Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer
Condition: Hepatocellular Carcinoma; Resectable Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Ipilimumab; Nivolumab
Intervention description: Given IV; Given IV
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies the side effects and how well nivolumab with or with ipilimumab
      works in treating patients with liver cancer that can be removed by surgery. Immunotherapy
      with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune
      system attack the cancer, and may interfere with the ability of tumor cells to grow and
      spread.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

             Target population

          2. Patients with histologically confirmed HCC (Documentation of original biopsy for
             diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by 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.

          3. 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 MRI
             or spiral CT scan.

          4. Patient can have had prior treatment for HCC including prior surgery, radiation
             therapy, local-regional therapy (abalation or arterial directed therapies), and
             systemic therapy including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4
             therapy)

          5. ECOG performance status ≤ 1.

          6. Within 14 days of the first dose of study drug, patients must have adequate organ and
             marrow function as defined below:

               -  Absolute neutrophil count ≥ 1,500/μL

               -  Platelets ≥100,000/μL

               -  Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to
                  maintain or exceed this level)

               -  Total bilirubin ≤ 1.5 mg/dl

               -  Serum creatinine ≤ 1.5 times the upper limit of normal or estimated CrCL
                  >40mL/min.

               -  AST (SGOT) and/or ALT (SGPT) ≤ 5 X institutional upper limit of normal Age and
                  Sex

          7. Men and women ≥ 18 years of age

          8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
             the start of study drug.

          9. Women must not be breastfeeding

         10. 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.

         11. 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.

         12. 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. Highly effective methods of
        contraception 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 (IUDs) such as Mirena by WOCBP
             subject or male subject's WOCBP partner.

          -  Nonhormonal IUDs, 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 (eg, 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 of the following criteria will disqualify the patient from participation:

        Target Disease Exceptions

          1. 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.

             Medical History and Concurrent Disease

          2. Patients who have organ allografts.

          3. 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); 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.

          4. 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]).

          5. Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).

          6. 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.

          7. Patients who have had a history of acute diverticulitis, abdominal fistula,
             gastrointestinal perforation, intra-abdominal abscess, GI obstruction, abdominal
             carcinomatosis which are known risks factors for bowel perforation, should be excluded
             from the study.

          8. 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.

          9. 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.

         10. 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.

         11. 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)

         12. Patients who have had influenza, hepatitis, or other vaccines within a month prior to
             initiation of study drugs.

         13. Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis
             within the past year.

         14. Patients who have serious, non-healing wound, ulcer, or bone fracture.

         15. Pregnancy (positive pregnancy test) or lactation.

         16. Patients with prior orthotropic liver transplantation.

         17. Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C).

             Prohibited Therapies and/or Medications

         18. 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.

         19. Patients must not be scheduled to receive another experimental drug while on this
             study.

         20. Patients who require ongoing anticoagulation will be excluded. Only aspirin will be
             permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted.

         21. Patients must not require total parenteral nutrition with lipids.

             Other Exclusion Criteria:

         22. Any patients who cannot be compliant with the appointments required in this protocol
             must not be enrolled in this study.