Nivolumab, Fluorouracil, and Interferon Alpha 2B for the Treatment of Unresectable Fibrolamellar Cancer
Nivolumab, Fluorouracil, and Interferon Alpha 2B for the Treatment of Unresectable Fibrolamellar Cancer
This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and
 interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that
 cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such
 as nivolumab, may help the body's immune system attack the cancer and may interfere with the
 ability of tumor cells to grow and spread. Chemotherapy drugs, such as fluorouracil, work in
 different ways to stop the growth of tumor cells, either by killing the cells, by stopping
 them from dividing, or by stopping them from spreading. Interferon alpha 2b may help
 stimulate the immune system to fight cancer. Giving nivolumab, fluorouracil, and interferon
 alpha 2b may work better in treating unresectable fibrolamellar cancer compared to
 fluorouracil and interferon alpha 2b alone.
PRIMARY OBJECTIVE:

 I. To evaluate the safety and tolerability of therapy with nivolumab + fluorouracil (5-FU) +
 recombinant interferon alpha 2b-like protein (IFN-alpha2b) in patients with unresectable
 fibrolamellar hepatocellular carcinoma (FLHCC) in the context of palliative systemic and
 prebiopsy therapy.

 SECONDARY OBJECTIVE:

 I. To assess the efficacy of nivolumab + 5-FU + IFN-alpha2b therapy in patients with
 unresectable FLHCC by estimating the overall response rate (ORR) and progression-free
 survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, and
 comparing those rates to those from historical controls in our published data.

 EXPLORATORY OBJECTIVES:

 I. To assess the immunological/biomarker changes in tumor tissues and peripheral blood in
 response to nivolumab + 5-FU + IFN-aplha2b therapy (pre- versus [vs] post-treatment).

 II. To explore any potential association between these biomarker measures and both antitumor
 response and immune-related response criteria (irRC) assessed by the University of Texas MD
 Anderson Cancer Center (MD Anderson) Department of Diagnostic Imaging.

 OUTLINE:

 Patients receive fluorouracil intravenously (IV) continuously on days 1-7 and 15-21 and
 recombinant interferon alpha 2b-like protein subcutaneously (SC) on days 1, 3, 5, 15, 17, and
 19. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or
 unacceptable toxicity. Beginning in cycle 3, patients receive nivolumab IV over 30 minutes on
 day 1, fluorouracil IV continuously on days 1-7 and 15-21, and recombinant interferon alpha
 2b-like protein interferon alpha 2b SC on days 1, 3, 5, 15, 17, and 19. Cycles repeat every
 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days and then every 12
 weeks for 6 years.
Inclusion Criteria:

 -  Patients, or their legal guardian, must give written informed consent prior to
 initiation of therapy, and patients under age 18 must give assent 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 FLHCC (or with documentation of original biopsy
 for diagnosis is acceptable if tumor tissue is unavailable). 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. The definition
 of resectability is as follows: hepatectomy can achieve a negative margin while
 preserving more than 30% of the total estimated liver volume, sparing two contiguous
 hepatic segments, and maintaining vascular inflow, vascular outflow, and biliary
 drainage. Patients with extrahepatic disease are defined as having unresectable
 disease

 -  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

 -  Eastern Cooperative Oncology Group performance status (ECOG PS =< 1), or for patients
 under age 18 Karnofsky performance status of >= 70

 -  No advanced cirrhosis, with Child-Pugh A

 -  Absolute neutrophil count (ANC) >= 1,000 /mm^3 (within 14 days of the first dose of
 study drug)

 -  Platelets >= 100,000 /mm^3 (within 14 days of the first dose of study drug)

 -  Hemoglobin > 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 (ULN) 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 times institutional ULN (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)
 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
 as described in these sections. Investigators shall counsel WOCBP and male subjects
 who are sexually active with WOCBP on the importance of pregnancy prevention and the
 implications of an unexpected pregnancy. Investigators shall advise WOCBP and male
 subjects who are sexually active with WOCBP on the use of highly effective methods of
 contraception, which have a failure rate of < 1% per year when used consistently and
 correctly. At a minimum, subjects must agree to the use of two methods of
 contraception, with one method being highly effective and the other method being
 either highly effective or less effective as listed below:

 -  HIGHLY EFFECTIVE METHODS OF CONTRACEPTION:

 -  Male condoms with spermicide

 -  Hormonal methods of contraception including combined oral contraceptive
 pills, vaginal ring, injectables, implants, and intrauterine devices such as
 Mirena by WOCBP subject or male subject's WOCBP partner

 -  Nonhormonal intrauterine devices, such as ParaGard

 -  Tubal ligation

 -  Vasectomy

 -  Complete Abstinence

 -  Complete abstinence is defined as complete avoidance of heterosexual
 intercourse and is an acceptable form of contraception for all study
 drugs. Abstinence is only acceptable when this is in line with the
 preferred and usual lifestyle of the subject. Periodic abstinence
 (e.g., calendar, ovulation, symptothermal, profession of abstinence for
 entry into a clinical trial, post-ovulation methods) and withdrawal are
 not acceptable methods of contraception. Subjects who choose complete
 abstinence are not required to use a second method of contraception,
 but female subjects must continue to have pregnancy tests. Acceptable
 alternate methods of highly effective contraception must be discussed
 in the event that the subject chooses to forego complete abstinence

 -  LESS EFFECTIVE METHODS OF CONTRACEPTION:

 -  Diaphragm with spermicide

 -  Cervical cap with spermicide

 -  Vaginal sponge

 -  Male condom without spermicide

 -  Progestin-only pills by WOCBP subject or male subject's WOCBP partner

 -  Female condom

 -  A male and female condom must not be used together

 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 have an anticipated need for major surgical procedure during the course of
 the study (other than defined by protocol). 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 or known acquired
 immunodeficiency syndrome

 -  Any underlying medical condition, which in the opinion of the investigator will make
 the administration of study drug hazardous or will obscure the interpretation of
 adverse events (AEs), 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 obstruction,
 or abdominal carcinomatosis which are known risks factors for bowel perforation

 -  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 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), or 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 have received any live or attenuated viral vaccines within a month prior
 to initiation of study drugs

 -  Patients who have active hepatitis B virus (HBV) infection (chronic or acute), defined
 as having a positive hepatitis B surface antigen (HBsAg) test at screening

 -  Patients with a past or resolved HBV infection, defined as having a negative
 HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and
 negative HBV deoxyribonucleic acid (DNA) test at screening, are eligible for the
 study

 -  Patients who have active hepatitis C virus (HCV) infection, defined as having a
 positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at
 screening

 -  The HCV RNA test will be performed only for patients who have a positive HCV
 antibody test

 -  Patients who have clinical history of coagulopathy, bleeding diathesis, or thrombosis
 within the past year

 -  Patients who have a serious, non-healing wound, ulcer, or bone fracture

 -  Patients who are pregnant (positive pregnancy test) or lactating

 -  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-PD-1 for FLHCC
 treatment. Patients receiving any concomitant systemic therapy for FLHCC 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

 -  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). Corticosteroid use
 will only be allowed during trial participation for grade 3/4 AEs or hypersensitivity
 reactions

 -  Any patients who cannot be compliant with the appointments required in this protocol
 must not be enrolled in this study