Vancomycin in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLC) Oral
Primary Purpose
Metastatic Hepatocellular Carcinoma, Hepatocellular Carcinoma
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
vancomycin
Sponsored by

About this trial
This is an interventional treatment trial for Metastatic Hepatocellular Carcinoma focused on measuring Gut Bacteria, Anti-Tumor Effects, NKT cells
Eligibility Criteria
- INCLUSION CRITERIA:
- Patients must have histopathological confirmation of FLC by the NCI Laboratory of Pathology.
- Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation.
- Patients must be greater than or equal to 18 years of age. Children are excluded from this study because this study has two mandatory biopsies performed for research purposes only and we do not want to put children into additional risk of biopsies.
- Patients must have evaluable or measurable hepatic disease per RECIST 1.1
- Patients must have hepatic lesion accessible for biopsy and be willing to undergo pre- and post-treatment mandatory biopsies.
- ECOG performance status of less than or equal to 2
Adequate renal function defined by:
- Creatinine <1.5 x institution upper limit of normal (ULN)
- Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m2 by 24 hours urine collection or eGFR as estimated using the chronic kidney disease (CKD)-EPI equation for participant with creatinine levels > 1.5 X institutional ULN.
Adequate hepatic function defined by:
- Total bilirubin level with upper limit of normal less than or equal to 1 (SqrRoot) ULN,
- AST level <5(SqrRoot) ULN, and
- ALT level <5 (SqrRoot) ULN.
Adequate hematological function defined by:
--Absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 109/L.
- Subjects must be co-enrolled onto protocol 11C0112.
- Ability of subject or Legally Authorized Representative to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
- Patients who have had standard-of-care anti-cancer therapy (e.g., chemotherapy,immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents) within 2 weeks of enrollment; or, therapy with investigational agents, large field radiotherapy, or major surgery within 4 weeks prior to enrollment.
- Patients who are currently receiving any other investigational agents for any indication.
- Patients who are actively receiving broad-spectrum antibiotics or have received such within 4 weeks prior to enrollment.
- Patients with history of recurrent C. diff colitis
Patients who are on anti-coagulation or anti-platelet medication that cannot be interrupted prior to study-specified biopsies, including:
- Aspirin that cannot be discontinued for 7 days prior to biopsy
- Clopidogrel and ticagrelor that cannot be discontinued for 5 days prior to biopsy
- Ticlopidine that cannot be discontinued for 10 days prior to biopsy
- Prasugrel that cannot be discontinued for 7 days prior to biopsy
- Dipyridamole that cannot be discontinued for at least 2 days prior to biopsy
- Cilostazol that cannot be discontinued for at least 3 days prior to biopsy
- Coumadin that cannot be discontinued for 7 days prior to biopsy
- Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours prior to biopsy and unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to biopsy. NOTE: LMWH or UFH may be used to transition patients on and off the above anti-coagulants, if deemed appropriate by the treating physician.
- Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban) that cannot be discontinued for 4 days prior to biopsy
- Any other uncontrolled intercurrent illness or medical condition that per PI discretion would limit compliance with study requirements.
- Pregnant women are excluded from this study because this study has two mandatory biopsies performed for research purposes only and biopsies can have abortifacient effect.
Sites / Locations
- National Institutes of Health Clinical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
1/Arm 1
Arm Description
Oral vancomycin
Outcomes
Primary Outcome Measures
To evaluate the effect of oral vancomycin therapy in the relative CXCR6 gene expression levels in the liver
Change from baseline to 4 weeks after starting treatment in the relative CXCR6 gene expression level in the liver as determined by mRNA with Nanostring
Secondary Outcome Measures
Full Information
NCT ID
NCT04025567
First Posted
July 18, 2019
Last Updated
March 13, 2020
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT04025567
Brief Title
Vancomycin in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLC) Oral
Official Title
Phase II Study of Oral Vancomycin in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLC)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Withdrawn
Why Stopped
slow/insufficient accrual.
Study Start Date
March 12, 2020 (Anticipated)
Primary Completion Date
December 31, 2021 (Anticipated)
Study Completion Date
December 31, 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Background:
Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer. It most often occurs in young people who have no history of liver disease. Unresectable FLC most often does not improve with surgery. Researchers think gut bacteria may affect liver cancer control. They want to see if a drug that controls a type of bacteria can help.
Objective:
To test if vancomycin is safe and tolerable for and can treat people with unresectable FLC.
Eligibility:
People ages 18 and older with FLC that isn t responsive to treatment
Design:
Participants will be screened with a medical history, physical exam, blood and urine tests, and CT or MRI scans. They will provide a tumor sample: If they do not have one, they will have a biopsy.
Participants will take vancomycin 3 times a day. They will take the drug by mouth. They will take the drug in 28-day cycles. They will take the drug daily for the first 3 weeks. They will not take the drug the last week.
Participants will keep a medication diary.
Participants will have blood and urine tests each cycle. They may provide stool samples.
Participants will have a biopsy before they start treatment. Then they will have one on day 1 of cycle 2.
Participants will have scans on day 1 of cycle 2. Then they will have scans about every 8 weeks.
Participants will continue treatment until their cancer gets worse or they can no longer tolerate the side effects.
Participants will have a follow-up visit about a month after they finish treatment. Then they will be followed every 6 months by phone or email.
Detailed Description
Background:
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer (0.5-9% of primary liver cancers), which affects younger age groups and is not associated with underlying liver disease or elevated serum alpha fetoprotein (AFP) levels.
Surgery, either liver resection (LR) or liver transplantation (LT), is the only potentially curative treatment for FLC patients with resectable disease. Disease recurrence after complete resection is high (33-100%). In patients with unresectable disease, median survival is less than 12 months; with no patient expected to survive beyond 5 years.
The role of systemic chemotherapy and radiotherapy is poorly defined, and has been reported to have only a modest or no therapeutic effect. To date no targeted therapy has been shown to be of any value in FLC.
In mouse models, oral vancomycin alters gut commensal bacteria thereby inducing a liver-selective anti-tumor effect by increasing hepatic CXCR6+ NKT cells via increased CXCL16 expression of liver sinusoidal endothelial cells.
Objective:
-To evaluate the effect of oral vancomycin therapy on the relative CXCR6 gene expression levels in the liver in paired pre- and on-treatment biopsy samples from hepatic lesions in patients with unresectable FLC
Eligibility:
Histologically confirmed FLC, not amenable to potentially curative resection, transplantation or ablation.
Liver lesion measurable by RECIST criteria, accessible for biopsy.
Age greater than or equal to 18 years
ECOG performance status less than or equal to 2
Acceptable renal and normal liver function.
Willingness to undergo pre- and on-treatment biopsies of liver tumor.
Design:
This is a phase II study of oral vancomycin in patients with unresectable FLC.
Up to 14 patients will be treated with oral vancomycin 500 mg tid daily (1,500 mg total daily dose) from days 1 to 21, in a 28-day cycles. After completion of the first cycle, initiation of concurrent treatment will be allowed. Patients will receive oral vancomycin until off treatment criteria are met.
Patients will be evaluated for toxicity every 4 weeks by CTCAE v5.0, and for response at the end of the first cycle and thereafter every 8 (+/-3) weeks by RECIST 1.1.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Hepatocellular Carcinoma, Hepatocellular Carcinoma
Keywords
Gut Bacteria, Anti-Tumor Effects, NKT cells
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1/Arm 1
Arm Type
Experimental
Arm Description
Oral vancomycin
Intervention Type
Drug
Intervention Name(s)
vancomycin
Intervention Description
1,500 mg total daily dose, on days 1-21 of every 28 days cycle.
Primary Outcome Measure Information:
Title
To evaluate the effect of oral vancomycin therapy in the relative CXCR6 gene expression levels in the liver
Description
Change from baseline to 4 weeks after starting treatment in the relative CXCR6 gene expression level in the liver as determined by mRNA with Nanostring
Time Frame
4 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
Patients must have histopathological confirmation of FLC by the NCI Laboratory of Pathology.
Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation.
Patients must be greater than or equal to 18 years of age. Children are excluded from this study because this study has two mandatory biopsies performed for research purposes only and we do not want to put children into additional risk of biopsies.
Patients must have evaluable or measurable hepatic disease per RECIST 1.1
Patients must have hepatic lesion accessible for biopsy and be willing to undergo pre- and post-treatment mandatory biopsies.
ECOG performance status of less than or equal to 2
Adequate renal function defined by:
Creatinine <1.5 x institution upper limit of normal (ULN)
Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m2 by 24 hours urine collection or eGFR as estimated using the chronic kidney disease (CKD)-EPI equation for participant with creatinine levels > 1.5 X institutional ULN.
Adequate hepatic function defined by:
Total bilirubin level with upper limit of normal less than or equal to 1 (SqrRoot) ULN,
AST level <5(SqrRoot) ULN, and
ALT level <5 (SqrRoot) ULN.
Adequate hematological function defined by:
--Absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 109/L.
Subjects must be co-enrolled onto protocol 11C0112.
Ability of subject or Legally Authorized Representative to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
Patients who have had standard-of-care anti-cancer therapy (e.g., chemotherapy,immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents) within 2 weeks of enrollment; or, therapy with investigational agents, large field radiotherapy, or major surgery within 4 weeks prior to enrollment.
Patients who are currently receiving any other investigational agents for any indication.
Patients who are actively receiving broad-spectrum antibiotics or have received such within 4 weeks prior to enrollment.
Patients with history of recurrent C. diff colitis
Patients who are on anti-coagulation or anti-platelet medication that cannot be interrupted prior to study-specified biopsies, including:
Aspirin that cannot be discontinued for 7 days prior to biopsy
Clopidogrel and ticagrelor that cannot be discontinued for 5 days prior to biopsy
Ticlopidine that cannot be discontinued for 10 days prior to biopsy
Prasugrel that cannot be discontinued for 7 days prior to biopsy
Dipyridamole that cannot be discontinued for at least 2 days prior to biopsy
Cilostazol that cannot be discontinued for at least 3 days prior to biopsy
Coumadin that cannot be discontinued for 7 days prior to biopsy
Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours prior to biopsy and unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to biopsy. NOTE: LMWH or UFH may be used to transition patients on and off the above anti-coagulants, if deemed appropriate by the treating physician.
Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban) that cannot be discontinued for 4 days prior to biopsy
Any other uncontrolled intercurrent illness or medical condition that per PI discretion would limit compliance with study requirements.
Pregnant women are excluded from this study because this study has two mandatory biopsies performed for research purposes only and biopsies can have abortifacient effect.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tim F Greten, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2019-C-0125.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Vancomycin in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLC) Oral
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