Tipifarnib, Doxorubicin, and Cyclophosphamide in Treating Women With Locally Advanced Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00049114
First received: November 12, 2002
Last updated: June 5, 2013
Last verified: June 2013
  Purpose

Drugs used in chemotherapy, such as doxorubicin and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining tipifarnib with doxorubicin and cyclophosphamide may kill more tumor cells. Phase II trial to study the effectiveness of combining tipifarnib with doxorubicin and cyclophosphamide in treating women who have locally advanced breast cancer.


Condition Intervention Phase
Inflammatory Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Drug: tipifarnib
Biological: filgrastim
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Pathological complete response in the breast [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    95% confidence intervals of these estimates will be obtained.


Secondary Outcome Measures:
  • Proportion of patients who have a clinical complete response [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    95% confidence intervals of these estimates will be obtained.

  • Grade 3 or 4 toxicities assessed using NCI CTCAE version 3.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicity will be summarized by type, frequency and severity. This will be compared with an historical database.

  • Median disease-free survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be summarized, and 95% confidence intervals of these estimates will be obtained.

  • Percentage of patients free of disease [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Will be summarized, and 95% confidence intervals of these estimates will be obtained.

  • Percentage of patients free of disease [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Will be summarized, and 95% confidence intervals of these estimates will be obtained.


Enrollment: 62
Study Start Date: February 2003
Primary Completion Date: January 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (doxorubicin, cyclophosphamide, tipifarnib, G-CSF)

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 G-CSF subcutaneously on days 2-13. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable 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.

Drug: doxorubicin hydrochloride
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: tipifarnib
Given orally
Other Names:
  • R115777
  • Zarnestra
Biological: filgrastim
Given subcutaneously
Other Names:
  • G-CSF
  • Neupogen
Procedure: therapeutic conventional surgery
Undergo complete resection
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00049114

Locations
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Sponsors and Collaborators
Investigators
Principal Investigator: Joseph Sparano Albert Einstein College of Medicine of Yeshiva University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00049114     History of Changes
Other Study ID Numbers: NCI-2012-02500, 02-05-125, AECM-0205125, NCI-5598, CDR0000257811, N01CM62204
Study First Received: November 12, 2002
Last Updated: June 5, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Inflammatory Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Tipifarnib
Doxorubicin
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on July 22, 2014