Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers

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Background: Current treatment options for patients with liver cancers, including hepatocellular carcinoma(HCC) and advanced liver cancers are limited and take no account of the known biological and genetic heterogeneity in these diseases. Median survival for advanced disease remains poor at approxim...

Background: Current treatment options for patients with liver cancers, including hepatocellular carcinoma(HCC) and advanced liver cancers are limited and take no account of the known biological and genetic heterogeneity in these diseases. Median survival for advanced disease remains poor at approximately 1 year. Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody that is specific for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface membrane receptor. Nivolumab has been approved by FDA for the treatment of HCC and other solid tumors. Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which have been approved by the FDA for the treatment of pulmonary arterial hypertension, benign prostatic hyperplasia and erectile dysfunction, with a relative safe clinical profile. PDE5 inhibitors have been examined in multiple malignancies and cancer cell lines for their direct anticancer activities, for their efficacy as chemo-sensitizers and for cancer chemoprevention. Oral vancomycin is antibiotic that has effect on altering gut commensal bacteria subsequently inducing a liver-selective anti-tumor effect. The aim of the study is to evaluate whether the immunomodulatory effect induced by PDE5 inhibitor and oral vancomycin can be enhanced by immune checkpoint inhibition in advanced liver cancer. Objective: -To determine the Best Overall Response (BOR) according to Response Evaluation Criteria (RECIST 1.1) to combined treatment of nivolumab, oral vancomycin and tadalafil in patients with refractory primary HCC or liver dominant metastatic cancer from colorectal cancer (CRC) or pancreatic adenocarcinoma (PDAC). Eligibility: Histologically confirmed, hepatocellular carcinoma (HCC) Or Histologically confirmed carcinoma highly suggestive of a diagnosis of HCC Or Histologically confirmed advanced colorectal or pancreatic malignancy with liver involvement as dominant site of metastasis Measurable lesion, accessible for biopsy. Age greater than or equal to 18 years ECOG less than or equal to 1 Acceptable renal, bone marrow and liver function. Willingness to undergo two mandatory tumor biopsies. Design: The proposed study is a phase II study of combined nivolumab, oral vancomycin and tadalafil treatment in patients with HCC or liver dominant metastatic cancer from colorectal or pancreatic cancers. Treatment will be delivered in cycles consisting of 4 weeks (+/- 3 days) until progression or unacceptable toxicity. Patients will be seen in Clinical Center on monthly basis with disease status evaluation every 8 (+/-1) weeks after start of study therapy.

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