Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic NSCLC

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed, refractory orrecurrent, advanced non-small cell lung carcinoma regardless of histology.

2. Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension in accordance with RECIST criteria v. 1.1 as described in detail in section 11.0

3. Patients must have completed one line of prior therapy in both cohorts. Forparticipation in the Cohort A, they must have completed at least 4 cycles ofplatinum doublet therapy. For participation in Cohort B, they must have receivedPD-1, PD-L1 and/or CTLA-4 immunotherapy, alone or in combination with chemotherapyor in combination with other IO agents. Treatment on this protocol may begin as longas the patient has recovered from toxicities of prior therapy at the discretion ofthe treating physician. A washout period of at least 2 weeks is required prior tostarting on this trial.

4. Patients with recurrent disease who had received adjuvant or neoadjuvant therapy orchemoradiotherapy for locally advanced disease if their disease has progressed up to 6 months after completion of adjuvant or neoadjuvant platinum-based therapy, or iftheir disease has progressed more than 6 months after therapy and during or after asubsequent platinum-based chemotherapy regimen

5. Patients with molecular targets (EGFR, ALK, ROS1) who have progressed on targetedagents and are not eligible for other treatments or trials specific for thispopulation are allowed.

6. Age > 18 years.

7. ECOG performance status 0 or 1

8. Patients must have normal organ and marrow function as defined below. Patientsshould be able to maintain ANC levels without the need for G-CSF transfusion. Ifblood transfusion is performed for achieving hemoglobin levels, the levels shouldstay at ≥ 9.0 mg/ml for at least a week after transfusion. Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcLTotal bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) < 3 times institutional normal limits, or up to 5 times institutional normal limitsif the patient has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN,OR > 40 Ml/min/1.73 m2 for patients with creatinine levels above institutionalnormal as per Cockcroft-Gault formula International Normalized Ratio (INR) orProthrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapyas long as PT or PTT is within therapeutic range of intended use of anticoagulantsActivated Partial Thromboplastin Time (aPTT) <1.5 X ULN unless subject is receivinganticoagulant therapy as long as PT or PTT is within therapeutic range of intendeduse of anticoagulants

9. Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14days) of oral anticoagulant or low molecular weight heparin (LMWH). If receivingwarfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be noactive bleeding (that is, no bleeding within 14 days prior to first dose of protocoltherapy) or pathological condition present that carries a high risk of bleeding (forexample, tumor involving major vessels or known varices).

10. Ability to understand and willingness to sign a written informed consent and HIPAAconsent document

11. A core tumor biopsy obtained after progression on the last treatment must beavailable at study entry for the study. The biopsy sample must not be more than 90days old at the time of registration and the sample must be adequate for analyses.If the sample is not adequate patient must agree to provide a fresh biopsy specimenbefore the start of treatment. Any available archival tissue will also be collected.

12. The patient's urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; ifurine dipstick or routine analysis is ≥2+, a 24-hour urine collection for proteinmust demonstrate <1000 mg of protein in 24 hours to allow participation in thisprotocol).

13. Female subject of childbearing potential should have a negative serum pregnancywithin 72 hours prior to receiving the first dose of study medication.

14. Female subjects of childbearing potential and male subjects must be willing to usean effective method of contraception - Contraception, for the course of the studythrough 150 days after the last dose of study medication.

15. Male patients who have women of child bearing potential (WOCBP) partners must agreeto use effective method of contraception - Contraception, for the course of thestudy through 210 days after the last dose of study medication.

16. Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the subject.

Exclusion Criteria:

1. Patients who have not recovered from their most recent chemotherapy or radiotherapyprior to entering the study at the discretion of investigators. Patients may not becurrently receiving any other investigational agents or immunomodulatory agents (e.g. ipilimumab). Patients treated with prior PD-1 or PD-L1 directed therapies areineligible Cohort A.

2. Prior ramucirumab treatment

3. The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to firstdose of protocol therapy.

4. The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), orany other significant thromboembolism (venous port or catheter thrombosis orsuperficial venous thrombosis are not considered "significant") during the 3 monthsprior to first dose of protocol therapy.

5. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and ahistory of hepatic encephalopathy or clinically meaningful ascites resulting fromcirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosisrequiring diuretics or paracentesis.

6. The patient has experienced any arterial thromboembolic events, including but notlimited to myocardial infarction, transient ischemic attack, cerebrovascularaccident, or unstable angina, within 6 months prior to first dose of protocoltherapy.

7. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolicor > 100 mmHg diastolic for >4 weeks) despite standard medical management.

8. The patient with history of hemoptysis (defined as bright red blood or ≥ 1/2teaspoon) within 2 months prior to first dose of protocol therapy or withradiographic evidence of intra-tumor cavitation or has radiologically documentedevidence of major blood vessel invasion or encasement by cancer.

9. The patient has a serious or non-healing wound, ulcer, or bone fracture (as perphysician's discretion) within 28 days prior to first dose of protocol therapy.

10. The patient has a prior history of GI perforation/fistula (within 6 months of firstdose of protocol therapy) or risk factors for perforation.

11. The patient has undergone major surgery within 28 days prior to first dose ofprotocol therapy, or minor surgery/subcutaneous venous access device placementwithin 7 days prior to first dose of protocol therapy. The patient has elective orplanned major surgery to be performed during the course of the clinical trial.

12. The patient is receiving chronic antiplatelet therapy other than aspirin, includingnonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, andothers), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. Occasional use of NSAIDS is allowed (occasional use would constitute daily use for less than a week; treating physiciandiscretion is permitted to differentiate between occasional Vs chronic use).

13. Patients who have not recovered from adverse events due to agents administeredearlier except neuropathy and alopecia. Physician's discretion is allowed to decidewhich unresolved adverse events from previous therapy (for NSCLC) prohibit patientparticipation in this study.

14. Patients with active autoimmune disease that has required systemic treatment in thepast 1 year (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Hormone replacement therapy (eg. thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

15. Patients requiring more than 10mg prednisolone (or its equivalent) per day areexcluded.

16. Patients with untreated symptomatic brain metastases are excluded. Patients withtreated brain metastases will be allowed if brain imaging obtained within 28 days oftrial enrollment reveals stable disease. Patients with small (<5mm) asymptomaticbrain metastasis are allowed to enroll.

17. Patients with interstitial lung disease or active, noninfectious pneumonitis.Patients with active tuberculosis infection are excluded.

18. Patient who have received a live vaccine within 30 days prior to Cycle1 Day 1.

19. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia (significant), cirrhosis, or psychiatric illness/social situations thatwould limit compliance with study requirements.

20. Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS)

21. Known history of chronic hepatitis B virus infection or chronic hepatitis C virusindicating chronic infection that is not cured.

22. Subjects with previous malignancies (except non-melanoma skin cancers, and in situcancers such as the following: bladder, gastric, colon, cervical/dysplasia,melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated tobe required during the study period.

23. Pregnant or breast-feeding.

24. Patients with prior grades 3 and 4 immune related adverse effects as a result ofprior therapy with a checkpoint inhibitor are excluded