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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00861705
• Collaborator: (none)
• Enrollment: 454
• Locations: 453
• Arms: 4
• Patients Per Site: 1

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well 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. Bevacizumab may 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.

Condition or Disease	Intervention/Treatment	Phase
Male Breast Carcinoma; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; Triple-Negative Breast Carcinoma	Biological: Bevacizumab; Drug: Carboplatin; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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/human epidermal growth factor receptor 2 (HER2) (-), resectable breast cancer.

2. 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.

3. 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.

4. 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:

1. To determine the pCR rates in the breast and axilla, using American Joint Committee On Cancer (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.

2. 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.

3. 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.

4. 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.

5. To determine overall survival (OS), defined as time from registration to death from any cause.

6. 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.

7. 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.

8. To evaluate residual cancer burden (RCB) as a predictor of RFS, TFF and OS.

9. To determine the correlation between clinical, radiographic, and pathologic response.

TERTIARY OBJECTIVES:

1. 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.

2. 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.

3. 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.

4. To determine the surgical practice patterns for breast conservation and sentinel lymphadenectomy in patients undergoing neoadjuvant chemotherapy.

5. To examine the practice patterns and use of sentinel lymphadenectomy (pre-chemotherapy or post-chemotherapy) in patients with T2 or T3 breast cancer.

6. To examine the proportion of patients who presented with T2 or T3 cancers who undergo mastectomy despite cytoreduction adequate for breast conservation.

7. To determine the radiotherapy practice patterns for post-mastectomy and regional nodal irradiation in patients undergoing neoadjuvant chemotherapy.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive paclitaxel intravenously (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.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 15, 2009
• Actual Primary Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I (paclitaxel, doxorubicin, 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.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat
Experimental: Arm II (paclitaxel, ddAC, 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.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat
Experimental: Arm III (paclitaxel, ddAC, 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.	Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat
Experimental: Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin) Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is). [At the time of definitive surgical removal, up to 28 weeks]

   Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain carboplatin (arms 3&4) versus not (arms 1&2) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods.

2. Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is). [At the time of definitive surgical removal, up to 28 weeks]

   Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods.

Secondary Outcome Measures

1. Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0). [At the time of definitive surgical removal, up to 28 weeks]

   Comparing regimens that contain carboplatin (arms 3&4) versus not (arms 1&2).

2. Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0). [At the time of definitive surgical removal, up to 28 weeks]

   Comparing regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3).

3. Pathologic Stage in the Breast and in the Breast Plus Axilla as Measured by American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Staging Criteria (Version 6) [at definitive surgery, up to 28 weeks]

   Stage II is (T2,T3, N0, M0) tumor size more than 2 cm but no deep extradermal structure invasion, no regional lymph node metastasis, and no distant metastasis. Stage III is (T4, N0, M0) tumor invasion of deep extradermal structures, no regional lymph node metasis, and no distant metasasis or (Any T, N1, M0) Any tumor size, regional lymph node metastasis, and no distant metastasis.

4. Radiographic Response Assessed by Tumor Measurement [Baseline; at completion of neoadjuvant therapy]

   Assessed by RECIST, each patient will have a pre-therapy baseline radiographic tumor measurement, preferably by MRI, however if logistic or practical or financial issues preclude MRI use, mammogram or ultrasound may be substituted. The longest diameter (LD) of the target lesion at the time of study initiation will be reported as the baseline LD. The baseline LD of the target lesion will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease. Radiographic complete response: Disappearance of the target lesion. Radiographic partial response (PR): At least a 30% decrease in the longest diameter (LD) of the target lesion taking as reference the baseline LD.

5. Clinical Response Assessed by Tumor Measurement [Baseline; at completion of neoadjuvant therapy]

   Assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Both target and, in the event of multifocal or multicentric invasive breast cancer, nontarget lesions should be followed clinically and their clinical size recorded at aseline. Measurements thereafter are required at the completion of 12 weeks of paclitaxel or paclitaxel/carboplatin and at the completion of all neoadjuvant chemotherapy. At any time point, these lesions should be categorized regarding whether there is evidence of progression. If "yes", the study chair should be notified in order to determine whether the patient should come off protocol treatment. In-situcarcinoma does not represent a non-target lesion and should not be recorded or followed.

6. Overall Survival [up to 10 years]

   Number of Participants who Died Due to Any Cause

7. Recurrence-free Survival [up to 10 years]

   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. Number of Participants who Died Due to Any Cause or had a recurrence.

8. Count of Participants With a 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 [up to 10 years]

   From study entry to first event.

9. Incidence and Severity of Post-op Complications, Namely Excessive Bleeding, Delayed Wound Healing, and Wound Dehiscence. [at definitive surgery, up to 28 weeks]

   Assessed by physician observation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Invasive breast cancer, diagnosed by core needle or incisional biopsy (excisional biopsy not permitted)

• The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor (ER) and progesterone receptor (PgR) negative or staining present in =< 10% of invasive cancer cells by immunohistochemistry (IHC)

• The invasive tumor must be HER2-negative, defined as IHC 0-1+ or with a fluorescent in situ hybridization (FISH) ratio (HER2 gene copy/chromosome 17) of < 2.0 if IHC 2+

• Clinical stage II-III invasive breast cancer with intent to perform surgical resection after neoadjuvant therapy; patients with inflammatory breast cancer are not eligible; staging to rule out metastatic disease is recommended for clinical stage III patients

• Patients with multicentric or bilateral disease are eligible if the target lesion meets eligibility criteria

• Patient agrees to undergo pretreatment research biopsies

• No prior chemotherapy, hormone therapy, or radiation therapy with therapeutic intent for this cancer

• The target lesion in the breast must be >= 1 cm, clinically or radiographically; palpable or radiographically measurable axillary adenopathy will be recorded but will not serve as measurable disease for the primary endpoint; patients with axillary disease only (no identifiable tumor in the breast that is >= 1 cm on physical exam or radiographic study) are not eligible to participate

• Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower gastrointestinal [GI] bleeding) within 6 months of registration are not eligible

• No serious or non-healing wound, skin ulcers or bone fracture; no abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the past 6 months; no major surgical procedure within 28 days prior to randomization or anticipation of need for major surgery during the course of study

• The following are not considered to be major surgical procedures that would be prohibited in the 28 days prior to, or following study randomization: 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; or pretreatment sentinel lymph node sampling

• No baseline neuropathy grade >= 2

• Zubrod performance status 0-1

• Pregnant or nursing women are not eligible; all women of reproductive potential must have a negative pregnancy test at baseline and agree to use an effective, non-hormonal method of contraception during the entire period of treatment on the study

• Patients with congestive heart failure are not eligible, nor are patients with myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack (TIA) within the past 12 months, uncontrolled hypertension (systolic blood pressure [SBP] > 160 or diastolic blood pressure [DBP] > 90), uncontrolled or symptomatic arrhythmia, or grade II or greater peripheral vascular disease

• Patients must have a pretreatment multi gated acquisition (MUGA) scan or echocardiogram with a left ventricular ejection fraction (LVEF) above the institutional lower limit of normal

• Granulocytes > 1,000/mcl

• Platelets > 100,000/mcl

• Total bilirubin =< 1.5 x upper limits of normal

• Calculated or measured > 30 ml/min

• Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1

• Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study

• Serum alanine aminotransferase (ALT) =< 2.5 x upper limits of normal

• Serum beta human chorionic gonadotropin (HCG) negative (for women of child bearing potential)

• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x upper limit of normal (ULN)

• Unless patient is on therapeutic doses of warfarin; if so, the patient must have an INR =< 3 on a stable dose of warfarin, must have not active bleeding or pathologic condition that is associated with a high risk of bleeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro	Jonesboro	Arkansas	United States	72401
2	NEA Baptist Memorial Hospital	Jonesboro	Arkansas	United States	72401
3	Highlands Oncology Group - Rogers	Rogers	Arkansas	United States	72758
4	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
5	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
6	Mills-Peninsula Medical Center	Burlingame	California	United States	94010
7	East Bay Radiation Oncology Center	Castro Valley	California	United States	94546
8	Eden Hospital Medical Center	Castro Valley	California	United States	94546
9	Valley Medical Oncology Consultants-Castro Valley	Castro Valley	California	United States	94546
10	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
11	Bay Area Breast Surgeons Inc	Emeryville	California	United States	94608
12	Epic Care Partners in Cancer Care	Emeryville	California	United States	94608
13	Valley Medical Oncology Consultants-Fremont	Fremont	California	United States	94538
14	Contra Costa Regional Medical Center	Martinez	California	United States	94553-3156
15	El Camino Hospital	Mountain View	California	United States	94040
16	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
17	Sutter Cancer Research Consortium	Novato	California	United States	94945
18	Highland General Hospital	Oakland	California	United States	94602
19	Alta Bates Summit Medical Center - Summit Campus	Oakland	California	United States	94609
20	Bay Area Tumor Institute	Oakland	California	United States	94609
21	Hematology and Oncology Associates-Oakland	Oakland	California	United States	94609
22	Tom K Lee Inc	Oakland	California	United States	94609
23	Saint Joseph Hospital - Orange	Orange	California	United States	92868
24	Desert Regional Medical Center	Palm Springs	California	United States	92262
25	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
26	Valley Care Health System - Pleasanton	Pleasanton	California	United States	94588
27	Valley Medical Oncology Consultants	Pleasanton	California	United States	94588
28	Salinas Valley Memorial	Salinas	California	United States	93901
29	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
30	Doctors Medical Center- JC Robinson Regional Cancer Center	San Pablo	California	United States	94806
31	Breastlink Medical Group Inc	Santa Ana	California	United States	92705
32	Sutter Pacific Medical Foundation	Santa Rosa	California	United States	95403
33	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
34	The Medical Center of Aurora	Aurora	Colorado	United States	80012
35	Boulder Community Hospital	Boulder	Colorado	United States	80301
36	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
37	Porter Adventist Hospital	Denver	Colorado	United States	80210
38	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
39	SCL Health Saint Joseph Hospital	Denver	Colorado	United States	80218
40	Rose Medical Center	Denver	Colorado	United States	80220
41	Western States Cancer Research NCORP	Denver	Colorado	United States	80222
42	Swedish Medical Center	Englewood	Colorado	United States	80113
43	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
44	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado	United States	81501
45	North Colorado Medical Center	Greeley	Colorado	United States	80631
46	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
47	Littleton Adventist Hospital	Littleton	Colorado	United States	80122
48	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
49	Longmont United Hospital	Longmont	Colorado	United States	80501
50	McKee Medical Center	Loveland	Colorado	United States	80539
51	Parker Adventist Hospital	Parker	Colorado	United States	80138
52	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
53	North Suburban Medical Center	Thornton	Colorado	United States	80229
54	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
55	Hartford HealthCare - Saint Vincent's Medical Center	Bridgeport	Connecticut	United States	06606
56	Greenwich Hospital	Greenwich	Connecticut	United States	06830
57	Hartford Hospital	Hartford	Connecticut	United States	06102
58	Manchester Memorial Hospital	Manchester	Connecticut	United States	06040
59	Norwalk Hospital	Norwalk	Connecticut	United States	06856
60	Beebe Medical Center	Lewes	Delaware	United States	19958
61	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
62	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
63	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
64	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
65	Jupiter Medical Center	Jupiter	Florida	United States	33458
66	Cancer Center of South Florida-Lake Worth	Lake Worth	Florida	United States	33461
67	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
68	AdventHealth Orlando	Orlando	Florida	United States	32803
69	Phoebe Putney Memorial Hospital	Albany	Georgia	United States	31701
70	Piedmont Hospital	Atlanta	Georgia	United States	30309
71	Atlanta Regional CCOP	Atlanta	Georgia	United States	30342
72	Emory Saint Joseph's Hospital	Atlanta	Georgia	United States	30342
73	Northside Hospital	Atlanta	Georgia	United States	30342
74	WellStar Cobb Hospital	Austell	Georgia	United States	30106
75	John B Amos Cancer Center	Columbus	Georgia	United States	31904
76	Dekalb Medical Center	Decatur	Georgia	United States	30033
77	Piedmont Fayette Hospital	Fayetteville	Georgia	United States	30214
78	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
79	Northside Hospital - Gwinnett	Lawrenceville	Georgia	United States	30046
80	Wellstar Kennestone Hospital	Marietta	Georgia	United States	30060
81	Southern Regional Medical Center	Riverdale	Georgia	United States	30274
82	Harbin Clinic Medical Oncology and Clinical Research	Rome	Georgia	United States	30165
83	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
84	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
85	Pali Momi Medical Center	'Aiea	Hawaii	United States	96701
86	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii	United States	96813
87	Queen's Medical Center	Honolulu	Hawaii	United States	96813
88	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
89	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
90	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii	United States	96817
91	Queen's Cancer Center - Kuakini	Honolulu	Hawaii	United States	96817
92	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii	United States	96817
93	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
94	Castle Medical Center	Kailua	Hawaii	United States	96734
95	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii	United States	96766
96	Maui Memorial Medical Center	Wailuku	Hawaii	United States	96793
97	Pacific Cancer Institute of Maui	Wailuku	Hawaii	United States	96793
98	Mount Sinai Hospital Medical Center	Chicago	Illinois	United States	60608
99	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
100	University of Illinois	Chicago	Illinois	United States	60612
101	Presence Resurrection Medical Center	Chicago	Illinois	United States	60631
102	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
103	Weiss Memorial Hospital	Chicago	Illinois	United States	60640
104	Advocate Good Samaritan Hospital	Downers Grove	Illinois	United States	60515
105	AMITA Health Adventist Medical Center	La Grange	Illinois	United States	60525
106	West Suburban Medical Center	River Forest	Illinois	United States	60305
107	Swedish American Hospital	Rockford	Illinois	United States	61104
108	Franciscan Saint Francis Health-Beech Grove	Beech Grove	Indiana	United States	46107
109	Elkhart Clinic	Elkhart	Indiana	United States	46514-2098
110	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
111	Elkhart General Hospital	Elkhart	Indiana	United States	46515
112	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
113	Community Howard Regional Health	Kokomo	Indiana	United States	46904
114	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
115	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
116	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
117	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana	United States	46563
118	Reid Health	Richmond	Indiana	United States	47374
119	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
120	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
121	South Bend Clinic	South Bend	Indiana	United States	46617
122	Northern Indiana Cancer Research Consortium	South Bend	Indiana	United States	46628
123	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
124	Physicians' Clinic of Iowa PC	Cedar Rapids	Iowa	United States	52402
125	Saint Luke's Hospital	Cedar Rapids	Iowa	United States	52402
126	Mercy Hospital	Cedar Rapids	Iowa	United States	52403
127	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
128	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
129	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
130	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
131	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
132	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
133	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
134	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
135	HaysMed University of Kansas Health System	Hays	Kansas	United States	67601
136	Hutchinson Regional Medical Center	Hutchinson	Kansas	United States	67502
137	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
138	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
139	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
140	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
141	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67905
142	Cancer Center of Kansas - McPherson	McPherson	Kansas	United States	67460
143	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
144	Menorah Medical Center	Overland Park	Kansas	United States	66209
145	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
146	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
147	Ascension Via Christi - Pittsburg	Pittsburg	Kansas	United States	66762
148	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
149	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
150	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
151	Salina Regional Health Center	Salina	Kansas	United States	67401
152	Advent Health - Shawnee Mission Medical Center	Shawnee Mission	Kansas	United States	66204
153	University of Kansas Health System Saint Francis Campus	Topeka	Kansas	United States	66606
154	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
155	Associates In Womens Health	Wichita	Kansas	United States	67208
156	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
157	Ascension Via Christi Hospitals Wichita	Wichita	Kansas	United States	67214
158	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
159	Wichita NCI Community Oncology Research Program	Wichita	Kansas	United States	67214
160	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
161	Eastern Maine Medical Center	Bangor	Maine	United States	04401
162	Maine Center for Cancer Medicine-Scarborough	Scarborough	Maine	United States	04074
163	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
164	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
165	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland	United States	21237
166	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
167	Christiana Care - Union Hospital	Elkton	Maryland	United States	21921
168	Frederick Memorial Hospital	Frederick	Maryland	United States	21701
169	TidalHealth Peninsula Regional	Salisbury	Maryland	United States	21801
170	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
171	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
172	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
173	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
174	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
175	Addison Gilbert Hospital	Gloucester	Massachusetts	United States	01930
176	Dana-Farber/Brigham and Women's Cancer Center at Milford Regional	Milford	Massachusetts	United States	01757
177	Newton-Wellesley Hospital	Newton	Massachusetts	United States	02462
178	Bixby Medical Center	Adrian	Michigan	United States	49221
179	Hickman Cancer Center	Adrian	Michigan	United States	49221
180	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
181	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
182	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
183	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
184	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
185	MyMichigan Medical Center Midland	Midland	Michigan	United States	48670
186	Mercy Memorial Hospital	Monroe	Michigan	United States	48162
187	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan	United States	48162
188	Lakeland Hospital Niles	Niles	Michigan	United States	49120
189	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
190	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
191	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
192	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
193	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
194	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
195	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
196	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
197	Unity Hospital	Fridley	Minnesota	United States	55432
198	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
199	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
200	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
201	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
202	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
203	New Ulm Medical Center	New Ulm	Minnesota	United States	56073
204	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
205	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
206	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
207	Regions Hospital	Saint Paul	Minnesota	United States	55101
208	United Hospital	Saint Paul	Minnesota	United States	55102
209	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
210	Lakeview Hospital	Stillwater	Minnesota	United States	55082
211	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
212	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
213	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
214	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
215	Central Care Cancer Center - Bolivar	Bolivar	Missouri	United States	65613
216	Cox Cancer Center Branson	Branson	Missouri	United States	65616
217	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
218	Saint Luke's Hospital	Chesterfield	Missouri	United States	63017
219	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
220	Capital Region Southwest Campus	Jefferson City	Missouri	United States	65109
221	Truman Medical Centers	Kansas City	Missouri	United States	64108
222	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
223	Saint Joseph Health Center	Kansas City	Missouri	United States	64114
224	North Kansas City Hospital	Kansas City	Missouri	United States	64116
225	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
226	Research Medical Center	Kansas City	Missouri	United States	64132
227	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
228	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
229	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
230	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
231	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
232	Saint Joseph Oncology Inc	Saint Joseph	Missouri	United States	64507
233	SSM Health Saint Louis University Hospital	Saint Louis	Missouri	United States	63104
234	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
235	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
236	Center for Cancer Care and Research	Saint Louis	Missouri	United States	63141
237	Comprehensive Cancer Care PC	Saint Louis	Missouri	United States	63141
238	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
239	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
240	CoxHealth South Hospital	Springfield	Missouri	United States	65807
241	Billings Clinic Cancer Center	Billings	Montana	United States	59101
242	Saint Vincent Healthcare	Billings	Montana	United States	59101
243	Montana Cancer Consortium NCORP	Billings	Montana	United States	59102
244	Saint Vincent Frontier Cancer Center	Billings	Montana	United States	59102
245	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
246	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
247	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
248	Great Falls Clinic	Great Falls	Montana	United States	59405
249	Northern Montana Hospital	Havre	Montana	United States	59501
250	Saint Peter's Community Hospital	Helena	Montana	United States	59601
251	Glacier Oncology PLLC	Kalispell	Montana	United States	59901
252	Kalispell Medical Oncology	Kalispell	Montana	United States	59901
253	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
254	Montana Cancer Specialists	Missoula	Montana	United States	59802
255	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
256	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire	United States	03301
257	Exeter Hospital	Exeter	New Hampshire	United States	03833
258	LRGHealthcare-Lakes Region General Hospital	Laconia	New Hampshire	United States	03246
259	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
260	Norris Cotton Cancer Center-Manchester	Manchester	New Hampshire	United States	03102
261	Elliot Hospital	Manchester	New Hampshire	United States	03103
262	Solinsky Center for Cancer Care	Manchester	New Hampshire	United States	03103
263	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
264	Monmouth Medical Center	Long Branch	New Jersey	United States	07740
265	Virtua Memorial	Mount Holly	New Jersey	United States	08060
266	Rutgers New Jersey Medical School	Newark	New Jersey	United States	07101
267	Virtua Voorhees	Voorhees	New Jersey	United States	08043
268	Maimonides Medical Center	Brooklyn	New York	United States	11219
269	Coney Island Hospital	Brooklyn	New York	United States	11235
270	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
271	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
272	Elmhurst Hospital Center	Elmhurst	New York	United States	11373
273	Glens Falls Hospital	Glens Falls	New York	United States	12801
274	Queens Hospital Center	Jamaica	New York	United States	11432
275	Garnet Health Medical Center	Middletown	New York	United States	10940
276	Mount Sinai Union Square	New York	New York	United States	10003
277	Mount Sinai West	New York	New York	United States	10019
278	Mount Sinai Hospital	New York	New York	United States	10029
279	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
280	Staten Island University Hospital	Staten Island	New York	United States	10305
281	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
282	Randolph Hospital	Asheboro	North Carolina	United States	27203
283	Mission Hospital	Asheville	North Carolina	United States	28801
284	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
285	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
286	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
287	Cone Health Cancer Center	Greensboro	North Carolina	United States	27403
288	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
289	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina	United States	28374
290	UNC Rex Cancer Center	Raleigh	North Carolina	United States	27607
291	Annie Penn Memorial Hospital	Reidsville	North Carolina	United States	27320
292	Nash General Hospital	Rocky Mount	North Carolina	United States	27804
293	Rutherford Hospital	Rutherfordton	North Carolina	United States	28139
294	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
295	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina	United States	27103
296	Southeast Clinical Oncology Research Consortium NCORP	Winston-Salem	North Carolina	United States	27104
297	Altru Cancer Center	Grand Forks	North Dakota	United States	58201
298	Summa Health System - Akron Campus	Akron	Ohio	United States	44304
299	Cleveland Clinic Akron General	Akron	Ohio	United States	44307
300	Summa Health System - Barberton Campus	Barberton	Ohio	United States	44203
301	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio	United States	43402
302	Aultman Health Foundation	Canton	Ohio	United States	44710
303	North Coast Cancer Care-Clyde	Clyde	Ohio	United States	43410
304	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
305	Grandview Hospital	Dayton	Ohio	United States	45405
306	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
307	Miami Valley Hospital	Dayton	Ohio	United States	45409
308	Miami Valley Hospital North	Dayton	Ohio	United States	45415
309	Dayton NCI Community Oncology Research Program	Dayton	Ohio	United States	45459
310	Hematology Oncology Center Incorporated	Elyria	Ohio	United States	44035
311	Mercy Cancer Center-Elyria	Elyria	Ohio	United States	44035
312	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
313	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
314	Wayne Hospital	Greenville	Ohio	United States	45331
315	Kettering Medical Center	Kettering	Ohio	United States	45429
316	Saint Rita's Medical Center	Lima	Ohio	United States	45801
317	Lima Memorial Hospital	Lima	Ohio	United States	45804
318	OhioHealth Mansfield Hospital	Mansfield	Ohio	United States	44903
319	Saint Luke's Hospital	Maumee	Ohio	United States	43537
320	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio	United States	43537
321	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio	United States	43537
322	Fisher-Titus Medical Center	Norwalk	Ohio	United States	44857
323	Saint Charles Hospital	Oregon	Ohio	United States	43616
324	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio	United States	43616
325	North Coast Cancer Care	Sandusky	Ohio	United States	44870
326	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
327	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
328	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
329	Saint Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
330	University of Toledo	Toledo	Ohio	United States	43614
331	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio	United States	43617
332	Mercy Health - Saint Anne Hospital	Toledo	Ohio	United States	43623
333	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
334	Upper Valley Medical Center	Troy	Ohio	United States	45373
335	Fulton County Health Center	Wauseon	Ohio	United States	43567
336	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
337	Greene Memorial Hospital	Xenia	Ohio	United States	45385
338	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
339	Cancer Care Associates	Oklahoma City	Oklahoma	United States	73120
340	Integris Cancer Institute of Oklahoma	Oklahoma City	Oklahoma	United States	73142
341	Bay Area Hospital	Coos Bay	Oregon	United States	97420
342	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
343	Butler Memorial Hospital	Butler	Pennsylvania	United States	16001
344	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
345	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
346	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
347	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
348	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania	United States	19114
349	Einstein Medical Center Philadelphia	Philadelphia	Pennsylvania	United States	19141
350	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania	United States	18840
351	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
352	WellSpan Health-York Hospital	York	Pennsylvania	United States	17403
353	Rhode Island Hospital	Providence	Rhode Island	United States	02903
354	Women and Infants Hospital	Providence	Rhode Island	United States	02905
355	Miriam Hospital	Providence	Rhode Island	United States	02906
356	Kent Hospital	Warwick	Rhode Island	United States	02886
357	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
358	AnMed Health Hospital	Anderson	South Carolina	United States	29621
359	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina	United States	29316
360	Roper Hospital	Charleston	South Carolina	United States	29401
361	Prisma Health Cancer Institute - Easley	Easley	South Carolina	United States	29640
362	Saint Francis Hospital	Greenville	South Carolina	United States	29601
363	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina	United States	29605
364	Prisma Health Cancer Institute - Faris	Greenville	South Carolina	United States	29605
365	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina	United States	29605
366	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina	United States	29615
367	Self Regional Healthcare	Greenwood	South Carolina	United States	29646
368	Prisma Health Cancer Institute - Greer	Greer	South Carolina	United States	29650
369	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina	United States	29672
370	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
371	Lexington Medical Center	West Columbia	South Carolina	United States	29169
372	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
373	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
374	Medical X-Ray Center	Sioux Falls	South Dakota	United States	57105
375	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota	United States	57117-5045
376	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
377	Erlanger Medical Center	Chattanooga	Tennessee	United States	37403
378	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
379	Nashville Oncology Associates PC	Nashville	Tennessee	United States	37203
380	Meharry Medical College	Nashville	Tennessee	United States	37208
381	Doctor's Hospital of Laredo	Laredo	Texas	United States	78041
382	Texas Tech University Health Sciences Center-Lubbock	Lubbock	Texas	United States	79430
383	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah	United States	84003
384	Sandra L Maxwell Cancer Center	Cedar City	Utah	United States	84720
385	Logan Regional Hospital	Logan	Utah	United States	84321
386	Intermountain Medical Center	Murray	Utah	United States	84107
387	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
388	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
389	Saint George Regional Medical Center	Saint George	Utah	United States	84770
390	Intermountain Health Care	Salt Lake City	Utah	United States	84103
391	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah	United States	84106
392	LDS Hospital	Salt Lake City	Utah	United States	84143
393	Fredericksburg Oncology Inc	Fredericksburg	Virginia	United States	22401
394	Hematology Oncology Associates of Fredericksburg Inc	Fredericksburg	Virginia	United States	22408
395	Virginia Oncology Associates-Hampton	Hampton	Virginia	United States	23666
396	Cancer Care Center at Island Hospital	Anacortes	Washington	United States	98221
397	MultiCare Auburn Medical Center	Auburn	Washington	United States	98001
398	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington	United States	98225
399	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
400	Highline Medical Center-Main Campus	Burien	Washington	United States	98166
401	Providence Regional Cancer System-Centralia	Centralia	Washington	United States	98531
402	Saint Francis Hospital	Federal Way	Washington	United States	98003
403	Swedish Cancer Institute-Issaquah	Issaquah	Washington	United States	98029
404	Kadlec Clinic Hematology and Oncology	Kennewick	Washington	United States	99336
405	Saint Clare Hospital	Lakewood	Washington	United States	98499
406	Skagit Valley Hospital	Mount Vernon	Washington	United States	98274
407	Providence - Saint Peter Hospital	Olympia	Washington	United States	98506-5166
408	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington	United States	98370
409	MultiCare Good Samaritan Hospital	Puyallup	Washington	United States	98372
410	Harborview Medical Center	Seattle	Washington	United States	98104
411	Minor and James Medical PLLC	Seattle	Washington	United States	98104
412	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
413	Kaiser Permanente Washington	Seattle	Washington	United States	98112
414	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
415	University of Washington Medical Center - Montlake	Seattle	Washington	United States	98195
416	PeaceHealth United General Medical Center	Sedro-Woolley	Washington	United States	98284
417	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
418	Evergreen Hematology and Oncology PS	Spokane	Washington	United States	99218
419	MultiCare Allenmore Hospital	Tacoma	Washington	United States	98405
420	MultiCare Tacoma General Hospital	Tacoma	Washington	United States	98405
421	Northwest NCI Community Oncology Research Program	Tacoma	Washington	United States	98405
422	Saint Joseph Medical Center	Tacoma	Washington	United States	98405
423	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
424	Wenatchee Valley Hospital and Clinics	Wenatchee	Washington	United States	98801
425	Saint Mary's Medical Center	Huntington	West Virginia	United States	25702
426	Princeton Community Hospital	Princeton	West Virginia	United States	24740
427	Fox Valley Surgical Associates Limited	Appleton	Wisconsin	United States	54911
428	ThedaCare Regional Cancer Center	Appleton	Wisconsin	United States	54911
429	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin	United States	53105
430	Aurora Cancer Care-Franklin	Franklin	Wisconsin	United States	53132
431	Aurora Health Care Germantown Health Center	Germantown	Wisconsin	United States	53022
432	Aurora Cancer Care-Glendale	Glendale	Wisconsin	United States	53212
433	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
434	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
435	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
436	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
437	Aurora BayCare Medical Center	Green Bay	Wisconsin	United States	54311
438	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin	United States	53142
439	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
440	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
441	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin	United States	54143
442	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
443	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
444	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
445	Aurora Cancer Care-Racine	Racine	Wisconsin	United States	53406
446	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
447	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
448	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
449	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin	United States	53188
450	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin	United States	53226
451	Aurora West Allis Medical Center	West Allis	Wisconsin	United States	53227
452	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
453	Welch Cancer Center	Sheridan	Wyoming	United States	82801

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: William M Sikov, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00861705
• Other Study ID Numbers: NCI-2009-01172; NCI-2009-01172; CALGB 40603/CTSU 40603; CALGB-40603; CDR0000636850; CALGB 40603; CALGB-40603; U10CA180821; U10CA031946
• First Posted: Mar 13, 2009
• Last Update Posted: Aug 8, 2022
• Last Verified: Jun 1, 2022

• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Breast Neoplasms, Male; Paclitaxel; Cyclophosphamide; Bevacizumab; Carboplatin; Doxorubicin; Liposomal doxorubicin; Albumin-Bound Paclitaxel; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors

Study Results

Participant Flow

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Period Title: Overall Study
STARTED	115	113	113	113
COMPLETED	108	110	113	112
NOT COMPLETED	7	3	0	1

Baseline Characteristics

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)	Total
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV	Total of all reporting groups
Overall Participants	115	113	113	113	454
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.2 (11.1)	48.3 (10.8)	50.9 (10.8)	47.1 (9.8)	49.1 (10.7)
Sex: Female, Male (Count of Participants)
Female	115 100%	113 100%	113 100%	113 100%	454 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	0 0%	2 1.8%	3 0.7%
Asian	1 0.9%	5 4.4%	4 3.5%	3 2.7%	13 2.9%
Native Hawaiian or Other Pacific Islander	1 0.9%	0 0%	0 0%	0 0%	1 0.2%
Black or African American	20 17.4%	21 18.6%	27 23.9%	21 18.6%	89 19.6%
White	86 74.8%	84 74.3%	80 70.8%	81 71.7%	331 72.9%
More than one race	1 0.9%	1 0.9%	1 0.9%	2 1.8%	5 1.1%
Unknown or Not Reported	5 4.3%	2 1.8%	1 0.9%	4 3.5%	12 2.6%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is).
Description	Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain carboplatin (arms 3&4) versus not (arms 1&2) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods.
Time Frame	At the time of definitive surgical removal, up to 28 weeks

Outcome Measure Data

Analysis Population Description

All patients who began protocol neoadjuvant therapy and are assessable for pCR endpoint (N=433).

Arm/Group Title	Factor A: Carboplatin	Factor A: No Carboplatin
Arm/Group Description	Factor A is the addition or not of carboplatin: the experimental regimens included carboplatin (Arms 3 & 4).	Factor A is the addition or not of carboplatin; the control regimens did not include carboplatin (Arms 1 & 2).
Measure Participants	221	212
Number (95% Confidence Interval) [percentage of participants with pCR]	60 52.2%	46 40.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments	The study was designed to detect an increase in the incidence of pCR from 35% in the control arm to 55% in the experimental arm using a 1-sided chi square test of proportions. With a target sample of 362 patients and assuming a 10% dropout rate, an overall assessable sample size of 326 patients resulted in > 95% power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Chi-squared
	Comments	Reported p-values are unadjusted and 1-sided

2. Primary Outcome

Title	Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is).
Description	Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods.
Time Frame	At the time of definitive surgical removal, up to 28 weeks

Outcome Measure Data

Analysis Population Description

All patients who began protocol neoadjuvant therapy and are assessable for pCR endpoint (N=433).

Arm/Group Title	Factor B: Bevacizumab	Factor B: No Bevacizumab
Arm/Group Description	Factor B is the addition or not of bevacizumab: the experimental regimens included bevacizumab (Arms 2 & 4).	Factor B is the addition or not of bevacizumab: the control regimens did not include bevacizumab (Arms 1 & 3)
Measure Participants	215	218
Number (95% Confidence Interval) [percentage of participants with pCR]	59 51.3%	48 42.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments	The study was designed to detect an increase in the incidence of pCR from 35% in the control arm to 55% in the experimental arm using a 1-sided chi square test of proportions. With a target sample of 362 patients and assuming a 10% dropout rate, an overall assessable sample size of 326 patients resulted in > 95% power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments
	Method	Chi-squared
	Comments	Reported p-values are unadjusted and 1-sided

3. Secondary Outcome

Title	Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0).
Description	Comparing regimens that contain carboplatin (arms 3&4) versus not (arms 1&2).
Time Frame	At the time of definitive surgical removal, up to 28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Factor A: Carboplatin	Factor A: No Carboplatin
Arm/Group Description	Factor A is the addition or not of carboplatin: the experimental regimens included carboplatin (Arms 3 & 4).	Factor A is the addition or not of carboplatin; the control regimens did not include carboplatin (Arms 1 & 2).
Measure Participants	221	212
Number (95% Confidence Interval) [percentage of participants with pCR]	54 47%	41 36.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	Chi-squared
	Comments	Reported p-values are unadjusted and 1-sided

4. Secondary Outcome

Title	Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0).
Description	Comparing regimens that contain bevacizumab (arms 2&4) versus not (arms 1&3).
Time Frame	At the time of definitive surgical removal, up to 28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Factor B: Bevacizumab	Factor B: No Bevacizumab
Arm/Group Description	Factor B is the addition or not of bevacizumab: the experimental regimens included bevacizumab (Arms 2 & 4).	Factor B is the addition or not of bevacizumab: the control regimens did not include bevacizumab (Arms 1 & 3)
Measure Participants	215	218
Number (95% Confidence Interval) [percentage of participants with pCR]	52 45.2%	44 38.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.057
	Comments
	Method	Chi-squared
	Comments	Reported p-values are unadjusted and 1-sided

5. Secondary Outcome

Title	Pathologic Stage in the Breast and in the Breast Plus Axilla as Measured by American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Staging Criteria (Version 6)
Description	Stage II is (T2,T3, N0, M0) tumor size more than 2 cm but no deep extradermal structure invasion, no regional lymph node metastasis, and no distant metastasis. Stage III is (T4, N0, M0) tumor invasion of deep extradermal structures, no regional lymph node metasis, and no distant metasasis or (Any T, N1, M0) Any tumor size, regional lymph node metastasis, and no distant metastasis.
Time Frame	at definitive surgery, up to 28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	107	105	111	110
Breast : Stage II	42 36.5%	49 43.4%	51 45.1%	70 61.9%
Breast : Stage III	42 36.5%	55 48.7%	57 50.4%	62 54.9%
Breast/Axilla : Stage II	41 35.7%	42 37.2%	47 41.6%	63 55.8%
Breast/Axilla : Stage III	36 31.3%	45 39.8%	51 45.1%	54 47.8%

6. Secondary Outcome

Title	Radiographic Response Assessed by Tumor Measurement
Description	Assessed by RECIST, each patient will have a pre-therapy baseline radiographic tumor measurement, preferably by MRI, however if logistic or practical or financial issues preclude MRI use, mammogram or ultrasound may be substituted. The longest diameter (LD) of the target lesion at the time of study initiation will be reported as the baseline LD. The baseline LD of the target lesion will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease. Radiographic complete response: Disappearance of the target lesion. Radiographic partial response (PR): At least a 30% decrease in the longest diameter (LD) of the target lesion taking as reference the baseline LD.
Time Frame	Baseline; at completion of neoadjuvant therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	108	110	112	112
Complete Response	11 9.6%	12 10.6%	19 16.8%	13 11.5%
Partial Response	16 13.9%	11 9.7%	16 14.2%	17 15%
Failures	81 70.4%	87 77%	77 68.1%	82 72.6%

7. Secondary Outcome

Title	Clinical Response Assessed by Tumor Measurement
Description	Assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Both target and, in the event of multifocal or multicentric invasive breast cancer, nontarget lesions should be followed clinically and their clinical size recorded at aseline. Measurements thereafter are required at the completion of 12 weeks of paclitaxel or paclitaxel/carboplatin and at the completion of all neoadjuvant chemotherapy. At any time point, these lesions should be categorized regarding whether there is evidence of progression. If "yes", the study chair should be notified in order to determine whether the patient should come off protocol treatment. In-situcarcinoma does not represent a non-target lesion and should not be recorded or followed.
Time Frame	Baseline; at completion of neoadjuvant therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	108	110	112	112
Complete Response	28 24.3%	35 31%	45 39.8%	40 35.4%
Partial Response	37 32.2%	38 33.6%	36 31.9%	37 32.7%
Failures	43 37.4%	37 32.7%	31 27.4%	35 31%

8. Secondary Outcome

Title	Overall Survival
Description	Number of Participants who Died Due to Any Cause
Time Frame	up to 10 years

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	107	110	112	112
Count of Participants [Participants]	22 19.1%	26 23%	30 26.5%	24 21.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.67 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 3 (Pac + Carboplatin --> ddAC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.82 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Recurrence-free Survival
Description	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. Number of Participants who Died Due to Any Cause or had a recurrence.
Time Frame	up to 10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	108	110	112	112
With event	32 27.8%	34 30.1%	37 32.7%	27 23.9%
Without event	76 66.1%	76 67.3%	75 66.4%	85 75.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 3 (Pac + Carboplatin --> ddAC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Count of Participants With a 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
Description	From study entry to first event.
Time Frame	up to 10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1 (Pac --> ddAC)	Arm 2 (Pac + Bev --> ddAC + Bev)	Arm 3 (Pac + Carboplatin --> ddAC)	Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	Patients receive paclitaxel (pac) 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. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive bevacizumab (bev) IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV	Patients receive pac and ddAC as in arm 1. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV carboplatin: Given IV	Patients receive pac and ddAC as in arm 1, bev as in arm 2, and carboplatin as in arm 3. doxorubicin hydrochloride: Given IV paclitaxel: Given IV cyclophosphamide: Given IV bevacizumab: Given IV carboplatin: Given IV
Measure Participants	108	110	112	112
With event	23 20%	26 23%	28 24.8%	22 19.5%
Without event	85 73.9%	84 74.3%	84 74.3%	90 79.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Factor A: No Carboplatin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.66 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 3 (Pac + Carboplatin --> ddAC)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.72 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Factor A: Carboplatin, Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Incidence and Severity of Post-op Complications, Namely Excessive Bleeding, Delayed Wound Healing, and Wound Dehiscence.
Description	Assessed by physician observation.
Time Frame	at definitive surgery, up to 28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Factor B: Bevacizumab	Factor B: No Bevacizumab
Arm/Group Description	Factor B is the addition or not of bevacizumab: the experimental regimens included bevacizumab (Arms 2 & 4).	Factor B is the addition or not of bevacizumab: the control regimens did not include bevacizumab (Arms 1 & 3)
Measure Participants	213	214
Excessive bleeding	0 0%	0 0%
Delayed healing	1 0.9%	0 0%
Wound dehiscence	1 0.9%	0 0%

Adverse Events

Adverse Event Reporting Description	Out of the 454 participants, 443 began treatment. Six participants were not evaluable for adverse events due to site non-compliance (2 in Arm 2 and 4 in Arm 3). Therefore, adverse events data are available for 437 participants (108 in Arm 1, 108 in Arm 2, 109 in Arm 3, and 112 in Arm 4).
Arm/Group Title	Arm 1 (Pac --> ddAC)		Arm 2 (Pac + Bev --> ddAC + Bev)		Arm 3 (Pac + Carboplatin --> ddAC)		Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
Arm/Group Description	cyclophosphamide: Given IV		bevacizumab: Given IV		carboplatin: Given IV		carboplatin: Given IV
All Cause Mortality
	Arm 1 (Pac --> ddAC)		Arm 2 (Pac + Bev --> ddAC + Bev)		Arm 3 (Pac + Carboplatin --> ddAC)		Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1 (Pac --> ddAC)		Arm 2 (Pac + Bev --> ddAC + Bev)		Arm 3 (Pac + Carboplatin --> ddAC)		Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/108 (13.9%)		27/108 (25%)		21/109 (19.3%)		39/112 (34.8%)
Blood and lymphatic system disorders
Blood disorder	11/108 (10.2%)	11	14/108 (13%)	17	17/109 (15.6%)	20	28/112 (25%)	33
Febrile neutropenia	4/108 (3.7%)	4	4/108 (3.7%)	5	9/109 (8.3%)	9	15/112 (13.4%)	16
Hemoglobin decreased	0/108 (0%)	0	2/108 (1.9%)	2	4/109 (3.7%)	5	6/112 (5.4%)	6
Cardiac disorders
Atrial tachycardia	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Myocardial ischemia	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Palpitations	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Sinus tachycardia	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Eye disorders
Dry eye syndrome	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Eye disorder	1/108 (0.9%)	1	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	2
Vision blurred	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	0/112 (0%)	0
Watering eyes	1/108 (0.9%)	1	0/108 (0%)	0	1/109 (0.9%)	2	0/112 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/108 (0.9%)	1	2/108 (1.9%)	2	3/109 (2.8%)	3	6/112 (5.4%)	7
Anal hemorrhage	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Anal mucositis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Anal ulcer	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Colitis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Colonic perforation	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Constipation	2/108 (1.9%)	2	9/108 (8.3%)	11	3/109 (2.8%)	4	18/112 (16.1%)	19
Diarrhea	4/108 (3.7%)	4	6/108 (5.6%)	6	7/109 (6.4%)	7	14/112 (12.5%)	15
Dry mouth	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Dyspepsia	2/108 (1.9%)	2	2/108 (1.9%)	2	5/109 (4.6%)	6	5/112 (4.5%)	5
Dysphagia	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Ear, nose and throat examination abnormal	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	8/112 (7.1%)	9
Esophagitis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Gastritis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	2
Gastrointestinal disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Hemorrhoidal hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Hemorrhoids	1/108 (0.9%)	1	3/108 (2.8%)	3	0/109 (0%)	0	3/112 (2.7%)	3
Ileal fistula	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Lower gastrointestinal hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Mucositis oral	1/108 (0.9%)	1	5/108 (4.6%)	5	4/109 (3.7%)	5	8/112 (7.1%)	8
Nausea	6/108 (5.6%)	6	13/108 (12%)	15	11/109 (10.1%)	12	21/112 (18.8%)	23
Oesophagoscopy abnormal	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Oral pain	0/108 (0%)	0	1/108 (0.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Rectal fistula	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Rectal hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	3/112 (2.7%)	3
Rectal pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Stomach pain	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Tooth disorder	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Vomiting	0/108 (0%)	0	7/108 (6.5%)	7	5/109 (4.6%)	6	15/112 (13.4%)	16
General disorders
Chest pain	0/108 (0%)	0	1/108 (0.9%)	1	2/109 (1.8%)	3	0/112 (0%)	0
Chills	1/108 (0.9%)	1	2/108 (1.9%)	2	3/109 (2.8%)	3	3/112 (2.7%)	4
Edema limbs	3/108 (2.8%)	3	3/108 (2.8%)	4	2/109 (1.8%)	2	2/112 (1.8%)	3
Fatigue	12/108 (11.1%)	12	22/108 (20.4%)	25	19/109 (17.4%)	22	36/112 (32.1%)	41
Fever	3/108 (2.8%)	3	3/108 (2.8%)	3	5/109 (4.6%)	5	3/112 (2.7%)	3
Flu-like symptoms	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
General symptom	1/108 (0.9%)	1	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Injection site reaction	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Localized edema	0/108 (0%)	0	2/108 (1.9%)	3	0/109 (0%)	0	0/112 (0%)	0
Pain	1/108 (0.9%)	1	4/108 (3.7%)	5	4/109 (3.7%)	5	5/112 (4.5%)	5
Immune system disorders
Hypersensitivity	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	1/112 (0.9%)	1
Infections and infestations
Anal infection	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Anorectal infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Bladder infection	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Catheter related infection	1/108 (0.9%)	1	5/108 (4.6%)	5	1/109 (0.9%)	2	2/112 (1.8%)	2
Device related infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Esophageal infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Infection	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Joint infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Mucosal infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Nail infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Pneumonia	2/108 (1.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	2	1/112 (0.9%)	1
Sepsis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Skin infection	0/108 (0%)	0	3/108 (2.8%)	4	0/109 (0%)	0	2/112 (1.8%)	2
Soft tissue infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Tooth infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Upper respiratory infection	1/108 (0.9%)	1	3/108 (2.8%)	3	0/109 (0%)	0	1/112 (0.9%)	1
Urinary tract infection	0/108 (0%)	0	2/108 (1.9%)	2	2/109 (1.8%)	2	5/112 (4.5%)	5
Uterine infection	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Wound infection	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Injury, poisoning and procedural complications
Bruising	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Fracture	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Postoperative hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Seroma	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Vascular access complication	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	1/112 (0.9%)	1
Wound dehiscence	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	0/112 (0%)	0
Investigations
Alanine aminotransferase increased	3/108 (2.8%)	3	4/108 (3.7%)	4	4/109 (3.7%)	5	9/112 (8%)	9
Alkaline phosphatase increased	0/108 (0%)	0	2/108 (1.9%)	2	3/109 (2.8%)	3	6/112 (5.4%)	6
Amylase increased	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Aspartate aminotransferase increased	1/108 (0.9%)	1	2/108 (1.9%)	2	4/109 (3.7%)	5	8/112 (7.1%)	8
Blood bilirubin increased	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	1/112 (0.9%)	1
Cardiac troponin T increased	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Creatinine increased	0/108 (0%)	0	2/108 (1.9%)	2	3/109 (2.8%)	3	2/112 (1.8%)	2
Haptoglobin decreased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
INR increased	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Laboratory test abnormal	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	3/112 (2.7%)	3
Leukocyte count decreased	6/108 (5.6%)	6	6/108 (5.6%)	7	13/109 (11.9%)	15	14/112 (12.5%)	15
Lipase increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Lymphocyte count decreased	2/108 (1.9%)	2	1/108 (0.9%)	1	5/109 (4.6%)	6	7/112 (6.3%)	7
Neutrophil count decreased	7/108 (6.5%)	7	12/108 (11.1%)	15	16/109 (14.7%)	18	22/112 (19.6%)	26
Platelet count decreased	6/108 (5.6%)	6	8/108 (7.4%)	10	16/109 (14.7%)	18	21/112 (18.8%)	25
Weight loss	1/108 (0.9%)	1	5/108 (4.6%)	5	2/109 (1.8%)	2	5/112 (4.5%)	6
Metabolism and nutrition disorders
Anorexia	3/108 (2.8%)	3	6/108 (5.6%)	7	8/109 (7.3%)	10	11/112 (9.8%)	12
Blood glucose increased	5/108 (4.6%)	5	5/108 (4.6%)	6	7/109 (6.4%)	8	10/112 (8.9%)	11
Dehydration	2/108 (1.9%)	2	2/108 (1.9%)	2	4/109 (3.7%)	4	8/112 (7.1%)	8
Serum albumin decreased	1/108 (0.9%)	1	2/108 (1.9%)	2	4/109 (3.7%)	4	9/112 (8%)	10
Serum calcium decreased	4/108 (3.7%)	4	5/108 (4.6%)	6	5/109 (4.6%)	5	8/112 (7.1%)	9
Serum calcium increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Serum magnesium decreased	0/108 (0%)	0	1/108 (0.9%)	1	5/109 (4.6%)	6	7/112 (6.3%)	7
Serum magnesium increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Serum phosphate decreased	1/108 (0.9%)	1	0/108 (0%)	0	2/109 (1.8%)	2	1/112 (0.9%)	1
Serum potassium decreased	3/108 (2.8%)	3	6/108 (5.6%)	6	7/109 (6.4%)	7	7/112 (6.3%)	8
Serum potassium increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	2/112 (1.8%)	2
Serum sodium decreased	1/108 (0.9%)	1	2/108 (1.9%)	3	5/109 (4.6%)	5	10/112 (8.9%)	11
Serum sodium increased	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Serum triglycerides increased	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	3/112 (2.7%)	3
Musculoskeletal and connective tissue disorders
Abdominal soft tissue necrosis	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Arthralgia	0/108 (0%)	0	2/108 (1.9%)	3	1/109 (0.9%)	1	4/112 (3.6%)	4
Back pain	0/108 (0%)	0	3/108 (2.8%)	3	2/109 (1.8%)	2	5/112 (4.5%)	5
Bone pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	4/112 (3.6%)	5
Chest wall pain	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	1/112 (0.9%)	1
Muscle weakness	1/108 (0.9%)	1	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Muscle weakness upper limb	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Musculoskeletal disorder	0/108 (0%)	0	2/108 (1.9%)	3	0/109 (0%)	0	1/112 (0.9%)	2
Myalgia	2/108 (1.9%)	2	2/108 (1.9%)	2	2/109 (1.8%)	3	2/112 (1.8%)	3
Myositis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Neck pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Pain in extremity	2/108 (1.9%)	2	4/108 (3.7%)	4	1/109 (0.9%)	1	1/112 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Nervous system disorders
Ataxia	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Cognitive disturbance	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Depressed level of consciousness	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Dizziness	1/108 (0.9%)	1	5/108 (4.6%)	5	3/109 (2.8%)	3	6/112 (5.4%)	6
Dysgeusia	2/108 (1.9%)	2	2/108 (1.9%)	3	4/109 (3.7%)	5	4/112 (3.6%)	4
Extrapyramidal disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Headache	2/108 (1.9%)	2	8/108 (7.4%)	8	6/109 (5.5%)	6	7/112 (6.3%)	9
Intracranial hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Memory impairment	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Neuralgia	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Neurological disorder NOS	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Peripheral motor neuropathy	0/108 (0%)	0	2/108 (1.9%)	2	3/109 (2.8%)	3	3/112 (2.7%)	4
Peripheral sensory neuropathy	8/108 (7.4%)	8	15/108 (13.9%)	17	13/109 (11.9%)	16	18/112 (16.1%)	21
Sinus pain	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Speech disorder	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Syncope	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	2/112 (1.8%)	2
Tremor	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Psychiatric disorders
Agitation	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Anxiety	1/108 (0.9%)	1	4/108 (3.7%)	4	2/109 (1.8%)	2	8/112 (7.1%)	8
Confusion	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Depression	1/108 (0.9%)	1	0/108 (0%)	0	1/109 (0.9%)	1	6/112 (5.4%)	7
Insomnia	3/108 (2.8%)	3	4/108 (3.7%)	5	5/109 (4.6%)	6	4/112 (3.6%)	4
Psychosis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Renal and urinary disorders
Bladder pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Bladder spasm	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Hemoglobin urine positive	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Hemorrhage urinary tract	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Proteinuria	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	3/112 (2.7%)	4
Urethral pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Urinary incontinence	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Urinary retention	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Reproductive system and breast disorders
Breast pain	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	2/112 (1.8%)	2
Irregular menstruation	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Reproductive tract disorder	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/108 (0.9%)	1	1/108 (0.9%)	1	3/109 (2.8%)	4	1/112 (0.9%)	1
Cough	4/108 (3.7%)	4	6/108 (5.6%)	6	5/109 (4.6%)	5	9/112 (8%)	9
Dyspnea	1/108 (0.9%)	1	10/108 (9.3%)	10	7/109 (6.4%)	8	14/112 (12.5%)	15
Epistaxis	0/108 (0%)	0	6/108 (5.6%)	7	1/109 (0.9%)	1	8/112 (7.1%)	8
Hypoxia	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Nasal congestion	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Pharyngeal examination abnormal	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Pharyngeal mucositis	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Pharyngolaryngeal pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Pleural effusion	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Pneumonitis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Respiratory disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	4/108 (3.7%)	4	8/108 (7.4%)	9	12/109 (11%)	14	18/112 (16.1%)	19
Dry skin	0/108 (0%)	0	3/108 (2.8%)	3	1/109 (0.9%)	1	4/112 (3.6%)	5
Erythema multiforme	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Hand-and-foot syndrome	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Nail disorder	1/108 (0.9%)	1	8/108 (7.4%)	8	3/109 (2.8%)	3	5/112 (4.5%)	5
Pain of skin	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Petechiae	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Pruritus	0/108 (0%)	0	1/108 (0.9%)	1	2/109 (1.8%)	2	2/112 (1.8%)	2
Rash desquamating	1/108 (0.9%)	1	3/108 (2.8%)	3	1/109 (0.9%)	1	2/112 (1.8%)	2
Skin disorder	0/108 (0%)	0	1/108 (0.9%)	2	1/109 (0.9%)	2	1/112 (0.9%)	1
Skin hyperpigmentation	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Skin ulceration	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Sweating	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Vascular disorders
Hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Hot flashes	3/108 (2.8%)	3	4/108 (3.7%)	4	1/109 (0.9%)	1	2/112 (1.8%)	2
Hypertension	2/108 (1.9%)	2	6/108 (5.6%)	8	2/109 (1.8%)	3	11/112 (9.8%)	11
Hypotension	1/108 (0.9%)	1	2/108 (1.9%)	2	0/109 (0%)	0	3/112 (2.7%)	3
Thrombosis	1/108 (0.9%)	1	3/108 (2.8%)	3	2/109 (1.8%)	2	1/112 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Arm 1 (Pac --> ddAC)		Arm 2 (Pac + Bev --> ddAC + Bev)		Arm 3 (Pac + Carboplatin --> ddAC)		Arm 4 (Pac + Carboplatin + Bev --> ddAC + Bev)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	107/108 (99.1%)		104/108 (96.3%)		106/109 (97.2%)		109/112 (97.3%)
Blood and lymphatic system disorders
Blood disorder	75/108 (69.4%)	196	64/108 (59.3%)	148	90/109 (82.6%)	277	92/112 (82.1%)	255
Febrile neutropenia	3/108 (2.8%)	3	8/108 (7.4%)	9	4/109 (3.7%)	5	11/112 (9.8%)	11
Hemoglobin decreased	9/108 (8.3%)	20	17/108 (15.7%)	30	11/109 (10.1%)	22	12/112 (10.7%)	31
Hemolysis	3/108 (2.8%)	5	1/108 (0.9%)	1	2/109 (1.8%)	4	1/112 (0.9%)	1
Lymph node pain	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Lymphatic disorder	1/108 (0.9%)	1	2/108 (1.9%)	2	1/109 (0.9%)	2	1/112 (0.9%)	1
Cardiac disorders
Cardiac disorder	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	2/112 (1.8%)	2
Cardiac pain	2/108 (1.9%)	3	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Left ventricular failure	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Palpitations	4/108 (3.7%)	5	8/108 (7.4%)	10	8/109 (7.3%)	10	4/112 (3.6%)	4
Sinus tachycardia	2/108 (1.9%)	5	3/108 (2.8%)	5	3/109 (2.8%)	4	6/112 (5.4%)	7
Stokes-Adams syndrome	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	2
Supraventricular extrasystoles	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Ear and labyrinth disorders
Ear disorder	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	0/112 (0%)	0
Ear pain	1/108 (0.9%)	1	3/108 (2.8%)	4	1/109 (0.9%)	2	0/112 (0%)	0
External ear inflammation	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
External ear pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	3
Middle ear inflammation	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Tinnitus	0/108 (0%)	0	2/108 (1.9%)	2	1/109 (0.9%)	1	1/112 (0.9%)	1
Endocrine disorders
Hypothyroidism	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Eye disorders
Conjunctivitis	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Diplopia	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Dry eye syndrome	4/108 (3.7%)	6	3/108 (2.8%)	3	1/109 (0.9%)	1	5/112 (4.5%)	7
Eye disorder	4/108 (3.7%)	6	4/108 (3.7%)	7	2/109 (1.8%)	5	1/112 (0.9%)	2
Eye pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Eyelid function disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Flashing vision	2/108 (1.9%)	2	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Keratitis	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Photophobia	0/108 (0%)	0	2/108 (1.9%)	4	1/109 (0.9%)	1	1/112 (0.9%)	1
Vision blurred	14/108 (13%)	23	10/108 (9.3%)	16	3/109 (2.8%)	5	13/112 (11.6%)	24
Watering eyes	9/108 (8.3%)	10	15/108 (13.9%)	21	8/109 (7.3%)	9	7/112 (6.3%)	14
Gastrointestinal disorders
Abdominal distension	1/108 (0.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	1	2/112 (1.8%)	2
Abdominal pain	14/108 (13%)	15	5/108 (4.6%)	8	8/109 (7.3%)	13	15/112 (13.4%)	24
Anal exam abnormal	1/108 (0.9%)	2	1/108 (0.9%)	2	0/109 (0%)	0	1/112 (0.9%)	4
Anal fistula	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Anal hemorrhage	1/108 (0.9%)	1	2/108 (1.9%)	4	0/109 (0%)	0	0/112 (0%)	0
Anal mucositis	1/108 (0.9%)	2	2/108 (1.9%)	4	0/109 (0%)	0	1/112 (0.9%)	1
Anal pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Cheilitis	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Constipation	47/108 (43.5%)	91	52/108 (48.1%)	103	47/109 (43.1%)	88	61/112 (54.5%)	117
Diarrhea	36/108 (33.3%)	60	37/108 (34.3%)	57	33/109 (30.3%)	52	35/112 (31.3%)	57
Dry mouth	5/108 (4.6%)	5	4/108 (3.7%)	7	2/109 (1.8%)	2	3/112 (2.7%)	3
Dyspepsia	28/108 (25.9%)	43	22/108 (20.4%)	37	30/109 (27.5%)	40	30/112 (26.8%)	51
Dysphagia	2/108 (1.9%)	3	3/108 (2.8%)	3	4/109 (3.7%)	5	3/112 (2.7%)	3
Ear, nose and throat examination abnormal	11/108 (10.2%)	16	12/108 (11.1%)	19	14/109 (12.8%)	16	22/112 (19.6%)	34
Esophageal mucositis	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Esophageal pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Esophageal stenosis	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Esophagitis	2/108 (1.9%)	2	1/108 (0.9%)	1	2/109 (1.8%)	2	3/112 (2.7%)	3
Fistula of small intestine	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Flatulence	4/108 (3.7%)	6	2/108 (1.9%)	2	2/109 (1.8%)	2	2/112 (1.8%)	2
Gastric ulcer	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Gastritis	4/108 (3.7%)	5	5/108 (4.6%)	5	1/109 (0.9%)	1	4/112 (3.6%)	5
Gastrointestinal disorder	2/108 (1.9%)	2	3/108 (2.8%)	4	4/109 (3.7%)	4	3/112 (2.7%)	3
Gingival pain	0/108 (0%)	0	1/108 (0.9%)	2	2/109 (1.8%)	2	1/112 (0.9%)	1
Hemorrhoidal hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Hemorrhoids	3/108 (2.8%)	4	7/108 (6.5%)	9	3/109 (2.8%)	3	9/112 (8%)	12
Lower gastrointestinal hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Mucositis oral	22/108 (20.4%)	37	34/108 (31.5%)	64	23/109 (21.1%)	42	30/112 (26.8%)	52
Nausea	78/108 (72.2%)	158	73/108 (67.6%)	148	74/109 (67.9%)	173	89/112 (79.5%)	202
Oesophagoscopy abnormal	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	0/112 (0%)	0
Oral hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	2/109 (1.8%)	3	2/112 (1.8%)	2
Oral pain	1/108 (0.9%)	1	3/108 (2.8%)	6	5/109 (4.6%)	5	4/112 (3.6%)	4
Periodontal disease	1/108 (0.9%)	3	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Rectal fistula	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Rectal hemorrhage	1/108 (0.9%)	1	3/108 (2.8%)	3	0/109 (0%)	0	4/112 (3.6%)	4
Rectal pain	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	2
Rectal ulcer	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Salivary gland disorder	2/108 (1.9%)	2	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Stomach pain	4/108 (3.7%)	6	2/108 (1.9%)	2	1/109 (0.9%)	1	1/112 (0.9%)	1
Tooth disorder	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Toothache	0/108 (0%)	0	2/108 (1.9%)	2	1/109 (0.9%)	1	2/112 (1.8%)	3
Vomiting	27/108 (25%)	37	28/108 (25.9%)	37	32/109 (29.4%)	57	31/112 (27.7%)	46
General disorders
Chest pain	4/108 (3.7%)	6	5/108 (4.6%)	6	2/109 (1.8%)	2	2/112 (1.8%)	2
Chills	12/108 (11.1%)	14	8/108 (7.4%)	9	5/109 (4.6%)	10	10/112 (8.9%)	12
Edema limbs	20/108 (18.5%)	38	12/108 (11.1%)	15	12/109 (11%)	19	7/112 (6.3%)	13
Facial pain	0/108 (0%)	0	1/108 (0.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Fatigue	96/108 (88.9%)	302	97/108 (89.8%)	296	97/109 (89%)	293	101/112 (90.2%)	299
Fever	13/108 (12%)	13	14/108 (13%)	14	8/109 (7.3%)	9	10/112 (8.9%)	13
Flu-like symptoms	4/108 (3.7%)	4	2/108 (1.9%)	4	0/109 (0%)	0	0/112 (0%)	0
Gait abnormal	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
General symptom	2/108 (1.9%)	2	4/108 (3.7%)	4	0/109 (0%)	0	2/112 (1.8%)	3
Ill-defined disorder	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	1/112 (0.9%)	1
Injection site reaction	2/108 (1.9%)	3	2/108 (1.9%)	2	1/109 (0.9%)	1	0/112 (0%)	0
Localized edema	5/108 (4.6%)	8	2/108 (1.9%)	3	2/109 (1.8%)	2	1/112 (0.9%)	2
Pain	17/108 (15.7%)	32	20/108 (18.5%)	35	13/109 (11.9%)	20	18/112 (16.1%)	22
Visceral edema	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Hepatobiliary disorders
Hepatic hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Immune system disorders
Autoimmune disorder	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Cytokine release syndrome	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Hypersensitivity	8/108 (7.4%)	8	11/108 (10.2%)	12	6/109 (5.5%)	7	12/112 (10.7%)	13
Immune system disorder	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Infections and infestations
Abdominal infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Anal infection	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Bladder infection	0/108 (0%)	0	1/108 (0.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Bone infection	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Bronchitis	2/108 (1.9%)	3	1/108 (0.9%)	1	0/109 (0%)	0	2/112 (1.8%)	2
Catheter related infection	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	2/112 (1.8%)	3
Colitis, infectious (e.g., Clostridium difficile)	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Conjunctivitis infective	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Device related infection	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Esophageal infection	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Eye infection	0/108 (0%)	0	1/108 (0.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Gingival infection	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Infection	4/108 (3.7%)	4	4/108 (3.7%)	4	6/109 (5.5%)	9	4/112 (3.6%)	8
Infective myositis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Laryngitis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Lip infection	1/108 (0.9%)	1	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Mucosal infection	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Nail infection	6/108 (5.6%)	8	7/108 (6.5%)	8	1/109 (0.9%)	1	4/112 (3.6%)	5
Otitis externa	1/108 (0.9%)	2	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Otitis media	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Paranasal sinus infection	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Pharyngitis	1/108 (0.9%)	1	2/108 (1.9%)	2	0/109 (0%)	0	0/112 (0%)	0
Pneumonia	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	0/112 (0%)	0
Rhinitis infective	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Sinusitis	2/108 (1.9%)	2	5/108 (4.6%)	5	3/109 (2.8%)	3	1/112 (0.9%)	1
Skin infection	6/108 (5.6%)	7	11/108 (10.2%)	14	4/109 (3.7%)	6	4/112 (3.6%)	6
Soft tissue infection	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Tooth infection	2/108 (1.9%)	5	4/108 (3.7%)	6	2/109 (1.8%)	2	1/112 (0.9%)	1
Upper aerodigestive tract infection	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Upper respiratory infection	5/108 (4.6%)	5	8/108 (7.4%)	10	6/109 (5.5%)	7	8/112 (7.1%)	9
Ureteritis	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Urinary tract infection	9/108 (8.3%)	11	7/108 (6.5%)	10	2/109 (1.8%)	3	10/112 (8.9%)	11
Vaginal infection	2/108 (1.9%)	2	4/108 (3.7%)	5	0/109 (0%)	0	1/112 (0.9%)	1
Viral hepatitis	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Vulvitis	0/108 (0%)	0	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Wound infection	0/108 (0%)	0	3/108 (2.8%)	3	1/109 (0.9%)	1	3/112 (2.7%)	4
Injury, poisoning and procedural complications
Bruising	2/108 (1.9%)	2	0/108 (0%)	0	1/109 (0.9%)	1	5/112 (4.5%)	8
Dermatitis radiation	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Fracture	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	2
Intraoperative gastrointestinal injury - Teeth	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Radiation recall reaction (dermatologic)	1/108 (0.9%)	3	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Seroma	1/108 (0.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	1	1/112 (0.9%)	1
Vascular access complication	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Wound dehiscence	0/108 (0%)	0	7/108 (6.5%)	12	3/109 (2.8%)	3	8/112 (7.1%)	9
Investigations
Alanine aminotransferase increased	19/108 (17.6%)	27	27/108 (25%)	45	22/109 (20.2%)	43	36/112 (32.1%)	55
Alkaline phosphatase increased	13/108 (12%)	24	10/108 (9.3%)	13	8/109 (7.3%)	16	17/112 (15.2%)	34
Aspartate aminotransferase increased	20/108 (18.5%)	36	27/108 (25%)	41	18/109 (16.5%)	34	29/112 (25.9%)	44
Blood bilirubin increased	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	5/112 (4.5%)	5
CD4 lymphocytes decreased	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	3	0/112 (0%)	0
Coagulopathy	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Creatinine increased	5/108 (4.6%)	9	2/108 (1.9%)	5	4/109 (3.7%)	7	4/112 (3.6%)	6
Electrocardiogram QTc interval prolonged	1/108 (0.9%)	1	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Gamma-glutamyltransferase increased	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
INR increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Laboratory test abnormal	5/108 (4.6%)	5	5/108 (4.6%)	10	4/109 (3.7%)	4	8/112 (7.1%)	12
Leukocyte count decreased	23/108 (21.3%)	45	31/108 (28.7%)	55	40/109 (36.7%)	77	39/112 (34.8%)	81
Lymphocyte count decreased	12/108 (11.1%)	15	11/108 (10.2%)	19	8/109 (7.3%)	11	17/112 (15.2%)	30
Neutrophil count decreased	35/108 (32.4%)	58	40/108 (37%)	62	85/109 (78%)	173	90/112 (80.4%)	185
Platelet count decreased	18/108 (16.7%)	26	19/108 (17.6%)	29	67/109 (61.5%)	154	77/112 (68.8%)	156
Serum cholesterol increased	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Weight gain	1/108 (0.9%)	1	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	2
Weight loss	10/108 (9.3%)	12	10/108 (9.3%)	12	11/109 (10.1%)	16	18/112 (16.1%)	23
Metabolism and nutrition disorders
Anorexia	28/108 (25.9%)	48	35/108 (32.4%)	61	33/109 (30.3%)	58	44/112 (39.3%)	75
Blood bicarbonate decreased	1/108 (0.9%)	1	1/108 (0.9%)	1	0/109 (0%)	0	3/112 (2.7%)	4
Blood glucose increased	31/108 (28.7%)	59	28/108 (25.9%)	49	26/109 (23.9%)	57	29/112 (25.9%)	57
Blood uric acid increased	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	2
Dehydration	6/108 (5.6%)	8	8/108 (7.4%)	12	10/109 (9.2%)	11	11/112 (9.8%)	13
Obesity	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Serum albumin decreased	9/108 (8.3%)	15	7/108 (6.5%)	12	6/109 (5.5%)	7	14/112 (12.5%)	21
Serum calcium decreased	13/108 (12%)	18	12/108 (11.1%)	14	10/109 (9.2%)	13	9/112 (8%)	12
Serum calcium increased	2/108 (1.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	2	2/112 (1.8%)	2
Serum glucose decreased	2/108 (1.9%)	2	4/108 (3.7%)	4	2/109 (1.8%)	2	4/112 (3.6%)	6
Serum magnesium decreased	0/108 (0%)	0	3/108 (2.8%)	4	11/109 (10.1%)	20	2/112 (1.8%)	2
Serum magnesium increased	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Serum phosphate decreased	2/108 (1.9%)	2	0/108 (0%)	0	2/109 (1.8%)	2	1/112 (0.9%)	1
Serum potassium decreased	17/108 (15.7%)	25	15/108 (13.9%)	21	28/109 (25.7%)	57	21/112 (18.8%)	32
Serum potassium increased	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	3/112 (2.7%)	3
Serum sodium decreased	9/108 (8.3%)	17	12/108 (11.1%)	20	11/109 (10.1%)	19	16/112 (14.3%)	18
Serum sodium increased	2/108 (1.9%)	2	2/108 (1.9%)	3	1/109 (0.9%)	1	0/112 (0%)	0
Serum triglycerides increased	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	24/108 (22.2%)	47	23/108 (21.3%)	39	16/109 (14.7%)	21	25/112 (22.3%)	41
Arthritis	1/108 (0.9%)	2	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Back pain	11/108 (10.2%)	13	11/108 (10.2%)	15	15/109 (13.8%)	19	17/112 (15.2%)	22
Bone pain	18/108 (16.7%)	21	14/108 (13%)	22	8/109 (7.3%)	10	16/112 (14.3%)	28
Buttock pain	2/108 (1.9%)	2	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Chest wall pain	2/108 (1.9%)	2	6/108 (5.6%)	6	4/109 (3.7%)	4	1/112 (0.9%)	1
Joint disorder	1/108 (0.9%)	1	3/108 (2.8%)	4	0/109 (0%)	0	3/112 (2.7%)	5
Muscle weakness	4/108 (3.7%)	4	0/108 (0%)	0	8/109 (7.3%)	12	2/112 (1.8%)	7
Muscle weakness lower limb	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Muscle weakness upper limb	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Musculoskeletal disorder	2/108 (1.9%)	4	6/108 (5.6%)	7	3/109 (2.8%)	3	2/112 (1.8%)	2
Myalgia	36/108 (33.3%)	58	20/108 (18.5%)	36	17/109 (15.6%)	24	25/112 (22.3%)	48
Neck pain	2/108 (1.9%)	4	4/108 (3.7%)	5	4/109 (3.7%)	5	2/112 (1.8%)	2
Pain in extremity	15/108 (13.9%)	22	14/108 (13%)	20	10/109 (9.2%)	13	9/112 (8%)	10
Upper extremity dysfunction	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor flare	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Tumor pain	1/108 (0.9%)	4	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	4
Nervous system disorders
Arachnoiditis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Ataxia	0/108 (0%)	0	1/108 (0.9%)	3	1/109 (0.9%)	3	1/112 (0.9%)	2
Cerebrospinal fluid leakage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Cognitive disturbance	3/108 (2.8%)	4	2/108 (1.9%)	2	0/109 (0%)	0	3/112 (2.7%)	3
Depressed level of consciousness	2/108 (1.9%)	2	2/108 (1.9%)	3	0/109 (0%)	0	0/112 (0%)	0
Dizziness	25/108 (23.1%)	40	20/108 (18.5%)	35	22/109 (20.2%)	31	20/112 (17.9%)	27
Dysgeusia	30/108 (27.8%)	56	22/108 (20.4%)	43	26/109 (23.9%)	48	34/112 (30.4%)	73
Extrapyramidal disorder	1/108 (0.9%)	1	2/108 (1.9%)	2	0/109 (0%)	0	1/112 (0.9%)	1
Facial muscle weakness	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Facial nerve disorder	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	2	1/112 (0.9%)	1
Headache	39/108 (36.1%)	75	45/108 (41.7%)	77	32/109 (29.4%)	50	43/112 (38.4%)	80
Hypoglossal nerve disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Memory impairment	3/108 (2.8%)	6	1/108 (0.9%)	3	2/109 (1.8%)	6	2/112 (1.8%)	2
Mini mental status examination abnormal	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Neuralgia	0/108 (0%)	0	3/108 (2.8%)	3	0/109 (0%)	0	1/112 (0.9%)	1
Neurological disorder NOS	0/108 (0%)	0	5/108 (4.6%)	5	1/109 (0.9%)	1	4/112 (3.6%)	5
Olfactory nerve disorder	0/108 (0%)	0	1/108 (0.9%)	3	0/109 (0%)	0	0/112 (0%)	0
Peripheral motor neuropathy	7/108 (6.5%)	13	10/108 (9.3%)	16	12/109 (11%)	22	12/112 (10.7%)	18
Peripheral sensory neuropathy	80/108 (74.1%)	221	82/108 (75.9%)	199	74/109 (67.9%)	195	83/112 (74.1%)	178
Seizure	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Sinus pain	1/108 (0.9%)	3	0/108 (0%)	0	0/109 (0%)	0	2/112 (1.8%)	2
Syncope	2/108 (1.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	1	2/112 (1.8%)	3
Tremor	0/108 (0%)	0	3/108 (2.8%)	6	2/109 (1.8%)	2	1/112 (0.9%)	1
Psychiatric disorders
Agitation	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	6/112 (5.4%)	10
Anxiety	26/108 (24.1%)	46	18/108 (16.7%)	34	15/109 (13.8%)	22	22/112 (19.6%)	38
Confusion	1/108 (0.9%)	1	1/108 (0.9%)	1	2/109 (1.8%)	2	0/112 (0%)	0
Depression	20/108 (18.5%)	35	13/108 (12%)	26	18/109 (16.5%)	23	17/112 (15.2%)	28
Insomnia	34/108 (31.5%)	72	32/108 (29.6%)	53	21/109 (19.3%)	37	30/112 (26.8%)	57
Libido decreased	0/108 (0%)	0	3/108 (2.8%)	11	0/109 (0%)	0	0/112 (0%)	0
Personality change	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Psychosis	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Renal and urinary disorders
Bladder hemorrhage	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	1/112 (0.9%)	1
Bladder pain	2/108 (1.9%)	2	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Cystitis	1/108 (0.9%)	1	3/108 (2.8%)	3	1/109 (0.9%)	1	4/112 (3.6%)	4
Dysuria (painful urination)	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Hemoglobin urine positive	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	2/112 (1.8%)	3
Hemorrhage urinary tract	0/108 (0%)	0	2/108 (1.9%)	2	1/109 (0.9%)	1	5/112 (4.5%)	5
Kidney pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Proteinuria	0/108 (0%)	0	7/108 (6.5%)	14	1/109 (0.9%)	1	13/112 (11.6%)	18
Ureteric hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Urethral pain	0/108 (0%)	0	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Urinary frequency	5/108 (4.6%)	8	1/108 (0.9%)	1	3/109 (2.8%)	3	7/112 (6.3%)	10
Urinary incontinence	1/108 (0.9%)	1	4/108 (3.7%)	7	1/109 (0.9%)	1	1/112 (0.9%)	1
Urogenital disorder	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	4/112 (3.6%)	5
Reproductive system and breast disorders
Breast pain	10/108 (9.3%)	15	6/108 (5.6%)	6	6/109 (5.5%)	10	5/112 (4.5%)	8
Irregular menstruation	2/108 (1.9%)	3	1/108 (0.9%)	1	3/109 (2.8%)	3	6/112 (5.4%)	10
Nipple deformity	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Pelvic pain	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Perineal pain	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Reproductive tract disorder	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Uterine hemorrhage	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	2
Vaginal discharge	0/108 (0%)	0	3/108 (2.8%)	4	1/109 (0.9%)	1	0/112 (0%)	0
Vaginal dryness	2/108 (1.9%)	3	4/108 (3.7%)	7	1/109 (0.9%)	1	2/112 (1.8%)	3
Vaginal hemorrhage	0/108 (0%)	0	5/108 (4.6%)	6	1/109 (0.9%)	1	3/112 (2.7%)	3
Vaginal inflammation	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	9/108 (8.3%)	14	16/108 (14.8%)	25	8/109 (7.3%)	11	15/112 (13.4%)	24
Aspiration	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Cough	31/108 (28.7%)	46	31/108 (28.7%)	61	22/109 (20.2%)	31	32/112 (28.6%)	49
Dyspnea	38/108 (35.2%)	63	39/108 (36.1%)	74	45/109 (41.3%)	84	48/112 (42.9%)	93
Epistaxis	10/108 (9.3%)	15	57/108 (52.8%)	114	18/109 (16.5%)	22	58/112 (51.8%)	97
Hiccups	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Hypoxia	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	0/112 (0%)	0
Laryngeal edema	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Laryngeal pain	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Laryngoscopy abnormal	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	2	0/112 (0%)	0
Nasal congestion	3/108 (2.8%)	6	14/108 (13%)	23	4/109 (3.7%)	6	9/112 (8%)	10
Pharyngeal examination abnormal	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Pharyngeal mucositis	1/108 (0.9%)	2	1/108 (0.9%)	1	0/109 (0%)	0	2/112 (1.8%)	2
Pharyngolaryngeal pain	8/108 (7.4%)	11	16/108 (14.8%)	19	6/109 (5.5%)	6	10/112 (8.9%)	16
Pulmonary hemorrhage	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	2
Respiratory disorder	4/108 (3.7%)	5	9/108 (8.3%)	13	6/109 (5.5%)	8	8/112 (7.1%)	11
Respiratory tract hemorrhage	0/108 (0%)	0	0/108 (0%)	0	1/109 (0.9%)	1	1/112 (0.9%)	1
Voice alteration	5/108 (4.6%)	8	14/108 (13%)	18	4/109 (3.7%)	5	13/112 (11.6%)	25
Skin and subcutaneous tissue disorders
Alopecia	71/108 (65.7%)	204	59/108 (54.6%)	162	55/109 (50.5%)	136	61/112 (54.5%)	159
Decubitus ulcer	1/108 (0.9%)	1	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Dry skin	12/108 (11.1%)	18	18/108 (16.7%)	26	9/109 (8.3%)	13	10/112 (8.9%)	20
Erythema multiforme	2/108 (1.9%)	3	4/108 (3.7%)	6	2/109 (1.8%)	3	2/112 (1.8%)	3
Hand-and-foot syndrome	6/108 (5.6%)	7	4/108 (3.7%)	5	3/109 (2.8%)	3	3/112 (2.7%)	5
Nail disorder	36/108 (33.3%)	73	38/108 (35.2%)	74	27/109 (24.8%)	37	27/112 (24.1%)	43
Pain of skin	2/108 (1.9%)	2	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Petechiae	0/108 (0%)	0	1/108 (0.9%)	2	1/109 (0.9%)	1	0/112 (0%)	0
Photosensitivity	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Pruritus	16/108 (14.8%)	22	13/108 (12%)	23	8/109 (7.3%)	9	12/112 (10.7%)	16
Rash acneiform	11/108 (10.2%)	21	10/108 (9.3%)	24	8/109 (7.3%)	14	9/112 (8%)	10
Rash desquamating	26/108 (24.1%)	45	30/108 (27.8%)	53	16/109 (14.7%)	22	19/112 (17%)	29
Scalp pain	3/108 (2.8%)	3	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Skin disorder	6/108 (5.6%)	10	8/108 (7.4%)	9	7/109 (6.4%)	9	11/112 (9.8%)	14
Skin hyperpigmentation	2/108 (1.9%)	4	10/108 (9.3%)	16	5/109 (4.6%)	7	8/112 (7.1%)	16
Skin hypopigmentation	1/108 (0.9%)	4	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Skin induration	0/108 (0%)	0	0/108 (0%)	0	2/109 (1.8%)	2	1/112 (0.9%)	2
Skin striae	3/108 (2.8%)	4	3/108 (2.8%)	4	1/109 (0.9%)	2	1/112 (0.9%)	1
Skin ulceration	0/108 (0%)	0	1/108 (0.9%)	3	0/109 (0%)	0	2/112 (1.8%)	2
Sweating	18/108 (16.7%)	33	4/108 (3.7%)	7	1/109 (0.9%)	1	6/112 (5.4%)	9
Urticaria	0/108 (0%)	0	1/108 (0.9%)	1	0/109 (0%)	0	0/112 (0%)	0
Vascular disorders
Flushing	2/108 (1.9%)	5	8/108 (7.4%)	10	1/109 (0.9%)	1	0/112 (0%)	0
Hematoma	0/108 (0%)	0	0/108 (0%)	0	0/109 (0%)	0	1/112 (0.9%)	1
Hemorrhage	1/108 (0.9%)	1	1/108 (0.9%)	1	2/109 (1.8%)	3	2/112 (1.8%)	3
Hot flashes	32/108 (29.6%)	82	23/108 (21.3%)	57	20/109 (18.3%)	38	19/112 (17%)	40
Hypertension	23/108 (21.3%)	46	38/108 (35.2%)	82	11/109 (10.1%)	16	50/112 (44.6%)	90
Hypotension	3/108 (2.8%)	5	3/108 (2.8%)	4	2/109 (1.8%)	2	3/112 (2.7%)	4
Lymphedema	2/108 (1.9%)	2	0/108 (0%)	0	0/109 (0%)	0	0/112 (0%)	0
Phlebitis	1/108 (0.9%)	2	1/108 (0.9%)	1	1/109 (0.9%)	1	0/112 (0%)	0
Thrombosis	2/108 (1.9%)	2	2/108 (1.9%)	2	1/109 (0.9%)	1	1/112 (0.9%)	1
Vascular disorder	0/108 (0%)	0	2/108 (1.9%)	3	0/109 (0%)	0	1/112 (0.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.