Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer

An Open-Label Preoperative Pilot Study Evaluating Nivolumab (Anti-PD-1 Antibody) Alone Versus Nivolumab Plus Ipilimumab (Anti-CTLA-4 Antibody) in Patients With Resectable (HCC)

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.

Primary Objective:

--To evaluate the safety and tolerability of therapy with nivolumab alone or nivolumab + ipilimumab in resectable HCC in the context of presurgical therapy.

Note: Note: As of January 8, 2020, 30 patients have been enrolled and 27 patients have been randomized. The PI decided to stop enrollment since the study has reached its target enrollment of 30 patients

Secondary Objectives:

--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 RECIST 1.1 progression-free survival (PFS).

Exploratory Objectives:

--To assess the immunological/biomarker changes in tumor tissues and peripheral blood in response to nivolumab alone or nivolumab + ipilimumab in HCC therapy (pre- 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.

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.