Palbociclib with or without Binimetinib or Binimetinib Alone in Treating Patients with Advanced KRAS Mutant Non-small Cell Lung Cancer

Inclusion Criteria

• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Participants must have histologically confirmed advanced NSCLC (with a confirmed KRAS mutation via any Clinical Laboratory Improvement Act [CLIA]-certified method) for which curable treatment modalities are not an option
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Part I dose escalation: Participants are required to have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 4 weeks of study entry
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: MTD expansion: 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 computed tomography (CT) scan
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Participants are permitted to have any number of prior therapies prior to enrollment
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Absolute neutrophil count >= 1,500 mm^3
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Hemoglobin >= 9 g/dL
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Platelets >= 100,000/mcL
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Total bilirubin =< 2 X institutional upper limit of normal (ULN)
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: AST (SGOT)/ALT (SGPT) =< 5.0 X ULN if hepatic metastases are present
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Creatinine =< 1.5 X the institutional ULN OR
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Calculated creatinine clearance (determined as per Cockcroft-Gault) >= 50 mL/min
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Ability to understand and the willingness to sign a written informed consent document
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: The availability of archival tissue to evaluate retrospectively the participant’s retinoblastoma (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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Patients must have recovered to =< grade 1 in terms of toxicity from prior treatments (excluding neuropathy which can be =< grade 2, and alopecia)
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Patients must be able to take oral medications
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Left ventricular ejection fraction (LVEF) >= 50% as determined by echocardiogram or multigated acquisition scan (MUGA)
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Corrected QT (QTc) =< 480 msec
• EXPANDED ACCESS COHORT: Participants must be currently enrolled to DFCI protocol number 13-506 or discontinued from protocol 13-506 solely because the study agents were no longer available via protocol 13-506
• EXPANDED ACCESS COHORT: Participants must be experiencing clinical benefit from the 13-506 study drug combination as judged by the treating investigator
• EXPANDED ACCESS COHORT: ECOG performance status =< 2
• EXPANDED ACCESS COHORT: Absolute neutrophil count >= 1,000/mcL
• EXPANDED ACCESS COHORT: Platelets >= 50,000/mcL
• EXPANDED ACCESS COHORT: Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• EXPANDED ACCESS COHORT: AST(SGOT)/ALT(SGPT) =< 2.5 x institutional ULN -OR- AST(SGOT)/ALT(SGPT) =< 5 x institutional ULN if liver metastases are present
• EXPANDED ACCESS COHORT: Serum creatinine =< 1.5 x institutional ULN OR
• EXPANDED ACCESS COHORT: Creatinine clearance >= 50 mL/min (determined by the Cockcroft-Gault method) for participants with creatinine levels above 1.5 x institutional ULN
• EXPANDED ACCESS COHORT: 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
• EXPANDED ACCESS COHORT: Ability to understand and the willingness to sign a written informed consent document
• EXPANDED ACCESS COHORT: Participants must have adequate cardiac function, defined as: * Left ventricular ejection fraction (LVEF) >= 50% as determined by echocardiogram (ECHO) or MUGA * Corrected QT using Fridericia's formula (QTcF) =< 480 msec on screening electrocardiogram (ECG)

Exclusion Criteria

• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Participants receiving any other study agents concurrently with the study drugs
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Participants with known untreated brain metastases are excluded; patients with a history of brain metastases are permitted to enroll if they have been treated, are no longer taking corticosteroids, and have been stable for a minimum of one month on imaging; exceptions for participants with asymptomatic sub-centimeter metastases that, in the opinion of the treating investigator, do not require intervention may be possible following discussion and agreement with the overall principal investigator
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Part I dose escalation: Concurrent use of proton-pump inhibitors (PPIs) is prohibited
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or Torsades de Pointes
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: History of Gilbert’s syndrome
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: History of neuromuscular disorders that are associated with elevated CK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Patients planning to embark on a new strenuous exercise regimen after the first dose of study treatment
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Pregnant women are excluded from this study; breastfeeding must be discontinued if the mother is treated
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Known human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Patients with known active hepatitis B and/or active hepatitis C infection
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: 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.)
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: History of retinal degenerative disease
• ENROLLMENT TO THE DOSE ESCALATION AND EXPANSION: Presence of neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration on screening ophthalmologic exam
• EXPANDED ACCESS COHORT: History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib or binimetinib
• EXPANDED ACCESS COHORT: History of QT syndrome, Brugada syndrome, known history of clinically significant QTc prolongation, or Torsades de Pointes
• EXPANDED ACCESS COHORT: History of neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• EXPANDED ACCESS COHORT: Pregnant women are excluded from this study; breastfeeding must be discontinued if the mother is treated
• EXPANDED ACCESS COHORT: Uncontrolled intercurrent illness including, but not limited to: * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Hypertension (defined as systolic blood pressure > 160 mmHg during screening examination despite maximal medical management) * Myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to screening * Psychiatric illness/social situations that would limit compliance with study requirements
• EXPANDED ACCESS COHORT: Presence of neurosensory retinal detachment or retinal vein occlusion (RVO) on screening ophthalmologic exam