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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00070564
Recruitment Status : Active, not recruiting
First Posted : October 7, 2003
Results First Posted : April 17, 2017
Last Update Posted : December 30, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group

Tracking Information
First Submitted Date  ICMJE October 3, 2003
First Posted Date  ICMJE October 7, 2003
Results First Submitted Date  ICMJE January 9, 2017
Results First Posted Date  ICMJE April 17, 2017
Last Update Posted Date December 30, 2019
Study Start Date  ICMJE November 2003
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 3, 2017)
  • Disease-free Survival [ Time Frame: every 6 months (annually for mammograms) for 5 years ]
    Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
  • Overall Survival [ Time Frame: Every 6 months for 5 years ]
    Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2017)
  • Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Toxicity assessment was evaluated every 4 weeks while on protocol therapy. ]
    Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
  • Disease-free Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. DFS were measured every 6 months for 5 years ]
    Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
  • Overall Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years ]
    Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
  • Disease-free Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years ]
    Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
  • Overall Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years ]
    Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
  • Disease-free Survival Comparison Between 2 Treatments in HER2-positive Group [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years ]
    Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
  • Overall Survival Comparison Between 2 Treatments in HER-2 Positive Group. [ Time Frame: Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years ]
    Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer
Official Title  ICMJE 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
Brief Summary

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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Biological: pegfilgrastim
    Given IV
  • Drug: AC regimen
    Given IV
  • Drug: cyclophosphamide
    Given IV
  • Drug: doxorubicin hydrochloride
    Given IV
  • Drug: paclitaxel
    Given IV
Study Arms  ICMJE
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
  • 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.
    Interventions:
    • Biological: pegfilgrastim
    • Drug: AC regimen
    • Drug: cyclophosphamide
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 3, 2017)
3294
Original Enrollment  ICMJE Not Provided
Estimated Study Completion Date  ICMJE January 2027
Actual Primary Completion Date January 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00070564
Other Study ID Numbers  ICMJE CDR0000334899
S0221 ( Other Identifier: SWOG )
U10CA032102 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Southwest Oncology Group
Study Sponsor  ICMJE Southwest Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: George Thomas Budd, MD The Cleveland Clinic
Study Director: Halle C Moore, MD The Cleveland Clinic
PRS Account Southwest Oncology Group
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP