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

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

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.

Study Overview

• Status: Completed
• Conditions: Inflammatory Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: tipifarnib; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Biological: filgrastim; Procedure: therapeutic conventional surgery

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.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College Of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response in the breast	95% confidence intervals of these estimates will be obtained.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who have a clinical complete response	95% confidence intervals of these estimates will be obtained.	8 weeks
Grade 3 or 4 toxicities assessed using NCI CTCAE version 3.0	Toxicity will be summarized by type, frequency and severity. This will be compared with an historical database.	Up to 5 years
Median disease-free survival	Will be summarized, and 95% confidence intervals of these estimates will be obtained.	Up to 5 years
Percentage of patients free of disease	Will be summarized, and 95% confidence intervals of these estimates will be obtained.	1 year
Percentage of patients free of disease	Will be summarized, and 95% confidence intervals of these estimates will be obtained.	2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joseph Sparano, Albert Einstein College Of Medicine

Study record dates

Study Major Dates

• Study Start: February 1, 2003
• Primary Completion (Actual): January 1, 2007

Study Registration Dates

• First Submitted: November 12, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): June 6, 2013
• Last Update Submitted That Met QC Criteria: June 5, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Inflammatory Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Tipifarnib
• Other Study ID Numbers: NCI-2012-02500; N01CM62204 (U.S. NIH Grant/Contract); 02-05-125; AECM-0205125; NCI-5598; CDR0000257811