Clinical Trials (PDQ®)
|Phase II||Biomarker/Laboratory analysis, Treatment||Closed||18 and over||NCI||NCI-2009-01172|
CALGB-40603, CALGB 40603/CTSU 40603, CDR0000636850, P30CA014236, U10CA031946, NCT00861705
This phase II study was designed for women with triple-negative (estrogen receptor, progesterone receptor and HER2 each negative) breast tumors that could be removed with surgery. Its overall purpose was to determine if adding one (carboplatin) or two (bevacizumab) agents to standard therapy (paclitaxel plus doxorubicin and cyclophosphamide) given for four months would result in the disappearance or decrease in size of the primary breast tumor.
All patients received a taxane (paclitaxel [also known as Taxol]) plus standard anthracycline-based chemotherapy (doxorubicin and cyclophosphamide [also known as Adriamycin and Cytoxan]) for four months. Some women additionally received another chemotherapy agent (carboplatin) and/or a monoclonal antibody (bevacizumab [also known as Avastin]). This resulted in four possible treatments: (1) paclitaxel, doxorubicin and cyclophosphamide, (2) paclitaxel, doxorubicin, cyclophosphamide and bevacizumab, (3) paclitaxel, doxorubicin, cyclophosphamide and carboplatin, and (4) paclitaxel, doxorubicin, cyclophosphamide, carboplatin and bevacizumab. Patients were assigned to one of the four treatments at random, with an equal chance of receiving any one. In each case, treatment was followed by surgery. In this setting where treatment was followed by surgery, treatment is also called 'neoadjuvant' therapy. Tissue taken at surgery was examined to determine the status of the breast cancer after neoadjuvant treatment. The amount of tumor change from before to after neoadjuvant treatment is called the pathologic response. This response was used to measure how well the neoadjuvant therapies controlled the breast cancer.
Study questions about the effect of carboplatin compared the neoadjuvant treatments with carboplatin (treatments 3 & 4) to those without carboplatin (treatments 1 & 2). Study questions about the effect of bevacizumab compared the neoadjuvant treatments with bevacizumab (treatments 2 & 4) to those without bevacizumab (treatments 1 & 3).
Further Study Information
I. To determine whether adding bevacizumab to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent dose-dense doxorubicin and cyclophosphamide (ddAC) significantly raises the rate of pathologic complete response (pCR) in the breast in patients with hormone receptor (HR)-poor/HER2 (-), resectable breast cancer.
II. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with HR-poor/HER2(-), resectable breast cancer.
III. To determine whether adding bevacizumab every 2 weeks to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent ddAC significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array.
IV. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array.
I. To determine the pCR rates in the breast and axilla, using AJCC TNM criteria (Version 6), to neoadjuvant weekly paclitaxel, with or without carboplatin, followed by ddAC, with or without bevacizumab, given concurrently with the weekly paclitaxel and ddAC, in (a) patients with HR-poor/HER2(-), resectable breast cancer and (b) the subset of patients with basal-like breast cancers, as defined by gene expression array.
II. To assess whether there is an interaction between the addition of carboplatin and bevacizumab to neoadjuvant chemotherapy (NAC) with weekly paclitaxel followed by ddAC as regards the path pCR rates in (a) patients with HR-poor/HER2(-), resectable breast cancer and (b) the subset of patients with basal-like breast cancers, as defined by gene expression array.
III. To assess the toxicity of the control regimen (weekly paclitaxel followed by ddAC) and any incremental toxicities associated with the addition of carboplatin and/or bevacizumab in this patient population, including the incidence of febrile neutropenia, grade > 3 thrombocytopenia, grade > 2 neurotoxicity, grade > 3 hypertension, and clinically significant bleeding or thrombotic (including cardiovascular and cerebrovascular) events.
IV. To determine the recurrence-free survival (RFS) measured from definitive surgery to first event, and time to first failure (TFF) measured from study entry to first event (see Section 16.2 of the Protocol).
V. To determine overall survival (OS), defined as time from registration to death from any cause.
VI. To assess the impact of NAC with weekly paclitaxel followed by ddAC, with or without carboplatin and/or bevacizumab, on axillary lymph node involvement at surgery, particularly in patients with clinically or histologically positive axillary lymph nodes prior to initiation of NAC.
VII. To assess the impact of the addition of bevacizumab to NAC on the incidence and severity of post-op complications, especially excessive bleeding, delayed wound healing, and thrombotic complications.
VIII. To evaluate residual cancer burden (RCB) as a predictor of RFS, TFF and OS.
IX. To determine the correlation between clinical, radiographic, and pathologic response.
I. To assess whether the impact of the addition of carboplatin and/or bevacizumab to NAC with weekly paclitaxel followed by ddAC on achievement of pathologic CRs in patients with HR-poor/HER2(-), resectable breast cancer is influenced by molecular subtype, as defined by gene expression array.
II. To obtain blood, fresh frozen and fixed tumor tissue to test specific hypotheses for which biomarker data exist and to evaluate biomarkers in tissue, blood, and serum that may influence response to and toxicity of weekly paclitaxel, ddAC, carboplatin, and/or bevacizumab.
III. To obtain blood samples to test specific hypotheses for which biomarker data exist and to evaluate biomarkers in blood that may influence response to and toxicity of weekly paclitaxel, ddAC, carboplatin and/or bevacizumab.
IV. To determine the surgical practice patterns for breast conservation and sentinel lymphadenectomy in patients undergoing neoadjuvant chemotherapy.
V. To examine the practice patterns and use of sentinel lymphadenectomy (pre-chemotherapy or post-chemotherapy) in patients with T2 or T3 breast cancer.
VI. To examine the proportion of patients who presented with T2 or T3 cancers who undergo mastectomy despite cytoreduction adequate for breast conservation.
VII. To determine the radiotherapy practice patterns for post-mastectomy and regional nodal irradiation in patients undergoing neoadjuvant chemotherapy.
- Histologically confirmed invasive breast cancer by core needle or incisional biopsy (excisional biopsy is not allowed)
- Clinical stage II-III disease
- No inflammatory breast cancer
- Resectable disease
- Intent to undergo surgery after completion of neoadjuvant therapy
- Hormone receptor status poor, defined as estrogen receptor-negative and progesterone receptor-negative tumor OR staining present in ≤ 10% of invasive cancer cells by IHC
- HER2-negative disease, defined as IHC0-1+ OR FISH ratio (HER2 gene copy/chromosome 17 of < 2.0 if IHC 2+)
- Measurable disease, defined as clinically orradiographically measurable target lesion in the breast that is ≥ 1 cm
- No axillary disease only (i.e., no identifiable tumor in the breast that is ≥ 1 cm onphysical exam or radiographic study)
- Multicentric or bilateral disease allowed provided the target lesion meets the above eligibility criteria
- Concurrent registration on CALGB-150709 required
- Menopausal status not specified
- Zubrod performance status 0-1
- Granulocytes ≥ 1,000/μL
- Platelets ≥ 100,000/μL
- Total bilirubin ≤ 1.5 times upper limit of normal(ULN)
- ALT ≤ 2.5 times ULN
- Creatinine clearance> 30 mL/min
- Urine protein ≤ 1+ by urinalysis OR urine protein:creatinine ratio < 1 OR 24-hour urine protein < 1 g
- PT/INR ≤ 1.5 times ULN (INR ≤ 3 times ULN if patient is on stable, therapeutic doses of warfarin and has no active bleeding or pathologic condition that is associated with a high risk of bleeding)
- LVEF > lower limit of normal by MUGA scan or echocardiogram
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective, non-hormonal contraception during the entire period of study treatment
- No significant history of bleeding (e.g., hemoptysis, upper or lower gastrointestinal bleeding) within the past 6 months
- No serious or non-healing wound, skin ulcer, or bone fracture
- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
- No baseline neuropathy ≥ grade 2
- No congestive heart failure
- No myocardial infarction, unstable angina pectoris, arterial thrombotic event, stroke, or transient ischemia attack within the past 12 months
- No uncontrolled hypertension (systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 90 mm Hg), uncontrolled or symptomatic arrhythmia, or peripheral vascular disease ≥ grade 2
- More than 28 days since prior and no concurrent major surgical procedure; the following are NOT considered to be major surgical procedures:
- Obtaining the required research needle biopsies
- Placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical resection
- Placement of a port for central venous access
- Fine needle aspiration of a prominent or suspicious axillary lymph node
- Needle biopsy of a clinically or radiographically detected lesion to rule out metastatic disease
- Pretreatment sentinel lymph node sampling
- No prior chemotherapy, hormonal therapy, or radiotherapy with therapeutic intent for this cancer
- No other concurrent chemotherapy
- No concurrent hormonal therapy, except steroids for adrenal failure or hormones for non-disease-related conditions (e.g., insulin for diabetes, dexamethasone as pre-treatment for paclitaxel, or dexamethasone as an antiemetic)
Trial Lead Organizations/Sponsors
National Cancer Institute
|William Sikov||Principal Investigator|
|Highlands Oncology Group - Bentonville|
|Joseph Thaddeus Beck||Ph: 800-381-6939|
|Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler|
|Mark A. Taylor||Ph: 912-350-8568|
|University of Illinois Cancer Center|
|Divyesh G. Mehta||Ph: 312-355-3046|
|Peter Rubin||Ph: 336-621-8374|
|Moses Cone Regional Cancer Center at Wesley Long Community Hospital|
|Peter Rubin||Ph: 336-621-8374|
|Annie Penn Cancer Center|
|Peter Rubin||Ph: 336-621-8374|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00861705
ClinicalTrials.gov processed this data on March 22, 2015
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