A Randomized, Double-Blind, Phase 2 Study of Erlotinib (Tarceva®) in Combination With OSI-906 or Placebo in Chemonaive Patients With Advanced NSCLC With Activating Mutations of the Epidermal Growth Factor Receptor (EGFR) Gene

Inclusion Criteria:

- Historically confirmed advanced NSCLC stages IIIB or IV

- Exon 19 deletion or exon 21 activating mutation in EGFR

- EGFR mutation status must be confirmed for participation in the study. EGFR can be
performed either by central or local laboratory. If analysis is done locally,
verifiable documentation confirming the EGFR mutation status must be submitted for
review and approval by sponsor prior to randomization. If no local result is
available, formalin-fixed, paraffin-embedded archival tissue representative of the
tumor or, in the absence of archival tissue, a fresh tumor tissue sample of
sufficient size to perform EGFR mutation analysis must be submitted centrally.
Results of the central analysis must be available prior to randomization.
Additionally, subjects should provide tissue blocks for biomarker central analysis
whenever possible. Ideal tissue requirement: block with ≥5 mm2 tumor area sufficient
to provide four 4-micron, and five 10-micron sections

- Measurable disease according to RECIST (version 1.1)

- ECOG performance status 0-1

- Must be able to take oral medication

- Fasting glucose <= 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic anti
hyperglycemic therapy is permitted if the dose has been stable for >= 4 weeks at the
time of randomization

- Adequate hematopoietic, hepatic, and renal function as follows:

- Neutrophil count >= 1500/uL

- Platelet count >= 100,000/uL

- Serum creatinine <= 1.5 x Upper Limit of Normal (ULN)

- Potassium, magnesium, and calcium within normal limits (supplementation and
re-testing is permitted)

- Total bilirubin <= 1.5 x ULN

- AST and ALT <= 2.5 x ULN, or <= 5 x ULN if patient has documented liver
metastases

- Patients - both male and female - with reproductive potential (ie, menopausal for
less than 1 year and not surgically sterilized) must agree to practice effective
contraceptive measure throughout the study. Women of childbearing potential must
provide a negative pregnancy test (serum or urine) within 14 days prior to
randomization. Men must agree not to donate sperm while on study drug and up to 90
days following the last dose of study drug

- Patients must provide written informed consent to participate in the study

- Patients may not have received chemotherapy for advanced NSCLC. Previous adjuvant
and/or neoadjuvant treatment for NSCLC is permitted

- Prior radiation therapy is permitted provided patients have recovered from the acute,
toxic effects of radiotherapy prior to randomization. A minimum of 28 days must have
elapsed between the end of radiotherapy and randomization

- Prior surgery is permitted provided that the surgery was done >= 28 days prior to
randomization and adequate wound healing has occurred prior to randomization

Exclusion Criteria:

- Prior exposure to agents directed at the Human Epidermal Receptor (HER) axis (eg,
erlotinib, gefitinib, and cetuximab)

- Prior insulin-like growth factor -1 receptor (IGF-1R) inhibitor therapy

- Malignancies other than NSCLC within the past 3 years (exceptions if curatively
treated; basal or squamous cell carcinoma of skin; locally advanced prostate cancer;
ductal carcinoma in situ of breast; in situ cervical carcinoma; and superficial
bladder cancer)

- Diabetes mellitus currently requiring insulinotropic or insulin therapy

- Use of proton pump inhibitors such as omeprazole within 14 days prior to
randomization. H2-receptor antagonists such as ranitidine are not excluded

- Symptomatic brain metastases that are not stable, require steroids, or have required
radiation and/or other related treatment (i.e., anti-epileptic medication) within 21
days prior to randomization

- Prior investigational agent within 21 days prior to randomization

- History of poorly controlled gastrointestinal disorders that could affect the
absorption of study drug (eg, Crohn's disease or ulcerative colitis)

- History (within last 6 months) of significant cardiovascular disease unless the
disease is well-controlled. Significant cardiac disease includes second/third degree
heart block; clinically significant ischemic heart disease; superior vena cava (SVC)
syndrome; poorly controlled hypertension; congestive heart failure of New York Heart
Association (NYHA) Class II or worse (slight limitation of physical activity;
comfortable at rest, but no ordinary physical activity results in fatigue,
palpitation, or dyspnea)

- History of arrhythmia (multifocal premature ventricular contractions [PVCs],
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
that is symptomatic or requires treatment (>= grade 3), left bundle branch block
(LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients
with atrial fibrillation controlled by medication are not excluded

- Mean QTcF interval >= 450 msec at screening

- Use of drugs that have a known risk of causing Torsades de Pointes (TdP) ('Torsades
List' on www.azcert.org/medical-pros/drug-lists/bycategory.cfm) are prohibited within
14 days prior to randomization

- Use of strong/moderate CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine. Other
less potent CYP1A2 inhibitors/inducers are not excluded

- Use of strong/moderate CYP3A4 inhibitors and inducers

- History of cerebrovascular accident (CVA) within 6 months prior to randomization or
that resulted in ongoing neurologic instability

- History of any psychiatric or neurologic condition that might impair the patient's
ability to understand or to comply with the requirements of the study or to provide
informed consent

- Pregnant or breast-feeding females

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the study drug

- Active infection, serious underlying medical condition (including any type of active
seizure disorder within 12 months prior to randomization), symptomatic brain
metastases, or serious chronic illness that would impair the ability of the patient
to receive study drug