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

Phase 2

Completed

Conditions: Hepatocellular Carcinoma
Metastatic Colorectal Cancer
Liver Metastasis
Hepatocellular Cancer
Metastatic Pancreatic Cancer

Interventions: Drug: nivolumab
Drug: tadalafil
Drug: oral vancomycin

Registration Number: NCT03785210

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

...

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin	tadalafil	Nivolumab, tadalafil and oral vancomycin
1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin	nivolumab	Nivolumab, tadalafil and oral vancomycin
1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin	oral vancomycin	Nivolumab, tadalafil and oral vancomycin

Primary Outcome Measures

Name	Time	Method
Best Overall Response (BOR)	Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years	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.

Secondary Outcome Measures

Name	Time	Method
Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment	From first study treatment, approximately 90 days	Adverse events were assessed by the by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
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.	Overall survival is calculated from the on-study date to the day of death using the Kaplan-Meier method.