Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
NSABP Foundation Inc
ClinicalTrials.gov Identifier:
NCT00004067
First received: December 10, 1999
Last updated: September 26, 2014
Last verified: September 2014
  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. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy plus trastuzumab is more effective than combination chemotherapy alone for treating breast cancer.

PURPOSE: This randomized phase III trial is studying how well giving combination chemotherapy together with trastuzumab works compared to combination chemotherapy alone in treating women with node-positive stage II or stage IIIA breast cancer that overexpresses HER2.


Condition Intervention Phase
Breast Cancer
Biological: herceptin
Drug: adriamycin
Drug: cyclophosphamide
Drug: taxol
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 Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2

Resource links provided by NLM:


Further study details as provided by NSABP Foundation Inc:

Primary Outcome Measures:
  • Disease Free Survival (DFS) [ Time Frame: Time from randomization through 5 years ] [ Designated as safety issue: No ]
    Breast cancer recurrence, second primary cancer, death from any cause as first event

  • Cardiotoxicity [ Time Frame: time from randomization through 4 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Survival [ Time Frame: time from randomization through 5 years ] [ Designated as safety issue: No ]
    Death from any cause.

  • Long term effect of trastuzumab on cardiac function [ Time Frame: At 5 and 10 years after randomization ] [ Designated as safety issue: Yes ]
    Ejection fraction will be measured by multigated acquisition scan (MUGA).


Enrollment: 2130
Study Start Date: February 2000
Estimated Study Completion Date: March 2015
Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1: adriamycin + cyclophosphamide then taxol Drug: adriamycin
60 mg/m2 IV push every 21 days for 4 cycles.
Other Name: doxorubicin
Drug: cyclophosphamide
600 mg/m2 IV every 21 days for 4 cycles
Drug: taxol
175 mg/m2 IV every 21 days for 4 cycles
Other Name: paclitaxel
Experimental: Arm 2: adriamycin + cyclophosphamide then taxol + herceptin Biological: herceptin
4 mg/kg loading dose then 2 mg/kg weekly for 1 year.
Other Name: trastuzumab
Drug: adriamycin
60 mg/m2 IV push every 21 days for 4 cycles.
Other Name: doxorubicin
Drug: cyclophosphamide
600 mg/m2 IV every 21 days for 4 cycles
Drug: taxol
175 mg/m2 IV every 21 days for 4 cycles
Other Name: paclitaxel

Detailed Description:

OBJECTIVES:

  • Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin®) in women with operable, node-positive breast cancer that overexpresses HER2.
  • Compare the effect of these regimens on disease-free and overall survival of these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy (tamoxifen vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs weekly), and participating center. Patients are randomized to one of two treatment arms.

  • Arm 1: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).
  • Arm 2: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over 90 minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered IV over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal therapy* for at least 5 years, beginning within 3-12 weeks after the last dose of chemotherapy. Patients who have received prior tamoxifen for prevention may be treated with additional tamoxifen for no more than 5 years at the discretion of the principal investigator (PI).

NOTE: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative to tamoxifen therapy.

All patients previously treated with lumpectomy undergo breast irradiation beginning after completion of chemotherapy and concurrently with trastuzumab (in arm 2) administration. Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is administered daily for 5-6 weeks.

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

PROJECTED ACCRUAL: A total of 2,700 patients will be accrued for this study within 4.75 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 have a life expectancy of at least 10 years, excluding her diagnosis of breast cancer. (Comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer.)
  • The interval between the last surgery for breast cancer treatment (lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins) and randomization must be less than or equal to 84 days.
  • All of the following staging criteria must be met:

    • Primary tumor must be T1-3 by clinical and pathologic evaluation.
    • Ipsilateral nodes must be cN0-1 by clinical evaluation.
    • Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.
    • M0
  • Patients must have undergone either a total mastectomy and an axillary dissection or a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must be followed by an axillary dissection.
  • The tumor must be invasive adenocarcinoma on histologic examination.
  • The tumor must be determined to be HER2-positive prior to randomization. Assays performed using fluorescent in situ hybridization (FISH) require gene amplification to be eligible. Assays using immunohistochemistry (IHC) must be performed at an NSABP-approved reference laboratory and require a strongly positive staining score.
  • Patients must have an analysis of both estrogen and progesterone receptors performed on the primary tumor prior to randomization. "Marginal," "borderline," etc., results (i.e., those not definitely negative) will also be considered positive regardless of the methodology used.
  • At the time of randomization, the patient must have had the following: history and physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam (for women who have a uterus and who will be taking tamoxifen) within the past year.
  • Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower limit of normal for the radiology facility. (If LVEF is > 75%, the investigator should consider having the LVEF determination reviewed prior to randomization. Following randomization, the LVEF determination may be reviewed up until the time of the post-AC MUGA. Please note that if a more accurate value is obtained from the review of the baseline MUGA, the corrected value must be submitted to the NSABP Biostatistical Center before the post-AC MUGA is performed.)
  • At the time of randomization:

    • The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or <1500/mm3 if, in the opinion of the investigator, this represents an ethnic or racial variation of normal).
    • Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying hematologic disorders must be excluded when the platelet count is above the upper limit of normal for the lab.
  • There must be postoperative evidence of adequate hepatic function, i.e., total bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation (>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar syndrome; and alkaline phosphatase must be <2.5 times the ULN for the lab; and the serum glutamic-oxaloacetic transaminase (SGOT [AST]) must be <1.5 times the ULN for the lab.
  • There must be postoperative evidence of adequate renal function (serum creatinine within or less than the institution's normal range).
  • Patients must have no clinical or radiologic evidence of metastatic disease. Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy. A patient with skeletal pain is eligible for inclusion in the study if bone scan and/or roentgenological examination fails to disclose metastatic disease.
  • 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, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
  • Prior to randomization, the investigator must designate whether the patients who had a lumpectomy will receive local or locoregional radiation therapy. For patients who had a mastectomy, the investigator must designate whether or not the patient will receive radiation therapy. (Pre-randomization discussion and/or consultation with a radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes is prohibited in this trial.
  • Special conditions for eligibility of lumpectomy patients: irradiation and surgery
  • Patients treated by lumpectomy and axillary node dissection to be followed by breast radiation therapy must meet all the eligibility criteria in addition to the following: Generally, lumpectomy should be reserved for tumors <5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are eligible. The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients in 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 dissection has been performed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. Whole breast irradiation is required. Irradiation of regional lymph nodes is optional, but partial breast irradiation and irradiation of any internal mammary nodes are prohibited in this trial. Intent to irradiate the axilla or other regional node groups must be declared by the investigator prior to randomization for stratification purposes.
  • Special conditions for eligibility of mastectomy patients: irradiation. The decision to use locoregional irradiation in patients who have undergone total mastectomy and axillary node dissection must be declared by the investigator prior to randomization for stratification purposes. Failure to adhere to the radiation therapy plan will be a protocol violation.

Exclusion criteria

  • Bilateral malignancy 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.
  • Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b, pN3b, or pN3c.
  • Prior history of breast cancer, including DCIS (patients with a history of lobular carcinoma in situ [LCIS] are eligible).
  • Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. The only exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before randomization. In such a case, hormonal therapy must stop at or before randomization and be re-started if indicated following chemotherapy.
  • Prior anthracycline or taxane therapy for any malignancy.
  • Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible only 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 prevention. (Patients are eligible only if these medications are discontinued prior to randomization. These medications are not permitted while on the study except for the use of tamoxifen as described in the protocol)
  • Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from being subjected to any of the treatment options or would prevent prolonged follow-up.
  • Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This includes:
  • Active cardiac disease:

    • angina pectoris that requires the use of antianginal medication;
    • cardiac arrhythmia requiring medication;
    • severe conduction abnormality;
    • clinically significant valvular disease;
    • cardiomegaly on chest x-ray;
    • ventricular hypertrophy on EKG; or
    • patients with poorly controlled hypertension, i.e., diastolic greater than 100 mm/Hg. (Patients with hypertension who are well controlled on medication are eligible for entry.)
  • History of cardiac disease:

    • myocardial infarction documented as a clinical diagnosis or by EKG or any other tests;
    • documented congestive heart failure; or
    • documented cardiomyopathy.
  • Psychiatric or addictive disorders that would preclude obtaining informed consent.
  • Pregnancy or lactation at the time of proposed randomization. This protocol excludes pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol which are listed as Pregnancy Category D agents. Pregnant women who received tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and vaginal bleeding. Women of reproductive potential must agree to use an effective barrier method of contraception. Hormonal birth control methods are not permitted.
  • Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria version 2.0.
  • Contraindications to corticosteroid use which, in the opinion of the investigator, would preclude participation in this study.
  • Concurrent treatment with other investigational agents.
  • Sensitivity to benzyl alcohol.
  • Special conditions for ineligibility of lumpectomy patients: irradiation and surgery. For patients treated by lumpectomy with axillary dissection, breast irradiation is required. Please see guidelines for radiation therapy in Appendix A. In addition, the following patients will also be ineligible:

    • Patients with diffuse tumors (as demonstrated on mammography) that would not be considered surgically amenable to lumpectomy.
    • 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 ductal carcinoma in situ (DCIS). Additional surgical resections to obtain free margins are allowed. Patients in whom tumor is still present after the additional resection(s) must undergo mastectomy to be eligible.
  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: NCT00004067

  Show 149 Study Locations
Sponsors and Collaborators
NSABP Foundation Inc
Investigators
Principal Investigator: Norman Wolmark, MD NSABP Foundation Inc
  More Information

Additional Information:
Publications:
Rastogi P, Jeong J, Geyer CE, et al.: Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab(H). [Abstract] J Clin Oncol 25 (Suppl 18): A-LBA513, 2007.
Geyer CE, Bryant JL, Romond EH, et al.: Update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab (H). [Abstract] J Clin Oncol 24 (Suppl 18): A-581, 2006.
Kim C, Bryant J, Horne Z, et al.: Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated cMYC in vivo. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-46, 2005.
Geyer CE Jr, Bryant J, Romond E: Cardiac safety analysis of the first stage of NSABP B-31, a randomized trial comparing the safety and efficacy of adriamycin® and cyclophosphamide (AC) followed by taxol® to that of AC followed by taxol® plus herceptin® in patients (Pts) with operable, node-positive (N+), HER-2 overexpressing breast cancer (HER2+BC). [Abstract] Breast Cancer Res Treat 82 (Suppl 1): A-23, S13, 2003.
Reinholz MM, Dueck AC, Lingle WL, et al.: The concordance between NCCTG's and NSABP's C-myc FISH assays. [Abstract] J Clin Oncol 26 (Suppl 15): A-22110, 2008.
Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007.
Garrison LP, Perez EA, Dueck A, et al.: Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2+ breast cancer. [Abstract] J Clin Oncol 24 (Suppl 18): A-6023, 306s, 2006.
Gupta AK, Mekan SF, Eckman MH: Trastuzumab for all? A decision analysis examining tradeoffs between efficacy and cardiac toxicity of adjuvant therapy in HER2 positive breast cancer. [Abstract] J Clin Oncol 24 (Suppl 18): A-6022, 306s, 2006.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: NSABP Foundation Inc
ClinicalTrials.gov Identifier: NCT00004067     History of Changes
Other Study ID Numbers: NSABP B-31, CDR0000067269
Study First Received: December 10, 1999
Last Updated: September 26, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

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

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Doxorubicin
Liposomal doxorubicin
Paclitaxel
Trastuzumab
Alkylating Agents
Antibiotics, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Tubulin Modulators

ClinicalTrials.gov processed this record on October 21, 2014