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• Must have histologically or cytologically confirmed stage IV non-squamous non-small cell lung cancer |
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Must have not harbor an EGFR mutation in exon 19 or exon 21, or without an ALK or ROS1 rearrangement |
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Must have measurable disease by CT or MRI, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v 1.1 |
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Age > 18 years |
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ECOG performance status of 0 or 1, or 2 |
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Must have normal organ and marrow function as defined below. The use of G-CSF should follow standard recommendations and physician discretion. 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 |
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Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL Total |
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bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) < 3 times |
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institutional normal limits, or up to 5 times institutional normal limits if the patient |
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has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR > 40 Ml/min/1.73 m2 |
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for patients with creatinine levels above institutional normal as per Cockcroft-Gault |
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formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless |
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subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range |
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of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) <1.5 X ULN |
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unless subject is receiving anticoagulant therapy as long as PT or PTT is within |
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therapeutic range of intended use of anticoagulants Thyroid stimulating hormone (TSH) |
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Within normal limits a |
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a: If TSH is not within normal limits at baseline, the subject will still be eligible if |
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total T3 or free T4 are within normal limits |
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Full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral |
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anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the |
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patient must have an INR ≤3.0. For heparin and LMWH there should be no clinically |
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significant active bleeding (with no bleeding within 14 days prior to first dose of |
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protocol therapy) or pathological condition present that carries a high risk of |
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bleeding (for example, tumor involving major vessels or known varices) |
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Ability to understand and willingness to sign a written informed consent and HIPAA |
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consent document |
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A biopsy, either core, cell block from FNA or cell block from surgical resection, must |
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be available for the study. If the sample is not adequate, the patient must agree to |
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provide a fresh biopsy specimen before the start of treatment. Any available archival |
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tissue will also be collected. While a biopsy sample must be adequate and available |
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for the study, an inadequate tissue sample would not be explicitly exclusionary and |
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further discussion with the sponsor is allowed to assess the eligibility of the |
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patient for the trial if, for clinical or other reasons, a new biopsy sample cannot be |
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obtained |
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Urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick |
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or routine analysis is ≥2+, a 24 hour urine collection for protein must demonstrate |
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<1000 mg of protein in 24 hours to allow participation in the protocol) |
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Received prior therapies targeting PD-1, PD-L1, CTLA-4 or other immune checkpoints
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Received prior platinum-based chemotherapy for advanced disease
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Patients who have received prior systemic anti-vascular therapy (e.g
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bevacizumab and small molecule VEGFR inhibitors) for advanced disease (Cohort 2)
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Treatment with any approved systemic anti-cancer therapy or systemic
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immune-stimulatory agents (including but not limited to interferons, interleukin
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IL-, and tumor necrosis factor) within 28 days prior to initiation of study
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treatment
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Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis
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or abdominal tapping for drainage within 2 weeks prior to initiation of study
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treatment
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Active leptomeningeal disease or uncontrolled brain metastasis
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History of allergic reactions to any study drugs
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CrCl < 45 mL/min
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Patients with active viral hepatitis that requires treatment
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Active autoimmune diseases that requires treatment and may affect study treatment
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estimated by investigator
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Any condition that required systemic treatment with either corticosteroids or any
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other immunosuppressive medication that may affect study treatment estimated by
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investigator
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Severe chronic or active infections requiring systemic antibacterial, antifungal
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or antiviral therapy
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History of hemoptysis, i.e., coughing up at least one-half teaspoon of fresh
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blood, within 3 months prior to enrollment. (Cohort 2)
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Imaging shows tumor invasion of a large vessel (e.g., pulmonary artery or
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superior vena cava) that the investigator determines is at risk for bleeding
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(Cohort 2)
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Had minor surgical procedures, such as tube placement, within 48 hours prior to
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first bevacizumab treatment. (Cohort 2)
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Recently treated with a full dose oral or parenteral anticoagulant or
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thrombolytic agent. Prophylactic using anticoagulants is allowed. (Cohort 2)
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History or test results indicating an inherited bleeding tendency or coagulation
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disorder that may increase the risk of bleeding (cohort 2)
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uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic
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blood pressure >100 mmHg) (cohort 2)
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Clinically meaningful (e.g., active) cardiovascular disease that, in the judgment
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of the investigator, is intolerant to bevacizumab therapy (cohort 2)
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