Domvanalimab and Zimberelimab in Advanced Liver Cancers

Inclusion Criteria:

1. Patient must have a histologically confirmed diagnosis consistent with HCC or bileduct cancer (including intrahepatic cholangiocarcinoma, extrahepaticcholangiocarcinoma, and gall bladder cancers); known fibrolamellar HCC, or combinedHCC-cholangiocarcinoma will be excluded.

2. Locally advanced or metastatic disease

• 2a. Patients with locally advanced or metastatic disease must have diseasedeemed not amenable to surgical and/or locoregional therapies or patients whohave progressed following surgical and/or locoregional therapies.

• 2b. Measurable disease, as defined as lesions that can accurately be measuredin at east one dimension according to RECIST version 1.1 at least 1 cm withcontrast enhanced dynamic imaging (magnetic resonance imaging or computedtomography).

3. Refractory to or relapsed after prior anti-PD-1/L1 antibody therapy. May havereceived anti-PD-1/L1 monotherapy or combination therapy as any line of therapyincluding in the neoadjuvant or adjuvant setting. Patients who discontinued priorimmune checkpoint inhibitor treatment due to toxicity are not eligible.

4. Availability of recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue blockor slides in which the biopsy or resection was performed within 3 years. Baselinetissue can be obtained after consent but must be prior to initiation of zimberelimaband domvanalimab. It is strongly recommended that tissue is obtained from biopsiesconfirming progression of disease on prior therapy so that the patient has notreceived any intervening systemic anti-cancer treatment from the time that thebaseline tissue was obtained.

5. Prior locoregional is allowed provided the following are met: 1) at least 2 weekssince prior locoregional therapy including surgical resection, chemoembolization,radiotherapy, or ablation; 2) target lesion has increased in size ≥25% or the targetlesion was not treated with locoregional therapy. Patients treated with palliativeradiotherapy for symptoms will be eligible as long as the target lesion is not thetreated lesion and radiotherapy will be completed at least 2 weeks prior to studydrug administration.

6. Age ≥ 18 years

7. Child-Pugh Score A or B7-8 (only for Cohort A)

8. ECOG Performance score of 0-1

9. Adequate organ and marrow function (without chronic, ongoing growth factor supportor transfusion in the last 2 weeks) as defined below:

• 9a. Platelet count ≥ 50,000/mm^3

• 9b. Hgb ≥ 8.5 g/dl

• 9c. Absolute neutrophil ≥ 1,000 cells/mm^3

• 9d. Total bilirubin ≤ 3.0 mg/ml (This will not apply to subjects with Gilbert'ssyndrome who have persistent or recurrent hyperbilirubinemia that ispredominantly unconjugated in the absence of hemolysis, and such patients maybe enrolled based in consultation with the principal investigator).

• 9e. INR ≤ 2

• 9f. AST, ALT ≤5 times ULN

• 9g. Calculated creatinine clearance (CrCl) ≥ 40 mL/min. CrCl can be calculatedusing the Cockroft-Gault method.

• 9h. Albumin ≥ 2.0 g/dl

10. All men, as well as women of child-bearing potential, defined as not surgicallysterilized and between menarche and 1-year post menopause, must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence) 4weeks prior to study entry, for the duration of study participation, and for 120days after the last dose of zimberelimab or domvanalimab. See contraceptionguidelines in Appendix 1. Should a woman become pregnant or suspect she is pregnantwhile participating in this study, she should inform her treating physicianimmediately. A female of child-bearing potential is any woman (regardless of sexualorientation, marital status, having undergone a tubal ligation, or remainingcelibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,has had menses at any time in the preceding 12 consecutive months).

11. Women of child-bearing potential must have a negative serum pregnancy test within 72hours prior to receiving the first dose of study medication

12. Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,or HCV-HCC defined as follows:

1. HBV-HCC: Hepatitis B subjects will be allowed if they meet the followingcriteria: On antiviral therapy for HBV or HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBVtherapy with viral loads under 100 IU/ml should stay on the same therapythroughout study treatment. Subjects who are anti-HBc (+), negative forHBsAg, negative for anti-HBs, and have an HBV viral load under 100 IU/mLdo not require HBV anti-viral prophylaxis.

2. HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCVRNA or antibody. Patients who have failed HCV therapy as evidenced bydetectable HCV RNA will be eligible. Subjects with chronic infection byHCV who are treated (successfully or treatment failure) or untreated areallowed on study. In addition, subjects with successful HCV treatment areallowed as long as there are ≥4 weeks between completion of HCV therapyand start of study drug. Successful HCV treatment definition: SVR12.

3. Ability to understand and the willingness to sign a written informed consent.

4. Willing and able to comply with the requirements and restrictions in this protocol.

5. Patients who have received the vector, protein subunit, or nucleic acid COVID-19vaccines are eligible to enroll.

Exclusion Criteria:

1. Prior liver transplant.

2. Known human immunodeficiency virus (HIV) positive (testing not required).

3. Use of any live vaccines against infectious diseases within 28 days of first dose ofstudy drug administration.

4. History of trauma or major surgery within 28 days prior to the first dose of studydrug administration. (Tumor biopsy or placement of central venous access catheter (eg, port or similar) is not considered a major surgical procedure).

5. Underlying medical conditions that, in the investigator's opinion, will make theadministration of study drugs hazardous, including but not limited to:

• 5a. Interstitial lung disease, including history of interstitial lung diseaseor non infectious pneumonitis (lymphangitic spread of cancer is notdisqualifying),

• 5b. Active viral, bacterial, or fungal infections requiring parenteraltreatment within 14 days of the initiation of study drugs,

• 5c. Clinically significant cardiovascular disease,

• 5d. A condition that may obscure the interpretation of toxicity determinationor AEs,

• 5e. History of prior solid-organ transplantation.

6. Hypersensitivity to IV contrast; not suitable for pre-medication.

7. Pre-existing thyroid abnormality with thyroid function that cannot be maintained inthe normal range with medication.

8. Any active autoimmune disease or a documented history of autoimmune disease orsyndrome that required systemic treatment in the past 2 years (ie, with use ofdisease-modifying agents, corticosteroids, or immunosuppressive drugs), except forvitiligo or resolved childhood asthma/atopy.

• 8a. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered aform of systemic treatment.

• 8b. Participants with asthma who require intermittent use of bronchodilators,inhaled corticosteroids, or local corticosteroid injections will not beexcluded from this study. Participants on chronic systemic corticosteroids willbe excluded from the study.

9. Known history of active bacillus tuberculosis.

10. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14days of study administration. Inhaled or topical steroids and adrenal replacementdoses ≤10 mg/day prednisone equivalents are permitted in the absence of autoimmunedisease.

11. Known severe hypersensitivity reactions to monoclonal antibodies (≥Grade 3).

12. Prior malignancy active within the previous 2 years except for locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostatecancer.

13. Prisoners or subjects who are involuntarily incarcerated.

14. If a participant has symptomatic or clinically active brain metastases includingleptomeningeal disease, they must be excluded if:

• Has evidence of progression by neurologic symptoms

• Has metastatic brain lesions that require immediate intervention.

• Has carcinomatous meningitis, regardless of clinical stability

15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after contraception and until the termination of gestation, confirmed by apositive hCG laboratory test.

16. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

17. Has significant dementia or other mental condition that precludes the participant'sability to consent to the study.

18. Use of other investigational drugs (drugs not marketed for any indication) within 28days or 5 half-lives (whichever is longer) of first dose of study drugs.

19. Known hypersensitivity to recombinant proteins, or any excipient contained in thestudy drug formulations.