, investigational agents, immunotherapy or anticancer
drugs for the treatment of metastatic NSCLC

- Note: Patients who have completed adjuvant or neo-adjuvant chemotherapy > 6
months ago are considered treatment naïve

- Prior radiotherapy, including CNS radiation, within 2 weeks of the first dose of study
treatment.

- No uncontrolled central nervous system (CNS) disease, including parenchymal brain
metastases, leptomeningeal disease, or spinal cord compression. Patients with
asymptomatic untreated brain metastases are eligible. Patients with treated CNS
disease will be allowed to enroll provided they have asymptomatic clinically confirmed
stable disease with ≥2 weeks since definitive CNS therapy (radiation or surgery) and
≥2 weeks without systemic steroids. Patients may undergo either whole brain radiation
or stereotactic radiosurgery prior to study entry.

- History of allergic reactions attributed to compounds, or any of its excipients, of
similar chemical or biologic composition to osimertinib.

- Patients currently receiving and unable to stop using medications or herbal
supplements known to be potent inhibitors or inducers of CYP3A4. The full list of
medications that would make a patient ineligible are provided in Appendix B, along
with indicated washout times.

- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 at the time of starting study treatment.

- Malignancies within the past 3 years excluding adequately treated basal or squamous
cell carcinomas of the skin without local or distant metastases.

- Refractory nausea and vomiting, chronic gastrointestinal diseases, previous
significant bowel resection, or any process that compromises the ability to swallow or
absorb oral medication

- Significant medical history or unstable medical comorbidities, including:

- heart disease including congestive heart failure (NYHA Grade II or greater);
unstable angina; prior myocardial infarction (NSTEMI or STEMI) within 6 months
prior to study enrollment; hypertension with a systolic blood pressure of >150 mm
Hg or diastolic blood pressure of >100 mm Hg while on antihypertensive medication

- any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG, e.g. complete left bundle branch block, third-degree heart block,
second-degree heart block, PR interval >250msec, have normal QT interval on ECG
evaluation QT corrected Fridericia (QTcF) of ≤ 450 ms in males or ≤ 470 ms in
females

- 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 the prolong the QT
interval and listed in Appendix B that a patient is unable to stop

- 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

- 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

- known active infection or ongoing antiviral medication for viral infections
including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
Screening for chronic conditions is not required. HIV-positive participants on
combination antiretroviral therapy are ineligible because of the potential for
pharmacokinetic interactions with osimertinib.

- cardiac ejection fraction of < 45%

- Any evidence of severe or uncontrolled systemic diseases, including 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

- Known to be T790M+ (on pre-treatment tumor or plasma) or known germline T790M. Note:
testing is not required for study entry.

- Ophthalmological conditions as follows:

- a. Current or past history of retinal pigment epithelial detachment
(RPED)/central serous retinopathy (CSR) or retinal vein occlusion

- b. Uncontrolled glaucoma (irrespective of IOP)

- Males and females of reproductive potential who are not using an effective method of
birth control and females who are pregnant or breastfeeding or have a positive (urine
or serum) pregnancy test prior to study entry. Women of child-bearing potential must
have a negative pregnancy test prior to start of dosing.

- Pregnant women are excluded from this study because the effects of osimertinib on the
development of the fetus are unknown, and there is potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with osimertinib,
breastfeeding should be discontinued if the mother is treated with osimertinib.