A Phase 2 Study of osimertinib with on-study and post-progression biopsy in the first line treatment of EGFR inhibitor naïve advanced EGFR mutant lung cancer

This research study is studying a targeted therapy as a possible treatment for Non-Small Cell
Lung Cancer (NSCLC) with an EGFR mutation.

The names of the study drug involved in this study is:

- Osimertinib (Tagrisso)

Inclusion Criteria:

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

--Note: recurrent stage IV disease initially diagnosed at an earlier stage is
considered eligible, provided prior treatment criteria is met.

- Participants must have measurable disease at baseline, 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.

- Note: For participants entering study after starting commercial osimertinib,
elevations in hepatic transaminases (AST/ALT) and/or total bilirubin < grade 2 at
study entry are acceptable (see protocol Table 2).

- Participants must have biopsy tissue at time of diagnosis available and sufficient for
targeted next-generation sequencing. The sequencing can be performed at a commercial
vendor such as Foundation Medicine. 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.

--Note: Cytology specimen may be acceptable for baseline NGS if tumor cellular content
is sufficient and following PI approval. If there is no cytology specimen or tissue
sample available for NGS, plasma-based NGS may be acceptable for enrollment following
discussion with PI.

- For participants entering study after starting commercial osimertinib: a tissue sample
from the time of diagnosis must be available and sufficient for NGS testing.
Participants who have had commercial tumor NGS testing performed on their
pre-osimertinib treated specimen do not need NGS repeated as part of this study.

- Participants must be willing to undergo a repeat tumor biopsy during study treatment
between cycles 4 and 8 (if considered medically safe) and 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 should be asked to use barrier contraceptives (i.e., by use of condoms)
during sex with all partners who are women of child bearing potential, including
pregnant women, during the trial and for a washout period of 4 months. Male patients
should avoid procreation for 4 months after completion of trial treatment. Patients
should refrain from donating sperm from the start of dosing until 4 months after
discontinuing study treatment.

- Female patients (women of child-bearing potential): 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 6 weeks 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.

- Subjects may enter the study even if they have started their treatment using
commercial osimertinib. Subjects may enter the study anytime during the first 3 months
of receiving commercial osimertinib therapy (up to 84 days of commercial osimertinib
before entering the study). In order to enter the study after starting commercial
osimertinib, subjects must meet all eligibility criteria listed above, have baseline
and follow up imaging available for review for response assessment, and must not have
developed disease progression during the first 3 months of commercial osimertinib
therapy.

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 except for subjects receiving first line osimertinib during the
first three months of therapy.

- 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.

- 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, including commercial osimertinib,
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 cause Torsades de Pointes 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.

- 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.