Atezolizumab in Combination With a Multi-Kinase Inhibitor for the Treatment of Unresectable, Locally Advanced, or Metastatic Liver Cancer

Inclusion Criteria:

• Provide written informed consent =< 28 days prior to randomization

• Willing to return to enrolling institution for follow-up (during the ActiveMonitoring Phase of the study)

• NOTE: During the Active Monitoring Phase of a study (i.e., active treatment andclinical follow-up), participants must be willing to return to the consentinginstitution for follow-up

• Age >= 18 years

• Hepatocellular carcinoma (HCC) confirmed by histological/cytological diagnosis orclinically per the American Association for the Study of Liver Diseases (AASLD) orWASL 2018 criteria

• Locally advanced, metastatic and/or unresectable disease that is not amendable tocurative treatment

• Previously progressed on atezolizumab in combination with bevacizumab as first linesystemic 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/mLobtained ≤ =< 28 days prior to randomization, and anti-HBV treatment (per localstandard of care; e.g., entecavir) for a minimum of 14 days prior torandomization and willingness to continue treatment for the length of the study

• At least one measurable untreated malignant lesion per RECIST v1.1. Subjects whopreviously received local therapy (e.g., ablation, percutaneous ethanol injection,trans-arterial embolization/chemo-embolization) are eligible provided the targetlesion(s) have not been previously treated with local therapy or the targetlesion(s) within the field of local therapy have subsequently progressed inaccordance 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 thefirst 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 granulocytecolony-stimulating factor support (obtained =< 28 days prior to randomization)

• Lymphocyte count >= 0.5 x 10^9/L (500/uL) (obtained =< 28 days prior torandomization)

• Platelet count >= 75 x 10^9/L (75,000/uL) (obtained =< 28 days prior torandomization)

• 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 alkalinephosphatase (ALP) =< 5 x upper limit of normal (ULN) (obtained =< 28 days prior torandomization)

• 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 normalizedratio (INR) or partial thromboplastin time (aPTT) =< 1.5 × ULN (obtained =< 28 daysprior to randomization)

• Serum creatinine =< 2 x ULN or creatinine clearance >= 30 mL/min (calculated usingthe Cockcroft-Gault formula) (obtained =< 28 days prior to randomization)

• Negative pregnancy test done =< 14 days prior to randomization, for women ofchildbearing potential only

• NOTE: If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

• Resolution of any acute, clinically significant treatment-related toxicity fromprior therapy to grade =< 1 prior to randomization, with the exception of alopeciaand peripheral sensory neuropathy.

• Subjects of childbearing potential agree to use two forms of medically approvedcontraception while taking the study drug and for at least 5 months after the lastdose of atezolizumab or multi-kinase inhibitor. Subjects with partners ofchildbearing potential agree to use condoms, even after vasectomy, to avoidpotential drug exposure to partner during study drug and for 5 months following thelast dose of study drug

• Ability to take oral medications

Exclusion Criteria:

• Known diagnosis of fibrolamellar carcinoma, sarcomatoid carcinoma or mixedhepatocellular cholangiocarcinoma

• Prior multi-kinase inhibitor treatment for advanced disease (e.g., cabozantinib,lenvatinib, sorafenib, regorafenib)

• NOTE: Use of multi-kinase inhibitor(s) for adjuvant or as part of loco-regionaltherapies is allowed as long as the therapy was completed >= 6 months prior torandomization

• Any of the following prior therapies:

• Major surgery =< 4 weeks prior to randomization; Minor surgery =< 7 days priorto randomization (e.g., simple excision, tooth extraction, insertion of centrallines/Mediport). Subjects with clinically relevant complications from priorsurgery are not eligible

• Any anti-cancer agent =< 2 weeks prior to randomization

• Radiation therapy =< 4 weeks (1 week for palliative radiation for bonemetastases and/or for pain control) or radionuclide treatment (e.g., I-131 orY-90) =< 6 weeks prior to randomization

• Treatment with investigational therapy =< 28 days prior to randomization

• Known brain or leptomeningeal metastasis

• Known co-infection of HBV and HCV. Subjects with a history of HCV infection but whoare negative for HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) willbe considered non-infected with HCV

• Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barresyndrome, or multiple sclerosis with the following exceptions:

• Subjects with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study

• Subjects with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study

• Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., subjects with psoriatic arthritis areexcluded) are eligible for the study provided all of the following conditionsare met:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids within the previous 12 months

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan

• NOTE: History of radiation pneumonitis in the radiation field (fibrosis) ispermitted

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the subject at high riskfrom treatment complication

• Treatment with a live, attenuated vaccine =< 4 weeks prior to randomization, oranticipation of need for such a vaccine during atezolizumab treatment or =< 5 monthsafter the last dose of atezolizumab

• History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

• Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

• Subjects with untreated or incompletely treated esophageal/gastric varices withbleeding or high risk for bleeding. Subjects treated with adequate endoscopictherapy (according to local institutional standards) without any episodes ofrecurrent gastrointestinal bleeding requiring transfusion or hospitalization for > 28 days prior to randomization are eligible

• Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and interleukin 2 [IL-2]) =< 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to randomization

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies,including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

• Note: Prior treatment with atezolizumab is permitted

• Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF alpha agents) =< 2 weeks prior to randomization, or anticipation of needfor systemic immunosuppressive medication during study treatment, with the followingexceptions:

• Subjects who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study

• Subjects who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible

• For subjects who are to receive cabozantinib: Treatment with strong inducers and/orstrong inhibitors of CYP3A4 =< 14 days prior to randomization, including rifampin (and its analogues) or St. John's wort. Seehttps://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers for lists of known stronginhibitors and strong inducers of CYP3A4

• Active tuberculosis

• Other uncontrolled, significant intercurrent or recent illness including, but notlimited to, the following conditions:

• Cardiovascular disorders including:

• Symptomatic congestive heart failure, unstable angina, or serious cardiacarrythmias

• Uncontrolled hypertensions defined as sustained blood pressure (BP) > 150mmHg systolic BP, or > 100 mmHg diastolic BP despite optimalantihypertensive treatment

• Stroke (including transient ischemic attack), myocardial infarction, orother ischemic event =< 3 months prior to randomization.

• Unstable arrythmia

• Thromboembolic event =< 3 months prior to randomization. Subjects withthromboses of portal/hepatic vasculature attributed to underlying liverdisease and/or liver tumor are eligible.

• Active bacterial infection requiring systemic treatment. Subjects onprophylactic antibiotics are eligible.

• Known human immunodeficiency virus (HIV) infection or known acquiredimmunodeficiency syndrome (AIDS) related illness. Subjects with known HIV butwithout clinical evidence of an immunocompromised state and receivinganti-retroviral therapy are eligible

• Prior allogenic stem cell or solid organ transplantation

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiringrecurrent drainage procedures (once monthly or more frequently)

• Subjects with indwelling catheters (e.g., PleurX) are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L,calcium > 12 mg/dL or corrected serum calcium > ULN)

• Uncontrolled tumor-related pain

• Patients requiring pain medication must be on a stable regimen at the timeof randomization

• Symptomatic lesions (e.g., bone metastases or metastases causing nerveimpingement) amenable to palliative radiotherapy should be treated priorto randomization. Patients should be recovered from the effects ofradiation. There is no required minimum recovery period.

• Asymptomatic metastatic lesions that would likely cause functionaldeficits or intractable pain with further growth (e.g., epiduralmetastasis that is not currently associated with spinal cord compression)should be considered for loco-regional therapy if appropriate prior torandomization

• Other malignancy(ies) =< 5 years prior to randomization except adequately treatednon-melanotic skin cancer, carcinoma-in-situ of the cervix, localized prostatecancer, ductal carcinoma in situ or stage I uterine cancer

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatmentor within at least 5 months after the last dose of study medication

• Uncontrolled hepatic encephalopathy occurring =< 6 weeks prior to randomizationNOTE: Patients with =< grade 2 encephalopathy =< 6 weeks prior to randomization areeligible and supportive measures such as lactulose and antibiotics are allowed