PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of therapy with nivolumab alone or nivolumab +
ipilimumab in resectable hepatocellular carcinoma (HCC) in the context of presurgical
therapy.
II. To evaluate the safety and tolerability of therapy with nivolumab + ipilimumab in
potentially resectable HCC in the context of pre-biopsy therapy.
SECONDARY OBJECTIVES:
I. To assess the efficacy of presurgical nivolumab alone or nivolumab + ipilimumab therapy in
HCC by estimating the objective response rate (ORR) and time to progression (TTP) per
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 progression-free survival (PFS).
II. To estimate the conversion rate to surgery for arm 3 potentially resectable patients.
EXPLORATORY OBJECTIVES:
I. To assess the immunological/biomarker changes in tumor tissues and peripheral blood in
response to nivolumab alone or nivolumab + ipilimumab in HCC therapy (pre- versus [vs]
post-treatment), and explore any potential association between these biomarker measures and
antitumor response and immune-related response criteria (iRC) assessed by MD Anderson
department of diagnostic imaging.
OUTLINE: Patients with resectable tumors are randomized to 1 of 2 arms and patients with
potentially resectable tumors are assigned to Arm C.
ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment
repeats every 2 weeks for up to 3 cycles in the absence of disease progression or
unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks
after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years
in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A.
Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease
progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7.
Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks
and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease
progression or unacceptable toxicity.
ARM C: Patients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment
biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and
nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of
disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients
receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4
weeks up to 2 years 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
9 weeks thereafter.
Inclusion Criteria:
- Patients must give written informed consent prior to initiation of therapy, in keeping
with the policies of the institution. Patients with a history of major psychiatric
illness must be judged able to fully understand the investigational nature of the
study and the risks associated with the therapy
- Patients with histologically confirmed HCC (documentation of original biopsy for
diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by
American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic
subjects is required (presence of arterial hypervascularity with venous washout). For
subjects without cirrhosis, histological confirmation is mandatory. The determination
of resectability status will ultimately lie in the clinical judgment of the surgical
oncologist and medical oncologist involved in the care of the patient
- Patient must have measurable disease defined as a lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) and measures >=
15 mm with conventional techniques or >= 10 mm with more sensitive techniques such as
magnetic resonance imaging (MRI) or spiral computed tomography (CT) scan
- Patient can have had prior treatment for HCC including prior surgery, radiation
therapy, local-regional therapy (ablation or arterial directed therapies), and
systemic therapy including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4
therapy)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Absolute neutrophil count >= 1,500/·L (within 14 days of the first dose of study drug)
- Platelets >= 100,000/·L (within 14 days of the first dose of study drug)
- Hemoglobin (Hgb) > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen]
to maintain or exceed this level) (within 14 days of the first dose of study drug)
- Total bilirubin =< 1.5 mg/dl (within 14 days of the first dose of study drug)
- Serum creatinine =< 1.5 times the upper limit of normal or estimated creatinine
clearance (CrCL) > 40 mL/min (within 14 days of the first dose of study drug)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 X institutional upper limit of normal (within 14 days of the first dose of study
drug)
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study drug
- Women must not be breastfeeding
- WOCBP must agree to follow instructions for method(s) of contraception from the time
of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
treatment completion
- Men who are sexually active with WOCBP must agree to follow instructions for method(s)
of contraception for the duration of treatment with study drug (s) plus 5 half-lives
of study drug (s) plus 90 days (duration of sperm turnover) for a total of 7 months
post-treatment completion
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However, WOCBP must still undergo pregnancy testing
Exclusion Criteria:
- Any other malignancy from which the patient has been disease-free for less than 2
years, except for non-melanoma skin cancer, or in situ carcinoma of any site
- Patients who have organ allografts
- Patients who have had a major surgical procedure, open biopsy, or significant
traumatic injury with poorly healed wound within 6 weeks prior to first dose of study
drug; or anticipation of need for major surgical procedure during the course of the
study (other than defined by protocol); or fine needle aspirations or core biopsies)
within 7 days prior to first dose of study drug. NOTE: Patients will be allowed to
start cycle 1 day 1 therapy after 24 hours from pre-treatment biopsy
- Autoimmune disease: Patients with a history of inflammatory bowel disease (including
Crohn's disease and ulcerative colitis) are excluded from this study as are patients
with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
Wegener's granulomatosis])
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)
- Any underlying medical condition, which in the opinion of the Investigator, will make
the administration of study drug hazardous or obscure the interpretation of adverse
events, such as a condition associated with frequent diarrhea
- Patients who have had a history of acute diverticulitis, abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess, gastrointestinal (GI)
obstruction, abdominal carcinomatosis which are known risks factors for bowel
perforation, should be excluded from the study
- Patients who have a primary brain tumor (excluding meningiomas and other benign
lesions), any brain metastases, leptomeningeal disease, seizure disorders not
controlled with standard medical therapy, or history of stroke within the past year
- History of serious systemic disease, including myocardial infarction or unstable
angina within the last 12 months, history of hypertensive crisis or hypertensive
encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the
time of enrollment, New York Heart Association (NYHA) grade II or greater congestive
heart failure, unstable symptomatic arrhythmia requiring medication (patients with
chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
tachycardia are eligible), significant vascular disease or symptomatic peripheral
vascular disease
- Patients who have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of an investigational drug or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications
- Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or
other more potent immune suppression medications (e.g. infliximab)
- Patients who have had influenza, hepatitis, or other vaccines within a month prior to
initiation of study drugs
- Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis
within the past year
- Patients who have serious, non-healing wound, ulcer, or bone fracture
- Pregnancy (positive pregnancy test) or lactation
- Patients with prior orthotropic liver transplantation
- Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C)
- Patients must not have received prior anticancer therapy with anti-CLTA-4 or anti-PD1
for HCC. Patients receiving any concomitant systemic therapy for HCC are excluded
- Patients must not be scheduled to receive another experimental drug while on this
study
- Patients who require ongoing anticoagulation will be excluded. Only aspirin will be
permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted
- Patients must not require total parenteral nutrition with lipids
- Any patient who cannot be compliant with the appointments required in this protocol
must not be enrolled in this study
