Clinical trial NCT00764322: Studying Blood Samples From Women With Breast Cancer or Ductal Carcinoma In Situ Who Are Receiving Tamoxifen
Official title: Validating CYP2D6 Genotype-Guided Tamoxifen Therapy for a Multiracial U.S. Population
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Menopausal Symptoms
Keywords: menopausal symptoms
recurrent breast cancer
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
ductal breast carcinoma in situ
breast cancer in situ
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-10-02
Enrollment: 501
Sex: FEMALE
Minimum age (years): 21
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Studying samples of blood from patients with cancer in the laboratory may help doctors learn more about differences in DNA and predict how well patients will respond to treatment and plan better treatment.

PURPOSE: This clinical trial is studying blood samples from women with breast cancer or ductal carcinoma in situ who are receiving tamoxifen.

Detailed description: OBJECTIVES:

Primary

* To evaluate the change in endoxifen levels after an increase in tamoxifen citrate dose from 20 mg to 40 mg in women with breast cancer or ductal breast carcinoma in situ with intermediate-metabolizing CYP2D6 genotypes.

Secondary

* To evaluate the tolerability of increasing the dose of tamoxifen citrate from 20 to 40 mg per day in these patients.
* To assess the feasibility of obtaining pharmacogenomic information from patients in the clinical setting and using it to guide changes in therapy.
* To examine CYP2D6 allele frequencies and endoxifen levels among African-American women taking tamoxifen citrate.
* To evaluate the change in plasma endoxifen levels after an increase in the tamoxifen citrate dose from 20 mg to 40 mg daily in patients with poor-metabolizing genotypes.
* To study patient understanding of pharmacogenomics and obstacles to participation in clinical trials based upon germline DNA.

OUTLINE: This is a multicenter study.

Blood samples are collected at baseline to determine CYP2D6 genotype and tamoxifen citrate metabolic status: poor-metabolizing (PM), intermediate-metabolizing (IM), or extensive-metabolizing (EM) alleles. Samples are also analyzed for plasma levels of endoxifen and N-desmethyltamoxifen and for endoxifen/N-desmethyltamoxifen ratio. Patients found to be IM or PM are notified to increased tamoxifen citrate to 40 mg/day for 4 months (in the absence of unacceptable toxicity) with repeat endoxifen and N-desmethyltamoxifen levels (and the ratio) at the end of this time.

All patients complete Quality Of Life (QOL) and Menopausal Symptoms Scale (MSS) questionnaires at baseline and after 4 months of treatment. Toxicities are assessed at the end of 4 months. Patients undergo repeat questionnaire assessment of their understanding of the use of pharmacogenomics in clinical decision-making. Some patients also undergo a 30-minute, baseline interview regarding attitudes and experience towards participation in a pharmacogenomics study.

Patients who choose to be informed of the results of their genotyping are contacted by letter, along with their physicians, and offered genetic counseling to discuss the significance of these results.

After completion of study therapy, patients are followed at 3-6 months, including toxicity assessment and QOL and MSS questionnaires.

Eligibility criteria: Inclusion:

Histologically confirmed invasive carcinoma of the breast or ductal breast carcinoma in situ Has been receiving tamoxifen citrate at a dose of 20 mg/day for at least 4 months either for the treatment of invasive or non-invasive carcinoma of the breast or for breast cancer recurrence prevention

* Expected duration of tamoxifen citrate treatment at least 6 months Hormone receptor status not specified Concurrent participation in non-treatment studies allowed provided it will not interfere with participation in this study Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 6 months Absolute Neutrophil Count (ANC) ≥ 1.0 x 10\^9/L Platelet count ≥ 100 x 10\^9/L Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal (ULN) Total bilirubin ≤ 2.5 times ULN Creatinine clearance ≥ 50 mL/min Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

* No limitations to number of prior therapies
* No limitations for prior radiotherapy
* More than 14 days since prior and no other concurrent investigational agent

Exclusion:

Not pregnant or nursing No active, serious infection or medical or psychiatric illness likely to preclude study participation No psychiatric conditions that would preclude study compliance or informed consent No history of venous thromboembolism, transient ischemic attack, or cerebral vascular accident No history of allergic reaction to tamoxifen citrate or any of its reagents No concurrent coumadin

No concurrent medications known to inhibit CYP2D6, including any of the following:

* Amiodarone
* Haloperidol
* Indinavir
* Ritonavir
* Quinidine

No concurrent selective serotonin reuptake inhibitors, except the following:

* Venlafaxine
* Citalopram

Primary outcomes:
measure: Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes
timeFrame: 4 months
Secondary outcomes:
measure: Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer
timeFrame: Approximately ten months from registration to last follow-up
measure: Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy
timeFrame: Baseline and 4 months after dose increase
measure: CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate
timeFrame: baseline
measure: Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes
timeFrame: Baseline and 4 months after dose increase
measure: Patient Understanding of Pharmacogenomics
timeFrame: baseline
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Blumenthal Cancer Center at Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Regional Cancer Center at Wesley Long Community Hospital
state: North Carolina
city: Greenville
country: United States
facility: Leo W. Jenkins Cancer Center at ECU Medical School
state: North Carolina
city: Raleigh
country: United States
facility: Rex Cancer Center at Rex Hospital
state: North Carolina
city: Spartanburg
country: United States
facility: Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
state: South Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Lisa A. Carey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bon Secours Virginia Health System / Bon Secours Cancer Institute
name: William J. Irvin, MD
role: PRINCIPAL_INVESTIGATOR
References: