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S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT00070564
First received: October 3, 2003
Last updated: May 22, 2013
Last verified: May 2013
History of Changes
  Purpose

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them after surgery may kill any remaining tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating resected breast cancer.

PURPOSE: This randomized phase III trial is comparing 2 different regimens of combination chemotherapy to see how well they work in treating patients who have undergone surgery for stage I, stage II, or stage III breast cancer.


Condition Intervention Phase
Breast Cancer
 Biological: pegfilgrastim
Drug: AC regimen
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: paclitaxel
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase III Trial of Continuous Schedule AC + G vs. Q 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Therapy in Node-Positive or High-Risk Node-Negative Breast Cancer

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Southwest Oncology Group:

Primary Outcome Measures:
  • Disease-free survival by medical history, physical exam, and mammograms every 6 months (annually for mammograms) for 5 years and then annually for 15 years or until death [ Time Frame: every 6 months (annually for mammograms) for 5 years and then annually for 15 years or until death ] [ Designated as safety issue: No ]
  • Compare overall survival of patients among the 2 treatment arms by medical history and physical exam every 6 months for 5 years and then annually [ Time Frame: Every 6 months for 5 years then annually ] [ Designated as safety issue: No ]
  • Compare toxicity among the 2 treatment arms by medical history and physical exam every 6 months for 5 years and then annually [ Time Frame: Every 6 months for 5 years and then annually ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Compare disease-free survival of patients among the 2 treatment arms by assessment of medical history, physical exam, and mammograms every 6 months (annually for mammograms) for 5 years and then annually for 15 years or until death [ Time Frame: every 6 months (annually for mammograms) for 5 years and then annually for 15 years or until death ] [ Designated as safety issue: No ]
  • Compare prognostic biomarkers with outcome and the interaction of these markers with treatment as measured by gene expression analysis before study entry [ Time Frame: pre-study ] [ Designated as safety issue: No ]

Estimated Enrollment: 3250
Study Start Date: November 2003
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I
(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
Experimental: Arm II
(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
Active Comparator: Arm III
(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
Experimental: Arm IV
(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
Experimental: Arm V
Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
Experimental: Arm VI
Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
 Biological: pegfilgrastim
Given IV
Drug: AC regimen
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV

  Hide Detailed Description

Detailed Description:

OBJECTIVES:

  • Compare the disease-free survival of patients with node-positive or high-risk node-negative breast cancer treated with 2 different schedules of adjuvant doxorubicin, cyclophosphamide, and paclitaxel.
  • Compare the overall survival of patients treated with these regimens.
  • Compare the toxic effects of these regimens in these patients.
  • Correlate outcome with putative prognostic markers in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms (arms V and VI) (arms I-IV closed 11/10/10).

  • Arm I: (closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

  • Arm II: (closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses.

Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I.

  • Arm III: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

  • Arm IV: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II.

Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III.

  • Arm V: Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

  • Arm VI: Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

In all arms patients with HER2/neu-positive tumors also receive trastuzumab (Herceptin®) weekly or every 3 weeks beginning concurrently with paclitaxel OR 3 months after the last dose of paclitaxel and continuing for up to 52 weeks.

In all arms, patients with estrogen-receptor or progesterone-receptor positive tumors receive hormonal therapy beginning within 28 days of the completion of adjuvant chemotherapy or radiotherapy (if given).

After finishing study treatment patients are followed up every 6 months for 5 years and then once a year for up to 15 years.

PROJECTED ACCRUAL: A total of 3,250 patients will be accrued for this study.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed stage I-III invasive breast cancer

    • Operable disease
    • Stage I, II, IIIA, and IIIC (T1-3, N3a only)
    • No T4 tumors

  • High-risk disease, defined by 1 of the following:

    • Tumor ≥ 2 cm in greatest diameter (includes both invasive and intraductal component)

      • Patients with nodal status of N0+ (i.e., no cluster of tumor cells in any node greater than 0.2 mm) are considered to be node negative and must have a primary tumor ≥ 2 cm in size or have a tumor ≥ 1 cm with high risk features
      • Patients who are node negative on the basis of a sentinel node procedure and fewer than 6 axillary nodes are removed are eligible OR at least 6 axillary or intramammary nodes must be negative

    • Tumor ≥ 1 cm in diameter and meeting 1 of the following criteria:

      • ER-negative and PgR-negative
      • ER-positive or PgR-positive with a Genomic Health Recurrence Score of ≥ 26

    • One or more axillary or intramammary nodes are involved by metastatic breast cancer

      • If one or more nodes is involved, a minimum of 6 axillary or intramammary nodes must have been examined histologically
      • Patients with N0(I+) disease will be considered node negative
  • HER2/neu-positive tumors (3+ by immunohistochemical staining or amplified by fluorescence in-situ hybridization) allowed
  • Bilateral synchronous breast cancer diagnosed within 1 month of each other allowed provided the higher TNM stage primary tumor meets the eligibility criteria

  • Prior modified radical mastectomy OR local excision of all tumors with axillary lymph node dissection or sentinel node resection required

    • No more than 84 days since prior surgery for the primary tumor and/or axilla
    • Final resection margins for the primary tumor must be histologically negative for invasive cancer and ductal carcinoma in situ
    • Resection margins positive for lobular carcinoma in situ are allowed

  • Hormone receptor status:

    • Estrogen receptor status known
    • Progesterone receptor status known

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Sex

  • Male or female

Menopausal status

  • Not specified

Performance status

  • Zubrod 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count at least 1,200/mm^3
  • Platelet count at least 100,000/mm^3

Hepatic

  • Bilirubin no greater than upper limit of normal (ULN)
  • Alkaline phosphatase no greater than 2 times ULN
  • SGOT or SGPT no greater than 2 times ULN

Renal

  • Creatinine no greater than ULN

Cardiovascular

  • No congestive heart failure
  • No active angina pectoris
  • LVEF greater than or equal to the lower limit of normal* by MUGA or echocardiogram NOTE: Patients age 60 and over OR with a history of hypertension

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

  • No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, in situ cervical carcinoma, or lobular carcinoma in situ of the breast

    • Prior invasive breast cancer or ductal carcinoma in situ allowed if disease-free for 5 years
  • HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Not specified

Chemotherapy

  • No prior cytotoxic chemotherapy for this breast cancer
  • No prior chemotherapy with an anthracycline, anthracenedione, or taxane

Endocrine therapy

  • Not specified

Radiotherapy

  • No prior radiotherapy for this malignancy
  • At least 2 weeks since prior radiotherapy for ductal carcinoma in situ

Surgery

  • See Disease Characteristics
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00070564

  Show 542 Study Locations
Sponsors and Collaborators
Southwest Oncology Group
National Cancer Institute (NCI)
Investigators
Study Chair: George Thomas Budd, MD The Cleveland Clinic
Study Director: Halle C Moore, MD The Cleveland Clinic
  More Information

Additional Information:
Clinical trial summary from the National Cancer Institute's PDQ® database  This link exits the ClinicalTrials.gov site
Featured trial article  This link exits the ClinicalTrials.gov site

Publications:
Budd GT, Barlow WE, Moore HC, et al.: First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early breast cancer. [Abstract] J Clin Oncol 29 (Suppl 15): A-1004, 2011.
Ambrosone CB, Sucheston LE, Zhao H, et al.: Variants in the BRCA1/Fanconi-anemia repair pathway and taxane-induced neuropathy in SWOG S0221. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-2001, 2009.

Responsible Party: Southwest Oncology Group
ClinicalTrials.gov Identifier: NCT00070564     History of Changes
Other Study ID Numbers: CDR0000334899, S0221, U10CA032102
Study First Received: October 3, 2003
Last Updated: May 22, 2013
Health Authority: United States: Federal Government

Keywords provided by Southwest Oncology Group:
stage II breast cancer
stage IA breast cancer
stage IB breast cancer
stage IIIC breast cancer
male breast cancer
 HER2-positive breast cancer
estrogen receptor-negative breast cancer
estrogen receptor-positive breast cancer
progesterone receptor-negative breast cancer
progesterone receptor-positive breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Doxorubicin
Paclitaxel
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
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on June 18, 2013