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A Phase I-II Study of R115777 (Tipifarnib, Zarnestra®) Plus Sequential Weekly Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide in Patients With Stage IIB-IIIC Breast Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Breast Cancer, Male 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 (Tipifarnib, Zarnestra®) Plus Sequential Weekly Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide in Patients With Stage IIB-IIIC Breast Cancer


I. To determine the recommended phase II dose of tipifarnib when given together with
paclitaxel in patients with stage IIB-IIIC breast cancer. (Phase I) II. To determine the
pathologic complete remission rate (including breast and breast plus axillary nodes) in
patients treated with sequential paclitaxel and tipifarnib followed by dose-dense
doxorubicin hydrochloride, cyclophosphamide, and tipifarnib. (Phase II) III. To determine
the feasibility and safety of this regimen in these patients. (Phase I and II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of tipifarnib followed by a
phase II study.

PHASE I: Paclitaxel plus tipifarnib: Patients receive paclitaxel IV over 1 hour on day 1 and
oral tipifarnib twice daily on days 1-3.

Treatment repeats weekly for 12 courses in the absence of disease progression or
unacceptable toxicity. Patients with no evidence of disease progression after 12 courses
proceed to AC chemotherapy plus tipifarnib. Cohorts of 3-6 patients receive escalating doses
of tipifarnib until the recommended phase II dose (RTPD) is determined. The RTPD is defined
as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting

AC chemotherapy plus tipifarnib: Patients receive doxorubicin hydrochloride IV over 5-10
minutes and cyclophosphamide IV over 30-60 minutes on day 1, oral tipifarnib twice daily on
days 2-7, and pegfilgrastim subcutaneously on day 2.

Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or
unacceptable toxicity.

PHASE II: Patients receive paclitaxel and tipifarnib at the RTPD and AC chemotherapy plus
tipifarnib as in phase I. After completion of AC plus tipifarnib (in both phases), patients
are re-evaluated for surgery (i.e., modified radical mastectomy, radical mastectomy,
segmental mastectomy or lumpectomy with an axillary lymph node dissection).

After completion of study treatment, patients are followed every 6 months for 5 years and
then annually for 5 years.

Inclusion Criteria:

- Bilirubin normal

- AST and ALT =< 2.5 times upper limit of normal

- LVEF normal by echocardiogram or nuclear scan

- Creatinine normal OR Creatinine clearance >= 60 mL/min

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

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to tipifarnib or other study drugs (e.g., imidazoles or

- No other uncontrolled illness including, but not limited to, any of the following:
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia or psychiatric illness/social situations that would
preclude study compliance

- Not pregnant or nursing

- Negative pregnancy test

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

- FEV1 >= 1 L* and DLCO >= 50%* [Note: *Only if baseline CT scan of chest shows
parenchymal lung disease OR there is a history of chronic obstructive or other
pulmonary disease]

- No prior chemotherapy, radiotherapy, or definitive therapeutic surgery (e.g.,
mastectomy, lumpectomy, or axillary dissection) for this cancer but prior sentinel
lymph node biopsy for this malignancy allowed

- No prior adjuvant chemotherapy for a previous breast malignancy

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- Histologically or cytologically confirmed adenocarcinoma of the breast; clinical
stage IIB, IIIA, IIIB, or IIIC disease

- HER-2/neu-negative by DAKO Herceptest or fluorescence in situ hybridization (FISH)

- The following prior or concurrent diagnoses are allowed:

- Lobular carcinoma in situ

- Contralateral ductal carcinoma in situ

- Contralateral invasive ductal and/or lobular cancer

- Hormone receptor status:

- Estrogen and/or progesterone receptor-positive* [Note: *Patients enrolled on the
phase I portion of the trial may have estrogen and progesterone
receptor-negative disease]

- WBC >= 3,000/mm^3

- Absolute neutrophil count >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- ECOG performance status 0-1

- Fertile patients must use effective contraception

Type of Study:


Study Design:

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

Outcome Measure:

Recommended phase II dose of tipifarnib when combined with weekly sequential paclitaxel (phase I)

Outcome Time Frame:

2 weeks

Safety Issue:


Principal Investigator

Dawn Hershman

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2007

Completion Date:

Related Keywords:

  • Breast Cancer
  • Male Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



Albert Einstein College of Medicine Bronx, New York  10461
H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612
Weill Medical College of Cornell University New York, New York  10021
Mount Sinai Medical Center New York, New York  10029
Montefiore Medical Center Bronx, New York  10467-2490
M D Anderson Cancer Center Houston, Texas  77030
Columbia University Medical Center New York, New York  10032