Difluoromethylornithine in Combination with Pembrolizumab For the Treatment of STK11-Mutant Advanced or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria

• Be willing and able to provide written informed consent/assent for the trial
• Be >= 18 years of age on day of signing informed consent
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
• Have archival tissue where available. Those patients enrolled on the phase 1 escalation trial where archival tissue is not available will undergo a fresh biopsy where clinically feasible after discussion with the sponsor
• In addition, patients enrolled on the phase II trial must be willing and able to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 3 months prior to initiation of treatment on day 1 and must be obtained after most recent treatment. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor)
• Tumor proportional score of PD-L1 >= 1%
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days of treatment initiation)
• Platelets >= 100,000 /mcL (within 10 days of treatment initiation)
• Hemoglobin >= 9 g/dL (within 10 days of treatment initiation)
• Serum creatinine =< 1.5 x upper limit of normal OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional upper limit of normal (ULN) (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (within 10 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN OR patients with Gilbert's syndrome with a total bilirubin =< 3.0 X ULN and direct bilirubin within normal limits (within 10 days of treatment initiation)
• Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)
• Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
• Left ventricular ejection fraction (LVEF) >= 45%
• Histologically confirmed NSCLC that is at advanced/metastatic stage and for which there is no standard therapy option likely to lead to cure
• Harbor an STK11 mutation via Clinical Laboratory Improvement Amendments (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 to EGFR, ALK, ROS1) are eligible if they were previously treated with targeted therapy
• Phase II: Be treatment naive in the stage IV setting, with the exception of patients whose tumors harbor an activating mutation (including but not limited to EGFR, ALK, ROS1) and were previously treated with targeted therapy. Subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease and developed recurrent (local or metastatic) disease >= 6 months of completing therapy are eligible for this arm * Note: Prior treatment with ICB in the adjuvant and neoadjuvant setting is allowed for patients that progressed > 6 months since last dose
• Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of barrier contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
• No clinically significant hearing loss that requires a hearing aid. Hearing will be evaluated by air conduction audiometry at baseline, every 12 months and at end of treatment if > 6 months from last assessment with bone conduction audiometry as needed. Air conduction audiometry will be performed at baseline and at 12 months/end of treatment. The testing will occur at the following frequencies: 250, 500, 1000, 2000, 4000, and 8000 Hz in both the left and the right ear using air conduction methodology. Evaluations will be performed by an audiologist, following the ASHA (American Speech-Language Hearing Association) guidelines for pure-tone threshold and/or site's standard clinical protocol. Threshold search audiometry will be determined the softest sound a subject could hear at each frequency 50 percent of the time. If a subject has a change from baseline of >= 15 decibels at 2 consecutive frequencies, bone conduction audiometry will be performed. Bone conduction audiometry measures pure-tone thresholds using a mechanical device that transmits sounds via vibration through the forehead or mastoid bone. This allows differentiation between conductive hearing loss and sensorineural hearing loss. Any subject with hearing loss on study will have a 6-month follow-up audiometry evaluation

Exclusion Criteria

• Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at doses >= 10 mg prednisone or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course (=< 28 days) of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Has a known history of tuberculosis (TB) disease (Mycobacterium tuberculosis)
• Hypersensitivity to pembrolizumab, DFMO or any of its excipients
• Patients enrolled on the phase II trial, who have had prior treatment with a PD1 or PDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway in the stage IV setting (i.e. not “immune therapy naive”) * Note: For those enrolled in the phase I dose escalation, prior use of a PD1 or PDL1, anti-CTLA4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway is allowed. For all patients in all phases, prior use of a vaccine for treatment of cancer is allowed
• Patients who have received thoracic radiation > 30Gy within six months of the first dose of pembrolizumab
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active 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
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to enrollment, have known treated and asymptomatic brain metastases and not using steroids in doses greater than 10 mg of prednisone daily (or equivalent). This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids in doses greater than 10 mg of prednisone daily [or equivalent] or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, that would substantially increase risk of incurring adverse events (AEs) from the study medications, that would 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
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist [registered trademark]) are live attenuated vaccines, and are not allowed
• Has a history of, or any evidence of active non-infectious pneumonitis that required or requires steroids
• Has evidence of interstitial lung disease
• Has a history of symptomatic (New York Heart Association [NYHA] class II-IV) heart failure
• Patients harboring STK11 variants listed in ClinVAR as benign or likely-benign will be excluded from this study * Note: The gnomAD browser will be used as a tool to help identify likely STK11 germline polymorphisms