A Study Evaluating Atezolizumab and Bevacizumab Plus ADI-PEG 20 in Patients With Locally Advanced / Metastatic Hepatocellular Carcinoma

Exclusion Criteria

• •Any of the following criteria will disqualify the patient from participation:
• •1. Any other malignancy from which the patient has been disease-free for less than 2 years (exceptions: non-melanoma skin cancer or in situ carcinoma of any site are allowed)
• •2. Fibrolamellar HCC, sarcomatoid HCC, or hepatocellular cholangiocarcinoma
• •3. Prior systemic therapy, anti-PD-1/PD-L1 or VEGF inhibitor or ADI-PEG 20 therapy.
• •Note: Prior surgery, radiation therapy, or local-regional therapy (ablation or arterial directed therapies) are allowed.
• •4. Receipt of organ allograft(s)
• •5. Major surgical procedure, open biopsy, or significant traumatic injury with poorly healed wound within 6 weeks prior to first dose of study drug; or anticipates needing for a major surgical procedure during the course of the study (other than defined by protocol such as the pre-treatment fine needle aspirations or core biopsies) within 7 days prior to first dose of study drug.
• •6. History of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) or a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\]).
• •7. History of testing positive for human immunodeficiency virus or has acquired immunodeficiency syndrome (AIDS).
• •8. Underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or will obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
• •9. Has a known risk factor for bowel perforation including a history of acute diverticulitis, abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or gastrointestinal obstruction.
• •10. History of primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, or (within the past year) a history of stroke.
• •11. History of serious systemic disease, including myocardial infarction or unstable angina within the last 12 months; a history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (systolic ≥ 150 mmHg and/or diastolic ≥ 100 mmHg at the time of enrollment); New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible); significant vascular disease or symptomatic peripheral vascular disease.
• •12. History of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.
• •13. History of seizure disorder not related to underlying cancer.
• •14. Known allergy to pegylated compounds.
• •15. Known allergy to E. coli drug products (such as granulocyte-macrophage colony stimulating factor).
• •16. Has had influenza-, hepatitis-, or other vaccines within a month prior to initiation of study drugs.
• •17. Has had a clinical history of coagulopathy, bleeding diathesis or thrombosis within the past year.
• •18. Significant pulmonary disease including tuberculosis, pneumonia, pneumonitis, etc.
• •19. Requires recurrent drainage procedures including pleural effusion, ascites, etc.
• •20. Surgical procedure within 6 weeks of initiation of study treatment.
• •21. History of severe allergic/anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• •22. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation.
• •23. Known hypersensitivity to bevacizumab.
• •24. Receipt of investigational agents within 28 days prior to initiation of study treatment.
• •25. History of severe infection within 4 weeks of initiation of treatment.
• •26. Receipt of stem cell transplantation, liver transplantation, or solid organ transplantation
• •27. Serious, non-healing wound, ulcer, or bone fracture.
• •28. Patient is pregnant (positive pregnancy test) or lactating.
• •29. Prior orthotropic liver transplantation.
• •30. Prohibited therapies and/or medications:
• •* Prior anticancer therapy with ADI-PEG 20 or anti-VEGF or anti-PD-1/PD-L1 for HCC. Must not be receiving any concomitant systemic therapy for HCC
• •* Complementary medications (e.g., herbal supplements or traditional Chinese medicines) intended to treat the disease under study unless patients agree to stop the complementary medicines at least 14 days before the first study dose. Such medications are permitted if they are used as supportive care.
• •* Live / attenuated vaccine (e.g., varicella; zoster; yellow fever; rotavirus; oral polio; or and measles, mumps, rubella) within a month prior to initiation of study drug or during treatment.
• •* Any other experimental drug while on this study.
• •* Ongoing anticoagulation therapy (although aspirin is permitted).
• •* total parenteral nutrition.
• •* high dose steroid (e.g., \> 10 mg prednisone daily or equivalent) or other more potent immune suppression medications (e.g., infliximab).
• •31. Inability to comply with the appointments required in this protocol.