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

Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00455533
• Other study ID #: CA163-100
• Secondary ID: EUDRACT 2006-003
• Status: Completed
• Phase: Phase 2
• First received: April 2, 2007
• Last updated: January 25, 2016
• Start date: October 2007
• Est. completion date: December 2009

Study information

• Verified date: January 2016
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 384
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Ixabepilone
Intravenous Solution, intravenous (IV), 40mg/m², Day 1 every 21 days, 12 Weeks
• Paclitaxel
Intravenous Solution, IV, 80mg/m², Weekly, 12 Weeks
• Cyclophosphamide
Intravenous Solution, IV, 600mg/m², Day 1 every 21 days, 12 Weeks
• Doxorubicin
Intravenous Solution, IV, 60mg/m², Day 1 every 21 days, 12 Weeks

Locations

Country	Name	City	State
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Capital Federal	Buenos Aires
Austria	Local Institution	Salzburg
Austria	Local Institution	Vienna
Austria	Local Institution	Wien
France	Local Institution	Bordeaux
France	Local Institution	Saint Herblain
Germany	Local Institution	Duesseldorf
Germany	Local Institution	Erlangen
Germany	Local Institution	Jena
India	Local Institution	Bangalore	Karnataka
India	Local Institution	Bhopal
India	Local Institution	Hyderabad
India	Local Institution	Mumbai
India	Local Institution	New Delhi	Delhi
India	Local Institution	Pune	Maharashtra
India	Local Institution	Trivandrum	Kerala
India	Local Institution	Vellore
Italy	Local Institution	Bologna
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Peru	Local Institution	Callao
Peru	Local Institution	Lima
Peru	Local Institution	Lima
Philippines	Local Institution	Cebu City
Philippines	Local Institution	Davao City
Philippines	Local Institution	Quezon City
Russian Federation	Local Institution	Kazan
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	St Petersburg
Singapore	Local Institution	Singapore
Spain	Local Institution	Barcelona
Spain	Local Institution	Jaen
Spain	Local Institution	Lleida
Taiwan	Local Institution	Taipei
Taiwan	Local Institution	Taipei
United Kingdom	Local Institution	Coventry	Warwickshire
United Kingdom	Local Institution	Nottingham	Nottinghamshire
United States	University Of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Albert Einstein Cancer Center	Bronx	New York
United States	Northwest Oncology & Hematology Associates	Coral Spring	Florida
United States	Florida Cancer Research Institute	Davie	Florida
United States	Medical Specialists Of Palm Beaches	Lake Worth	Florida
United States	University Medical Center, Inc	Louisville	Kentucky
United States	Comprehensive Cancer Center	Palm Springs	California
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Providence Cancer Center	Spokane	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  France,  Germany,  India,  Italy,  Korea, Republic of,  Peru,  Philippines,  Russian Federation,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Primary	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.	No
Primary	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.	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]), to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of ß-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.	No
Secondary	Randomized Participants With Non-missing pCR & Biomarker Expression (GENE [Probe Set]) to Explore Whether Gene Expression Patterns for GTSE1, Isoforms of ß-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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Number of Participants by Dose for AC		12 weeks (4 3-week cycles)	Yes
Secondary	Number of Participants by Dose for Ixabepilone/Paclitaxel		12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel)	Yes
Secondary	Reason for First Dose Reduction of AC		12 weeks (4 3-week cycles)	Yes
Secondary	Reason for First Dose Reduction of Ixabepilone/Paclitaxel		12 weeks (4 3-week cycles for ixabepilone and 12 weekly doses for paclitaxel)	Yes
Secondary	Number of Participants With Course Delay and Reason for Delay for AC		12 weeks (4 3-week cycles)	Yes
Secondary	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)	Yes

External Links

•   BMS Clinical Trials Disclosure
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