Afatinib and Necitumumab in Patients With EGFR Mutation Positive Advanced or Metastatic Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of combination afatinib and necitumumab therapy in
EGFR mutation positive non-small cell lung cancer (NSCLC) patients who have progressed
following first- and third-generation EGFR tyrosine kinase inhibitors (TKIs).

II. To determine the efficacy and safety profile of afatinib and necitumumab combination
therapy in patients with EGFR mutation positive NSCLC patients who have progressed following
first- and third-generation EGFR TKIs.

OUTLINE: This is a dose-escalation study.

Patients receive afatinib orally (PO) once daily (QD) on days 1-28 and necitumumab
intravenously (IV) over 60 minutes on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 3
months for up to 1 year.

Inclusion Criteria:

- Signed and dated written informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

- Histologically or cytologically-confirmed advanced or metastatic non-small cell lung
cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed

- Progression on a first generation EGFR TKI (T790M negative), or progression on a third
generation TKI (if T790M positive at time of progression on a first or second
generation TKI)

- At least one measurable lesion as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic
resonance imaging (MRI)

- Patient consents to undergo a medically safe tumor biopsy at time of disease
progression for mutation analysis

- Leukocytes >= 3,000/uL

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.5 g/dL

- Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)

- Total bilirubin =< 1.5 times upper limit of normal (ULN)

- Alkaline phosphatase (ALP) =< 3.0 x ULN

- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for
patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable

* Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin >
2 x ULN, clinical and laboratory monitoring should be initiated by the investigator;
for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at
ALT > 2 x baseline

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 14 days prior to receiving first dose of study medication; and additionally
agree to use at least two methods of birth control or abstain from heterosexual
intercourse from the time of signing consent, and until 6 months after patient's last
dose of study drug

* WOCBP of childbearing potential are defined as those not surgically sterile or not
post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a
bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24
months in the absence of an alternative medical cause, then patient will be considered
a female of childbearing potential); postmenopausal status in females under 55 years
of age should be confirmed with a serum follicle-stimulating hormone (FSH) level
within laboratory reference range for postmenopausal women

- WOCBP must agree to follow instructions for method(s) of contraception from the time
of signing consent and until 6 months after last dose of study therapy

- Men able to father children who are sexually active with WOCBP must agree to follow
instructions for method(s) of contraception from the time of signing consent and until
6 months after last dose of study therapy; men able to father children are defined as
those who are not surgically sterile (i.e. patient has not had a vasectomy)

Exclusion Criteria:

- Prior treatment against NSCLC with an EGFR monoclonal antibody

- Prior afatinib therapy, unless patient received an intervening third generation EGFR
TKI after concluding prior afatinib and before enrollment on this clinical study

- Less than 3 days from prior treatment with EGFR TKI; patients with adverse events
related to prior EGFR TKI must recover to Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 to be eligible

- History of arterial or venous thromboembolism within 3 months prior to study
enrollment; patients with a history of venous thromboembolism beyond 3 months prior to
study enrollment can be enrolled if they are appropriately treated with low molecular
weight heparin

- Subjects with a history of interstitial lung disease (e.g., sarcoidosis) that is
symptomatic or may interfere with the detection or management of suspected
drug-related pulmonary toxicity; subjects with chronic obstructive pulmonary disease
(COPD) whose disease is controlled at study entry are allowed

- Symptomatic brain metastases; stable and treated central nervous system (CNS) disease
allowed; patients with treated, asymptomatic brain metastases are eligible if there
has been no change in brain disease status for at least two (2) weeks prior to
initiating study treatment; anticonvulsant therapy will be allowed if patient is on a
stable or decreasing dose of anticonvulsant treatment for at least two (2) weeks prior
to initiating study treatment

- Subjects with carcinomatous meningitis

- Prior radiotherapy or radiosurgery < 2 weeks prior to starting study treatment

- Current symptomatic congestive heart failure (New York Heart Association
classification >= grade III), unstable cardiac arrhythmia requiring therapy (e.g.
medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest
discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100
mmHg); or any of the following occurring within 6 months (180 days) prior to first
dose of study treatment: myocardial infarction, coronary/peripheral artery bypass
graft, cerebrovascular accident or transient ischemic attack; use of antihypertensive
medication to control blood pressure is allowed

- Patient is pregnant or breastfeeding, or plans to become pregnant or father children
from time of signing consent and lasting until 6 months after the last dose of trial
treatment

- Previous or concomitant malignancies at other sites, except effectively treated
non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ
or effectively treated malignancy that has been in remission for more than 3 years and
is considered to be cured AND no additional therapy is ongoing and required during the
study period with the exception of bisphosphonates and anti-androgens and/or
gonadorelin analogues for the treatment of prostate cancer are permitted; subjects
with other active malignancy requiring concurrent intervention are excluded

- Requiring treatment with any of the prohibited concomitant medications listed that
cannot be stopped for the duration of trial participation

- Any history or presence of poorly controlled gastrointestinal disorders that could
affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis,
chronic diarrhea, malabsorption)

- Recent (within 30 days before enrollment) or concurrent yellow fever vaccination

- All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue,
or peripheral neuropathy must have resolved to grade 1 (National Cancer Institute
[NCI] CTCAE version 4) or baseline before administration of study drug

- The patient has any ongoing or active infection, including active tuberculosis; Note:
a urinary tract infection controlled with oral antibiotics initiated at least 7 days
prior to study entry is acceptable

- Known positive test for hepatitis B, hepatitis C, human immunodeficiency virus (HIV),
or acquired immunodeficiency syndrome (AIDS)

- The patient has a known allergy/history of hypersensitivity reaction to any of the
treatment components, including any ingredient used in the formulation of necitumumab,
or any other contraindication to one of the administered treatments

- Known hypersensitivity to afatinib or the excipients of any of the trial drugs

- History of severe hypersensitivity reactions to other monoclonal antibodies

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g. infectious disease) illness

- Any other serious or uncontrolled medical disorder, active infection, physical exam
finding, laboratory finding, altered mental status, or psychiatric condition that, in
the opinion of the investigator, would limit a subject's ability to comply with the
study requirements, substantially increase risk to the subject, or impact the
interpretability of study results