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Paclitaxel With or Without Carboplatin and/or Bevacizumab Followed By Doxorubicin and Cyclophosphamide in Treating Patients With Breast Cancer That Can Be Removed by Surgery

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00861705
First received: March 12, 2009
Last updated: May 7, 2014
Last verified: May 2014

March 12, 2009
May 7, 2014
May 2009
August 2013   (final data collection date for primary outcome measure)
Pathologic complete response (pCR), defined as the absence of residual invasive carcinoma in the breast [ Time Frame: At the time of definitive surgical removal ] [ Designated as safety issue: No ]
Will use two separate chi-square tests, one for each factor, to assess the difference in proportion of pCR in the breast between the control and experimental groups. Will use exact binomial methods to construct 95% confidence intervals around the pCR incidence by factor.
Pathologic complete response [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00861705 on ClinicalTrials.gov Archive Site
  • Pathologic stage in the breast and in the breast plus axilla as measured by AJCC TNM criteria (version 6) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Clinical response assessed by tumor measurement [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Time-to-event distributions will be shown graphically using the Kaplan-Meier product-limit technique. The difference between two or more distributions will be assessed using the logrank test.
  • Radiographic response assessed by tumor measurement [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Time-to-event distributions will be shown graphically using the Kaplan-Meier product-limit technique. The difference between two or more distributions will be assessed using the logrank test.
  • Overall survival [ Time Frame: From study entry to death due to any cause, up to 10 years ] [ Designated as safety issue: No ]
    Time-to-event distributions will be shown graphically using the Kaplan-Meier product-limit technique. The difference between two or more distributions will be assessed using the logrank test.
  • Recurrence-free survival [ Time Frame: From definitive surgery to first instance of ipsilateral invasive breast tumor recurrence, local/regional invasive breast cancer recurrence, distant recurrence, or death from any cause, up to 10 years ] [ Designated as safety issue: No ]
    Time-to-event distributions will be shown graphically using the Kaplan-Meier product-limit technique. The difference between two or more distributions will be assessed using the logrank test.
  • Time to first failure, defined as first instance of ipsilateral invasive breast tumor recurrence, local/regional invasive breast cancer recurrence, distant recurrence, or death from any cause [ Time Frame: From study entry to first event, up to 10 years ] [ Designated as safety issue: No ]
    Time-to-event distributions will be shown graphically using the Kaplan-Meier product-limit technique. The difference between two or more distributions will be assessed using the logrank test.
  • Incidence and severity of post-op complications, especially excessive bleeding, delayed wound healing, and thrombotic complications assessed by NCI Common Terminology Criteria for Adverse Events version 3 [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  • Frequency and severity of toxicity incidents assessed by Common Terminology Criteria for Adverse Events version 3.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
  • Pathologic stage in the breast and in the breast plus axilla as measured by AJCC TNM criteria (version 6) [ Designated as safety issue: No ]
  • Clinical response [ Designated as safety issue: No ]
  • Radiographic response [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Recurrence-free survival [ Designated as safety issue: No ]
  • Time to first failure [ Designated as safety issue: No ]
  • Impact of the addition of bevacizumab to neoadjuvant chemotherapy on the incidence and severity of post-op complications, especially excessive bleeding, delayed wound healing, and thrombotic complications [ Designated as safety issue: No ]
  • Toxicity as measured by NCI CTCAE version 3 [ Designated as safety issue: Yes ]
  • Relationship between biomarker expression and response and toxicity [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Paclitaxel With or Without Carboplatin and/or Bevacizumab Followed By Doxorubicin and Cyclophosphamide in Treating Patients With Breast Cancer That Can Be Removed by Surgery
Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer

This randomized phase II trial is studying how well giving paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PRIMARY OBJECTIVES:

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 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.

SECONDARY OBJECTIVES:

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 Sec 16.2).

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.

X. Given the prevalence of the triple-negative phenotype in young African-American women, the study team, the CALGB Committee on Advocacy, Research Communications and Ethics (CARE) and the CARE Disparities Subcommittee will collaborate to develop a plan intended to enhance accrual of this patient subgroup.

TERTIARY OBJECTIVES:

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.

OUTLINE: This is a multicenter study. Patients are stratified according to clinical stage of disease (II vs III). Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 3-10 minutes and cyclophosphamide IV over 5-60 minutes (ddAC) once in weeks 13, 15, 17, and 19.

ARM II: Patients receive paclitaxel and ddAC as in arm I. Patients also receive bevacizumab IV over 30-90 minutes once in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.

ARM III: Patients receive paclitaxel and ddAC as in arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.

ARM IV: Patients receive paclitaxel and ddAC as in arm I, bevacizumab as in arm II, and carboplatin as in arm III. Patients in all arms undergo definitive surgery (i.e., modified radical mastectomy or breast-conserving surgery with appropriate management of the axilla) between 4-8 weeks after completion of neoadjuvant therapy. Patients undergo core tissue biopsies at baseline for correlative biomarker studies.

After completion of study treatment, patients are followed periodically for up to 10 years.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Triple-negative Breast Cancer
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • ADM
    • ADR
    • Adria
    • Adriamycin PFS
    • Adriamycin RDF
  • Drug: paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • TAX
    • Taxol
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Biological: bevacizumab
    Given IV
    Other Names:
    • anti-VEGF humanized monoclonal antibody
    • anti-VEGF monoclonal antibody
    • Avastin
    • rhuMAb VEGF
  • Drug: carboplatin
    Given IV
    Other Names:
    • Carboplat
    • CBDCA
    • JM-8
    • Paraplat
    • Paraplatin
  • Active Comparator: Arm I (doxorubicin, paclitaxel, cyclophosphamide)
    Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19.
    Interventions:
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
    • Drug: cyclophosphamide
  • Experimental: Arm II (doxorubicin, combination chemotherapy, bevacizumab)
    Patients receive paclitaxel and ddAC as in arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
    Interventions:
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
    • Drug: cyclophosphamide
    • Biological: bevacizumab
  • Experimental: Arm III (doxorubicin, combination chemotherapy, carboplatin)
    Patients receive paclitaxel and ddAC as in arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
    Interventions:
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
    • Drug: cyclophosphamide
    • Drug: carboplatin
  • Experimental: Arm IV (doxorubicin, chemotherapy, carboplatin, bevacizumab)
    Patients receive paclitaxel and ddAC as in arm I, bevacizumab as in arm II, and carboplatin as in arm III.
    Interventions:
    • Drug: doxorubicin hydrochloride
    • Drug: paclitaxel
    • Drug: cyclophosphamide
    • Biological: bevacizumab
    • Drug: carboplatin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
446
Not Provided
August 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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
  • 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)
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00861705
NCI-2009-01172, NCI-2009-01172, CALGB-40603, CALGB 40603/CTSU 40603, CDR0000636850, CALGB 40603, CALGB-40603, P30CA014236, U10CA031946
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: William Sikov Cancer and Leukemia Group B
National Cancer Institute (NCI)
May 2014

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