Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...

Background:

Lung Cancer is the leading cause of death among both men and women. Of the approximately
172,000 patients that are diagnosed every year with non small cell lung cancer (NSCLC) in
the US, 55% present with advanced stage disease. The current treatment for advanced NSCLC is
first line chemotherapy with a platinum-based doublet. Second line treatment for recurrent
or progressive disease includes treatment with chemotherapy or treatment with an oral EGFR
(epidermal growth factor receptor) tyrosine kinase inhibitor. Several mechanisms of
resistance to EGFR tyrosine kinase inhibitors have been discovered. Presence of KRAS
mutations is one of them. AZD6244 (ARRY-142886) is an investigational drug that is orally
available and targets the critical kinase (MEK) in the mitogen-activated protein (MAP)
kinase signal transduction pathway which is activated in NSCLC and is downstream of EGFR.

Objectives:

- Determine the progression free survival (PFS) using the combination of AZD6244 and
erlotinib in patients with wild type KRAS advanced NSCLC

- Determine the clinical response rate (PR (partial response) + CR (complete response))
either monotherapy AZD6244 or the combination AZD6244 plus erlotinib in patients with
mutated KRAS advanced NSCLC

- Evaluate disease control rate (PR+CR+SD (stable disease)) and overall survival in both
patient groups.

- Determine a safety profile for use of AZD6244 in combination with erlotinib in patients
with advanced NSCLC.

- Measure serological markers to evaluate if these markers are correlated with tumor
response.

- Measure changes in a tumors MIB-1 (Ki-67) rate and pERK levels in response to treatment
with AZD6244.

Eligibility:

- Patients with pathologically confirmed NSCLC not amenable to potentially curative
therapy and having progressed after being treated with at least one prior platinum
containing chemotherapy regimen, or having refused cytotoxic chemotherapy.

- Progressive disease should be documented prior to enrollment on the study.

- Patient should not have more than 2 prior chemotherapy regimens.

- Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.

- Adequate renal, cardiac, hepatic and hematopoietic functions

- No major surgery, radiotherapy, or chemotherapy within 28 days of enrollment.

Design:

- Patients will be stratified on the basis on their KRAS mutational status. Wild-Type
KRAS patients will be randomized to receive either single agent erlotinib 150 mg/day or
the combination of erlotinib 100 mg/day plus AZD6244 at 150 mg/day. KRAS mutant
patients will be randomized to receive AZD6244 monotherapy at a dose of 75 mg twice per
day, or the combination AZD6244 at 150 mg/day plus erlotinib 100 mg/day.

- Treatment will continue until disease progression.

- Toxicity will be assessed every cycle by the CTCAE (Common Terminology Criteria for
Adverse Events) Version 4.0.

- Tumor assessments by RECIST 1.1 criteria will be performed every 2 cycles (one cycle is
28 days).

- Correlative studies including initial tumor mutational analysis and tissue
immunohistochemistry (IHC) studies will be done on existing tumor blocks, or
re-biopsied tissue prior to enrollment.

- Patients will be evaluated for the potential to undergo repeat tumor biopsy after 1
cycle of therapy. Tumors will be assessed for MIB-1 (Ki-67) and pERK levels by IHC.

- The study will accrue up to 40 patients with wild-type KRAS NSCLC and up to 60 patients
with mutated KRAS NSCLC.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed advanced (Stage IV) Non
Small Cell Lung Cancer that has been verified by the enrolling institution s
pathology department. Mixed histologies, with small cell lung cancer components are
not eligible.

- Patients must have measurable disease by RECIST criteria, defined as at least one
lesion that can be accurately measured in at least one dimension (longest diameter to
be recorded) as greater than or equal to 20 mm with conventional techniques or as
greater than or equal to 10 mm with spiral CT (computed tomography) scan.

- Patients must have had at least one prior platinum-containing chemotherapy regimen,
or have refused cytotoxic chemotherapy. Patients should have no more than two prior
chemotherapy regimens. Chemotherapy regimens have no limit on the maximum or minimum
number of cycles. Patients enrolled on the trial should have completed their last
chemotherapy regimen at least 4 weeks ago. Patients should have completed radiation
therapy at least 4 weeks prior to enrollment. Adjuvant and neoadjuvant chemotherapy
does not count as prior chemotherapy for advanced disease if more than a year before
enrollment.

- Age greater than or equal to 18 years, because no dosing or adverse event data are
currently available on the use of AZD6244 (ARRY-142886) as monotherapy or in
combination with erlotinib in patients less than 18 years of age. Children are
excluded from this study but will be eligible for future pediatric phase 2
combination trials.

- Life expectancy of greater than 3 months.

- ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2
(Karnofsky greater than or equal to 60%).

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

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits

- AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic
transaminase)) /ALT (alanine aminotransferase) ((SGPT (serum glutamic pyruvic
transaminase)) less than or equal to 2.5 X institutional upper limit of normal

- creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal

- Patients must have adequate archival material from a previous biopsy to determine
KRAS status at the time of enrollment, or undergo a biopsy of fresh tissue of the
primary cancer lesion or a metastatic site in order to make this determination.

- The effects of AZD6244 and erlotinib on the developing human fetus at the
recommended therapeutic dose are unknown. However preclinical data showing
adverse effects on fetal survival and development with AZD6244 have been
reported. For this reason since there is a potential risk of teratogenicity,
women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation, and for four weeks
after dosing with AZD6244 ceases. Women of child-bearing potential must have a
negative pregnancy test prior to entry. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately. Please note that the AZD6244 manufacturer
recommends that adequate contraception for male patients should be used for 16
weeks post-last dose due to sperm life cycle.

- Ability to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered to less than or equal to grade 1 toxicities
from adverse events due to agents administered more than 4 weeks earlier.

- Patients may not be receiving any other investigational agents.

- In general, patients with known brain metastases should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. However, patients who have completed primary treatment of
their brain metastasis by surgery or radiotherapy and have been off steroids (with
the exception of maintenance replacement steroids) and anti-seizure medications for
greater than one month without progression of neurological symptoms are eligible for
enrollment in this trial. Stability of treated brain metastases should be confirmed
by repeat imaging studies (CT brain or MRI (magnetic resonance imaging) brain)
performed at least one month after completion of treatment.

- Previous MEK (methyl ethyl ketone) inhibitor or prior treatment with EGFR TKI
(tyrosine kinase inhibitor).

- Major surgery or significant traumatic injury occurring within 21 days prior to
treatment.

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogrens
syndrome), congenital abnormality (e.g., Fuchs dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test).

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV (intravenous) alimentation, prior surgical procedures affecting
absorption, or active peptic ulcer disease.

- Patients with uncontrolled hypertension already on optimal medication, patients with
class II or greater heart failure, any current or prior history of cardiomyopathy.
Patient with baseline LVEF (left ventricular ejection fraction) less than 50%, atrial
fibrillation, recent myocardial infarction, or unstable ischemic heart disease.

- Patients with QTc (corrected QT interval) interval greater than 450 msecs or other
factors that increase the risk of QT (Q wave, T wave) prolongation or arrhythmic
events (e.g., heart failure, hypokalemia, family history of long QT interval
syndrome) including heart failure that meets New York Heart Association (NYHA) class
III and IV definitions are excluded. This does not include QTc prolongation secondary
to a paced rhythm. If a patient has a paced rhythm, QTc levels less than or equal to
500 (Grade 1) are allowed and patients with QTc > 500 are excluded.

- Required use of a concomitant medication that can prolong the QT interval. A
comprehensive list of agents with the potential to cause QTc prolongation can be
found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm.

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, Hepatitis B or C, 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 AZD6244 is a MEK- Inhibitor agent
with the 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 AZD6244, breastfeeding should be discontinued if the
mother is treated with AZD6244. These potential risks may also apply to other agents
used in this study.

- HIV (human immunodeficiency virus) -positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
AZD6244. In addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women and members of all races and ethnic groups are eligible for this trial.