A Phase 1/2 Study of osimertinib in combination or alternating with gefitinib in EGFR inhibitor naïve advanced EGFR mutant lung cancer

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

The interventions involved in this study are:

- Osimertinib (Tagrisso)

- Gefitinib (Iressa)

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. 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, 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 can have no prior history of any EGFR-directed therapy, including TKIs or
antibodies, and must also be chemotherapy and immunotherapy naïve. Patients who have
completed adjuvant or neo-adjuvant chemotherapy or immunotherapy >6 months ago are
considered treatment naive.

- Participants must be aged ≥ 18 years

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

- Participants must have a life expectancy of greater than 12 weeks

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

- leukocytes ≥3,000/mcL

- 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 within normal institutional limits OR

- creatinine clearance ≥50 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- Participants should have biopsy tissue at time of diagnosis available for
next-generation sequencing testing at the Dana-Farber Cancer Institute. Biopsy can be
performed at an outside institution as long as sufficient tissue is available. If next
generation sequencing has already been performed prior to study enrollment it does not
need to be repeated. 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.

- Participants must be ≥4 weeks since any major surgery (excluding vascular access
placement, mediastinoscopy, or biopsies performed by an interventional service)

- Participants must be ≥2 weeks since any prior radiation, including CNS radiation

- 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) 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 prior to start of dosing 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 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.

- 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:

- 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, or anticancer drugs for the
treatment of metastatic NSCLC

- Prior radiotherapy within 2 weeks of the first dose of study treatment. Patients who
have received radiation to more than 25% of the bone marrow are not eligible at any
time.

- 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 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 of similar chemical or biologic
composition to gefitinib or osimertinib.

- Patients currently receiving (or unable to stop use prior to receiving the first dose
of study treatment) medications or herbal supplements known to be potent inhibitors of
CYP3A4 (Appendix B). All patients must try to avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known inducer effects
on CYP3A4. The full list of medications that would make a patient ineligible are
provided in Appendix B.

- 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, mean resting corrected QT value
(QTc) of >470msec

- 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

- 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

- 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 gefitinib or osimertinib.

- ongoing use of warfarin (injectable low-molecular weight heparins are permitted).
Patients must be off warfarin for >7 days prior to enrollment

- Identification of EGFR T790M in baseline cfDNA analysis

- Active pregnancy or breast-feeding.

- Pregnant women are excluded from this study because the effects of gefitinib and
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
gefitinib or osimertinib, breastfeeding should be discontinued if the mother is
treated with these agents