PRIMARY OBJECTIVES:
I. Maximum tolerated dose (MTD) of sorafenib tosylate (sorafenib) in combination with
standard dose nivolumab with Child Pugh A-B7 liver function. (Part 1: Escalation Cohort).
II. Safety in patients with Child Pugh B liver function. (Part 2: Child Pugh B Escalation
Cohort)
SECONDARY OBJECTIVES:
I. Safety and tolerability of combination overall. (Parts 1 and 2). II. Rate of
immune-related adverse event (irAE) for combination overall and in patients with Child Pugh B
liver function. (Parts 1 and 2).
III. Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
in patients with Child Pugh B liver function. (Parts 1 and 2).
IV. Duration of response (DOR), progression free survival (PFS), and overall survival (OS)
for escalation cohort and Child Pugh B expansion cohort and overall. (Parts 1 and 2).
EXPLORATORY OBJECTIVES:
I. Relationship between peripheral blood mononuclear cell (PBMC) immune cell subset
frequencies, baseline liver function, and clinical outcomes.
II. Relationship between PBMC T cell receptor (TCR) clonotype frequency and diversity,
baseline liver function, and clinical outcomes.
III. Tumor tissue immune cell subsets and TCR clonotype frequency and diversity in
pre-treatment archival tumor tissue samples.
IV. Tumor and immune cell PD-L1 status in pre-treatment archival tumor tissue samples and
relationship to clinical outcomes.
V. Changes in hepatitis B virus (HBV) and/or hepatitis C virus (HCV) viral load on treatment.
VI. Alpha-fetoprotein (AFP) changes on treatment and relationship to clinical outcomes.
VII. Relationship between clinical outcomes and clinicopathologic features including
race/ethnicity, etiology of liver disease including HBV/HCV status, baseline liver function,
presence of cirrhosis, macrovessel invasion, extrahepatic spread, site(s) of metastatic
disease, prior treatment history including prior radiation and arterial therapies.
OUTLINE: This is a dose-escalation and expansion study of sorafenib tosylate.
DOSE-ESCALATION (Part 1 - CLOSED TO ENROLLMENT):
Between 3-12 patients will be enrolled in Part 1. Patients receive sorafenib tosylate orally
(PO) once daily (QD) or twice daily (BID) on days 1-28, and nivolumab intravenously (IV) over
30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
New patients are assigned to 1 of 2 arms. (Part 2: Child Pugh B Expansion Cohort).
LEAD-IN ARM I: Patients receive nivolumab IV over 30 minutes on days 1 and 15, and sorafenib
tosylate PO beginning on day 15 of cycle 1, then on days 1-28 of subsequent cycles. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
LEAD-IN ARM II: Patients receive sorafenib tosylate PO on days 1-28, and nivolumab IV over 30
minutes beginning on day 15 of cycle 1, then on days 1 and 15 of subsequent cycles. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 100 days, then every
3 months for up to 2 years.
Inclusion Criteria:
1. Histologic or cytologic diagnosis of unresectable, locally advanced and/or metastatic
hepatocellular carcinoma (HCC) not amenable to curative surgery, transplantation, or
ablative therapies based upon assessment of treating investigator.
2. Radiographically measurable disease by RECIST version 1.1 in at least one site not
previously treated with chemoembolization, radioembolization, radiation, or other
local/liver-directed procedures (i.e. must have at least one measurable target lesion,
either within the liver or in a measurable metastatic site); a new area of tumor
progression within or adjacent to a previously-treated lesion, if clearly measurable
by a radiologist, is acceptable.
3. Untreated/pretreatment archival tumor tissue must be available for correlative
analyses
4. Age at least 18 years at enrollment.
5. Eastern Cooperative Oncology Group (ECOG) 0 or 1 at enrollment
6. At least 4 weeks after any prior chemoembolization, radioembolization, local ablative
therapies, or hepatic radiation and recovery to =< grade 1 treatment-related toxicity.
7. At least 6 weeks after any major surgery including prior hepatic resection and
recovery to =< grade 1 treatment-related toxicity.
8. At least 7 days after minor surgery (such as central venous access) or biopsy and
recovery to =< grade 1 treatment-related toxicity
9. At least 2 weeks after any prior palliative radiation (e.g. to focal metastatic lesion
such as bone metastases) and recovery to =< grade 1 treatment-related toxicity.
10. Blood pressure =< 140/90 mm Hg with or without anti-hypertensive therapy
a. Patients may be rescreened after initial ineligibility if due to elevated blood
pressure, if adequately medically managed within approximately 30 days.
11. Adequate baseline organ and marrow function as defined below:
1. Adequate bone marrow function:
- Absolute neutrophil count at least 1,200/microliter (mcL).
- Platelets at least 75,000/mcL.
- Hemoglobin at least 9 g/dL.
2. Adequate hepatic function:
- Part 1: Total bilirubin less than 2.6 mg/dL or 2 times upper limit of normal
(ULN), whichever is higher, and albumin at least 2.5 g/dL, if otherwise
meets criteria for Child Pugh A or B7.
- Part 2: Total bilirubin less than 3.9 mg/dL or 3 times ULN, whichever is
higher, and albumin at least 2.0 g/dL, if otherwise meets criteria for Child
Pugh B.
- Both Parts: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic
transaminase (SGOT)) and alanine aminotransferase (ALT) (serum
glutamic-pyruvic transaminase (SGPT)) less than 5 X ULN, International
normalized ratio (INR) less than 1.7.
3. Creatinine less than 1. 5 X ULN and/or creatinine clearance >= 60 mL/min.
12. Child Pugh A or B7 (Part 1); Child Pugh B7-9 (Part 2).
13. If HBV surface antigen (sAg) and/or core antibody (Ab) positive, must be treated with
appropriate antiviral therapy according to institutional practice with HBV
deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) less than 500 IU/mL.
14. If clinical or histologic diagnosis of cirrhosis and/or clinical or radiographic
evidence esophageal or gastric varices, must have had esophagogastroduodenoscopy (EGD)
surveillance and adequate endoscopic therapy according to institutional standards.
15. Able to swallow and retain oral medications
16. Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 28
days before study enrollment.
17. WOCBP and male partners of WOCBP must agree to use two methods of contraception until
at least 5 months after last dose of each study drug for WOCBP subjects, and 7 months
for male partners of WOCBP.
18. Able to understand and willingness to provide informed consent, and the willingness to
comply with the requirements of the protocol.
1. Subjects must have signed and dated an Institutional Review Board
(IRB)/Independent Ethics Committees (IEC) approved written informed consent form
in accordance with regulatory and institutional guidelines and before the
performance of any protocol related procedures that are not part of standard of
care.
Exclusion Criteria:
1. Any prior systemic therapy for HCC.
2. Known fibrolamellar or mixed HCC-cholangiocarcinoma histology.
3. Requirement for paracentesis to control ascites within 6 months before enrollment.
a. Ascites which is not clinically detectable or mild on stable doses of diuretics
during screening is allowed provided meets criteria for Child Pugh A or B7 (Part 1) or
B7-9 (Part 2).
4. Symptomatic hepatic encephalopathy requiring medication (such as lactulose or
rifaximin) (Part 1) or any hospitalization for encephalopathy within 6 months before
enrollment (Part 1 or 2).
1. Hepatic encephalopathy that is adequately controlled on stable doses of lactulose
and/or rifaximin per assessment of treating investigator is allowed in Part 2,
provided no hospitalization for encephalopathy within 6 months before enrollment.
2. Medications such as lactulose used for other indications (e.g. constipation) are
allowed in both Part 1 and 2.
5. History of upper gastrointestinal (GI) bleeding from esophageal and/or gastric varices
within 12 months before enrollment.
6. Requirement for systemic corticosteroids unless used for adrenal replacement, acute
therapy for asthma or bronchitis exacerbation (=< 2 weeks), or premedication for
contrast allergy.
a. Topical, intranasal, or inhaled steroids are not excluded.
7. Active autoimmune condition requiring systemic immunosuppressive medication.
8. Known human immunodeficiency virus (HIV) infection.
9. Active coinfection with HBV plus hepatitis delta (D) virus (HDV) or HCV:
1. Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV DNA
and detectable HCV ribonucleic acid (RNA).
2. Hepatitis D infection (HDV antibody positive) in subjects with detectable
hepatitis B surface antigen or HBV DNA.
10. Prior allogeneic transplant of any solid organ or bone marrow/stem cells.
11. Symptomatic hypothyroidism without replacement.
a. Patients may be rescreened after initiating adequate replacement therapy
12. History of seizure disorder requiring antiepileptic medication or brain metastases
with seizures.
13. Non-healing wound, ulcer, non-healing traumatic bone fracture, or abscess within 30
days of enrollment.
a. Nondisplaced, uncomplicated pathologic fracture due to tumor may be eligible
provided adequately treated with radiation, surgery or other treatments with full
recovery based upon investigator assessment.
14. Central or necrotic lung metastases.
15. Known brain or leptomeningeal metastases.
16. Uncontrolled hypertension (systolic pressure > 140 mm Hg and/or diastolic pressure >
90 mm Hg (National Cancer Institute (NCI)-Common Terminology Criteria for Adverse
Events (CTCAE) v4.0) on repeated measurement) despite optimal medical management.
17. Active or clinically significant cardiac disease including:
1. Congestive heart failure - New York Heart Association (NYHA) > class II.
2. Active coronary artery disease including unstable or newly diagnosed angina or
myocardial infarction within 6 months prior to study entry.
3. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin.
4. Corrected QT interval (QTc) (Fridericia) > 450 msec on two consecutive
electrocardiograms (ECGs) (baseline ECG should be repeated if QTc is found to be
> 450 msec).
18. Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 grade 2 or
higher within 6 months before first dose of study treatment any other
hemorrhage/bleeding event of NCI-CTCAE v4.0 grade 3 or higher within 6 months before
first dose of study treatment.
19. Subjects with arterial or venous thrombotic or embolic, such as cerebrovascular
accident (including transient ischemic attacks), myocardial infarction, or deep venous
thrombosis (DVT) within 6 months of informed consent.
1. Tumor or bland thrombus in hepatic vasculature is not an exclusion provided
hepatic function criteria are met.
2. Asymptomatic thromboembolic events such as incidentally-detected sub-segmental
pulmonary emboli or superficial thromboses are not an exclusion provided the
patient does not require treatment with therapeutic anticoagulation.
20. Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine,
phenobarbital, St. John's wort (hypericum perforatum), dexamethasone at a dose of
greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days
before first dose of study treatment.
21. Subjects who require therapeutic anticoagulation or anti-platelet therapy.
1. Low dose aspirin (=< 100 mg/day) is allowed
2. Prophylactic doses of low molecular weight heparin (LMWH) are allowed if approved
by study chair or designee.
22. Subjects with any previously untreated and concurrent cancer that is distinct in
primary site or histology from HCC except cervical cancer in-situ, treated nonmelanoma
skin cancers, localized prostate cancer not requiring systemic therapy undergoing
surveillance, or superficial bladder tumor; subjects surviving a cancer that was
curatively treated and without evidence of disease for more than 2 years before
enrollment are allowed provided that cancer therapy was completed at least 2 years
prior to study entry (date of the informed consent form).
23. Any uncontrolled intercurrent illness including, but not limited to: ongoing or active
infection requiring antibiotic therapy, pulmonary disease impairing functional status
or requiring oxygen, impairment in gastrointestinal function that may affect or alter
absorption of oral medications (such as malabsorption or history of gastrectomy or
bowel resection), or uncontrolled diarrhea.
24. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
classes, or excipients of the formulations given during the course of this trial
25. Women who are pregnant or breast-feeding at enrollment
26. Inability to comply with the protocol and/or not willing or not available for
follow-up assessments.
27. Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation
