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

Study Overview
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Brief Summary
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The study will evaluate the effectiveness of ixabepilone when given after doxorubicin plus cyclophosphamide (AC) compared to standard treatment of paclitaxel given after doxorubicin plus cyclophosphamide in patients with early stage breast cancer. In addition the study will verify predefined biomarkers as well as discover new biomarkers that could identify patients who are more likely to respond to ixabepilone than standard paclitaxel based therapy.

Official Title
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A Randomized Phase II Biomarker Neoadjuvant Study of Sequential AC Followed by Ixabepilone Compared to Sequential AC Followed by Paclitaxel in Women With Early Stage Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ixabepilone
* Drug: Paclitaxel
* Drug: Cyclophosphamide
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Histologically confirmed primary invasive adenocarcinoma of the breast , T2-3, N0-3, M0, with tumor size of ≥ 2 cm All patients with early stage breast adenocarcinoma may enroll irrespective of receptor status No prior treatment for breast cancer excluding therapy for DCIS Karnofsky performance status of 80 - 100 left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or multiple gated acquisition (MUGA) Adequate hematologic, hepatic and renal function Exclusion Criteria women of child-bearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy during and up to 8 weeks after the last dose of the investigational drug Women who are pregnant or breastfeeding Inflammatory or metastatic breast cancer Unfit for breast and/or axillary surgery Evidence of baseline sensory or motor neuropathy Significant history of cardiovascular disease, serious intercurrent illness or infections including known human immu immunodeficiency virus (HIV) infection History of prior anthracycline therapy Allergies to any study medication or Cremophor® EL

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: Ixabepilone<br>* Intravenous Solution, intravenous (IV), 40mg/m², Day 1 every 21 days, 12 Weeks<br>* Other names: BMS-247550;Drug: Cyclophosphamide<br>* Intravenous Solution, IV, 600mg/m², Day 1 every 21 days, 12 Weeks<br>Drug: Doxorubicin<br>* Intravenous Solution, IV, 60mg/m², Day 1 every 21 days, 12 Weeks<br>|
| Active Comparator: B<br> | Drug: Paclitaxel<br>* Intravenous Solution, IV, 80mg/m², Weekly, 12 Weeks<br>Drug: Cyclophosphamide<br>* Intravenous Solution, IV, 600mg/m², Day 1 every 21 days, 12 Weeks<br>Drug: Doxorubicin<br>* Intravenous Solution, IV, 60mg/m², Day 1 every 21 days, 12 Weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Pathologic Complete Response (pCR) | 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. | at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy) | 
| Percentage of Participants Achieving Pathologic Complete Response (pCR) in Biomarker-Defined Populations | 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%). | pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment. | 
| Percentage of Participants Achieving Pathologic Complete Response (pCR) in 20- and 26-Gene Model Subgroups | 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. | pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Objective Response | 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. | 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) | 
| Percentage of Participants Requiring Breast Conservation Surgery | Number of randomized participants requiring breast conservation surgery following study treatment. | at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy) | 
| Percentage of Participants Achieving Combined pCR and Minimal Residual Cancer Burden (RCB) 1 | 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. | at surgery (performed 4-6 weeks after the last dose of 12 weeks of therapy) | 
| Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]), to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of β-tubulin, Kallikreins 5, 6, 10 Are Differentially Predictive of pCR | 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. | 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. | 
| Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]) to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of β-tubulin, Kallikreins 5, 6, 10 Are Differentially Predictive of pCR/RCB1 | 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. | pCR evaluated at time of surgery (4-6 weeks after the last dose of therapy); mandatory tumor tissue biopsy obtained prior to treatment. | 
| Percentage of Participants With pCR and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-Specified Thresholds | 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. | : 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. | 
| Percentage of Participants With pCR/RCB1 and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-specified Thresholds | 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 . | 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. | 
| Percentage of Participants With pCR and MDR1 Immunohistochemistry (IHC) Positivity Using Two Pre-specified Thresholds, Estrogen-Receptor (ER) Negative Participants | 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. | 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. | 
| Prevalence of Biomarker Based on Optimal Threshold (Biomarker Positive Participants) | 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. | 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 | 
| Overall Safety Summary: Deaths, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Drug-Related AEs, and Most Common Treatment-Related Non-Hematologic Adverse Events (TNAEs) Occuring in >=10% of Participants | 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 | 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 | 
| Severity of Any Drug-Related AEs and Gastrointestinal AEs by System Organ Class | 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) | 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 | 
| On-Study Hematology: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase | 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) | 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 | 
| On-Study Liver Function: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase | 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) | 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 | 
| On-Study Renal Function: Worst Common Terminology Criteria of Adverse Events (CTCAE Version 3) Grade Per Participant in Ixabepilone/Paclitaxel Phase | 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) | 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 | 
| Number of Participants by Dose for AC |  | 12 weeks (4 3-week cycles) | 
| Number of Participants by Dose for Ixabepilone/Paclitaxel |  | 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel) | 
| Reason for First Dose Reduction of AC |  | 12 weeks (4 3-week cycles) | 
| Reason for First Dose Reduction of Ixabepilone/Paclitaxel |  | 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel) | 
| Number of Participants With Course Delay and Reason for Delay for AC |  | 12 weeks (4 3-week cycles) | 
| Number of Participants With Dose Delay and Reason for Dose Delay for Ixabepilone/Paclitaxel |  | 12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Breast Cancer