Phase II study of nivolumab (anti-PD1), tadalafil, and oral vancomycin in patients with refractory primary hepatocellular carcinoma or liver dominant metastatic cancer from colorectal or pancreatic cancers.

Abstract

TPS4656 Background: Treatment options for advanced hepatocellular carcinoma (HCC) and liver dominant metastatic disease from colorectal or pancreatic cancers are limited with poor overall survival. Tadalafil has shown to increase anti-tumor immunity by decreasing myeloid derived suppressor cells (MDSC) and impair tumor growth in preclinical HCC models. Oral vancomycin affects bile acid metabolizing gut commensal bacteria leading to increased CXCL16 expression in the liver resulting in NKT mediated liver-selective anti-tumor effects. This study combines immune checkpoint inhibition (ICI) treatment with nivolumab in combination with tadalafil and oral vancomycin. We aim to evaluate the synergy of the antitumor effect induced by the change in gut microbiome with oral vancomycin and the immunomodulatory effect of PDE5 inhibition combined with ICI with nivolumab in advanced liver cancer or liver metastasis. Correlative Studies: Paired liver tumor biopsies are analyzed for genomic analysis (WES, RNA-seq), immune cell infiltration, proteomics and metabolomic studies (bile acids) and chemokine expression. Stool samples are analyzed for microbiota. Blood samples are analyzed for immune monitoring, cytokine profiles and pharmacokinetics of study drugs. Serum bile acid levels are determined in blood in the 2 hour period after test meal ingestion. Methods: This is a single-arm study of nivolumab, oral vancomycin and tadalafil. Treatment is delivered in 4-week cycles (C) and continues until off treatment. Imaging is done every 8 weeks. Biopsies are done at baseline and during week 3 of C2. Nivolumab is administered on day (D)1 of each C at a dose of 480 mg IV. Tadalafil is administered orally (PO); 10 mg daily starting on D1 of C1 and continues daily until off study. Vancomycin administration starts on D1 of C1 at 125 mg PO every 6 hours for a total daily dose of 500 mg. Patients will be on vancomycin 3 weeks on, 1 week off per regimen. The study is currently enrolling without DLT. Clinical trial information: NCT03785210 .