| Eligibility |
Inclusion Criteria:
1. Age = 18 years.
2. Able to understand and provide a signed informed consent that fulfills the relevant
IRB or Independent Ethics Committee (IEC) guidelines.
3. Histologically-confirmed advanced, unresectable and untransplantable HCC.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
5. Have at least 1 measurable lesion of = 1.0 cm.
6. Must have Child-Pugh class A only.
7. Must have a recent formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimen
following the conclusion of the most recent anticancer treatment and be willing to
release the specimen for prospective and exploratory tumor molecular profiling. If an
historic specimen is not available, the subject must be willing to undergo a biopsy
during the screening period, if considered safe by the Investigator. If safety
concerns preclude collection of a biopsy during the screening period, a tumor biopsy
specimen collected prior to the conclusion of the most recent anticancer treatment may
be used.
8. Must be willing to provide blood samples prior to the start of treatment on this study
for prospective tumor molecular profiling and exploratory analyses.
9. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of
treatment for exploratory analyses, if considered safe by the Investigator.
10. Ability to attend required study visits and return for adequate follow-up, as required
by this protocol.
11. Agreement to practice effective contraception for female subjects of child-bearing
potential and non-sterile males. Female subjects of child-bearing potential must agree
to use effective contraception for up to 1 year after completion of therapy, and
non-sterile male subjects must agree to use a condom for up to 4 months after
treatment. Effective contraception includes surgical sterilization (eg, vasectomy,
tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with
spermicide, intrauterine devices (IUDs), and abstinence.
12. Any prior locoregional therapy allowed.
Phase 1b only
13. Must have progressed or experienced unacceptable toxicity on sorafenib prior to
enrollment in the study.
Phase 2 single-arm component only
14. Must have progressed on or after sorafenib monotherapy in the randomized phase 2
portion of the study OR progressed or experienced unacceptable toxicity on sorafenib
prior to enrollment on the study.
Exclusion Criteria:
1. Serious uncontrolled concomitant disease that would contraindicate the use of the
investigational drug used in this study or that would put the subject at high risk for
treatment-related complications.
2. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's
disease, or autoimmune disease associated with lymphoma).
3. History of organ transplant requiring immunosuppression.
4. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis).
5. Inadequate organ function, evidenced by the following laboratory results:
1. Absolute neutrophil count < 1,000 cells/mm^3
2. Medically uncorrectable grade 3 anemia (hemoglobin < 8 g/dL).
3. Platelet count < 75,000 cells/mm^3.
4. Total bilirubin greater than the upper limit of normal (ULN; unless the subject
has documented Gilbert's syndrome).
5. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT])
= 2.5 × ULN (= 5 × ULN in subjects with liver metastases).
6. Alkaline phosphatase levels > 2.5 × ULN (> 5 × ULN in subjects with liver
metastases, or >10 × ULN in subjects with bone metastases).
7. Serum creatinine > 2.0 mg/dL or 177 µmol/L.
8. International normalized ratio (INR) = 2.0
9. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3.
6. Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or
clinically significant (ie, active) cardiovascular disease, cerebrovascular
accident/stroke, or myocardial infarction within 6 months prior to first study
medication; unstable angina; congestive heart failure of New York Heart Association
grade 2 or higher; or serious cardiac arrhythmia requiring medication.
7. Episode of portal hypertension-related GI bleeding within prior 6 months.
8. Serious myocardial dysfunction defined by echocardiogram (ECHO) as absolute left
ventricular ejection fraction (LVEF) 10% below the institution's lower limit of normal
(LLN).
9. Dyspnea at rest due to complications of advanced malignancy or other disease requiring
continuous oxygen therapy.
10. Positive results of screening test for human immunodeficiency virus (HIV).
11. Participants with dual active hepatitis B virus (HBV) infection (hepatitis B surface
antigen [HBsAg] positive [+] and /or detectable HBVDNA) and hepatitis C virus (HCV)
infection (anti-HCV antibody [Ab] [+] and detectable HCV ribonucleic acid [RNA]) at
study entry. Subjects with chronic infection by HCV who are treated with
anti-hepatitis B therapy (successfully or treatment failure) or untreated are allowed
on study. Controlled (treated) hepatitis B subjects will be allowed if they meet the
following criteria:
1. 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.
2. Subjects who are positive for anti-hepatitis B core Abs (HBc[+]), negative for
HBsAg, negative for anti-hepatitis B surface Ab (HBs[-]), and have a HBV viral
load under 100 IU/mL do not require HBV anti-viral prophylaxis.
3. Subjects with successful HCV treatment are allowed as long as there are at least
4 weeks between achieving sustained viral response (SVR) and start of study drug.
12. Current chronic daily treatment (continuous for > 3 months) with systemic
corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone),
excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic
reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
13. Known hypersensitivity to any component of the study medication(s).
14. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug
reaction with any of the study medications.
15. Concurrent or prior use of a strong cytochrome P450 (CYP)3A4 inhibitor (including
ketoconazole, itraconazole, posaconazole, clarithromycin, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, and grapefruit
products) or strong CYP3A4 inducers (including phenytoin, carbamazepine, rifampin,
rifabutin, rifapentin, phenobarbital, and St John's Wort) within 14 days before study
day 1.
16. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8
inducer (rifampin) within 14 days before study day 1.
17. Participation in an investigational drug study or history of receiving any
investigational treatment within 14 days prior to screening for this study, except for
testosterone-lowering therapy in men with prostate cancer.
18. Assessed by the Investigator to be unable or unwilling to comply with the requirements
of the protocol.
19. Concurrent participation in any interventional clinical trial.
20. Pregnant and nursing women.
Phase 2 randomized component only -
21. Prior sorafenib treatment.
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