Study to Assess Effectiveness of Giving Combination of Standard Chemotherapy Drugs Versus Combination of Standard Chemotherapy and New Drug Ixabepilone When Given Before Surgical Removal of Early Stage Breast Cancer

The pCR was defined as no histologic evidence of residual invasive adenocarcinoma in the breast and axillary lymph nodes, with or without the presence of ductal carcinoma in situ (DCIS) in the breast.

Time frame: at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy)

Population: All randomized participants

For each of the 2 biomarker sets (20-gene or 26-gene), a multi-gene model was built using penalized logistic regression on all pharmacogenomic evaluable subjects for each treatment arm separately. Receiver Operating Characteristic (ROC) plots for separate arm using 5 fold cross validation were generated. ROC for separate arms using cross over were also added. Further analysis on the multiple gene models (as mentioned in the SAP) was planned only based on the initial findings from the 2 ROC plots. For 20- and 26-gene models, ROC curves generated for each study arm did not indicate that these multi-gene models differentially predicted for pCR between the treatment arms, so further analyses to estimate the optimal cut-off and the pCR rates were not conducted.

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Population: For 20- and 26-gene models, ROC curves generated for each study arm did not indicate that these multi-gene models differentially predicted for pCR between the treatment arms, so further analyses to estimate the optimal cut-off and the pCR rates were not conducted.

Beta III tubulin positivity determined by cross-validation method. Optimal cutoff: ≥46% tumor cells staining at 2 plus or 3 plus intensity (corresponding Beta III tubulin positivity=39.4%). Pre-specified cutoff of Beta III tubulin positivity: ≥50% 2plus or 3plus cells (corresponding prevalence=38.5%). Optimal cutoffs for TACC3 and CAPG positivity determined by cross-validation method: 6.889 and 6.844 \[log2 normalized intensity units\], respectively (corresponding to prevalence rates of 43.3% and 44.3%).

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Population: For all subgroups other than Beta-III positive/negative subgroup based on a pre-determined cutoff, results were estimated using a cross-validation method (a resampling based technique, making individual sample size \[N\] not applicable).

Time frame: 12 weeks (4 3-week cycles)

Population: ixabepilone- and paclitaxel-treated participants

Time frame: 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel)

Population: ixabepilone- and paclitaxel-treated participants

Time frame: 12 weeks (4 3-week cycles)

Population: ixabepilone- and paclitaxel-treated participants with at least 2 courses of AC

Time frame: 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel)

Population: ixabepilone- and paclitaxel-treated participants with at least 2 courses of Ixabepilone/Paclitaxel

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)

Time frame: prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy during ixabepilone or paclitaxel treatment phase

Population: Ixabepilone/Paclitaxel treated participants for whom on-study labs were recorded.

Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST). AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)

Time frame: prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of study therapy during ixabepilone or paclitaxel treatment phase

Population: Ixabepilone/Paclitaxel treated participants for whom on-study labs were recorded; n=number of participants with specific laboratory evaluation.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)

Time frame: prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy during ixabepilone or paclitaxel treatment phase

Population: Ixabepilone/Paclitaxel treated participants for whom on-study labs were recorded.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. By Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grades

Time frame: prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy

Clinical response was defined as the number of participants who achieved modified World Health Organization's tumor response criteria of clinical complete response (complete disappearance of all clinically palpable detectable malignant disease and/or disappearance of radiological evidence of tumor in the breast and ipsilateral axillary lymph nodes) or clinical partial response (clinical evidence of a reduction in total tumor size of \>= 50% in the overall sum of the products of diameters of breast and axillary lesions), divided by the number of randomized participants in that arm.

Time frame: after the last dose of either ixabepilone or paclitaxel (at 12 weeks) but before surgery (4-6 weeks after the last dose of 12 weeks of therapy)

Population: All randomized participants

Combined pCR and RCB-1 was defined as participants with no histologic evidence of residual invasive adenocarcinoma in the breast and axillary lymph nodes, with or without the presence of DCIS in the breast plus subjects with RCB-1 following the RCB calculation based on data entered by the investigator sites in each arm.

Time frame: at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy)

Population: All randomized participants

Number of randomized participants requiring breast conservation surgery following study treatment.

Time frame: at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy)

Population: All randomized participants

Percentage of participants with pCR in MDR1 IHC positive and negative groups using 2 pre-specified thresholds,. The first pre-specified threshold for MDR1-positivity (Mem) =Any membrane staining. The second pre-specified threshold for MDR1-positivity (Mem+Cyto)=Any membrane staining or at least 200 Cytoplasmic H-score.

Time frame: : pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Population: Randomized participants with non-missing pCR and biomarker expression

Percentage of ER negative participants with pCR and MDR1 immunohistochemistry (IHC) positivity using 2 pre-specified thresholds, stratified by biomarker status. The first pre-specified threshold for MDR1-positivity (Mem)=Any membrane staining. The second pre-specified threshold for MDR1-positivity (Mem+Cyto)=Any membrane staining or at least 200 Cytoplasmic H-score.

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Population: Randomized estrogen negative participants with non-missing pCR and biomarker expression

Percentage of participants with pCR/RCB1 in MDR1 IHC positive and negative groups using 2 pre-specified thresholds,. The first pre-specified threshold for MDR1-positivity (Mem) =Any membrane staining. The second pre-specified threshold for MDR1-positivity (Mem+Cyto)=Any membrane staining or at least 200 Cytoplasmic H-score .

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Population: Randomized participants with non-missing pCR/RCB1 and biomarker expression

Percentage of participants having the following optimal biomarker thresholds as computed from the cross-validation method (cutoff of biomarker positive \[with 90% confidence interval by Bootstrap method\]): Beta 3 Tubulin IHC (45.866 \[5, 83.9\]); TACC3 mRNA (6.714 \[6.312, 7.192\]); CAPG mRNA (6.739 \[5.728, 7.298\]). Optimal thresholds for a 20-gene model and a 26-gene model were also planned; however, these were not determined because preliminary analyses did not indicate that they would not differentiate pCR rates between treatment arm.

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy and mRNA samples obtained prior to treatment

Population: Randomized participants with non-missing pCR and biomarker expressions. n=the number of participants with specific biomarker expression.

Relevance of biomarker in differentiation between ixabepilone & paclitaxel evaluated by logistic regression with pCR as response. Statistical analyses include: 1) the likelihood ratio test between the full model (PCR\ Biomarker:Treatment:estrogen receptor \[ER\]) & reduced model (PCR\ Treatment:ER); 2) the likelihood ratio test between the full model (PCR\ Biomarker:Treatment) & reduced model (PCR\ Biomarker+Treatment); 3) the contrast of the interaction between treatment & biomarker expression within ER Negative subjects from the full model(PCR\ Biomarker:Treatment:ER). A:B represents A,B & A\*B.

Time frame: pCR evaluated at time of surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Relevance of biomarker in differentiation between ixabepilone & paclitaxel evaluated by logistic regression with pCR/RCB1 as response. Statistical analyses include: 1) likelihood ratio test between the full model (pCR/RCB1\ Biomarker:Treatment: ER) & reduced model (pCR/RCB1\ Treatment:ER); 2) likelihood ratio test between the full model (pCR/RCB1 Biomarker:Treatment) & reduced model (pCR/RCB1\ Biomarker+Treatment); 3) contrast of the interaction between treatment & biomarker expression within ER Negative subjects from the full model (pCR/RCB1\ Biomarker:Treatment:ER). A:B represents A,B & A\*B.

Time frame: pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment.

Time frame: 12 weeks (4 3-week cycles)

Population: ixabepilone- and paclitaxel-treated participants with at least 2 courses of AC

Time frame: 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel)

Population: ixabepilone- and paclitaxel-treated participants with at least 2 courses of Ixabepilone/Paclitaxel

MCT=musculoskeletal and connective tissue, GDASC=general disorders and administration site conditions, RTM=respiratory, thoracic and mediastinal disorders, NBMUCP=neoplasms benign, malignant and unspecified (including cysts and polyps). Drug related adverse events are those events with relationship to study therapy of certain, probable, possible or missing. Subjects may have more than one event within a class. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)

Time frame: prior to the first study treatment, at the beginning of each subsequent cycle, weekly during the treatment period and a minimum of 4 weeks after the last dose of 12 weeks of study therapy

Population: Ixabepilone- and Paclitaxel-treated participants