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A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer

Phase 2
18 Years
Not Enrolling
Inflammatory Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Thank you

Trial Information

A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer


I. Determine the maximum tolerated dose of tipifarnib when administered with doxorubicin and
cyclophosphamide in women with metastatic breast cancer (non-regional stage IV disease).
(Phase I closed to accrual as of 1/19/04) II. Determine the pathologic complete remission
rate in patients with locally advanced breast cancer (stages IIB, IIIA, IIIB, or IIIC)
treated with the recommended phase II dose of this regimen.


I. Determine the clinical complete response rate in patients treated with this regimen.

II. Determine the toxicity profile of this regimen in these patients. III. Correlate
pretreatment levels of ErbB1, 2, 3, 4 and phosphorylated levels of Akt, STAT3, and Erk ½
with clinical response in these patients and with percent inhibition of proliferation
(Ki-67) and percent induction of apoptosis in post-treatment tumor specimens.

IV. Correlate percent decrease of farnesyltransferase (FTase) activity levels, HDJ-2
farnesylation, phospho-Akt, phospho-STAT3, and phospho-Erk ½ with clinical response rates in
these patients and with percent inhibition of proliferation (Ki-67) and percent inhibition
of apoptosis.

OUTLINE: This is a multicenter, dose-escalation study of tipifarnib. Patients are stratified
according to presence of inflammatory carcinoma (yes vs no).

PHASE I (nonregional stage IV disease) (closed to accrual as of 1/19/04): Patients receive
doxorubicin IV over 10-15 minutes and cyclophosphamide IV over 30 minutes on day 1, oral
tipifarnib twice daily on days 2-7, and filgrastim (G-CSF) subcutaneously on days 2-13.
Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

PHASE II (stage IIB, IIIA, IIIB, or IIIC): Patients receive tipifarnib at the MTD and
doxorubicin, cyclophosphamide, and G-CSF as in phase I (phase I closed to accrual as of
1/19/04). After the fourth course, patients may undergo complete resection.

Patients are followed every 3-4 months for 3 years, every 6 months for 2 years, and then
annually thereafter.

PROJECTED ACCRUAL: Approximately 3-12 patients will be accrued for phase I (closed to
accrual as of 1/19/04) of this study. A total of 21-50 patients will be accrued for phase II
of this study.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the breast

- Phase I (closed to accrual as of 1/19/04):

- Nonregional stage IV disease

- Phase II:

- Locally advanced disease, according to AJCC staging criteria:

- Stage IIB

- Stage IIIA

- Stage IIIB

- Stage IIIC

- At least 1 bidimensionally or unidimensionally measurable indicator lesion

- Hormone receptor status:

- Not specified

- Female

- Performance status - ECOG 0-1

- Performance status - Karnofsky 70-100%

- Not specified

- WBC at least 3,000/mm^3

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Bilirubin normal

- AST/ALT no greater than 2.5 times upper limit of normal

- Creatinine normal

- Creatinine clearance at least 60 mL/min

- LVEF normal

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No cardiac arrhythmia

- No other invasive malignancies within the past 5 years except curatively treated
basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

- No prior allergic reactions attributed to compounds of similar chemical or
biological composition to tipifarnib or other agents used in the study (e.g.,
imidazoles or quinolones)

- No ongoing or active infection

- No other concurrent uncontrolled illness that would preclude study participation

- No psychiatric illness or social situation that would preclude study compliance

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Not specified

- Phase I (closed to accrual as of 1/19/04):

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or
mitomycin) and recovered

- No more than 1 prior adjuvant/neoadjuvant regimen and 1 prior regimen for
metastatic disease

- Prior doxorubicin allowed provided the following are true:

- Used in adjuvant setting

- Cumulative dose was no greater than 240 mg/m^2

- At least 1 year between completion of adjuvant therapy and relapse

- Phase II:

- No prior chemotherapy for locally advanced breast cancer

- At least 1 week since prior tamoxifen or other selective estrogen receptor
modulators for prevention or other indications (e.g., osteoporosis, ductal carcinoma
in situ, or invasive breast cancer)

- Phase I (closed to accrual as of 1/19/04):

- More than 4 weeks since prior radiotherapy

- Phase II:

- No prior radiotherapy for locally advanced breast cancer

- Not specified

- No antacids within 2 hours of study drug administration

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer therapy

- No other concurrent investigational agents

Type of Study:


Study Design:

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

Outcome Measure:

Pathological complete response in the breast

Outcome Description:

95% confidence intervals of these estimates will be obtained.

Outcome Time Frame:

8 weeks

Safety Issue:


Principal Investigator

Joseph Sparano

Investigator Role:

Principal Investigator

Investigator Affiliation:

Albert Einstein College of Medicine of Yeshiva University


United States: Food and Drug Administration

Study ID:




Start Date:

February 2003

Completion Date:

Related Keywords:

  • Inflammatory Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Breast Neoplasms
  • Inflammatory Breast Neoplasms



Albert Einstein College of Medicine Bronx, New York  10461