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

Brief summary public domain (ClinicalTrials.gov)

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. ...

Detailed description public domain (ClinicalTrials.gov)

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 the Food and Drug Administration (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.

Intervention public domain (ClinicalTrials.gov)

Drug: nivolumab. 480 mg intravenous (IV) every 4 weeks

Intervention public domain (ClinicalTrials.gov)

Drug: tadalafil. 10 mg by mouth (PO) daily

Intervention public domain (ClinicalTrials.gov)

Drug: oral vancomycin. 125 mg every 6-hour (500 mg total daily dose) by mouth (PO) from week 1 to week 3, week 4 off.

Arm public domain (ClinicalTrials.gov)

1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin (experimental): Nivolumab, tadalafil and oral vancomycin

Primary outcome public domain (ClinicalTrials.gov)

Best Overall Response (BOR). Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Time frame: Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years.

Secondary outcome public domain (ClinicalTrials.gov)

Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment. Time frame: From first study treatment, approximately 90 days.

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC). Time frame: Participants were followed from the on-study date to post discontinuation of treatment until the day of death, an average of 8 months..

Eligibility public domain (ClinicalTrials.gov)

* 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 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 22 participants (actual).

Why stopped public domain (ClinicalTrials.gov)

Study was terminated due to poor accrual.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Best Overall Response (BOR) [Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years]. Count Of Participants, Participants. Complete Response: Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 0; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 0. Partial Response: Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 0; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 0. Stable Disease: Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 1; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 1. Progressive Disease: Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 4; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 9. Not Evaluable: Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 1; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 6.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment [From first study treatment, approximately 90 days]. Number, adverse events. Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 0; Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) of Nivolumab Combined With Oral Vancomycin and Tadalafil in Participants With Refractory Hepatocellular Carcinoma (HCC) or Liver Dominant Metastatic Cancer From Colorectal Cancer or Pancreatic Ductal Adenocarcinoma (PDAC) [Participants were followed from the on-study date to post discontinuation of treatment until the day of death, an average of 8 months.]. Median, Months (95% Confidence Interval). Cohort 1, Arm 1, Treatment Assignment Code 1, Participants With Hepatocellular Carcinoma (n=6): 9.4 (2.4 to 18.3); Cohort 2, Arm 1, Treatment Assignment Code 1, Participants With Liver Metastases (n=16): 3.4 (2.6 to 8.7).