A Phase II Randomized Study of Atezolizumab Plus Multi-Kinase Inhibitor Versus Multi-Kinase Inhibitor Alone in Subjects With Unresectable, Advanced Hepatocellular Carcinoma Who Previously Received Atezolizumab Plus Bevacizumab
This phase II trial tests whether atezolizumab in combination with a multi-kinase inhibitor (cabozantinib or lenvatinib) compared to multi-kinase inhibitor alone in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic), for which the patient has received treatment in the past (previously treated). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib and lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cabozantinib or lenvatinib may kill more tumor cells in patients with liver cancer.
• Provide written informed consent =\< 28 days prior to randomization
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
⁃ NOTE: During the Active Monitoring Phase of a study (i.e., active treatment and clinical follow-up), participants must be willing to return to the consenting institution for follow-up
• Age \>= 18 years
• Hepatocellular carcinoma (HCC) confirmed by histological/cytological diagnosis or clinically per the American Association for the Study of Liver Diseases (AASLD) or WASL 2018 criteria
• Locally advanced, metastatic and/or unresectable disease that is not amendable to curative treatment
• Previously progressed on atezolizumab in combination with bevacizumab as first line systemic therapy for advanced disease
⁃ NOTE: 2nd line patients only
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Child Pugh class A
• Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) serology tests.
⁃ For subjects with active HBV, HBV deoxyribonucleic acid (DNA) \< 500 IU/mL obtained ≤ =\< 28 days prior to randomization, and anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to randomization and willingness to continue treatment for the length of the study
• At least one measurable untreated malignant lesion per RECIST v1.1. Subjects who previously received local therapy (e.g., ablation, percutaneous ethanol injection, trans-arterial embolization/chemo-embolization) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1
• Consent to using archival tumor tissues, if available
⁃ NOTE: Non-availability of tumor tissue does not exclude the subject.
• Willingness to provide mandatory blood specimens for correlative research
• Willingness to provide mandatory tissue specimens for correlative research for the first 10 patients per arm (Mayo Clinic Rochester and Mayo Clinic Arizona ONLY)
• Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (1500/uL) without granulocyte colony-stimulating factor support (obtained =\< 28 days prior to randomization)
• Lymphocyte count \>= 0.5 x 10\^9/L (500/uL) (obtained =\< 28 days prior to randomization)
• Platelet count \>= 75 x 10\^9/L (75,000/uL) (obtained =\< 28 days prior to randomization)
• Hemoglobin \>= 90 g/L (9 g/dL) (obtained =\< 28 days prior to randomization)
⁃ Subjects may be transfused to meet this criterion
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =\< 5 x upper limit of normal (ULN) (obtained =\< 28 days prior to randomization)
• Total bilirubin =\< 3 x ULN (obtained =\< 28 days prior to randomization)
• Serum albumin \>= 30 g/L (3.0 g/dL) (obtained =\< 28 days prior to randomization)
• For subjects not receiving therapeutic anticoagulation: international normalized ratio (INR) or partial thromboplastin time (aPTT) =\< 1.5 × ULN (obtained =\< 28 days prior to randomization)
• Serum creatinine =\< 2 x ULN or creatinine clearance \>= 30 mL/min (calculated using the Cockcroft-Gault formula) (obtained =\< 28 days prior to randomization)
• Negative pregnancy test done =\< 14 days prior to randomization, for women of childbearing potential only
⁃ NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to grade =\< 1 prior to randomization, with the exception of alopecia and peripheral sensory neuropathy.
• Subjects of childbearing potential agree to use two forms of medically approved contraception while taking the study drug and for at least 5 months after the last dose of atezolizumab or multi-kinase inhibitor. Subjects with partners of childbearing potential agree to use condoms, even after vasectomy, to avoid potential drug exposure to partner during study drug and for 5 months following the last dose of study drug
• Ability to take oral medications