Study of Palbociclib in Combination With Binimetinib for Patients With Advanced KRAS Mutant Non-Small Cell Lung Cancer

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.

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.

What this study is about