Ligufalimab and Cadonilimab for the Treatment of Advanced Hepatobiliary Cancers

Inclusion Criteria

• Histological confirmation of specific disease * Cohort A (hepatocellular carcinoma [HCC]): Patient must have a diagnosis confirmed by histology or clinically by the American Association for the Study of Liver Diseases (AASLD) criteria in patients with cirrhosis. Known fibrolamellar HCC will be excluded * Cohort B (BTC, biliary tract cancers): Patients must have histologically confirmed biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancers). Patients with combined HCC-cholangiocarcinoma may be enrolled in cohort B
• Locally advanced or metastatic disease * Patients with locally advanced or metastatic disease must have disease deemed not amenable to surgical and/or locoregional therapies or patients who have progressed following surgical and/or locoregional therapies * Measurable disease, as defined as lesions that can accurately be measured in at least one dimension according to RECIST version 1.1 at least 1 cm with contrast enhanced dynamic imaging (magnetic resonance imaging or computed tomography)
• Refractory to or relapsed after prior anti-PD-1/L1 antibody therapy. May have received anti-PD-1/L1 monotherapy or combination therapy as any line of therapy including in the neoadjuvant or adjuvant setting. Patients who discontinued prior immune checkpoint inhibitor treatment due to a high-grade toxicity (grade 4) are not eligible
• For patients in cohort A who do not have a clinical diagnosis of HCC according to the AASLD criteria, formalin-fixed, paraffin-embedded (FFPE) tumor diagnostic tissue samples must have been obtained within 4 years from the time of consent. Baseline tissue will be requested any time after consent. It is strongly recommended that tissue is obtained from standard-of-care biopsies confirming progression of disease on prior therapy so that the patient has not received any intervening systemic anti-cancer treatment from the time that the baseline tissue was obtained
• Prior locoregional therapy is allowed provided the following are met: 1) at least 2 weeks since prior locoregional therapy including surgical resection, chemoembolization, radiotherapy, or ablation; 2) target lesion has increased in size ≥ 25% since the cessation of locoregional therapy or the target lesion was not treated with locoregional therapy. Patients treated with palliative radiotherapy for symptoms will be eligible as long as the target lesion is not the treated lesion and radiotherapy will be completed at least 2 weeks prior to study drug administration
• Age ≥ 18 years
• Child-Pugh Score A or B7 (only applicable for cohort A)
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
• Platelet count ≥ 50,000/mm^3 (without chronic, ongoing growth factor support or transfusion in the last 2 weeks)
• Hemoglobin (Hgb) ≥ 9 g/dl (without chronic, ongoing growth factor support or transfusion in the last 2 weeks)
• Absolute neutrophil ≥ 1,000 cells/mm^3 (without chronic, ongoing growth factor support or transfusion in the last 2 weeks)
• Total bilirubin ≤ 3 mg/ml (This will not apply to subjects with Gilbert’s syndrome who have persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis, or patients with hyperbilirubinemia secondary to distal malignant obstruction where endoscopic, surgical, or percutaneous bypass/stenting has been attempted. Such patients may be enrolled based in consultation with the principal investigator)
• International normalized ratio (INR) ≤ 2
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 5 times upper limit of normal (ULN)
• Calculated creatinine clearance (CrCl) ≥ 40 mL/min. CrCl can be calculated using the Cockroft-Gault method
• Albumin ≥ 2.0 g/dl
• All men, as well as women of child-bearing potential, defined as not surgically sterilized and between menarche and 1-year post menopause, must agree to use highly effective contraception methods (hormonal or barrier method of birth control) 4 weeks prior to study entry, for the duration of study participation, and for 120 days after the last dose of ligufalimab or cadonilimab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: ** Highly effective methods that have low user dependency (failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly) *** Implantable progestogen-only hormone contraception associated with inhibition of ovulation *** Intrauterine device (IUD) *** Intrauterine hormone-releasing system (IUS) *** Bilateral tubal occlusion *** Azoospermic partner (vasectomized or due to a medical cause). Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview ** Highly effective methods that are user dependent (failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly) *** Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (male condoms must be used in addition to hormonal contraception) **** Oral **** Intravaginal **** Transdermal **** Injectable *** Progestogen-only hormone contraception associated with inhibition of ovulation (male condoms must be used in addition to hormonal contraception) **** Oral **** Injectable *** Sexual abstinence. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant ** Effective methods that are not considered highly effective (failure rate of ≥ 1% per year when used consistently and correctly) *** Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action *** Male or female condom with or without spermicide *** Cervical cap, diaphragm, or sponge with spermicide *** A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double- barrier methods) * Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should not be used together (due to risk of failure from friction) A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate 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)
• Women of child-bearing potential must have a negative serum pregnancy test at screening
• Subjects are eligible to enroll if they have non-viral-HCC, or if they have hepatitis B virus (HBV)-HCC, or hepatitis C virus (HCV)-HCC defined as follows: * HBV-HCC: Hepatitis B subjects will be allowed if they meet the following criteria: On antiviral therapy for HBV. Subjects who are hepatitis B virus core antibody (anti-HBc) (+), negative for hepatitis B virus surface antigen (HBsAg), negative for hepatitis B virus surface antibody (anti-HBs), and have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis * HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV ribonucleic acid (RNA) or antibody. Patients who have failed HCV therapy as evidenced by detectable HCV RNA will be eligible. Subjects with chronic infection by HCV who are treated (successfully or treatment failure) or untreated are allowed on study
• Ability to understand and the willingness to sign a written informed consent
• Willing and able to comply with the requirements and restrictions in this protocol
• Patients who have received the vector, protein subunit, or nucleic acid coronavirus disease 2019 (COVID-19) vaccines are eligible to enroll

Exclusion Criteria

• Prior liver transplant
• Known human immunodeficiency virus (HIV) positive (testing not required)
• Use of any live vaccines against infectious diseases within 28 days of first dose of study drug administration
• History of trauma or major surgery within 28 days prior to the first dose of study drug administration. (Tumor biopsy or placement of central venous access catheter [eg, port or similar] is not considered a major surgical procedure)
• Underlying medical conditions that, in the investigator’s opinion, will make the administration of study drugs hazardous, including but not limited to: * Interstitial lung disease, including history of interstitial lung disease or non infectious pneumonitis (lymphangitic spread of cancer is not disqualifying) * Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of the initiation of study drugs * Clinically significant cardiovascular disease * A condition that may obscure the interpretation of toxicity determination or adverse events (AEs) * History of prior solid-organ transplantation
• Hypersensitivity to IV contrast; not suitable for pre-medication
• Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy * Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment * Participants with asthma who require intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections will not be excluded from this study. Participants on chronic systemic corticosteroids will be excluded from the study
• Known history of active bacillus tuberculosis
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of study administration. Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg/day prednisone equivalents are permitted in the absence of autoimmune disease
• Patients who discontinued prior immune checkpoint inhibitor treatment due to grade ≥ 3 or grade 2 serious toxicity (i.e., pneumonitis, uveitis, neurological symptoms, cardiac toxicity, etc.) immune-related adverse events
• Known severe hypersensitivity reactions to monoclonal antibodies (≥ grade 3)
• Prior malignancy that required systemic treatment within the previous 2 years except for locally curable cancers 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 prostate cancer
• Prisoners or subjects who are involuntarily incarcerated
• If a participant has symptomatic or clinically active brain metastases including leptomeningeal 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
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after contraception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has significant dementia or other mental condition that precludes the participant’s ability to consent to the study
• Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of study drugs
• Known hypersensitivity to recombinant proteins, or any excipient contained in the study drug formulations