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

NCT03785210 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 19003319-C-0033
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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. ...

Conditions

Hepatocellular Carcinoma; Hepatocellular Cancer; Metastatic Pancreatic Cancer; Metastatic Colorectal Cancer; Liver Metastasis

Keywords

Anticancer Activities; Altering Gut Commensal Bacteria; Immunomdulatory Effect; Checkpoint Inhibition

Outcome Measures

Primary Outcomes (1)

• 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.

  Every 2 months and then every 6 months after discontinuation of treatment, for survival purposes, up to 3 years

Secondary Outcomes (2)

• Serious Adverse Events Possibly, Probably, and/or Definitely Related to Treatment

  From first study treatment, approximately 90 days

• 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.

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 41 months/11 days and 36 months/22 days for the first and second group respectively.

Study Arms (1)

1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin

EXPERIMENTAL

Nivolumab, tadalafil and oral vancomycin

Drug: nivolumab; Drug: tadalafil; Drug: oral vancomycin

Interventions

oral vancomycin DRUG

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

Also known as: Vancocin

1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin

nivolumab DRUG

480 mg intravenous (IV) every 4 weeks

Also known as: Opdivo

1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin

tadalafil DRUG

10 mg by mouth (PO) daily

Also known as: Cialis

1/Arm 1 - Nivolumab, Tadalafil and Oral Vancomycin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms; Pancreatic Neoplasms; Colorectal Neoplasms

Interventions

Nivolumab; Tadalafil; Vancomycin

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring; Glycopeptides; Glycoconjugates; Carbohydrates; Peptides

Results Point of Contact

• Title: Dr. Tim F. Greten
• Organization: National Cancer Institute

gretentf@mail.nih.gov

240-760-6114

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 20, 2018
• First Posted: December 24, 2018
• Study Start: June 5, 2019
• Primary Completion: October 31, 2022
• Study Completion: December 31, 2022
• Last Updated: February 23, 2026
• Results First Posted: July 11, 2023

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the Database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)