Targeting ODC as an Immunotherapeutic Target in STK11 (LKB1) Pathway-Deficient NSCLC (DFMO)

Inclusion Criteria:

• Patients must be willing and able to provide written informed consent/assent for thetrial.

• Patients must be ≥ 18 years of age on day of signing informed consent.

• Patients must have measurable disease based on RECIST 1.1

• Patients must have archival tissue where available. Patients enrolled on the phase 1escalation trial where archival tissue is not available will undergo a fresh biopsywhere clinically feasible after discussion with the sponsor.

• Patients enrolled on the Phase II trial must be willing and able to provide tissuefrom a newly obtained core or excisional biopsy of a tumor lesion.

• Tumor proportional score of PD-L1 ≥1%

• Patients must have a performance status of 0 or 1 on the Eastern CooperativeOncology Group (ECOG) Performance Scale.

• Patients must demonstrate adequate organ function on all screening labs. Screeninglabs should be performed within 10 days of treatment initiation.

• Histologically confirmed NSCLC that is at advanced/metastatic stage and for whichthere is no standard therapy option likely to convey clinical benefit.Advanced/metastatic is defined as unresectable or metastatic disease. Patients musthave exhausted all approved available therapies.

• Patients must harbor an STK11 mutation via CLIA-certified assay.

• Phase I: Maybe treatment naïve or pretreated for advance or metastatic NSCLC.Patients whose tumors harbor an activating mutation (including but not limited toEGFR, ALK, ROS1) are eligible if they were previously treated with targeted therapy.

• Phase II: Patients must be treatment naïve in the stage IV setting, with theexception of patients whose tumors harbor an activating mutation (including but notlimited to EGFR, ALK, ROS1) and were previously treated with targeted therapy.

• Female patients of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication.

• Female patients of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile or abstain from heterosexual activity for thecourse of the study through 120 days after the last dose of study medication.

• Male patients should agree to use an adequate method of barrier contraceptionstarting with the first dose of study therapy through 120 days after the last doseof study therapy.

• Patients cannot have clinically significant hearing loss that requires a hearingaid.

Exclusion Criteria:

• Patients who are currently participating in and receiving study therapy or hasparticipated in a study of an investigational agent and received study therapy orused an investigational device within 4 weeks of the first dose of treatment.

• Patients that have a diagnosis of immunodeficiency or is receiving systemic steroidtherapy at doses ≥ 10 mg prednisone or any other form of systemic immunosuppressivetherapy within 7 days prior to the first dose of trial treatment.

• Patients that have a known history of TB Disease (Mycobacterium tuberculosis).

• Patients that have a hypersensitivity to pembrolizumab, DFMO or any of itsexcipients.

• Patients enrolled on the phase II trial, who have had prior treatment with a PD1 orPDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that specificallytargets immune checkpoint pathway in the stage IV setting (i.e. not "immune therapynaïve").

• Patients who have received thoracic radiation >30Gy within six months of the firstdose of pembrolizumab.

• Patients that had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks priorto study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) fromadverse events due to agents administered more than 4 weeks earlier.

• Patients that have received major surgery must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting therapy.

• Patients that have a known additional malignancy that is progressing or requiresactive treatment.

Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.

• Patients that have a known active central nervous system (CNS) metastasis and/orcarcinomatous meningitis. Subjects with previously treated brain metastases mayparticipate provided they have stable CNS disease for at least 4 weeks prior toenrollment, have known treated and asymptomatic brain metastases and not usingsteroids in doses greater than 10 mg of prednisone daily (or equivalent). Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability.

• Patients that have active autoimmune disease that has required systemic treatment inthe past 2 years.

• Patients that have an active infection requiring systemic therapy.

• Patients that have a history or current evidence of any condition, therapy, orlaboratory abnormality that might confound the results of the trial, that wouldsubstantially increase risk of incurring adverse events (AEs) from the studymedications, that would interfere with the subject's participation for the fullduration of the trial or is not in the best interest of the subject to participate,in the opinion of the treating investigator.

• Patients that have a known psychiatric or substance abuse disorder that wouldinterfere with cooperation with the requirements of the trial.

• Patients that have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2antibodies).

• Patients that have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Patients that have received a live vaccine within 30 days of planned start of studytherapy.

• Patients that have a history of, or any evidence of active non-infectiouspneumonitis that required or requires steriods.

• Patients that have evidence of interstitial lung disease (ILD).

• Patients that have a history of symptomatic (NYHA class II-IV) heart failure.

• Patients harboring STK11 variants listed in ClinVAR as benign or likely-benign willbe excluded from this study.