Protocol Number: 03-C-0037

Title:

A Phase I/II Trial of Tipifarnib (R115777, ZARNESTRA) in Combination with Tamoxifen in Subjects with Metastatic Breast Cancer

Number:

03-C-0037

Summary:

This study will determine the maximum dose of tipifarnib that can be given safely with tamoxifen for patients with advanced (Stage IV) breast cancer and evaluate the effectiveness of the drug combination. Tamoxifen blocks the action of estrogen in some breast cancers and is commonly used to treat this disease, particularly in patients with hormone receptor-positive tumors. Tipifarnib (also known as R115777 or ZARNESTRA) is an experimental drug that is thought to block the signal that tells cancer cells to grow.

Patients 18 years of age or older with breast cancer that has recurred or spread beyond the breast may be eligible for this study. Patients must have hormone-receptor positive cancer and have received at least one course of hormonal therapy with either an aromatase inhibitor or estrogen receptor-modulating drug.

All participants will receive a standard dose of tamoxifen. They will also receive tipifarnib, but the dose of this drug will vary among patients according to when they enter the study. The first patients will receive a low dose of tipifarnib, and the dose will be increased gradually in subsequent groups of patients as long as it does not cause unacceptable side effects. Once the optimum dose of tipifarnib in combination with tamoxifen is determined, the rest of the patients in the study will receive that dose.

Patients will take the drugs in 28-day treatment cycles. They will take tipifarnib twice a day by mouth on days 1 through 21 of each cycle. On day 8 of the first cycle they will start taking tamoxifen and will continue taking this drug by mouth once a day every day for the duration of the study. In addition to drug therapy, patients will undergo the following tests and procedures:

-Medical history, physical examination and blood tests before starting treatment, and possibly a chest x-ray, CT scans, bone scans, or mammograms.

-Biopsies of tumors where the cancer has spread beyond the breast. T hese will be done before starting therapy, after 1 week of tipifarnib, and at some point after combination treatment with tipifarnib and tamoxifen.

-Blood tests at least once a month, plus two studies to measure the amount of tipifarnib and tamoxifen in the blood. The latter studies will be done one day during the first week of therapy and one day during the second month of therapy and may require an overnight hospital stay. For each study, blood will be drawn 14 times within 12 hours at intervals of 30 minutes to 4 hours. If possible, an indwelling catheter will be placed in an arm vein to obtain the blood samples without multiple needle sticks.

-CT scans and bone scans after 2 and 4 months of therapy to evaluate the cancer's response to treatment.

Patients whose disease worsens with treatment will stop the drugs and be advised of other options. Those in whom the tumor remains stable, or shrinks, and who do not have severe drug side effects, may continue treatment indefinitely as long as tipifarnib is available and there is no disease progression or serious side effects.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Phase II -ARM 1: Homone Responsive:

Subjects must have a diagnosis of metastatic (Stage IV) breast cancer with evidence of disease progression. If available, pathologic or cytological material will be reviewed at the NIH CC Laboratory of Pathology.

Subjects must have ER and/or PR positive breast cancer. As few as 1% ER or PR positive cells will be considered hormone receptor positive.

Subjects must be 18 years of age or older.

Subjects must have received no chemotherapy for at least 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to initiating investigational therapy.

Subjects must have been treated with at lest one prior hormonal therapy with either an aromatase inhibitor or an estrogen receptor-modulating drug either in the adjuvant or metastatic setting.

Subjects must have a history of either stable disease (no recurrence or progression) for greater than or equal to 6 months or an objective response with a prior hormonal therapy.

Subjects may have received tamoxifen. However, at least 6 months must have elapsed since prior tamoxifen therapy.

Subjects must have measurable disease as defined further in the protocol.

Subjects must have no evidence of CNS metastases.

Subjects must have had no more than two prior chemotherapy regimens for metastatic disease (there are no limitations on prior neoadjuvant or adjuvant chemotherapy regimens).

Subjects must have recovered from the effects of prior therapy with resolution of any toxicities to less than or equal to grade 1.

Performance Status of Zubrod 0-1

Female subjects of child-bearing potential and male subjects and male partners of female subjects must be willing to use effective non-hormonal contraception while receiving study drugs and for 2 months thereafter.

Subjects must be willing to provide written informed consent.

INCLUSION CRITERIA:

Phase II - Arm 2: Hormone Unresponsive:

Subjects must have a diagnosis of metastatic (Stage IV) breast cancer with evidence of disease progression. If available, pathologic or cytological material will be reviewed at the NIH CC Laboratory of Pathology.

Subjects must have ER and or PR positive breast cancer. As few as 1% ER or PR positive cells will be considered hormone receptor positive.

Subjects must be 18 years of age or older.

Subjects must have received no chemotherapy for at least 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to initiating investigational therapy.

Subjects must have been treated with at lest one prior hormonal therapy with either an aromatase inhibitor or an estrogen receptor-modulating drug either in the adjuvant or metastatic setting.

Subjects must have NO history of either stable disease (no recurrence or progression) for greater than or equal to 6 months or an objective response with a prior hormonal therapy.

Subject may have received tamoxifen. However, at least 6 months must have elapsed since prior tamoxifen therapy.

Subjects must have measurable disease as defined further in the protocol.

Subjects must have no evidence of CNS metastases.

Subjects must have had no more than two prior chemotherapy regimens for metastatic disease (there are no limitations on prior neoadjuvant or adjuvant chemotherapy regimens).

Subjects must have recovered from the effects of prior therapy with resolution of any toxicities to less than or equal to grade 1.

Performance Status of Zubrod 0-1

Female subjects of child-bearing potential and male subjects and male partners of female subjects must be willing to use effective non-hormonal contraception while receiving study drugs and for 2 months thereafter.

Subjects must be willing to provide written informed consent.

EXCLUSION CRITERIA:

Subjects with an absolute neutrophil count of less than 1500/(micro)L

Subjects with a platelet count of less than 100,000/(micro)L

Subjects with no evidence of disease

Subjects who have any medical or psychiatric condition that in the opinion of the Principal Investigator would preclude them from participating in this study

Subjects with a SGOT and SGPT greater than or equal to 3 times the upper limit of normal unless there is liver involvement by tumor.

Subjects with a total bilirubin greater than 2.0 unless there is clinical evidence of Gilbert's disease.

Subjects with a creatinine of greater than 1.5 mg/dL.

Subjects with CNS metastases.

Subjects taking cytochrome p450-inducing anticonvulsants.

Subjects taking warfarin.

Subjects who are pregnant.

Special Instructions: Currently Not Provided

Keywords:

R115777

ZARNESTRA

Selective Estrogen Receptor

Modulator

Pharmacokinetics

Recruitment Keywords:

Breast Cancer

Conditions:

Breast Neoplasms

Investigational Drug(s):

Zarnestra, R115777, Tipifarnib

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000 Jan-Feb;50(1):7-33. PMID: 10735013

[No authors listed] Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998 May 16;351(9114):1451-67. PMID: 9605801

Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779-827. Review. No abstract available. PMID: 3304147

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

Warren Grant Magnuson Clinical Center (CC)
National Institutes of Health (NIH)
Bethesda, Maryland 20892. Last update: 10/23/2004