Trial Information

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

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.