Tamoxifen Citrate in Patients With Breast Cancer

Tamoxifen Metabolism and the Impact of Tamoxifen Dose on the Level of the Active Metabolites in Endocrine Sensitive Breast Cancer Patients

RATIONALE: Estrogen can promote growth of endocrine sensitive breast cancer cells. Endocrine therapy with tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells. Pharmacokinetics and -genomics can have an impact on the efficacy of the treatment.

PURPOSE: This phase III trial is studying blood samples to see if the level of active metabolites of tamoxifen can be improved in patients with breast cancer.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: tamoxifen citrate

Detailed Description

OBJECTIVES:

Primary

• To determine how the increase of tamoxifen citrate dose influences the level of its major metabolites in patients with hormone-sensitive breast cancer.

Secondary

• To characterize the population pharmacokinetic profile
• To investigate the role of the other CYPs
• To assess the relation between clinical symptoms and CYP2D6 genotypes and/or active metabolites levels
• To explore the correlation between genotypes/metabolites levels and clinical outcomes in terms of tumor relapse.
• To assess the feasibility, efficacy, and safety of concentration-guided adjustment of tamoxifen citrate dosage.
• To conduct other exploratory analysis based on the eventual new data coming up in the future.

OUTLINE: Patients receive oral tamoxifen citrate (at a dose of 40 mg/day) daily for 4 months in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for PK, genotyping, phenotyping, and further analysis.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Genève, Switzerland, 1211
    • Recruiting
    • Hopitaux Universitaire de Geneve
    • Contact: Alexandre Bodmer, MD; Phone Number: 41 22 382 40 14
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Centre Hospitalier Universitaire Vaudois
    • Contact: Khalil Zaman, MD; Phone Number: 41-21-314-0168; Email: Khalil.Zaman@chuv.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of breast cancer

  • Hormone-sensitive breast cancer defined as > 10% estrogen receptor and/or > 10% progesterone receptor positivity by immunohistochemistry
• Receiving treatment with tamoxifen citrate and must be eligible for exposure to higher doses

PATIENT CHARACTERISTICS:

• No history of deep venous thrombosis or pulmonary embolism
• No history of endometrial carcinoma
• No known history of vaginal bleeding, endometriosis, endometrial hyperplasia, endometrial hypertrophy, and/or polyps
• Not pregnant or nursing
• No contraindication to tamoxifen citrate treatment
• No known allergy to midazolam or dextromethorphan

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tamoxifen	Other: pharmacological study; Other: laboratory biomarker analysis; Drug: tamoxifen citrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determination of CYP2D6 genotype and determination of plasma concentrations of tamoxifen citrate and its metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen) under the 20 mg daily and 40 mg daily schedules	Jan 2013

Secondary Outcome Measures

Outcome Measure	Time Frame
Patients' characteristics	prospectively
Tumor characteristics	prospectively
Cancer treatments history	prospectively
CYP3A4 (phenotype), and possibly other cytochromes involved in the metabolism and transport of drugs	prospectively
Characteristics of drug intake (date of tx initiation, current dosage and frequency, time of last intake) along with patient-reported adherence, assessed by questionnaire	prospectively
Concomitant medication	prospectively
Presence and quantitation of clinical symptoms	prospectively
Detection and classification of general comorbidities and side effects according to NCI-CTC v3.0	prospectively
Detection of tumor relapse during the observation period of the study	prospectively

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois
• Investigators: Principal Investigator: Khalil Zaman, MD, Centre Hospitalier Universitaire Vaudois

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Anticipated): September 1, 2013
• Study Completion (Anticipated): December 1, 2013

Study Registration Dates

• First Submitted: August 20, 2009
• First Submitted That Met QC Criteria: August 20, 2009
• First Posted (Estimate): August 21, 2009

Study Record Updates

• Last Update Posted (Estimate): August 2, 2013
• Last Update Submitted That Met QC Criteria: July 31, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: breast cancer; Pharmacokinetics; tamoxifen; phenotyping; endocrine sensitive; genotyping; Endoxifen
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: CDR0000650376; CHUV-CEPO-TM; EU-20973