Nivolumab and Ramucirumab for the Treatment of Recurrent, Advanced, or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria

• Patients must have histologically or cytologically confirmed, refractory or recurrent, advanced non-small cell lung carcinoma regardless of histology
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v.) 1.1
• Patients must have completed one line of prior therapy and must have received PD-1, PD-L1 and/or CTLA-4 immunotherapy, alone or in combination with chemotherapy or in combination with other IO agents. Treatment on this protocol may begin as long as the patient has recovered from toxicities of prior therapy at the discretion of the treating physician. A washout period of at least 2 weeks is required prior to starting on this trial
• Patients who have received immunotherapy (anti-PD-1/L1 or anti-CTLA-4), either alone or in combination with each other or with chemotherapy, for non-small cell lung cancer for any indication/stage (e.g. including, but not limited to adjuvant treatment for resected disease, part of multimodality therapy for locally advanced disease or for metastatic disease)
• Patients with molecular targets (EGFR, ALK, ROS1) who have progressed on targeted agents and are not eligible for other treatments or trials specific for this population are allowed
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Patients must have normal organ and marrow function as defined below. Patients should be able to maintain absolute neutrophil count (ANC) levels without the need for granulocyte colony-stimulating factor (G-CSF) transfusion. If blood transfusion is performed for achieving hemoglobin levels, the levels should stay 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/mcL
• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) < 3 times institutional normal limits, or up to 5 times institutional normal limits if the patient has liver metastases
• Creatinine OR creatinine clearance =< 1.5 X ULN, OR > 40 Ml/min/1.73 m^2 for patients with creatinine levels above institutional normal as per Cockcroft-Gault formula
• 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
• 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
• Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR =< 3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices)
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
• A core tumor biopsy at progression is highly desired. Prior to study treatment, investigators should make every attempt at obtaining one if patients agree. If one biopsy attempt is unsuccessful a repeat biopsy is not required. If an investigator determines that attempting a biopsy is not in the best interest of the patient the biopsy should not be pursued. Archival tumor biopsies should be collected
• The patient’s urinary protein must be =< 1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is >= 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol)
• Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication
• Female subjects of childbearing potential and male subjects must be willing to use an effective method of contraception as outlined for the course of the study through 150 days after the last dose of study medication
• Male patients who have WOCBP partners must agree to use effective method of contraception as outlined for the course of the study through 210 days after the last dose of study medication
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• Patients who have not recovered from their most recent chemotherapy or radiotherapy prior to entering the study at the discretion of investigators. Patients must not be currently receiving any other investigational agents or immunomodulatory agents (e.g. ipilimumab)
• Prior ramucirumab treatment
• The patient has experienced any grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to first dose of protocol therapy
• The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to first dose of protocol therapy
• Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy
• The patient has uncontrolled or poorly-controlled hypertension (> 140 mmHg systolic or > 90 mmHg diastolic for > 4 weeks pre-dose ramucirumab) despite standard medical management
• The patient with history of hemoptysis (defined as bright red blood or >= 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intra-tumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer
• The patient has a serious or non-healing wound, ulcer, or bone fracture (as per physician’s discretion) within 28 days prior to first dose of protocol therapy
• The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation
• The patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial
• The patient is receiving chronic antiplatelet therapy other than aspirin, including nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 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 physician discretion is permitted to differentiate between occasional versus [vs] chronic use)
• Patients who have not recovered from adverse events due to agents administered earlier except neuropathy and alopecia. Physician’s discretion is allowed to decide which unresolved adverse events from previous therapy (for non-small cell lung carcinoma [NSCLC]) prohibit patient participation in this study
• Patients with active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Hormone replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients requiring more than 10 mg prednisolone (or its equivalent) per day are excluded
• Patients with untreated symptomatic brain metastases are excluded. Patients with treated brain metastases will be allowed if brain imaging obtained within 28 days of trial enrollment reveals stable disease. Patients with small (< 5 mm) asymptomatic brain metastasis are allowed to enroll
• Patients with interstitial lung disease or active, noninfectious pneumonitis. Patients with active tuberculosis infection are excluded
• Patient who have received a live vaccine within 30 days prior to cycle 1 day 1
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (significant), cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Known history of chronic hepatitis B virus infection or chronic hepatitis C virus indicating chronic infection that is not cured
• Subjects with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. * Subjects may not be excluded if they have the following exceptions: non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) * Subjects with a low grade, controlled and confined carcinoma that is not expected to interfere with protocol assessments of the treatment or toxicity, may be considered. In such situations, the treating physician must provide the rationale to the Sponsor-Investigator and receive written approval before proceeding
• Pregnant or breast-feeding
• Patients with prior grades 3 and 4 immune related adverse effects as a result of prior therapy with a checkpoint inhibitor are excluded