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A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6


Phase 4
18 Years
N/A
Open (Enrolling)
Both
Breast Cancer

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Trial Information

A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6


Endocrine therapy has proven to be an extremely effective therapy in breast cancer. For
women with hormone-receptor-positive tumors, tamoxifen given for as little as two years
results in a statistically significant recurrence and survival benefit. The benefits
increase as the duration of treatment increase, up to 5 years, so that among women treated
for five years, tamoxifen can result in up to a 46 percent annual reduction in the
recurrence rate and up to a 28 percent annual reduction in the death rate. This means that
about half of the recurrences and more than one fourth of the deaths each year are prevented
by tamoxifen treatment. However, despite initial successful responses, many patients on
tamoxifen relapse and die from progressive disease. Consequently, tamoxifen resistance
remains a major clinical problem in the management of breast cancer.

Tamoxifen is metabolized by cytochrome P450 2D6 (CYP2D6) to the more potent metabolites
4-hydroxy-tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Variations in
the metabolic capacity of this enzyme have shown to be an independent predictor of breast
cancer relapse and death. To date, studies have not correlated tamoxifen doses to CYP2D6
genotype status or associated tamoxifen doses to endoxifen and 4-OH-tamoxifen.

We plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients
with a genetic CYP2D6 polymorphism. We also plan to investigate other genetic variations in
the metabolism of tamoxifen. The possible identification of gene variants that alter
tamoxifen's metabolism may improve initial dose selection and therefore optimize treatment
outcome in the future.

In addition to examining polymorphisms in CYP2D6, we will examine other genes that may
influence the metabolism of medications.


Inclusion Criteria:



- Women taking tamoxifen 20mg a day

- Tamoxifen use for > 90 days.

- Use an accepted barrier form of contraception.

Exclusion Criteria:

- Patients are excluded if they are pregnant or lactating; if pre- menopausal, the
patient will have a documented negative pregnancy test and use an accepted barrier
form of contraception.

- Patients are excluded if they have a medical history of Hepatitis B. Hepatitis C or
HIV

- Patients are excluded if they use Tobacco

- Patients are excluded if they have a medical history of hereditary hemochromatosis

- Patients are excluded if they have elevated AST (SGOT), ALT (SGPT), Biliribin or
Alkaline Phosphate

o Defined as greater than 2 1/2 times the upper limit of normal

- Patients are excluded if they are being treated with chemotherapy

- Patients are excluded if they are taking any of the following oral medications, as
they are potent CYP2D6 inhibitors:

- Fluoxetine (Prozac)

- Miconazole (Monistat)

- Paroxetine (Paxil)

- Quinidine

- Ritonavir (Norvir)

- Atorvastatin (Lipitor)

- Carvedilol (Coreg)

- Clarithromycin (Biaxin)

- Dipyridamole (Persantine)

- Erythromycin

- Grapefruit Juice

- Itraconazole (Sporanox)

- Ketoconazole

- Mefloquine

- Nelfinavir (Viracept)

- Nicardipine (Cardene)

- Nilotinib

- Propranolol (Inderal)

- Ranolazine (Ranexa)

- Saquinavir ( Invirase)

- Verapamil Covera-HS

- Warfarin (Coumadin)

- Chlorpromazine (Thorazine)

- Cinacalcet (Sensipar)

- Delavirdine (Rescriptor)

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Specific human 2D6 variants measurement(s) or observation(s)

Outcome Time Frame:

every two weeks

Safety Issue:

No

Principal Investigator

Myra Barginear, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mount Sinai School of Medicine

Authority:

United States: Institutional Review Board

Study ID:

GCO# 08-1373

NCT ID:

NCT00900744

Start Date:

January 2009

Completion Date:

January 2010

Related Keywords:

  • Breast Cancer
  • Tamoxifen
  • Breast Cancer
  • Breast Neoplasms

Name

Location

Mount Sinai School of MedicineNew York, New York  10029