A Study of EGF816 and Gefitinib in TKI-naïve EGFR-mutant Non-Small Cell 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 or patient population. "Investigational" means that the drug or drugs are
being studied and have not been approved together for patients.

The FDA (the U.S. Food and Drug Administration) has approved gefitinib as a treatment option
for EGFR mutation-positive lung cancer.

The FDA has not approved EGF816 as a treatment for any disease at this time.

In this research study, the investigators are studying the safety and efficacy of the
combination of the study drugs EGF816 and gefitinib.

Both EGF816 and gefitinib are inhibitors which target a specific mutation in cancer and may
stop tumors growing and multiplying.

Inclusion Criteria:

- Participants must have a pathologically-confirmed diagnosis of non-small cell lung
cancer (NSCLC).

- Participants must have advanced disease - either stage IV disease, stage IIIB disease
not amenable to definitive multi-modality therapy, or recurrent disease after a prior
diagnosis of stage I-III disease. All staging is via the American Joint Committee on
Cancer (AJCC)/IASLC 7th edition proposed staging criteria

- An EGFR sensitizing mutation must be detected in tumor tissue. Specifically, patients
harboring the most common mutations, deletions in exon 19 or the L858R mutation in
exon 21 are eligible. Other EGFR sensitizing mutations may be eligible after
discussion with the principal investigator. Patients may be enrolled in the study
based on an activating EGFR mutation detected by a CLIA-certified tissue or
plasma-based assay, but will be required to undergo a mandatory tumor biopsy during
study screening.

- Participants must have measurable disease, per RECIST 1.1. See Section 11 for the
evaluation of measurable disease.

- Patients in the six patient safety run-in cohort may have had a prior EGFR TKI in the
metastatic setting (to allow for patients who started initial therapy at an outside
hospital), but treatment duration must have been less than three months. After the
initial six-patient safety run-in, no prior EGFR TKI therapy in the metastatic setting
is allowed. An EGFR TKI given in the adjuvant setting (i.e. with no measurable disease
at the time of administration) is allowable provided the subject has been off of EGFR
TKI therapy for at least six months at the time of enrollment.

- Patients may have had no more than one prior line of chemotherapy or immunotherapy in
the metastatic setting. At least 14 days must have elapsed from the last
chemo/immunotherapy administration until the start of protocol treatment, and patients
must have recovered from the side effects of any of these agents.

- Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA
positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st
dose of study treatment and continue on antiviral therapy for at least 4 weeks after
the last dose of EGF816. Additional management of the patients would be provided by a
physician with expertise in management of HBV, if needed. Patients must have negative
hepatitis C antibody (HCV-Ab) or positive HCV-Ab but undetectable level of HCV-RNA.
Note: patients with detectable HCV-RNA are not eligible for the study.

- Patients must receive insurance approval for or be willing to pay for commercial
gefitinib.

- Age >/= 18 years.

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix 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

- Total bilirubin >1.5 x upper limit of normal (ULN)

*For patients with Gilbert's syndrome total bilirubin >3.0 x ULN

- AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal; for patients with
known hepatic metastases AST and/or ALT > 5x ULN

- Creatinine ≤1.5 × institutional upper limit of normal

- The effects of EGF816 and gefitinib on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use highly
effective contraception during the study and for 3 months after stopping the study
treatment. Highly effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptom thermal,
postovulation methods) and withdrawal are not acceptable methods of contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment.
In case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment

- Male Partner: male sterilization (at least 6 months prior to screening). For
female subjects on the study the vasectomized male partner should be the sole
partner for that subject.

- Combination of any two of the following (a+b or a+c, or b+c):

- A. Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate <1%),
for example hormone vaginal ring or transdermal hormone contraception.

- B. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- C. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

- D. In case of use of oral contraception women should have been stable on the same
pill for a minimum of 30 days before taking study treatment.

- Women are considered post-menopausal and not of childbearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation at least six weeks ago. In the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of childbearing potential.

- Sexually active males must agree to use a condom during intercourse while taking
drug and for 3 months after stopping treatment; men should not father a child in
this period. A condom is required to be used also by vasectomized men in order to
prevent delivery of the drug via seminal fluid.

- Ability to understand and the willingness to sign a written informed consent document.
Written informed consent must be obtained prior to any screening procedures.

Exclusion Criteria:

- Participants with clinically active or symptomatic interstitial lung disease or
interstitial pneumonitis (i.e., affecting activities of daily living or requiring
therapeutic intervention) and patients with history of clinically significant
interstitial lung disease or radiation pneumonitis.

- Patients with clinically symptomatic brain metastases or leptomeningeal disease.
Patients may be on a stable dose of corticosteroids to control brain metastases if
they have been on a stable dose for two weeks prior to study treatment and are
clinically asymptomatic.

- Patients who have had radiation to the lung fields within four weeks of starting
treatment. For patients receiving palliative radiation to thoracic vertebrae, ribs or
other sites where the radiation field includes the lungs, radiation must be completed
at least two weeks before starting treatment. For all palliative radiation to all
other sites, at least 7 days must have elapsed prior to starting to treatment. At
least six months must have elapsed from radiation given with curative intent.

- Patients who have had major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) within 2 weeks prior to starting study drug or who have not recovered
from side effects of such procedure. Video-assisted thoracic surgery (VATS) and
mediastinoscopy will not be counted as major surgery and patients can be enrolled in
the study ≥1 week after the procedure.

- Patients unable or unwilling to undergo a biopsy for research during the screening
period, 2-3 weeks into the course of therapy and at the time of progression.

- Patients with a second, clinically active, cancer. Patients with second cancers which
have been treated with curative intent and/or are currently inactive are allowed.

- Patients who have undergone a bone marrow or solid organ transplant.

- Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not
mandatory).

- Participants who are receiving any other investigational agents. Patients previously
treated with investigational agents must complete a washout period of at least one
week or five half-lives, whichever is longer, before starting treatment.

- Patients receiving concomitant immunosuppressive agents or chronic corticosteroid use,
except those on steroid to control brain metastases, those on topical or inhaled
steroids, or steroids given via local injection.

- Patients with clinically significant, uncontrolled cardiovascular disease, such as:

- Unstable angina within 6 months prior to screening

- Myocardial infarction within 6 months prior to screening

- Patients with a history of documented congestive heart failure (New York Heart
Association functional classification III-IV)

- Peripheral vascular disease

- Patients with uncontrolled hypertension defined as a Systolic Blood Pressure
(SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or
without anti-hypertensive medication. Initiation or adjustment of
antihypertensive medication(s) is allowed prior to screening

- Ventricular arrhythmias

- Supraventricular and nodal arrhythmias not controlled with medication

- Other cardiac arrhythmia not controlled with medication

- Patients with corrected QT (QTc) ≥450 ms (male patients) or ≥460 ms (female
patients) using Fridericia correction (QTcF) on the screening ECG (using
triplicate ECGs)

- Patients with history of congenital long QT syndrome or history of torsade de
pointes

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to EGF816 or gefitinib.

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.

- Unable or unwilling to swallow tablets or capsules.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because the effects of EGF816 and
gefitinib on a developing fetus are unknown. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
EGF816 or gefitinib, breastfeeding should be discontinued if the mother is treated
with EGF816 and gefitinib