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Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
NSABP Foundation Inc
ClinicalTrials.gov Identifier:
NCT00093795
First received: October 6, 2004
Last updated: September 26, 2014
Last verified: September 2014
  Purpose

RATIONALE: Drugs used in chemotherapy, such as docetaxel, doxorubicin , cyclophosphamide, paclitaxel, and gemcitabine work in different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: This randomized phase III trial is studying three different combination chemotherapy regimens and comparing how well they work in treating women who have undergone surgery for node-positive breast cancer.


Condition Intervention Phase
Breast Cancer
Drug: Cyclophosphamide
Drug: Docetaxel
Drug: Gemcitabine
Drug: Paclitaxel
Drug: Doxorubicin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III, Adjuvant Trial Comparing Three Chemotherapy Regimens in Women With Node-Positive Breast Cancer: Docetaxel/Doxorubicin/Cyclophosphamide (TAC); Dose-Dense (DD) Doxorubicin/Cyclophosphamide Followed By DD Paclitaxel (DD AC→P); DD AC Followed By DD Paclitaxel Plus Gemcitabine (DD AC→PG)

Resource links provided by NLM:


Further study details as provided by NSABP Foundation Inc:

Primary Outcome Measures:
  • Disease-free survival: any recurrence, contralateral breast cancer, second primary cancer, death from any cause prior to recurrence or second primary cancer [ Time Frame: Every 6 months for 5 years and then annually thereafter. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Survival: any death [ Time Frame: Every 6 months for 5 years and then annually thereafter. ] [ Designated as safety issue: No ]
  • Recurrence-free interval: time to first local, regional, or distant recurrence [ Time Frame: Every 6 months for 5 years and then annually thereafter. ] [ Designated as safety issue: No ]
  • Distant recurrence-free interval; the time to distant disease recurrence only [ Time Frame: Every 6 months for 5 years and then annually thereafter. ] [ Designated as safety issue: No ]
  • Toxicity assessed by adverse events [ Time Frame: After each cycle and 3 months after completion of study treatment. ] [ Designated as safety issue: Yes ]

Enrollment: 4894
Study Start Date: October 2004
Estimated Study Completion Date: March 2016
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group 1: TAC X 6
Doxorubicin, cyclophosphamide, and docetaxel.
Drug: Cyclophosphamide

Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: cyclophosphamide 600 mg/m2 IV every 14 days for 4 cycles

Other Name: C
Drug: Docetaxel
75 mg/m2 IV every 21 days for 6 cycles
Other Names:
  • Taxotere
  • T
Drug: Doxorubicin

Group 1: 50 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: 60 mg/m2 IV every 14 days for 4 cycles

Other Names:
  • A
  • Adriamycin
Active Comparator: Group 2: AC X 4 then P X 4
Doxorubicin, cyclophosphamide, and paclitaxel
Drug: Cyclophosphamide

Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: cyclophosphamide 600 mg/m2 IV every 14 days for 4 cycles

Other Name: C
Drug: Paclitaxel
175 mg/m2 IV every 14 days for 4 cycles
Other Names:
  • Taxol
  • P
Drug: Doxorubicin

Group 1: 50 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: 60 mg/m2 IV every 14 days for 4 cycles

Other Names:
  • A
  • Adriamycin
Experimental: Group 2: AC X 4 then PG X 4
Doxorubicin, cyclophosphamide, paclitaxel and gemcitabine
Drug: Cyclophosphamide

Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: cyclophosphamide 600 mg/m2 IV every 14 days for 4 cycles

Other Name: C
Drug: Gemcitabine
2000 mg/m2 IV every 14 days for 4 cycles
Other Names:
  • Gemzar
  • G
Drug: Paclitaxel
175 mg/m2 IV every 14 days for 4 cycles
Other Names:
  • Taxol
  • P
Drug: Doxorubicin

Group 1: 50 mg/m2 IV every 21 days for 6 cycles

Group 2 and Group 3: 60 mg/m2 IV every 14 days for 4 cycles

Other Names:
  • A
  • Adriamycin

Detailed Description:

OBJECTIVES:

Primary

  • Compare disease-free survival in women with node-positive breast cancer treated with 3 different adjuvant chemotherapy regimens comprising dose-dense doxorubicin, cyclophosphamide, paclitaxel, and gemcitabine vs docetaxel, doxorubicin, and cyclophosphamide vs dose-dense doxorubicin, cyclophosphamide, and paclitaxel.

Secondary

  • Compare overall survival, recurrence-free interval, and distant recurrence-free interval, in patients treated with these regimens.
  • Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive lymph nodes (1-3 vs 4-9 vs ≥ 10), hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]- negative vs ER- and/or PgR-positive), type of prior surgery and planned radiotherapy (lumpectomy and local radiotherapy [RT] without regional RT vs lumpectomy and local RT with regional RT vs mastectomy without RT vs mastectomy with local or regional RT). Patients are randomized to 1 of 3 treatment arms.

  • Group 1: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses.
  • Group 2: Patients receive AC chemotherapy comprising doxorubicin IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 14 days for 4 courses. Beginning 14 days after the last dose of AC, patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses.
  • Group 3: Patients receive AC chemotherapy as in Group 2. Beginning 14 days after the last dose of AC, patients receive paclitaxel as in Group 2 and gemcitabine IV over 30-60 minutes on day 1. Treatment repeats every 14 days for 4 courses.

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

Beginning 3-12 weeks after the last dose of chemotherapy, patients with ER-positive and/or PgR-positive tumors receive hormonal therapy.

Beginning no sooner than 3 weeks after the last dose of chemotherapy, patients treated with lumpectomy undergo whole-breast radiotherapy. Patients treated with mastectomy may undergo chest wall and/or regional nodal radiotherapy.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 4,800 patients will be accrued for this study within 4 years.

  Eligibility

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

Inclusion Criteria:

  • The patient must consent to participate in the study and must have signed an approved consent form conforming with federal and institutional guidelines.
  • The patient must have a life expectancy of at least 10 years and a Zubrod performance status of 0 or 1. (Comorbid conditions but not the diagnosis of breast cancer should be taken into consideration when determining life expectancy.)
  • The interval between the last surgery for breast cancer staging or treatment and randomization must be no more than 84 days.
  • The tumor must be invasive carcinoma of the breast on histologic examination.
  • All of the following staging criteria must be met:

    • By clinical and pathologic evaluation, primary tumor must be T1-3;
    • By clinical evaluation, ipsilateral nodes must be cN0, cN1, or cN2a;
    • By pathologic evaluation, ipsilateral nodes must be pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b (only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection and with more than 3 positive axillary lymph nodes).
  • Patients must have an estrogen receptor (ER) analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must be performed. If ER analysis is positive, PgR analysis is desired, but not mandatory. ("Marginal" or "borderline" results [i.e., those not definitely negative] will be considered positive regardless of the methodology used.)
  • Patients must have had either a lumpectomy or a total mastectomy. Patients must have completed one of the following procedures for evaluation of pathologic nodal status.

    • Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes (This approach is strongly recommended.)
    • Sentinel lymphadenectomy alone if one of the following criteria is met:
    • Pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1b
    • Surgeon elects not to remove additional non-sentinel nodes (This approach is strongly discouraged, but will not preclude participation in B-38.)
    • Axillary lymphadenectomy without sentinel node isolation procedure.
  • Patients must have no clinical or radiologic evidence of metastatic disease.
  • Patients with either skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if bone scans fail to demonstrate metastatic disease. Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy.
  • Patients with aspartate transaminase (AST) or alkaline phosphatase greater than ULN are eligible for inclusion in the study if liver imaging fails to demonstrate metastatic disease and the following requirements are met at the time of randomization.

    • Postoperative absolute granulocyte count (AGC) must be greater than or equal to 1200/mm3.
    • Postoperative platelet count must be greater than or equal to 100,000/mm3.
    • The following criteria for postoperative evidence of adequate hepatic function must be met:

      • total bilirubin must be less than or equal to ULN for the lab unless the patient has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN) due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and
      • alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and
      • the AST must be less than or equal to 1.5 x ULN for the lab; and
      • alkaline phosphatase and AST cannot both be greater than ULN.
    • Postoperative serum creatinine must be less than or equal to ULN.
  • At the time of randomization, the patient must have had the following: history and physical exam, EKG, and imaging of the chest within the past 3 months and bilateral mammogram within the past 6 months.
  • Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF), measured by Multiple Gated Acquisition (MUGA) scan or echocardiogram, greater than or equal to lower limit of normal (LLN) for the facility performing the procedure and no evidence of regional wall abnormalities.
  • Patients with a history of non-breast malignancies are eligible if they have been disease-free for 5 or more years prior to randomization and are deemed by their physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
  • Special conditions for eligibility of lumpectomy patients: radiation therapy and surgery. Patients treated by lumpectomy must meet all the eligibility criteria in addition to the following:

    • Generally, lumpectomy should be reserved for tumors less than 5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors greater than or equal to 5 cm are eligible if eligibility criteria for lumpectomy are met.
    • The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients for whom pathologic examination demonstrates tumor present at the line of resection, additional operative procedures may be performed to obtain clear margins. This is permissible even if axillary evaluation has been completed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.)
    • Irradiation of regional lymph nodes is optional, but plans for radiation therapy must be declared by the investigator prior to randomization for stratification purposes.
  • Special conditions for eligibility of mastectomy patients: radiation therapy o Postmastectomy chest wall and/or regional nodal irradiation is optional. Plans for radiation in mastectomy patients must be declared by the investigator prior to randomization for stratification purposes.

Ineligibility Criteria

  • Male patients are not eligible for this study. Women with one or more of the following conditions or prior therapies are also ineligible for this study:
  • Tumor that has been determined to be human epidermal growth factor receptor 2 (HER2)-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization (positive for gene amplification).
  • Contralateral breast cancer (invasive or DCIS) or a mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy proof that the mass is not malignant.
  • Primary tumor staged as T4 for any reason.
  • Clinical nodal stages including cN2b and cN3 or pathologic nodal stages including pN0(i+), pN2b, pN3b with clinically apparent internal mammary nodes, or pN3c.
  • Suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes. Patients with these conditions are considered ineligible unless there is biopsy evidence that these are not involved with tumor.
  • Prior history of breast cancer, including DCIS (patients with a history of LCIS are eligible).
  • Treatment, including radiation therapy, chemotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. One exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before study entry. In such a case, hormonal therapy must stop at or before randomization and be re-started, if indicated, following chemotherapy. A second exception is radiation therapy for patients enrolled in NSABP B-39 and assigned to partial breast irradiation (Group 2). These patients may have received RT prior to B-38 study entry.
  • Prior therapy with anthracyclines or taxanes for any malignancy.
  • Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible if this therapy is discontinued prior to randomization.)
  • Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other selective estrogen-receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Patients are eligible only if these medications are discontinued prior to randomization.
  • Cardiac disease that would preclude the use of anthracyclines. This includes:

    • history of myocardial infarction documented by elevated cardiac enzymes or regional wall abnormalities on assessment of left ventricular (LV) function;
    • angina pectoris that requires the use of anti-anginal medication;
    • any history of documented congestive heart failure;
    • serious cardiac arrhythmia requiring medication;
    • severe conduction abnormality;
    • valvular disease with documented cardiac function compromise; and
    • uncontrolled hypertension defined as blood pressure greater than 160/100 on antihypertensive therapy.
  • Conditions that would prohibit administration of corticosteroids.
  • Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's Common Terminology Criteria for Adverse Events Version 3.0.
  • Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from receiving any of the treatment options or would prevent prolonged follow-up.
  • History of hepatitis B or C.
  • Pregnancy or lactation at the time of proposed randomization. Women of reproductive potential must agree to use an effective non-hormonal method of contraception.
  • Concurrent treatment with other investigational agents for the treatment of breast cancer.
  • Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
  • Special conditions for ineligibility of lumpectomy patients: radiation therapy and surgery

    • For patients treated by lumpectomy, whole breast irradiation is required.
    • The following patients will be ineligible:
    • Patients with diffuse tumors (as demonstrated on mammography) treated with lumpectomy. (These patients are eligible if they undergo mastectomy.)
    • Patients treated with lumpectomy in whom there is another clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biopsied and demonstrated to be histologically benign prior to randomization or, if malignant, must be surgically removed with clear margins.
    • Patients in whom the margins of the resected specimen are involved with invasive tumor or DCIS.
  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: NCT00093795

Locations
United States, Alabama
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
Birmingham, Alabama, United States, 35294
United States, Alaska
Providence Cancer Center
Anchorage, Alaska, United States, 99508
United States, Florida
Robert and Carol Weissman Cancer Center at Martin Memorial
Stuart, Florida, United States, 34994
United States, Kentucky
Lucille P. Markey Cancer Center at University of Kentucky
Lexington, Kentucky, United States, 40536-0093
United States, Massachusetts
South Shore Hospital
South Weymouth, Massachusetts, United States, 02190
United States, Nebraska
Methodist Estabrook Cancer Center
Omaha, Nebraska, United States, 68114
United States, New Jersey
CCOP - Northern New Jersey
Hackensack, New Jersey, United States, 07601
United States, North Carolina
Blumenthal Cancer Center at Carolinas Medical Center
Charlotte, North Carolina, United States, 28232-2861
United States, North Dakota
Altru Cancer Center at Altru Hospital
Grand Forks, North Dakota, United States, 58201
United States, Ohio
Community Oncology Group at Cleveland Clinic Cancer Center
Independence, Ohio, United States, 44131
United States, Pennsylvania
Chestnut Hill Healthcare Cancer Center
Philadelphia, Pennsylvania, United States, 19118
United States, Washington
Madigan Army Medical Center - Tacoma
Tacoma, Washington, United States, 98431
Sponsors and Collaborators
NSABP Foundation Inc
Investigators
Principal Investigator: Norman Wolmark, MD NSABP Foundation Inc
  More Information

Additional Information:
No publications provided by NSABP Foundation Inc

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: NSABP Foundation Inc
ClinicalTrials.gov Identifier: NCT00093795     History of Changes
Obsolete Identifiers: NCT00191958
Other Study ID Numbers: NSABP B-38, U10CA012027
Study First Received: October 6, 2004
Last Updated: September 26, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board
Canada: Ethics Review Committee
Canada: Health Canada
Ireland: Irish Medicines Board
Ireland: Research Ethics Committee

Keywords provided by NSABP Foundation Inc:
stage II breast cancer
stage IIIA breast cancer
stage IIIC breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Docetaxel
Doxorubicin
Gemcitabine
Liposomal doxorubicin
Paclitaxel
Alkylating Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 27, 2014