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Tamoxifen to Treat Barrett's Metaplasia

Primary Purpose

Barrett Metaplasia

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tamoxifen
Endoscopy
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Barrett Metaplasia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Biopsy-proven Barrett's esophagus that is non-dysplastic or with low grade dysplasia.
  • At least 18 years of age.
  • ECOG performance status ≤ 2

  • Normal bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥1,500/mcl
    • Platelets ≥ 100,000/mcl
    • AST(SGOT)/ALT(SGPT) ≤1.5 x IULN
    • Serum creatinine within normal institutional limits or less than the lower limit of normal institutional limits; or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Ability to understand and willingness to sign an IRB approved written informed consent document.

Exclusion Criteria:

  • Prior history of esophageal cancer.
  • Prior history or current use of tamoxifen or anti-estrogen therapy.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen.
  • 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.
  • Pregnant and/or breastfeeding. Female patients must have a negative urine pregnancy test within 14 days of study entry.
  • Known HIV-positivity and on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with tamoxifen. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • Taking medications known to affect drug metabolism via the CYP3A4, CYP2C9, or CYP2D6 pathways.
  • History of blood clots (i.e. pulmonary embolism, DVTs).
  • Concurrent use of anticoagulants (i.e. Coumadin/warfarin).

Sites / Locations

  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tamoxifen

Arm Description

Tamoxifen 20 mg daily for 12 weeks

Outcomes

Primary Outcome Measures

Extent of Barrett's involvement and changes in histology
The biopsy procedures with 4 quadrant biopsies/2 cm for histology and additional biopsies for freezing for macromolecular analysis to assess the preliminary diagnostic value of this marker pair in identifying levels of metaplasia in BE and as an indicator of response to tamoxifen treatment. The tissue from the two endoscopic procedures will be assessed for changes in the following related to tamoxifen therapy.

Secondary Outcome Measures

Changes in SOX2 and CDX2 expression
The main outcome measurements are SOX2 and CDX2, analyzed as a ratio. We will use a one sample paired non-parametric Wilcoxon test to test the significant difference if the ratio difference is not normally distributed. Normality assumption can be examined by visual Q-Q plot and formal Kolmogorov-Smirnov statistic. In addition, we will explore the patient level characteristics on treatment effect using a linear regression model. Specifically, we will use the difference ratio as the response variable and patient characteristics of interest as explanatory variables. Regression coefficients associated with the explanatory variables quantify the effect of these variables on the difference ratio, with t or F statistic testing for the statistical significance.
Tolerance of tamoxifen
As measured by toxicities using CTCAE version 4.0
Changes in the length of Barrett's esophagus involvement

Full Information

First Posted
March 13, 2014
Last Updated
March 9, 2017
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT02089386
Brief Title
Tamoxifen to Treat Barrett's Metaplasia
Official Title
Tamoxifen to Treat Barrett's Metaplasia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Terminated
Why Stopped
Insufficient funding
Study Start Date
July 9, 2014 (Actual)
Primary Completion Date
June 21, 2016 (Actual)
Study Completion Date
June 21, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Treat Barrett's esophagus (BE) patients with tamoxifen to Barrett's metaplasia as measured by changes in Barrett's esophagus appearance by endoscopy and histology as well as changes in SOX2 and CDX2.
Detailed Description
Treat Barrett's esophagus (BE) patients with tamoxifen to determine the effects on Barrett's metaplasia as measured by changes in Barrett's esophagus appearance by endoscopy and histology. Tamoxifen treatment may induce SOX2 expression, decrease CDX2 and promote esophageal stem cell activity, leading to regression of Barrett's metaplasia. To test this hypothesis, we will conduct a prospective, pilot study where patients with BE, without high grade dysplasia, are treated with tamoxifen and assessed for changes in the appearance of their BE by endoscopy and histology as well as changes in the SOX2/CDX2 ratio indicative of an improvement in BE metaplasia

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Barrett Metaplasia

7. Study Design

Primary Purpose
Prevention
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tamoxifen
Arm Type
Experimental
Arm Description
Tamoxifen 20 mg daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Tamoxifen
Other Intervention Name(s)
Nolvadex®, Soltamox®
Intervention Type
Procedure
Intervention Name(s)
Endoscopy
Primary Outcome Measure Information:
Title
Extent of Barrett's involvement and changes in histology
Description
The biopsy procedures with 4 quadrant biopsies/2 cm for histology and additional biopsies for freezing for macromolecular analysis to assess the preliminary diagnostic value of this marker pair in identifying levels of metaplasia in BE and as an indicator of response to tamoxifen treatment. The tissue from the two endoscopic procedures will be assessed for changes in the following related to tamoxifen therapy.
Time Frame
End of 12 weeks (at the time of second endoscopy)
Secondary Outcome Measure Information:
Title
Changes in SOX2 and CDX2 expression
Description
The main outcome measurements are SOX2 and CDX2, analyzed as a ratio. We will use a one sample paired non-parametric Wilcoxon test to test the significant difference if the ratio difference is not normally distributed. Normality assumption can be examined by visual Q-Q plot and formal Kolmogorov-Smirnov statistic. In addition, we will explore the patient level characteristics on treatment effect using a linear regression model. Specifically, we will use the difference ratio as the response variable and patient characteristics of interest as explanatory variables. Regression coefficients associated with the explanatory variables quantify the effect of these variables on the difference ratio, with t or F statistic testing for the statistical significance.
Time Frame
End of 12 weeks (at the time of second endoscopy)
Title
Tolerance of tamoxifen
Description
As measured by toxicities using CTCAE version 4.0
Time Frame
4 months (30 days after cessation of tamoxifen or after second endoscopy - whichever occurs later)
Title
Changes in the length of Barrett's esophagus involvement
Time Frame
End of 12 weeks (at the time of second endoscopy)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Biopsy-proven Barrett's esophagus that is non-dysplastic or with low grade dysplasia. At least 18 years of age. ECOG performance status ≤ 2 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥1,500/mcl Platelets ≥ 100,000/mcl AST(SGOT)/ALT(SGPT) ≤1.5 x IULN Serum creatinine within normal institutional limits or less than the lower limit of normal institutional limits; or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document. Exclusion Criteria: Prior history of esophageal cancer. Prior history or current use of tamoxifen or anti-estrogen therapy. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen. 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. Pregnant and/or breastfeeding. Female patients must have a negative urine pregnancy test within 14 days of study entry. Known HIV-positivity and on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with tamoxifen. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. Taking medications known to affect drug metabolism via the CYP3A4, CYP2C9, or CYP2D6 pathways. History of blood clots (i.e. pulmonary embolism, DVTs). Concurrent use of anticoagulants (i.e. Coumadin/warfarin).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason Mills, M.D., Ph.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
16404367
Citation
Lindblad M, Garcia Rodriguez LA, Chandanos E, Lagergren J. Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer. 2006 Jan 16;94(1):136-41. doi: 10.1038/sj.bjc.6602906.
Results Reference
background
PubMed Identifier
22001866
Citation
Huh WJ, Khurana SS, Geahlen JH, Kohli K, Waller RA, Mills JC. Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach. Gastroenterology. 2012 Jan;142(1):21-24.e7. doi: 10.1053/j.gastro.2011.09.050. Epub 2011 Oct 14.
Results Reference
background
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Tamoxifen to Treat Barrett's Metaplasia

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