Combination Chemotherapy in Treating Patients With High-Risk Breast Cancer

Randomized Phase II Study of Adriamycin/Cytoxan/Taxol (ACT) vs. Cytoxan, Thiotepa, Carboplatin (STAMP V) in Patients With High-Risk Primary Breast Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying two different regimens of combination chemotherapy and comparing them to see how well they work in treating patients with high-risk primary stage II or stage III breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: paclitaxel; Drug: carboplatin; Drug: thiotepa; Biological: filgrastim; Procedure: peripheral blood stem cell transplantation

Detailed Description

OBJECTIVES:

• Compare the toxic effects of doxorubicin, cyclophosphamide, and paclitaxel vs cyclophosphamide, thiotepa, and carboplatin in patients with high-risk primary breast cancer. (Arm I closed to accural as of 4/6/2006.)
• Compare the efficacies of these regimens followed by peripheral blood stem cell rescue in these patients.
• Determine the efficacy of a bisphosphonate to prevent relapse/metastasis after high-dose chemotherapy in these patients.

OUTLINE: This is a randomized study. Patients are stratified by stage of disease.

Peripheral blood stem cells (PBSC) are collected after mobilization with filgrastim (G-CSF), administered subcutaneously or IV, twice daily beginning 3 days before collection and continuing until collection is complete.

All patients receive conventional-dose adjuvant chemotherapy, probably comprising doxorubicin IV, cyclophosphamide IV, and fluorouracil IV over 1 hour on days 1, 22, 43, and 64. Patients are then randomized to receive 1 of 2 treatment arms of high-dose chemotherapy. (Arm I closed to accrual as of 4/6/2006.)

• Arm I (ACT) (closed to accrual as of 4/6/2006): Patients receive doxorubicin IV over 24 hours on days -9 to -6, cyclophosphamide IV over 2 hours on day -5, and paclitaxel IV over 24 hours on day -2. PBSC are reinfused on days -2 and 0. G-CSF is administered beginning on day 0 and continuing until blood counts recover.
• Arm II (STAMP V): Patients receive cyclophosphamide IV, carboplatin IV, and thiotepa IV over 24 hours on days -7 to -4. PBSC are reinfused and G-CSF is administered as in arm I.

Within 4-6 weeks of day 0 of high-dose chemotherapy, patients with estrogen and/or progesterone receptor positive tumors receive oral tamoxifen twice daily for 5 years. Patients are also randomized to receive a bisphosphonate comprising pamidronate IV every 4 weeks for 2 years.

Quality of life is assessed before therapy, at 30 days after high-dose chemotherapy, and at 6 and 12 months.

Patients are followed every 3 months for 1 year and then every 6 months for at least 10 years.

PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study within 3 years.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically proven high-risk primary breast cancer with less than 60% chance of progression-free survival of 3 years from diagnosis

  • Stage II with at least 10 positive axillary nodes OR
  • Stage IIIA or IIIB
• No histologically proven bone marrow metastasis
• No CNS metastasis

• Hormone receptor status:

  • Hormone receptor status known

PATIENT CHARACTERISTICS:

Age:

• Physiological age 60 or under

Menopausal status:

• Not specified

Performance status:

• Karnofsky 80-100%

Life expectancy:

• See Disease Characteristics

Hematopoietic:

• Neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• SGOT or SGPT no greater than 2 times upper limit of normal
• Hepatitis B antigen negative

Renal:

• Creatinine no greater than 1.2 mg/dL
• Creatinine clearance at least 70 mL/min
• No prior hemorrhagic cystitis

Cardiovascular:

• Ejection fraction at least 55% by MUGA
• No prior significant valvular heart disease or arrhythmia

Pulmonary:

• FEV_1 at least 60% of predicted
• pO_2 at least 85 mm Hg on room air
• pCO_2 at least 43 mm Hg on room air
• DLCO at least 60% lower limit of predicted

Other:

• No other prior malignancy except squamous cell or basal cell skin cancer or stage I or carcinoma in situ of the cervix
• No CNS dysfunction that would preclude compliance
• HIV negative
• No sensitivity to E. coli-derived products
• Not pregnant
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 4 weeks since prior chemotherapy
• No prior doxorubicin of total dose exceeding 240 mg/m^2
• No prior paclitaxel of total dose of at least 750 mg/m^2
• No more than 12 months since prior conventional-dose adjuvant chemotherapy

Endocrine therapy:

• At least 4 weeks since prior hormonal therapy

Radiotherapy:

• At least 4 weeks since prior radiotherapy
• No prior radiation to the left chest wall

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (ACT) (closed to accrual as of 4/6/2006); Patients receive doxorubicin IV over 24 hours on days -9 to -6, cyclophosphamide IV over 2 hours on day -5, and paclitaxel IV over 24 hours on day -2. PBSC are reinfused on days -2 and 0. G-CSF is administered beginning on day 0 and continuing until blood counts recover.	Drug: cyclophosphamide; Given IV; Drug: doxorubicin hydrochloride; Given IV; Drug: paclitaxel; Given IV; Biological: filgrastim; Given IV or subcutaneously; Procedure: peripheral blood stem cell transplantation; Patients receive autologous peripheral blood stem cells
Active Comparator: Arm II (STAMP V); Patients receive cyclophosphamide IV, carboplatin IV, and thiotepa IV over 24 hours on days -7 to -4. PBSC are reinfused and G-CSF is administered as in arm I.	Drug: cyclophosphamide; Given IV; Drug: carboplatin; Given IV; Drug: thiotepa; Given IV; Biological: filgrastim; Given IV or subcutaneously; Procedure: peripheral blood stem cell transplantation; Patients receive autologous peripheral blood stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Five-Year Relapse-free Survival	RFS events included death or disease recurrence. Patients who did not experience disease recurrence or death were censored at the date of last follow-up. Survival rates were estimates using the Kaplan-Meier method.	Five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Five-Year Overall Survival	Patients who were still alive were censored at the date of last follow-up. Survival rates were estimates using the Kaplan-Meier method.	Five Years

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: George Somlo, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 1999
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: December 10, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): August 4, 2015
• Last Update Submitted That Met QC Criteria: July 7, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Carboplatin; Paclitaxel; Doxorubicin; Liposomal doxorubicin; Thiotepa
• Other Study ID Numbers: 98096; P30CA033572 (U.S. NIH Grant/Contract); U01CA063265 (U.S. NIH Grant/Contract); CHNMC-IRB-98096; CHNMC-PHII-18; NCI-H99-0038; CDR0000067305 (Registry Identifier: NCI PDQ)