This study will examine whether taking garlic supplements affects blood levels of the chemotherapy drug docetaxel in patients with breast cancer. Many cancer patients use herbal dietary supplements, such as garlic, but little is known about how these supplements interact with conventional drugs. Garlic may cause the body to eliminate docetaxel quicker than usual, resulting in lower blood levels of the drug and possibly reducing its effectiveness.

Patients 18 years of age or older with locally advanced or metastatic breast cancer may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, and possibly imaging studies, such as x-rays and CT and MRI scans to evaluate the extent of disease.

Participants receive docetaxel in 4-week cycles. They receive one dose of the drug by vein (intravenous tube) over 60 minutes once a week for 3 consecutive weeks, and no drug the fourth week. They also take dexamethasone 12 hours and 1 hour before and 12 hours after the docetaxel to help prevent fluid retention caused by the drug. Patients will also receive famotidine, diphenhydramine and ondansetron prior to docetaxel. Four days after receiving the first dose of docetaxel, patients start taking garlic tablets twice a day.

Patients have multiple blood draws during the first month of study to measure the docetaxel concentrations in the blood. These blood draws will enable the researchers to determine if there is any changes in the break down and elimination of docetaxel. Additional blood draws for other experimental factors will also be drawn. This may include genetic testing to determine if the patient's cells produce substances that affect the breakdown of different drugs used to fight cancer. Imaging studies are done about every 2 months to determine if the cancer is responding to the treatment. Patients are eligible for treatment until they experience severe side effects or disease progression. After 6 months, patients have a monthly chest x-ray to check for fluid around the lining of the lungs, which may develop as a result of docetaxel therapy.

Docetaxel treatment is given on an outpatient basis, except for the first cycle, in which patients may spend the first night each week in the NIH Clinical Center. After the first cycle, patients may choose to be treated by a cancer doctor closer to their home. In that case, they return to the Clinical Center on the first day of every cycle for a doctors' appointment and refill of their garlic capsules.

Condition	Treatment or Intervention	Phase
Breast Neoplasms	Drug: Docetaxel  Procedure: Blood draw	Phase I

Further Study Details: 

Expected Total Enrollment:  12

Herbal dietary supplements are widely used, but few data are available on their interactions with conventional drugs used in the treatment of cancer. The study described in this proposal will evaluate the effects of a widely used supplement, garlic, on the in vivo pharmacokinetics of docetaxel, a substrate of cytochrome P450 3A (CYP3A). Garlic has been shown to induce CYP3A and several transferases, suggesting the simultaneous administration of this herb stimulates docetaxel metabolism and compromises antitumor activity. Patients will receive docetaxel at a dosage of 30 mg/m2 given as a 60-minute intravenous infusion once every week for 3 out of 4 consecutive weeks. Patients will be treated on a 28-day cycle. On day 5 of cycle 1, patients will begin taking garlic caplets (600 mg two times a day). All patients will continue this comedication through day 17. Patients have the option of continuing garlic as long as they remain on study. Blood samples will be obtained on days 1-2, 8-9, and 15-16 for determination of docetaxel plasma pharmacokinetic parameters. Differences in the parameters between treatment periods will be analyzed by paired t-test or Wilcoxon signed rank test. Nine patients will be needed for analysis, with an estimated accrual of 12. All agents used in the study are commercially available. Patients will also consent to single polymorphism nucleotide genotyping to assess transporter or enzyme polymorphisms.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Patients must have histologically confirmed adenocarcinoma of the breast. All specimens will be reviewed by the Laboratory of Pathology, NCI. Patients are not required to have measurable disease.
Patients with incurable, locally advanced or metastatic breast cancer, in whom therapy with docetaxel is a reasonable option.
Age at least 18 years.
Patients with an ECOG performance status less than or equal to 2
Patients must have a life expectancy of at least 12 weeks.
Patients must have adequate organ function as defined by:
Neutrophils greater than or equal to 1.2 times 10(9)/L,
Platelets greater than or equal to 100 times 10(9)/L,
Creatinine within normal institutional limits or if above institutional ULN, measured creatinine clearance greater than or equal to 60 ml/min, Total bilirubin within normal institutional limits
LDH, SGOT/AST and SGPT/ALT less than or equal to 2 times the upper limit of normal (unless due to liver metastases, then less than or equal to 3 times the upper limit of normal).
Patients must be able to sign written informed consent.
EXCLUSION CRITERIA:
Patients who have progressed on docetaxel therapy within the preceding two months.
Patients who have had immunotherapy, chemotherapy or radiotherapy less than 3 weeks (less than 6 weeks for nitrosureas or mitomycin C) or hormonal therapy less than 2 weeks prior to entering the study.
HIV-positive patients receiving combination anti-retroviral therapy will be excluded because of possible pharmacokinetic interactions with garlic, docetaxel or other agents administered during the study.
Patients that require antiepileptic medications.
Patients on alprazolam, cyclosporine, diltiazem, dofetilide, erythromycin, fluvoxamine, itraconazole, ketoconazole, quinine, St. John's Wort, tacrolimus (FK506), theophylline, warfarin, or zolpidem will be excluded. Patients will be asked to refrain from grapefruit juice during the first month of study, as well as other herbal therapies.
Present clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan. A patient with brain and/or leptomeningeal metastases may be included only if he/she is asymptomatic on neurological examination, is not receiving corticosteroid therapy to control symptoms, and has stable lesions.
Patients who are on concurrent investigational agent(s).
Patients with a history of Grade 3 or 4 allergic reaction attributed to compounds of similar or biologic composition to garlic, docetaxel, or Tween 80.
Patients with uncontrolled intercurrent illness including active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes mellitus, psychiatric illness or social situation that would limit compliance with study requirements.
Patients who are pregnant or lactating.
Concurrent severe medical problems unrelated to the malignancy that would limit full compliance with the study or expose the patient to extreme risk.
Patients who have received an investigational drug within 30 days or 5 half-lives prior to entry in the study (whichever is longer).
Patients of childbearing potential, not practicing adequate contraception. Adequate contraception will include a form of barrier contraception during the trial period.
Patients that are unable to ingest oral medication, known to have gastric emptying disorders, or have persistent diarrhea.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040084; 04-C-0084
Record last reviewed:  November 17, 2004
Last Updated:  November 23, 2004
Record first received:  January 14, 2004
ClinicalTrials.gov Identifier:  NCT00076193
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08