Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab

Exclusion Criteria

• •Patients who meet any of the following criteria will be excluded from study entry:
• •1. Extrahepatic metastases that are not candidates for treatment of curative aim (e.g. resection, radiation or radiofrequency ablation)
• •2. Presence of central nervous system (CNS) metastases
• •3. Concurrent or previous history of another primary cancer within 3 years prior to study treatment except for curatively treated cervical cancer in situ, non-melanomatous skin cancer, superficial bladder cancer (pTis or pT1) and curatively treated thyroid cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without distant metastasis could be allowed with the agreement of the principal investigator.
• •4. Chronic alcoholic hepatitis or cirrhosis
• •5. Chronic hepatitis B, defined as HBV DNA (\> 2,000 IU / mL) and ALT\> upper limit of normal range, must be treated with antiviral drugs before enrollment to reach appropriate viral suppression (HBV DNA \<2000 IU / mL), and the antiviral drugs must be maintained during the study treatment period and for 6 months after the last dose of study treatment.
• •6. Prior chemotherapy for metastatic disease
• •7. Uncontrolled medical illness congestive heart failure, myocardial infarction within 6 months including medically uncontrolled infection, uncontrolled hypertension, unstable angina, symptomatic congestive heart failure, myocardial infarction within 6 months
• •8. Prior adjuvant FOLFOX chemotherapy
• •9. Prior adjuvant chemotherapy, if administered within 6 months before study entry
• •10. Current or recent (within 10 days of start of study treatment) use of aspirin (\>325mg/day), clopidogrel (\>75mg/day), therapeutic or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (therapeutic anticoagulation on a stable dose for at least 2 weeks prior to the start of study treatment is allowed)
• •11. Known alcohol or drug abuse
• •12. Active infection requiring intravenous antibiotics at the start of study treatment
• •13. Inadequately controlled hypertension (defined as systolic blood pressure \>150mmHg and/or diastolic blood pressure \>100mmHg)
• •14. Prior history of hypertensive crisis or hypertensive encephalopathy
• •15. History or evidence upon physical or neurological examination of CNS disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy
• •16. Uncontrolled chronic peripheral neuropathy ≥ CTCAE grade 2
• •17. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of start of study treatment
• •18. Any previous venous thromboembolism \> CTCAE Grade 3 within 12 months prior to start of study treatment
• •19. History of haemoptysis ≥ Grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month of start of study treatment
• •20. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)
• •21. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to start of study treatment, or anticipation of need for major surgical procedure (other than hepatic metastasectomy) during the course of the study
• •22. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to start of study treatment
• •23. Serious, non-healing wound, active ulcer, or untreated bone fracture
• •24. Known hypersensitivity to any component of any of the study medication
• •25. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins
• •26. Known dihydropyrimidine dehydrogenase deficiency
• •27. Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the last dose of study treatment
• •28. Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to initiation of study treatment.
• •29. Known hypersensitivity or allergy to Chinese hamster ovary cell products
• •30. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
• •* Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
• •* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• •* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• •* Rash must cover 10% of body surface area
• •* Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• •* No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
• •31. Prior allogeneic bone marrow transplantation or prior solid organ transplantation
• •32. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted.)
• •33. Positive test for human immunodeficiency virus (HIV)
• •34. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening
• •* The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• •* Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• •35. Active tuberculosis
• •36. Administration of a live, attenuated vaccine within 4 weeks prior to start of study maintenance treatment or anticipation that such a live attenuated vaccine will be required during the study
• •37. Prior treatment with Cluster of differentiation(CD)137 agonists, anti-cytotoxic T-lymphocyte-associated antigen(CTLA)4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• •38. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study maintenance treatment
• •39. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-Tumour Necrosis Factor agents) within 2 weeks prior to start of study maintenance treatment, or requirement for systemic immunosuppressive medications during the trial.