| Eligibility |
Inclusion Criteria:
1. Ability to understand the purpose of the study, provide signed and dated informed
consent, and able to comply with all procedures
2. Male or female subjects aged = 18 years
3. Histologically or cytologically proven advanced hepatocellular carcinoma not eligible
for surgical and/or locoregional therapies; or progressive disease after surgical and
/or locoregional therapies.
4. Patients who were intolerant to sorafenib or for whom sorafenib failed.
5. At least one RECIST 1.1 measurable untreated lesion. All subjects must have at least
one previously untreated, unidimensionally measurable lesion by contrast-enhanced
spiral computed tomography (CT) = 10 mm or contrast enhanced dynamic magnetic
resonance imaging (MRI) scan = 10 mm (malignant lymph nodes must be = 15 mm on short
axis)
6. ECOG performance status of 0 to 1 at trial entry
7. Child-Pugh Class A
8. Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,
or HCV-HCC defined as follows:
i) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody,
detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface
antigen) or Chronic HBV infection (as evidenced by detectable HBV surface antigen or
HBV DNA). Subjects with chronic HBV infection must have HBV DNA < 100 IU/mL and must
be on antiviral therapy.
ii) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA or
antibody
9. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test. Highly effective contraception for both male and female subjects throughout the
study and for at least 30 days after last avelumab treatment administration if the
risk of conception exists.
10. Males who are sexually active with WOCBP must agree to follow instructions for method
of contraception as indicated in the informed consent form, for the duration of
treatment with study drug plus 5 half-lives of the study drug plus 90 days.
Exclusion Criteria:
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
2. Prior liver transplant
3. Active, known, or suspected autoimmune disease
4. Pregnancy or lactation period
5. Participation in another clinical trial within the past 30 days
6. Inadequate hepatic function defined by a total bilirubin level > 3.0 mg/dl, an AST
level > 5 × the upper limit of normal range (ULN), and an ALT level > 5 × ULN.
7. Inadequate renal function defined by an estimated creatinine clearance < 50 mL/min
according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24
hour urine collection
8. Inadequate hematologic function defined by WBC < 2000/µL, Platelets < 60,000/µL,
Hemoglobin < 8.5 g/dL.
9. Active brain metastases or leptomeningeal metastases, requiring immunosuppressive
doses of corticosteroids (> 10 mg/day prednisone equivalents).
10. IMMUNOSUPRESSANTS: "Current use of immunosuppressive medication, EXCEPT for the
following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection); b. Systemic corticosteroids at physiologic doses = 10
mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication)."
11. AUTOIMMUNE DISEASE: "Active autoimmune disease that might deteriorate when receiving
an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or
hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are
eligible."
12. ORGAN TRANSPLANTATION: "Prior organ transplantation including allogenic stem-cell
transplantation."
13. INFECTIONS: "Active infection requiring systemic therapy. "
14. HIV/AIDS: "Known history of testing positive for HIV or known acquired
immunodeficiency syndrome."
15. VACCINATION: "Vaccination within 4 weeks of the first dose of avelumab and while on
trials is prohibited except for administration of inactivated vaccines "
16. HYPERSENSITIIVTY TO STUDY DRUG: "Known prior severe hypersensitivity to
investigational product or any component in its formulations, including known severe
hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade = 3)"
17. CARDIOVASCULAR DISEASE: "Clinically significant (i.e., active) cardiovascular disease:
cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial
infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure
(= New York Heart Association Classification Class II), or serious cardiac arrhythmia
requiring medication."
18. OTHER PERSISTING TOXICITIES: "Persisting toxicity related to prior therapy (NCI CTCAE
v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade = 2, or other Grade =
2 not constituting a safety risk based on investigator's judgment are acceptable."
19. Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
conditions including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.
20. Any history of clinically meaningful variceal bleeding within the last three months
21, Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
antibodies (or other agents specifically targeting immune checkpoint pathway)
22. Prior malignancy active within the previous 3 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 prostate, cervix, or breast.
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