Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS Mutant Non-Small Cell Lung Cancer

1. Metastatic or incurable NSCLC
2. Presence of a non-synonymous mutation in KRAS
3. Patient must have received at least one prior systemic therapy for metastatic NSCLC or be intolerant/ineligible/refuse available therapies with known benefit
4. Ability and willingness to sign a written informed consent document
5. Age ≥18 years old
6. At least one measureable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
7. ECOG performance status 0-1
8. Adequate organ function
9. Women of childbearing potential must have a negative serum pregnancy test performed within 72hours of the first dose of study therapy. Subjects of reproductive potential must agree to use acceptable birth control methods (see Appendix B for childbearing potential).
10. Qtc \< 500 mSec on EKG
11. Must be able to swallow tablets
12. Must be willing to comply with protocol procedures (including completion of diaries and outcome measures

Exclusion Criteria:

1. Currently participating in or has participated in a study of an investigational agent or anticipated use of an investigational device within 4 weeks of the first dose of study treatment.
2. Untreated symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis.
3. Prior monoclonal antibody within 4 weeks prior to enrollment, or individuals who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-invasive bladder tumors, or in situ cervical cancer
5. Active infection requiring systemic therapy with IV antibiotics
6. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
7. Known psychiatric or substance abuse disorders as documented in the chart that, in the opinion of the investigator, would interfere with cooperation with the requirements of the trial.
8. Pregnant or breastfeeding women
9. Anticipated receipt of any live vaccine within 30 days prior to the first dose of trial treatment.
10. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

11. Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e.

    phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study treatment

12. Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted)
13. Patients with a previously documented retinal vein occlusion.

14. History or evidence of increased cardiovascular risk including any of the following:

    • Current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible.
    • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
    • Ejection fraction of ≤50% as measured by echocardiography or MUGA
15. Any other conditions judged by the investigator that would limit the evaluation of the subject