| Eligibility |
Inclusion Criteria:
1. Patient must have a histologically confirmed diagnosis consistent with HCC; known
fibrolamellar HCC, or combined HCC-cholangiocarcinoma will be excluded.
2. Locally advanced or metastatic disease
1. 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.
2. 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).
3. Availability of recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or
slides (biopsied tumor lesion should not be a RECIST target lesion): 1) the biopsy or
resection was performed within 2 years of AND 2) the patient has not received any
intervening systemic anti-cancer treatment from the time the tissue was obtained.
4. Prior therapy is allowed provided the following are met: at least 4 weeks since prior
locoregional therapy including surgical resection, chemoembolization, definitive
radiotherapy with intent of disease control, or ablation. Provided target lesion has
increased in size by 25% or more 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.
5. Age = 18 years
6. Child-Pugh Score A
7. ECOG Performance score of 0-1
8. Adequate organ and marrow function as defined below:
1. Platelet count = 50,000/mm3
2. Hgb = 8.5 g/dl
3. Absolute neutrophil = 1,500 cells/mm3
4. Total bilirubin = 2.0 mg/ml
5. INR = 1.7
6. AST, ALT =5 times ULN
7. Serum creatinine = 1.5 mg/dL or creatinine clearance = 50 mL/min
8. albumin = 2.5 g/dl
9. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) 4 weeks prior
to study entry, for the duration of study participation, and for 90 days following
completion of therapy. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
a. 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).
10. Women of childbearing potential must have a negative serum pregnancy test within 72
hours prior to receiving the first dose of study medication.
11. 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: Controlled (treated) hepatitis B subjects will be allowed if they meet
the following criteria: Antiviral therapy for HBV must be given for at least 12
weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study
drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay
on the same therapy throughout study treatment. Subjects who are anti-HBc (+),
negative for HBsAg, negative for anti-HBs, and have an HBV viral load under 100
IU/mL do not require HBV anti-viral prophylaxis.
2. HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV 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. In
addition, subjects with successful HCV treatment are allowed as long as there are
=4 weeks between completion of HCV therapy and start of study drug. Successful
HCV treatment definition: SVR12.
12. Ability to understand and the willingness to sign a written informed consent.
13. Patients who have received the vector, protein subunit, or nucleic acid COVID-19
vaccines are eligible to enroll.
Exclusion Criteria:
1. Prior liver transplant.
2. Prior systemic therapy directed at advanced or metastatic HCC.
3. Prior immunotherapy with IL-2, or anti-PD-1, anti-PD-L1, or anti-cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways.
4. Prior therapy with axitinib or any prior therapies with other VEGF pathway inhibitors.
5. Clinically significant, uncontrolled heart disease and/or recent events including any
of the following:
1. History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 12 months prior to screening).
2. History of documented congestive heart failure (New York Heart Association
functional classification III-IV).
3. History of cerebrovascular accident, transient ischemic attack, deep vein
thrombosis, or pulmonary embolism within 6 months of screening.
4. Patient has a left ventricular ejection fraction <40% as determined by MUGA scan
or ECHO (MUGA and ECHO are not required prior to enrollment).
6. Known human immunodeficiency virus (HIV) positive (testing not required).
7. History of cerebrovascular accident, transient ischemic attack, or thromboembolic
events (including both pulmonary embolism and deep venous thrombus but not including
tumor thrombus) within the last 6 months.
8. Hypersensitivity to IV contrast; not suitable for pre-medication.
9. Active or fungal infections requiring systemic treatment within 7 days prior to
screening.
10. Known history of, or any evidence of, interstitial lung disease or active
noninfectious pneumonitis.
11. Evidence of poorly controlled hypertension which is defined as systolic blood pressure
>159 mmHg or diastolic pressure >99 mmHg despite optimal medical management.
12. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication.
13. Active, known, or suspected autoimmune disease with the exception of subjects with
vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy. Subjects with
suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid
or with residual hypothyroidism requiring only hormone replacement. Subjects with
psoriasis requiring systemic therapy must be excluded from enrollment.
14. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
patient participation in the study or compromise compliance with the protocol (e.g.
chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral
infections, etc.).
15. Known history of active bacillus tuberculosis.
16. 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.
17. Patient who has received definitive radiotherapy with the sole intent of disease
control = 4 weeks prior to study entry. Palliative radiotherapy for symptomatic
control (such as to bone metastases) is acceptable (if completed at least 2 weeks
prior to study drug administration and no additional radiotherapy for the same lesion
is planned).
18. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects (tumor biopsy is not considered as major surgery).
19. Clinically apparent ascites on physical examination, ascites present on imaging
studies is allowed.
20. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3).
21. Active gastrointestinal bleeding within previous 2 months.
22. History of any condition requiring anti-platelet therapy (aspirin >300 mg/day,
clopidogrel >75 mg/day).
23. Diagnosis of any other malignancy within 5 years prior to screening visit, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on
surveillance with no plans for treatment intervention (eg, surgery, radiation, or
castration).
24. Prisoners or subjects who are involuntarily incarcerated.
25. History of leptomeningeal disease.
26. Symptomatic or clinically active brain metastases.
27. 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 hCG laboratory test.
28. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
(anti-HCV Ab(+) and detectable HCV RNA) at study entry.
29. Known prior or suspected hypersensitivity to study drugs or any component in their
formulations.
30. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers,
including their administration within 10 days prior to patient receiving the first
study treatment, eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin,
rifapentin, clevidipine, St John's wort.
31. Patients with 2+ proteinuria on urine dipstick analysis and confirmed to have =2 grams
of protein in a 24-hour urine collection.
32. Current use or anticipated need for treatment with drugs or foods that are known
strong CYP3A4/5 inhibitors, including their administration within 10 days prior to
patient receiving the first study treatment, (eg, grapefruit juice or
grapefruit/grapefruit-related citrus fruits, ketoconazole, miconazole, itraconazole,
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir,
ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir,
troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if
applicable), such as 2% ketoconazole cream, is allowed.
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