Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers
Condition: Hepatocellular Carcinoma; Hepatocellular Cancer; Metastatic Pancreatic Cancer; Metastatic Colorectal Cancer; Liver Metastasis
MeSH terms: Carcinoma; Neoplasm Metastasis; Pancreatic Neoplasms; Carcinoma, Hepatocellular; Liver Neoplasms
Intervention: nivolumab; tadalafil; oral vancomycin
Intervention description: 480 mg intravenous (IV) every 4 weeks; 10 mg by mouth (PO) daily; 125 mg every 6-hour (500 mg total daily dose) by mouth (PO) from week 1 to week 3, week 4 off.
Intervention MeSH terms: Vancomycin; Nivolumab; Tadalafil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anticancer Activities; Altering Gut Commensal Bacteria; Immunomdulatory Effect; Checkpoint Inhibition

Summary:

      Background:

      A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer
      happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study
      if a combination of drugs helps people with these cancers. The drugs are nivolumab,
      tadalafil, and vancomycin.

      Objective:

      To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to
      shrink.

      Eligibility:

      Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from
      colorectal or pancreatic cancer for which standard treatment has not worked

      Design:

      Participants will be screened with:

      Medical and cancer history

      Review of symptoms and ability to perform normal activities

      Physical exam

      Heart test. Some participants may meet with a cardiologist and/or have another heart test.

      Scan of the chest, abdomen, and pelvis

      Blood and urine tests

      Tumor sample review. This can be from a previous procedure.

      Participants will receive the study drugs in 4-week cycles. In each cycle participants will:

      Get nivolumab through a small plastic tube in the arm on Day 1.

      Take tadalafil by mouth 1 time every day.

      Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not
      take it for week 4.

      Complete a medicine diary of dates, times, missed doses and symptoms.

      Throughout the study, participants will repeat screening tests and will give stool samples or
      rectal swabs.

      After their last cycle, participants will have 3 follow-up visits over 3 months. Then they
      will be contacted every 6 months by phone or email and asked about their general well-being.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have

               -  histopathological confirmation of Hepatocellular Carcinoma (HCC) (Cohort 1) OR

               -  histopathological confirmation of carcinoma by in the setting of clinical and
                  radiological characteristics which, together with the pathology, are highly
                  suggestive of a diagnosis of HCC (Cohort 1) OR

               -  histopathological confirmation of advanced colorectal or pancreatic malignancy
                  with liver involvement as dominant site of metastasis (Per multidiscipline tumor
                  board review and approval) (Cohort 2).

          -  Patients must have disease that is not amenable to potentially curative resection,
             transplantation or ablation.

          -  Patients must have progressed on, been intolerant to, or refused prior
             sorafenib/lenvatinib and/or atezolizumab/bevacizumab therapy (Cohort 1 only).

          -  Subjects must have progressed on or after standard systemic chemotherapy (at least one
             line of chemotherapy for patients with liver metastasis from pancreatic ductal
             adenocarcinoma (PDAC), at least two lines of chemotherapy for patients with liver
             metastasis from colorectal cancer (CRC) (Cohort 2 only).

          -  Patients must have evaluable or measurable disease per Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1

          -  Patients must have lesion accessible for biopsy and be willing to undergo pre- and
             posttreatment biopsies.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

          -  If liver cirrhosis is present, patient must have a Child-Pugh score less than or equal
             to 7

          -  Active chronic hepatitis B virus (HBV) infected subjects must be on antivirals and
             have HBV deoxyribonucleic acid (DNA) <100IU/mL. hepatitis C virus (HCV) infected
             subjects can be enrolled with close HCV RNA level monitoring.

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of nivolumab in combination with tadalafil and
             vancomycin in patients less than 18 years of age, children are excluded from this
             study, but will be eligible for future pediatric trials

          -  Adequate hematological function defined by:

               -  white blood cell (WBC) count greater than or equal to 3x10^9/L

               -  absolute neutrophil count (ANC) greater than or equal to 1.5x10^9/L,

               -  lymphocyte count greater than or equal to 0.5x10^9/L,

               -  platelet count greater than or equal to 60x10^9/L, and

               -  Hemoglobin (Hgb) greater than or equal to 9 g/ dL (more than 48 hours
                  post-completion of blood transfusion)

          -  Adequate hepatic function defined by:

               -  a total bilirubin level less than or equal to 1.5 X Upper limit of normal (ULN),

               -  an aspartate transaminase (AST) level <5xULN,

               -  an alanine aminotransferase (ALT) level <5xULN.

          -  Adequate renal function defined by:

               -  Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m^2 by 24
                  hours urine collection or as predicted by the Cockcroft-Gault formula:

               -  CrCl = (140 age (y)) x (weight in kg) x (0.85, if female) x1.73 m^2/72 x Serum
                  Creatinine (mg/dL) x patient's body surface area (BSA) (m^2) Or

          -  The effects of nivolumab on the developing human fetus are unknown. For this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation and up to 5 months (women) and 7 months (men)
             after the last dose of the drug. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

          -  Patients with a history of cardiovascular disease may be enrolled per cardiology
             consultation and approval with echocardiogram and troponin level in normal range at
             the time of enrollment.

          -  Patient must be able to understand and willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          -  Patients who have had standard-of-care anti-cancer therapy or therapy with
             investigational agents (e.g., chemotherapy, immunotherapy, endocrine therapy, targeted
             therapy, biologic therapy, tumor embolization, monoclonal antibodies or other
             investigation agents), large field radiotherapy, or major surgery within 4 weeks prior
             to enrollment.

          -  Therapy with antibiotics within 30 days prior to enrollment.

          -  Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within
             7- days prior to enrollment and for whom stopping is unsafe and/or a safe substitute
             is not medically recommended. Use of PDE5 inhibitors such as vardenafil (Levitra),
             tadalafil (Cialis), and sildenafil citrate (Viagra) less than or equal to 15-days
             prior to enrollment.

          -  The patient must not be currently on a corticosteroid dose greater than physiologic
             replacement dosing defined as 10 mg of cortisone per day or its equivalent.

          -  For PDAC patients with liver metastases, primary PDAC has not been resected (unless
             the primary is in the tail of the pancreas).

          -  Patients with known brain metastases will be excluded from this clinical trial because
             of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  Have signs of liver failure, e.g., clinical significant ascites, encephalopathy, or
             variceal bleeding within 6 months prior to enrollment.

          -  Prior major liver resection: remnant liver <50% of the initial liver volume. Patients
             with a biliary stent can be included.

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including systemic corticosteroids. These include but are not limited to patients with
             a history of immune related neurologic disease, multiple sclerosis, autoimmune
             (demyelinating) neuropathy, Guillain-Barre syndrome or Chronic Inflammatory
             Demyelinating Polyneuropathy (CIDP), myasthenia gravis; systemic autoimmune disease
             such as Systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma,
             inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients
             with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
             phospholipid syndrome. Such diseases should be excluded because of the risk of
             recurrence or exacerbation of disease.

        Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with
        replacement hormones including physiologic corticosteroids are eligible. Patients with
        rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled
        with topical medication and patients with positive serology, such as antinuclear antibodies
        (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
        involvement and potential need for systemic treatment but should otherwise be eligible.

          -  Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
             organizing pneumonia) or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Patients with myocardial infarction or myocarditis within 12 months prior to
             enrollment.

          -  History of severe or unstable cerebrovascular disease.

          -  Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg)

          -  Stroke within 6 months prior to enrollment.

          -  Human immunodeficiency virus (HIV)-positive patients are excluded because HIV causes
             complicated immune deficiency and study treatment can possess more risks for these
             patients.

          -  Have had prior transplant of any kind.

          -  Have ascites.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab, tadalafil or vancomycin.

          -  History of severe hypersensitivity reaction to any monoclonal antibody.

          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 3 years prior to enrollment.

          -  Pregnant women are excluded from this study because nivolumabs potential for
             teratogenic or abortifacient effects is unknown. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with nivolumab, breastfeeding should be discontinued if the mother is treated
             with nivolumab