Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether combination chemotherapy is more effective with trastuzumab in treating breast cancer.
PURPOSE: This randomized phase III clinical trial is studying chemotherapy with or without trastuzumab after surgery to see how well they work in treating women with invasive breast cancer.
Condition | Intervention | Phase |
---|---|---|
Breast Cancer |
Biological: trastuzumab Drug: cyclophosphamide Drug: docetaxel Drug: doxorubicin hydrochloride Drug: paclitaxel |
Phase 3 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Masking: Open Label Primary Purpose: Treatment |
Official Title: | A Randomized Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women With Node- Positive or High-Risk Node-Negative HER2-Low Invasive Breast Cancer |
- Invasive disease-free survival [ Designated as safety issue: No ]
- Disease-free survival [ Designated as safety issue: No ]
- Breast cancer-free survival [ Designated as safety issue: No ]
- Recurrence-free interval [ Designated as safety issue: No ]
- Distant recurrence-free interval [ Designated as safety issue: No ]
- Overall survival [ Designated as safety issue: No ]
- Frequencies of adverse events using the NCI CTCAE v4.0 [ Designated as safety issue: Yes ]
Estimated Enrollment: | 3260 |
Study Start Date: | January 2011 |
Estimated Primary Completion Date: | January 2017 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
---|---|
Active Comparator: Arm IA
Patients receive docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 courses.
|
Drug: cyclophosphamide
Given IV
Drug: docetaxel
Given IV
|
Active Comparator: Arm IB
Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks (at the investigator's discretion) for 4 courses. Patients then receive paclitaxel IV over 60 minutes once weekly for 12 doses.
|
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
|
Experimental: Arm IIA
Patients receive chemotherapy as in arm IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Trastuzumab treatment repeats every 3 weeks for 11 courses.
|
Biological: trastuzumab
Given IV
Drug: cyclophosphamide
Given IV
Drug: docetaxel
Given IV
|
Experimental: Arm IIB
Patients receive chemotherapy as in arm IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses. After completion of paclitaxel, patients receive trastuzumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for 13 courses.
|
Biological: trastuzumab
Given IV
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: paclitaxel
Given IV
|
Show Detailed Description
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Female |
Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
- The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
All of the following staging criteria (according to the 7th edition of the AJCC Cancer Staging Manual) must be met:
- By pathologic evaluation, primary tumor must be pT1-3
By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b
If pN0, one of the following criteria must be met:
- pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR) negative
- pT2 and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX® Recurrence Score of ≥ 25
- pT3 regardless of hormone-receptor status, histologic grade, and Oncotype DX® Recurrence Score
- No T4 tumors including inflammatory breast cancer
No definitive clinical or radiologic evidence of metastatic disease
- NOTE: Chest imaging (mandatory for all patients) and other imaging (if required) must have been performed within 90 days prior to randomization
- No synchronous or previous contralateral invasive breast cancer (patients with synchronous and/or previous contralateral DCIS or LCIS are eligible)
- No previous ipsilateral invasive breast cancer or ipsilateral DCIS (patients with synchronous or previous ipsilateral LCIS are eligible)
HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low as defined below:
- IHC must be performed and the IHC staining results must indicate a score of 1+ (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be performed and must indicate that the tumor is HER2-low as described below)
If ISH (FISH or CISH) testing is performed, test results must be as follows and IHC must be 1+ or 2+:
- If FISH is performed, the ratio of HER2 to CEP17 must be < 2.0 or, if a ratio was not performed, the HER2 gene copy number must be < 4 per nucleus
- If CISH is performed, the result must indicate a HER2 gene copy number of < 4 per nucleus
- NOTE: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the higher intensity score in the range should be used to determine eligibility.
No primary tumor with any of the following HER2 testing results:
IHC staining intensity:
- 0 on all evaluations of specimens
- 3+ on evaluation of any specimen
- ISH with a ratio of HER2 to CEP17 ≥ 2.0 on evaluation of any specimen
- ISH result indicating HER2 gene copy number ≥ 4 per nucleus on evaluation of any specimen
The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy) (patients who have had a nipple-sparing mastectomy are eligible)
- For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible (patients with margins positive for LCIS are eligible without additional resection)
- For patients who undergo mastectomy, margins must be free of gross residual tumor (patients with microscopic positive margins are eligible as long as post-mastectomy RT of the chest wall will be administered)
- The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days
The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below:
Sentinel lymphadenectomy alone:
- If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b
- If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes
- Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive
- Axillary lymphadenectomy with or without SN isolation procedures
- The patient must have ER analysis performed on the primary tumor prior to randomization; if ER analysis is negative, then PgR analysis must also be performed (either the core biopsy or surgical resection specimen can be used for ER/PgR testing); patients with a primary tumor that is hormone receptor-positive or receptor-negative are eligible
PATIENT CHARACTERISTICS:
- Pre- or postmenopausal
- ECOG performance status of 0 or 1
- ANC must be ≥ 1,200/mm^3
- Platelet count must be ≥ 100,000/mm^3
- Hemoglobin must be ≥ 10 g/dL
- Total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert disease or similar syndrome involving slow conjugation of bilirubin
- Alkaline phosphatase must be ≤ 2.5 x ULN for the lab
- AST must be ≤ 1.5 x ULN for the lab (if ALT is performed instead of AST [per institution's standard practice], the ALT value must be ≤ 1.5 x ULN; if both were performed, the AST must be ≤ 1.5 x ULN)
- Alkaline phosphatase and AST may not both be > the ULN
- Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the above requirements are met
- Patients with alkaline phosphatase that is > ULN but ≤ 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease
- The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be ≤ ULN for the lab
- Not pregnant or nursing
- Negative pregnancy test
LVEF assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-D echocardiogram is preferred, however, MUGA scan may be substituted based on institutional preferences
- For patients who will receive the TC chemotherapy regimen, the LVEF must be ≥ 50% regardless of the cardiac-imaging facility's lower limit of normal
- For patients who will receive the AC→WP chemotherapy regimen, the LVEF must be ≥ 55% regardless of the cardiac-imaging facility's lower limit of normal
- NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment. If the baseline LVEF is > 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain.
- No history of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization
No cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens, including, but not limited to:
Active cardiac disease:
- Angina pectoris that requires the current use of anti-anginal medication
- Ventricular arrhythmias except for benign premature ventricular contractions
- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
- Conduction abnormality requiring a pacemaker
- Valvular disease with documented compromise in cardiac function
- Symptomatic pericarditis
History of cardiac disease:
- Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function
- History of documented CHF
- Documented cardiomyopathy
No hypertension defined according to the following ineligibility criteria:
- For patients who will receive TC (regardless of the patient's age): uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
- For patients < 50 years old who will receive AC→WP: uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
- For patients ≥ 50 years old who will receive AC→WP: uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg OR controlled hypertension (systolic BP ≤ 150 mm Hg and diastolic BP ≤ 90 mm Hg), if anti-hypertensive medication(s) are needed
- NOTE: Patients who are not eligible based on the AC→WP regimen BP criteria but who meet the TC regimen BP criteria are eligible for B-47 if the intended chemotherapy regimen is changed to TC.
- No active hepatitis B or hepatitis C with abnormal liver function tests
- No intrinsic lung disease resulting in dyspnea
- No poorly controlled diabetes mellitus
- No active infection or chronic infection requiring chronic suppressive antibiotics
- No nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ grade 2, per the CTCAE v4.0
- No conditions that would prohibit administration of corticosteroids
- No known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor® EL
- No other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
- No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- No previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy
- No chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization
- No whole-breast RT prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization
- No use of any investigational product within 30 days prior to randomization
- No continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor (patients are eligible if these medications are discontinued prior to randomization)
- No continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy (patients are eligible if these medications are discontinued prior to randomization)
- No chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylprednisolone equivalent (excluding inhaled steroids)
- No other concurrent chemotherapy
- No other concurrent targeted therapy for malignancy
- No partial-breast irradiation following randomization
- Concurrent participation in NSABP-B-39 allowed
Show 672 Study Locations
Principal Investigator: | Louis Fehrenbacher, MD | Kaiser Permanente Medical Center - Vallejo |
Additional Information:
No publications provided
Responsible Party: | Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project |
ClinicalTrials.gov Identifier: | NCT01275677 History of Changes |
Other Study ID Numbers: | CDR0000692574, NSABP-B-47 |
Study First Received: | January 11, 2011 |
Last Updated: | February 7, 2012 |
Health Authority: | Unspecified |
Keywords provided by National Cancer Institute (NCI):
stage IA breast cancer stage IB breast cancer stage II breast cancer stage IIIA breast cancer stage IIIC breast cancer recurrent breast cancer |
estrogen receptor-negative breast cancer estrogen receptor-positive breast cancer HER2-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 Docetaxel Trastuzumab 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 October 18, 2012