Citrate and Tamoxifen and Dextromethorphan in Breast Cancer - Clinical Trials Registry

Study Overview

Status

Terminated

Conditions

Breast Cancer

Intervention / Treatment

Detailed Description

OBJECTIVES:

To assess the operating characteristics of the ¹³C-dextromethorphan (^13 C-DM) breath test in identifying women with breast cancer (or at high risk) who are CYP2D6-genotypic poor metabolizers.
To examine the correlation between CYP2D6 enzyme activity (as measured by the breath test) and plasma endoxifen (and 4-hydroxyTAM) levels in patients who carry one or more CYP2D6 functional alleles.
To examine the change in CYP2D6 enzyme activity (as measured by the ¹³C-DM breath test), in patients who start a CYP2D6 inhibitor while taking tamoxifen.
To determine whether CYP2D6 enzyme activity (as measured by the breath test) changes over time (either as a consequence of drug-induced inhibition or other).
To measure genetic variation in additional genes that are later identified to affect the metabolism, uptake, or distribution of tamoxifen (e.g., SULT1A1, UGT).

OUTLINE: Patients receive tamoxifen citrate for 6 months. ^13C-dextromethorphan breath tests are conducted at baseline and periodically during the 6 months.

13C-dextromethorphan breath test: Patients receive oral Alka-Seltzer® Gold (ASG; citric acid, potassium bicarbonate, and sodium bicarbonate) in water, then, 15 minutes later, another ASG dose and oral ¹³C-dextromethorphan. Patients breathe into a bag 1-2 times, and the is bag sealed. ¹³CO_2 levels in the bags are measured.

Blood samples are collected at baseline and periodically for pharmacogenetic and pharmacokinetic studies by reverse phase HPLC with fluorescence detection.

After completion of study therapy, patients are followed annually for 5 years.

Study Type

Observational

Enrollment (Actual)

92

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Arizona
  - Scottsdale, Arizona, United States
    - Mayo Clinic in Arizona
- Minnesota
  - Rochester, Minnesota, United States, 55905
    - Mayo Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 116 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Female breast cancer

Description

DISEASE CHARACTERISTICS:

Eligible to receive tamoxifen for 6 months for either the prevention or treatment of non-invasive or invasive, stage I-III breast cancer
CYP2D6 genotype known
- Patients determined to be CYP2D6 poor metabolizers (by determination of a genotype test by their Mayo physician prior to study registration) are eligible to proceed with the initial breath test only
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Menopausal status not specified
ECOG performance status 0-2
Life expectancy > 6 months
No known impaired hepatic activity defined as ≥ grade 3 AST, alkaline phosphatase, or total bilirubin
No pulmonary disease (e.g., asthma or other respiratory disease) associated with hypercapnia
No uncontrolled metabolic disease (e.g., diabetes in the presence of gastroparesis, uncontrolled congestive heart failure, or uncontrolled gastrointestinal disorders [e.g., GERD])
No prior adverse reaction to dextromethorphan
No history of chronic liver disease (e.g., hepatitis B or hepatitis C, alcoholic liver disease, cirrhosis, or fibrotic disease)
Able and willing to fast overnight prior to the study session
Willing to return to Mayo Clinic for follow-up
Willing to provide biologic specimens

PRIOR CONCURRENT THERAPY:

More than 24 hours since prior medications known to slow gastric emptying or gastrointestinal motility (e.g., alcohol, opioid analgesics, anticholinergics [e.g., antihistamines], and loperamide)
More than 4 weeks since prior and no concurrent CYP2D6 inhibitors or concurrent serotonin-reuptake inhibitors known to be potent CYP2D6 inhibitors (e.g.,paroxetine [Paxil®] and fluoxetine [Prozac®]
- If mild to moderate inhibitors of CYP2D6 are medically necessary, patients may go back on after the 8-week time point
More than 4 weeks since prior and no concurrent monoamine-oxidase inhibitors (e.g., furazolidone, phenelzine, procarbazine, selegiline, and tranylcypromine)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Observational Models: Case-Only
Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Operating Characteristics of the ¹³C-dextromethorphan (13C-DM) Breath Test in Identifying Those Who Are CYP2D6 Genotypic Poor Metabolizers Time Frame: Baseline	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The distribution of CYP2D6 genotypes grouped by CYP2D6 metabolism phenotype for each participants are summarized below.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spearman's Rank Correlation Coefficient Between CYP2D6 Genotype and ¹³Cdextromethorphan Breath Test (DM-BT) Time Frame: Baseline, 3 month and 6 month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and DM-BT values.	Baseline, 3 month and 6 month
Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen Steady State Concentrations (Endx Css) Time Frame: 3 Month and 6 Month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx Css	3 Month and 6 Month
Spearman's Rank Correlation Coefficient Between CYP2D6 Activity Score and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio Time Frame: 3 Month and 6 Month	Spearman rank order correlation coefficients were used to assess the strength of the association between CYP2D6 genotype activity score and Endx/NDMT ratio	3 Month and 6 Month
Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen Steady State Concentrations Time Frame: Baseline, 3 month	Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css)	Baseline, 3 month
Spearman's Rank Correlation Coefficient Between Baseline DM-BT and 3 Month Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio Time Frame: Baseline, 3 month	Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen/N-desmethyl-tamoxifen (Endx/NDMT) Ratio	Baseline, 3 month
Spearman's Rank Correlation Coefficient Between 3 Month DM-BT and 3 Month Endoxifen Steady State Concentrations Time Frame: 3 month	Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css)	3 month
Spearman's Rank Correlation Coefficient Between 6 Month DM-BT and 6 Month Endoxifen Steady State Concentrations Time Frame: 6 month	Spearman rank order correlation coefficients were used to assess the strength of the association between baseline ¹³Cdextromethorphan breath test (DM-BT) and Endoxifen steady state concentrations (Endx Css)	6 month
Median of 3 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 3 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 3 month Tamoxifen steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	3 Month
Median of 6 Month Tamoxifen Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 6 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 6 month Tamoxifen steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	6 Month
Median of 3 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 3 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 3 month NDMT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	3 Month
Median of 6 Month N-desmethyl-tamoxifen (NDMT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 6 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 6 month NDMT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	6 Month
Median of 3 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 3 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 3 month 4HT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	3 Month
Median of 6 Month 4-hydroxy-tamoxifen (4HT) Steady State Plasma Concentrations According to CYP2D6 Phenotype Group Time Frame: 6 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 6 month 4HT steady state plasma concentrations for each CYP2D6 phenotype group are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	6 Month
Median of 3 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score Time Frame: 3 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 3 month Endx Css for each CYP2D6 phenotype group and the corresponding activity score are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	3 Month
Median of 6 Month Endoxifen Steady State Concentrations (Endx Css) According to CYP2D6 Phenotype Group and Activity Score Time Frame: 6 Month	Participants were classified as having CYP2D6 decreased or non-decreased metabolism based on genotype and the co-prescription of inhibitors of the enzyme system. The specific phenotype, alleles and their associated activity score (AS) assessed were as follows: Ultrarapid metabolism (UM) or AS=2.0 (1XN or 2XN), Extensive metabolism (EM) or AS=1.0 (1, 2, and 2A), Intermediate metabolism (IM) or AS=0.5 (9, 10, 17 and 41), and Poor metabolism (PM) or AS=0.0 (3, 4, 5, 7, 8, 11, and *12). The median of 6 month Endx Css for each CYP2D6 phenotype group and the corresponding activity score are summarized below. Refer to Outcome Measure 1 Data Table for details on the combination of genotype for each participant that are defined for each CYP2D6 phenotype group.	6 Month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair: Matthew P. Goetz, M.D., Mayo Clinic
Principal Investigator: Donald W. Northfelt, M.D., Mayo Clinic

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

September 23, 2015

Study Completion (Actual)

September 23, 2015

Study Registration Dates

First Submitted

March 31, 2009

First Submitted That Met QC Criteria