A Phase II Study of Nivolumab + Ipilimumab in Advanced HCC Patients Who Have Progressed on First Line Atezolizumab + Bevacizumab

Inclusion Criteria:

• Age >= 18 years.

• HCC diagnosis confirmed by histology/cytology or clinically by American Associationfor Study of Liver Diseases (AASLD) criteria in cirrhotic patients.

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1

• Locally advanced, metastatic, or unresectable disease.

• Child Pugh class A.

• Barcelona clinic liver cancer (BCLC) stage B (not amenable to liver directedtherapy) or stage C.

• Prior treatment with atezolizumab and bevacizumab combination with radiographicprogression that necessitates change in treatment per treating physician. Patientswith rapid progression on atezolizumab and bevacizumab (defined as patients whoprogressed radiographically in the first restaging scan that necessitates change intreatment) are excluded.

• Washout period >= 4 weeks prior to registration is required since last atezolizumaband bevacizumab dose.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. (Form isavailable on the Academic and Community Cancer Research United [ACCRU] website).

• Absolute neutrophil count (ANC) >= 1000/mm ^ 3 (obtained =< 28 days prior toregistration).

• Platelet count >= 60,000/mm^3 (obtained =< 28 days prior to registration).

• Hemoglobin >= 8.5 g/dL (obtained =< 28 days prior to registration).

• Total bilirubin =< 3 x upper limit of normal (ULN) (obtained =< 28 days prior toregistration).

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 5 x ULN (obtained =< 28 days prior to registration).

• International normalized ratio (INR) =< 2.3 or Prothrombin time (PT) =< 6 secondsabove control OR if patient is receiving anticoagulant therapy and INR is withintarget range of therapy creatinine =< 1.5x ULN (obtained =< 28 days prior toregistration).

• Negative pregnancy test done =< 7 days prior to registration, for women ofchildbearing potential only.

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

• Provide informed written consent =< 28 days prior to registration.

• 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),participants must be willing to return to the consenting institution forfollow-up.

• Willing to provide mandatory tissue specimens and blood specimens for correlativeresearch purposes.

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whosegenotoxic, mutagenic and teratogenic effects on the developing fetus and newborn areunknown

• Pregnant persons

• Nursing persons

• Persons of childbearing potential who are unwilling to employ adequatecontraception.

• Major surgery =< 4 weeks prior to registration.

• Liver directed therapy (transarterial chemoembolization [TACE], Y-90, liver directedradiation) =< 28 days prior to registration. Prior liver directed therapy > 28 daysprior to registration is allowed as long as patient has at least one measurableuntreated lesion by RECIST v1.1.

• Patients with rapid progression on atezolizumab and bevacizumab (who progressedradiographically in the first restaging scan that necessitates change in treatment)are excluded.

• Prior treatment =< 4 weeks prior to registration with anti-CTLA-4 antibody for HCC.

• Comorbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens.

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

• Note: Patients known to be HIV positive, but without clinical evidence of animmunocompromised state, are eligible for this trial.

• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection excluding hepatitis C virus (HCV)

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Unstable cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with studyrequirements.

• Active infection including tuberculosis (clinical evaluation that includesclinical history, physical examination and radiographic findings, andtuberculosis [TB] testing in line with local practice), hepatitis B (knownpositive hepatitis B virus [HBV] surface antigen [HBsAg] result). Patients witha past or resolved HBV infection (defined as the presence of hepatitis B coreantibody [anti-HBc] and absence of HBsAg) are eligible. Patients with chronicHBV infection as evidenced by detectable HBV surface antigen or HBVdeoxyribonucleic acid (DNA) are eligible if on antiviral therapy and have HBVDNA < 100 IU/mL. Patients with active or resolved hepatitis C (HCV) infectionas evidenced by detectable HCV ribonucleic acid (RNA) or antibody are eligible.

• Receiving any other investigational agent which would be considered as a treatmentfor the primary neoplasm =< 4 weeks prior to registration.

• Other active malignancy =< 2 years prior to registration. Exceptions: Non-melanoticskin cancer or carcinoma-in-situ of the cervix.

• History of myocardial infarction =< 6 months, or congestive heart failure requiringuse of ongoing maintenance therapy for life-threatening ventricular arrhythmias.

• History of allogenic organ transplantation.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

• History of leptomeningeal carcinomatosis.

• Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

• Current or prior use of immunosuppressive medication =< 14 days prior toregistration. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., computedtomography [CT] scan premedication).

• Receipt of live attenuated vaccine =< 30 days prior to registration; Note: Patients,if enrolled, should not receive live vaccine whilst on study treatment and up to 30days after the last dose of study treatment.

• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteriafor Adverse Events (CTCAE) v5.0 grade >= 2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria.

• History of grade 3 or 4 immunotherapy related toxicity NCI CTCAE v5.0 due to priorregimen attributed to atezolizumab.