PBF-1129 and Nivolumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria:

• Age >= 18 years

• Confirmed recurrent or metastatic non-small cell carcinoma of the lung of anyhistology without curative options

• Measurable disease based on RECIST 1.1

• Patients must have received standard of care chemotherapy and immunotherapy. Nolimits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies arerequired. Prior CTLA4 therapy is permitted. Patients may have received no more than 3 prior lines of therapy in the metastatic setting (excluding targeted therapies)

• Patients with known actionable mutations with Food and Drug Administration (FDA)-approved treatment options must have received all approved and standard ofcare treatment options (ie osimertinib for EGFR, alectinib for ALK, etc)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Absolute neutrophil count (ANC) >= 1,500 /mcL

• Platelets >= 100,000 / mcL

• Serum creatinine OR measured or calculated creatinine clearance (glomerularfiltration rate [GFR] can also be used in place of creatinine or creatinineclearance [CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subjectwith creatinine levels > 1.5 X institutional ULN

• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects withtotal bilirubin levels > 1.5 ULN

• AAspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X ULN OR =< 5 X ULN for subjects with liver metastases

• Albumin >= 2.5 mg/dL

• International normalized ratio (INR) or prothrombin time (PT) or activated partialthromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulanttherapy as long as PT or PTT is within therapeutic range of intended use ofanticoagulants =< 1.5 X ULN unless subject is receiving anticoagulant therapy aslong as PT or PTT is within therapeutic range of intended use of anticoagulants

• Anticipated life expectancy of >= 3 months

• Willing to comply with study procedures

• Must be able to swallow pills

• Female subjects of childbearing potential must be willing to use an adequate methodof contraception

• For female patients of childbearing potential, a negative serum pregnancy testwithin 7 days prior to first dose of protocol therapy is required

• Be willing and able to understand and sign the written informed consent document

• Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissueblock. A recently obtained archival FFPE tumor tissue block (if an FFPE tissue blockcannot be provided, 15 unstained slides (10 minimum) will be acceptable) from aprimary or metastatic tumor resection or biopsy can be provided if it was obtainedwithin 1 year of trial screening. Patients with archival tissue that does not meetthis criteria may still be eligible in the dose escalation cohort only upon approvalfrom PI.

• For patients in dose expansion cohort: Be willing to provide tissue from apre-treatment and on-treatment fin needle aspirate (FNA) or core biopsy of a tumorlesion. Subjects must consent to pre-treatment and on-treatment biopsy prior toinitiation of clinical trial, however subjects for whom newly-obtained samplescannot be provided (e.g. inaccessible or subject safety concern) may still continueon study

• Be willing to provide peripheral blood samples for correlative studies

Exclusion Criteria:

• Has active autoimmune disease, including myasthenic syndrome, which has requiredsystemic treatment in the past 12 months (i.e. with use of disease modifying agents,corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine,insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. Patients witheczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologicmanifestations only (e.g., patients with psoriatic arthritis are excluded) areeligible for the study provided that disease is well controlled at baseline andrequires only topical corticosteroids.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at adose > 10 mg prednisone or equivalent) or any other form of immunosuppressivetherapy within 7 days prior to the first dose of trial treatment

• Known active chronic infections - human immunodeficiency virus (HIV)/acquiredimmunodeficiency syndrome (AIDS), known active (ie with detectable polymerase chainreaction [PCR]) Hepatitis B or C

• Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepaticencephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinicallymeaningful ascites is defined as ascites from cirrhosis requiring diuretics orparacentesis

• Symptomatic central nervous system (CNS) metastases. Patients with treated brainmetastases are eligible if they are clinically stable with regard to neurologicfunction, on stable dose of steroids after cranial irradiation with maximum of 10 mgprednisone equivalent. Treatment (whole brain radiation therapy, focal radiationtherapy, and stereotactic radiosurgery) must be completed at least 2 weeks prior tostudy entry, or after surgical resection performed at least 28 days prior totreatment initiation. Patients with asymptomatic lesions will be eligible ifconsidered appropriate by the treating physician.

• Pregnancy or breastfeeding

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator

• Any of the following cardiac criteria:

• Mean resting corrected QT interval (corrected QT [QTc] using Fredericia'sformula [QTcF]) > 470 msec (Fridericia's Criteria for Corrected QT interval [QTc] Calculation: Fridericia's formula QTcF = (QT/RR0.33). RR is the time fromthe interval of 1 QRS complex to the next measured in seconds and is commonlycalculated as (60/heart rate [HR])

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting electrocardiogram (ECG) (e.g., complete left bundle branch block, thirddegree heart block, second degree heart block

• Any patient who experience unacceptable toxicity on prior checkpoint inhibitortherapy:

• >= grade 3 adverse event (AE) related to checkpoint inhibitor with theexception of grade 3 pneumonitis that has resolved to grade 1 at time of studyentry.

• Ongoing >= grade 2 immune-related AE associated with checkpoint inhibitor withthe exception of endocrine toxicities as detailed below

• CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor

• NOTE: Patients with a prior endocrine AE are permitted to enroll if they arestably maintained on appropriate replacement therapy and are asymptomatic