Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the MEK Inhibitor Binimetinib (MEK162) for Patients With Advanced KRAS Mutant Non-Small Cell Lung Cancer

This research study is a Phase I/II clinical trial. Participants are being asked to
participate in the Phase I portion of the study. A Phase I clinical trial tests the safety of
an investigational intervention and also tries to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that the
intervention is being studied.

Palbociclib is an oral drug which has been shown to stop the cell cycle, which is the way a
cell initiates growth. Binimetinib is also an oral drug which stops a signal that a cell
receives, instructing it to grow. By putting these two drugs together the investigators hope
that it will have a greater affect on cancer growth than either drug alone. The FDA (the U.S.
Food and Drug Administration) has not approved binimetinib as a treatment for any disease.
The FDA has not approved palbociclib for use in lung cancer but it has been approved for
other cancer types.

The purpose of this study is to:

- Test the combination of these two drugs, Palbociclib and Binimetinib, in order to
determine a safe and tolerable dose of the combination

- Determine the response rate of the combination

- Further evaluate the safety and side effect profile for the combination of palbociclib
and binimetinib.

Inclusion Criteria:

- Participants must have histologically confirmed advanced NSCLC (with a confirmed KRAS
mutation via any CLIA-certified method) for which curable treatment modalities are not
an option

- Part I Dose Escalation: Participants are required to have measurable disease per
RECIST 1.1 within 4 weeks of study entry

- MTD Expansion and Part II: 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) as > 20 mm with conventional techniques or as > 10 mm with
spiral CT scan. See section 10 for the evaluation of measureable disease.

- Age ≥ 18 years. Because no dosing or adverse event data are currently available in
participants < 18 years of age, children are excluded from this study

- Participants are permitted to have any number of prior therapies prior to enrollment

- ECOG performance status < 2 (see Appendix A).

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

- Absolute neutrophil count > 1,500mm3

- Hemoglobin > 9 g/dL

- Platelets > 100,000/mcL

- Total bilirubin < 2 X institutional upper limit of normal (ULN)

- AST (SGOT)/ALT (SGPT) < 2.5 X ULN -OR-

- AST (SGOT)/ALT (SGPT) < 5.0 X ULN if hepatic metastases are present

- Creatinine < 1.5 X the institutional ULN -OR-

- Calculated creatinine clearance (determined as per Cockcroft-Gault) > 50 mL/min

- The effects of palbociclib and binimetinib on the developing human fetus are not fully
known. For this reason, women of child-bearing potential and men must agree to use
adequate contraception (combination hormonal and barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 90
days after discontinuation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

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

- The availability of archival tissue to evaluate retrospectively the participant's Rb
status. The requirement is a minimum of 5 unstained slides with each tissue cut
measuring 4 microns in width. Ideally 15 slides will be requested. Patients without
available archival tissue may be enrolled at the discretion of the principal
investigator.

- Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments
(excluding neuropathy which can be ≤ Grade 2, and alopecia).

- MTD Expansion: Patients must be willing to undergo pre- and on-treatment tumor
biopsies. Patients are exempt from this requirement if, in the opinion of the
investigator, the biopsy procedure would pose a significant risk or if they have only
pulmonary metastatic disease.

- Patients must be able to take oral medications.

- Patients must have adequate cardiac function, defined as:

- Left ventricular ejection fraction (LVEF) > 50% as determined by echocardiogram
or multigated acquisition scan (MUGA).

- QTc < 480 msec.

Exclusion Criteria:

- Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study.

- Participants receiving any other study agents concurrently with the study drugs.

- Participants with symptomatic brain metastases that require chronic steroids. Patients
with a history of brain metastases are permitted to enroll as long as they have been
treated, are off of steroids, and have been stable for a minimum of one month on
imaging.

- MTD Expansion: Patients currently taking anticoagulants and who cannot safely hold the
medication to facilitate pre and on-treatment tumor biopsies are excluded from
participation.

- Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug
interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with
caution (see Appendix C).

- Part I Dose Escalation: Concurrent use of proton-pump inhibitors (PPIs) is prohibited.

- Uncontrolled intercurrent illness including, but not limited to:

- ongoing or active infection requiring systemic treatment

- symptomatic congestive heart failure

- cardiac arrhythmia

- psychiatric illness/social situations that would limit compliance with study
requirements

- hypertension, defined as systolic blood pressure > 160 mmHg despite medical
management

- myocardial infarction, unstable angina, coronary artery bypass grafting, coronary
angioplasty, or stenting < 6 months prior to screening

- History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or
Torsades de Pointes.

- History of Gilbert's syndrome.

- History of neuromuscular disorders that are associated with elevated CK (e.g.
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
muscular atrophy).

- History of other malignancy which could affect compliance with the protocol or
interpretation of results. History of curatively treated basal or squamous cell
carcinoma of the skin or in situ carcinoma of the cervix are allowed. Subjects with a
malignancy that has been treated with curative intent will also be allowed if the
malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, Day
1. Subjects with localized prostate cancer that has been treated with curative intent
will be allowed

- Patients planning to embark on a new strenuous exercise regimen after the first dose
of study treatment.

- History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that
may interfere with the absorption of oral study medication in the opinion of the
investigator.

- Pregnant women are excluded from this study because the study agents have the
potential for teratogenic or abortifacient effects. As there is an unknown but
potential risk of adverse events in nursing infants secondary to treatment of the
mother with the study agents, breastfeeding must be discontinued if the mother is
treated.

- Part II: Individuals with a history of a different malignancy are ineligible except
for the following circumstances:

- They have been disease-free for at least 3 years and are deemed by the
investigator to be at low risk for recurrence of that malignancy.

- Individuals with the following cancers are eligible if diagnosed and curatively
treated within the past 5 years: cervical cancer in situ, and basal or squamous
cell carcinoma of the skin.

- Known HIV-positive individuals on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions. Appropriate studies will be
undertaken in participants receiving combination antiretroviral therapy when
indicated.

- Patients with known active hepatitis B and/or active hepatitis C infection.

- Evidence of visible retinal pathology on screening ophthalmologic examination that
places the participant at an unacceptable risk for retinal vein occlusion (e.g.
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity, etc.).

- History of retinal degenerative disease.

- Presence of neurosensory retinal detachment, retinal vein occlusion (RVO), or
neovascular macular degeneration on screening ophthalmologic exam.