Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
Ixabepilone and capecitabine combination has demonstrated to be an active regimen in patients with metastatic breast cancer after failing other treatments. Cetuximab is active against tumors expressing epidermal growth factor receptor w/demonstrated activity in head \& neck and colorectal tumors and may be effective in some breast cancers known to express EGFR. Study seeks to evaluate Ixabepilone alone or in combination with cetuximab as a an antitumor therapy w/randomization stratified by stage (T1N1-3M0 or T2-4 N0-3M0).

Detailed description:
Ixabepilone and capecitabine combination has demonstrated to be an active regimen in patients with metastatic breast cancer (MBC) after failing an anthracycline and a taxane regimen. Cetuximab is active in tumors that express epidermal growth factor receptor (EGFR) with demonstrated activity in head and neck and colorectal tumors. A proportion of breast cancers are known to express EGFR. Cetuximab's mechanism of action suggests the possibility of efficacy in breast cancer patients, and several studies show that it may be efficacious in Triple Negative Breast Cancer (TNBC). This study seeks to evaluate Ixabepilone alone or in combination with cetuximab as a possible way to increase antitumor activity. In this randomized open-label phase II trial, patients will be randomized equally between 1) Ixabepilone or 2) Ixabepilone plus Cetuximab. Randomization will be stratified by disease stage (T1N1-3M0 or T2-4 N0-3M0).

The study's primary objective is to determine the pathologic complete response rate (pCR) (breast and axilla) of Ixabepilone versus Ixabepilone when combined with cetuximab in patients with invasive breast adenocarcinoma T1N1-N3M0 or T2-4 N0-3M0 disease who are triple negative and who are candidates for preoperative chemotherapy. The secondary objectives are to evaluate overall objective response rate in both treatment groups and to assess safety and toxicity of each regimen. There are also tertiary, exploratory objectives that will hopefully allow for the correlation of biomarker expression and response to treatment.

Arms:
arm 1: Brand name is Ixempra ®; it is an epothilone B analog used in combination with other chemotherapeutics against cancer. arm 2: Cetuximab, brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor and monoclonal antibody used with Ixabepilone against cancer.

Interventions: intervention 1: Cetuximab intervention 2: Ixabepilone
Intervention descriptions: intervention 1: Cetuximab will be given at 400mg/m\^2 IV over 120 minutes for its initial loading dose on day 1 of the first of four 21 day cycles. It will then be administered on a weekly basis at 250 mg/m\^2 IV over 60 minutes. intervention 2: Ixabepilone will be given at 40mg/m\^2 IV over 180 minutes on day 1 of each of four 21 day cycles.

Protocol document:
Prot_SAP_000.pdf: 
Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 1 of 83 
 
 
 
 
 
 
 
TMHRI IRB#T 0908-0265T 
BMS Protocol #: CA163-157 
ICE Trial 
RANDOMIZED OPEN-LABEL NEO-ADJUVANT PHASE II STUDY 
COMPARING IXABEPILONE (I) Vs IXABEPILONE PLUS CETUXIMAB (IC) IN 
TRIPLE NEGATIVE BREAST CANCER PATIENTS (ICE) 
 
 
VERSION: 8.0 
DATE: 8/9/2012 
PHASE: II 
IND Number:  104,307 
 
Jenny Chang, MD. 
Director, Methodist Cancer Center 
The Methodist Hospital/Weill Cornell University 
6445 Main Street, P21-341 
Houston Texas, 77030 
Phone: 713-441-0681 
Fax: 713-793-1642 
jcchang@tmhs.org 
 
 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 2 of 83 
 
STUDY SUMMARY 
 
Title:      
Randomized open-label neo-adjuvant phase II study comparing 
ixabepilone (I) vs. ixabepilone plus cetuximab (IC) in Triple negative breast 
cancer patients 
 
Objectives: Primary Objective: 
1. To determine the pathologic complete response rate (pCR) (breast and 
axilla) of  Ixabepilone versus Ixabepilone when combined with cetuximab 
in patients with invasive breast adenocarcinoma  T1N1-N3M0 or  
T2-4 N0-3M0 disease who are Triple negative and who are candidates for 
preoperative chemotherapy. 
Secondary Objective(s): 
1. To evaluate overall objective response rate in both treatment groups. 
2. To assess toxicity of each regimen. 
Exploratory Objectives: 
1. To correlate the expression of biomarkers such as PTEN, EGFR 
and EGFR-pathway associated genes (including, but not limited to, 
TGF-, CRYAB, NRAS, KRAS, AKT3, PTEN, MEK1 and KRAS 
amplicon genes) with the objective clinical and pathologic response.  
2. To potentially explore other gene/protein expression patterns, 
mutations and gene/chromosomal copy number alterations related 
to sensitivity or resistance to ixabepilone, other anti-microtubule 
agents and cetuximab.  These additional exploratory analyses may 
include, but are not limited to, beta tubulin isoforms, ABC 
transporters, TACC3, HCAPG, GTSE1, Kallikreins and defined 
gene models associated with ixabepilone response. 
 
 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 3 of 83 
Study 
population: 
-Patients with either T1N1-N3M0 or T2-4 N0-3M0 disease who are Triple 
negative and who are candidates for preoperative chemotherapy. 
 
 
Sample 
Size: 
 
116 patients. 
 
Number of 
Centers: 
 
Single Institution: The Methodist Hospital Research Institute. 
 
 
Treatment 
Plan: 
 
This is a randomized open-label phase II trial; 116 triple negative breast 
cancer patients will be randomized equally between 1) Ixabepilone or  
2) Ixabepilone plus Cetuximab. 
TThe study population will include subjects ≥ 18 years of age diagnosed 
with invasive ductal carcinoma (IDC).    TRandomization will be stratified by 
disease stage (T1N1-3M0 or T2-4 N0-3M0).  
Prior to randomization, all patients will have a physical assessment, 
imaging, a blood draw, and a diagnostic biopsy prior to the start of 
treatment.    
The study doctor will determine if the subject qualified to be enrolled in this 
study. If subjects are enrolled, the duration of their participation is 
expected to be approximately 6 months  
 
Treatment Arm 1 
Patients will receive Ixabepilone 40mg/m P2
P given over approximately  
3-hours on day 1.  
Patients will receive a total of four cycles of this drug with each cycle  
given 21 (+/- 3) days.   
Subjects will be premedicated approximately 1 hour before the ixabepilone 
 infusion with 1) both an oral H1 blocker (diphenhydramine 50 mg or  
equivalent) and an oral H2 blocker (e.g., ranitidine 150 300 mg or  
cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 20–40 mg); 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 4 of 83 
 or 2) with premedication per institutional standards.  
Premedication with steroids is indicated in subjects who developed a 
hypersensitivity reaction to ixabepilone in previous cycles. Patients with  
severe reaction (see dose modification chart below)should not be  
retreated. 
 
Treatment Arm 2 
Patients will receive Ixabepilone 40mg/mP2
P given over approximately  
3-hours on day 1followed by cetuximab given on day 1 at 400 mg/m P
2 
Pas  
an initial loading dose (first infusion) administered as approximately a  
120-minute IV  
infusion (maximum infusion rate 5 mL/min) followed by 250 mg/mP
2 
P 
infused over approximately 60 minutes (maximum infusion rate 5 mL/min) as
subsequent weekly dose.  
 Patients will receive a total of 4 cycles of this combination with each 
cycle being 21 (+/-2) days.  S 
Subjects will be premedicated approximately 1 hour before the ixabepilone  
infusion with either 1) both an oral H1 blocker (diphenhydramine 50 mg or  
equivalent) and an oral H2 blocker (e.g., ranitidine 150-300 mg or  
cimetidine 300–800 mg or  nizatidine 150 - 300 mg or famotidine  
20–40 mg); or 2) with premedication per institutional standards.   
Premedication with steroids is indicated  in subjects who  
developed a hypersensitivity reaction to ixabepilone in   previous cycles.   
Patients with severe reaction (see dose modification chart below)should  
not be retreated. 
Subjects who are to receive cetuximab are to be premedicated with an  
HB1 Bantagonist (e.g., 50 mg of diphenhydramine IV or equivalent). 
Inclusion 
Criteria: 
 Inclusion Criteria: 
 Patients with histologic confirmation of invasive breast carcinoma. 
 Patients must have intact primary tumor. 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
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Page 5 of 83 
 Patients ≥ 18 years. 
 Invasive breast carcinoma must be determined to be ER (-), PR (-) 
and HER2Neu (-) prior to study entry. 
 Patients should have T1N1-3M0 or T2-4 N0-3M0. 
 Patients with bilateral breast cancer are eligible. 
 Patients with second primary breast cancers are eligible. 
 Patients should have a Karnofsky performance scale of ≥ 70%. 
 Patients must have clinically measurable disease by physical exam 
to be treated in the neoadjuvant setting. 
 Patients should have adequate bone marrow function, as defined 
by peripheral granulocyte count of ≥1500/mmP3
P, and platelet count 
≥100000mmP3
P. 
 Patients must have adequate liver function with a bilirubin within 
normal laboratory values. Alkaline phosphatase and transaminases 
(ALT and AST) may be up to 1.5 x upper limit of normal (ULN) of 
the institution. 
 Patients should have adequate renal function with creatinine levels 
within normal range. 
 Patients should have a normal left ventricular ejection fraction 
(LVEF) of ≥ 50%. 
 Negative serum or urine pregnancy test for a woman of childbearing 
potential (WOCBP). 
 WOCBP must use a reliable and appropriate contraceptive method 
during the study and six months after chemotherapy is completed. 
WOCBP are women who are not menopausal for 12 months or had 
no previous surgical sterilization. 
 
Patients must sign an informed consent indicating that they are 
aware of the investigational nature of the study, in keeping with 
institutional policy 
Exclusion 
Criteria: 
Exclusion Criteria: 
 Patients with a history of other invasive malignancies diagnosed 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
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V. 8 TMHRI&BMS 
Page 6 of 83 
and treated within the previous 5 years, except non-melanoma skin 
cancer and non-invasive cervical cancer. 
 Her2Neu, ER and PR positive patients should be excluded. 
 Patients with an organ allograft or other history of immune 
compromise. 
 Prior treatment with any investigational drug within the preceding 4 
weeks. 
 Chronic treatment with systemic steroids or another 
immunosuppressive agent. 
 Uncontrolled chronic viral infections or patients requiring parenteral 
antibiotics will be excluded. Patients taking highly active anti-viral 
therapies and with controlled disease will be allowed to participate.  
 Patients with an active, bleeding diathesis or on oral anti-vitamin K 
medication (except low dose coumarin defined as 1 mg a day) 
 Other concurrent and/or uncontrolled medical disease which could 
compromise participation in the study (i.e., uncontrolled diabetes, 
uncontrolled hypertension, severe infection, severe malnutrition, 
unstable angina, or congestive heart failure - New York Heart 
Association Class III or IV, ventricular arrhythmias, active ischemic 
heart disease, myocardial infarction within six months, chronic liver 
or renal disease, active upper GI tract ulceration). 
 Patients with a pre-existing peripheral neuropathy(> grade1). 
 
Statistical 
Design: 
 
Blocked randomization will be used to randomly assign patients either to 
arm 1 or arm 2. A total of 116 patients will be enrolled to allow for 6.5% 
dropout before randomization of 108 patients, given sample size of 54 
patients in each arm to be able to detect 25% difference in pathological 
complete response rates between the arm with Ixabelpilone plus 
Cetuximab and the arm with Ixabepilone with 81.9% power and a two-
sided significance level of 0.05. 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 7 of 83 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                                                                                                 
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 8 of 83 
                                                        
                                                            
IXABEPILONE 40mg/m2 3-hours infusion every 21 days
(including, but not limited to) 
EGFR 
PTEN 
TGF-
CRYAB
NRAS
KRAS
AKT3 
MEK1 
KRAS amplicon genes
beta tubulin isoforms
ABC transporters
TACC3
HCAPG
GTSE1
Kallikreins and defined gene 
models associated with 
ixabepilone response. 
Baseline
STUDY DESIGN AND TREATMENT
RANDOMIZED OPEN-LABEL NEO-ADJUVANT PHASE II STUDY COMPARING 
IXABEPILONE (I) Vs IXABEPILONE PLUS CETUXIMAB (IC) IN  TRIPLE NEGATIVE 
BREAST CANCER PATIENTS  (ICE).
Surgery
IXABEPILONE 40mg/m2 3-hours infusion every 21 days
x   4 cycles
CETUXIMAB 400mg/m2 2-hours infusion initial dose on
Cycle1 day 1 followed by  250mg/m2 over one hour Infusion on a weekly 
basis thereafter. 
PLUS
Additional 
Chemotherapy 
per PI Discretion
x   4 cycles
Biomarkers
Biomarkers
(including, but not limited to) 
EGFR 
PTEN 
TGF-
CRYAB
NRAS
KRAS
AKT3 
MEK1 
KRAS amplicon genes
beta tubulin isoforms
ABC transporters
TACC3
HCAPG
GTSE1
Kallikreins and defined gene 
models associated with 
ixabepilone response. 
                                                                                  


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 9 of 83 
Randomized open-label neo-adjuvant phase II study comparing ixabepilone 
(I) vs. ixabepilone plus cetuximab (IC) in Triple negative breast cancer 
patients. 
 
0.0 STUDY SUMMARY……………………………………………………………...2 
0.0 Schema …………………………………………………………………………..7 
1.0 Synopsis ………………………………………………………………….....…11 
    1.1 Primary Objective(s) ………………………………………………………...11 
    1.2 Secondary Objective(s)….……………………………………………….....11 
    1.3 Exploratory Objective (s)…………………………………………………....12 
2.0 Study Flow chart or Schedule of Events………………………………….14 
    2.1 Study Procedures by Visit and Treatment Cycle……………………..…..16 
    2.2 Screening/Baseline visit…………………………………………………….16 
    2.2.1 Radiological Evaluation Visit……………………………..…...…….…....17 
       2.3 Cycle 1 Clinic Visit……………………………………………………........17 
          2.3.1 Cycle 1 Post-Infusion Laboratory Visits………………...……….….18 
       2.3.2 Cycle 2 Pre-Infusion Laboratory Visit…………………………………18 
          2.3.2.1 Cycle 2 Clinic Visit…………………………………………………..19 
          2.3.2.2 Cycle 2 Post-Infusion Laboratory Visits…………………….…….19 
       2.3.3 Cycle 3 Pre-Infusion Laboratory Visit…………………………….…...19 
          2.3.3.1 Cycle 3 Clinic Visit……………………………………………...…...20 
          2.3.3.2 Cycle 3 Post-Infusion Laboratory Visits………………………..…20 
      2.3.4 Cycle 4 Pre-Infusion Laboratory Visit…………………………..……....20 
         2.3.4.1 Cycle 4 Clinic Visit……………………………………………..….....21 
         2.3.4.2 Cycle 4 Post-Infusion Laboratory Visits…………………………...21 
    2.4 End-of-Treatment/Early Termination Visit………………………………...21 
    2.5 Post-neoadjuvant Surgical Intervention………………………………..….22 
    2.6 End of Study Assessments/ Follow-up ……………………………..…..…22 
    2.7 Details of Procedure……………………………………………….….…….23 
       2.7.1 Safety Assessments……………………………………………………23 
       2.7.2 Efficacy Assessments……………………………………………… …24 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
V. 8 TMHRI&BMS 
Page 10 of 83 
3.0 Biomarkers Research Assessment…………………………………..…...24 
    3.0.1 Biomarkers Exploratory Research Tumor Tissue Collection………...24 
    3.0.2 Biomarkers Exploratory Research Blood Collection…………........... 24 
    3.0.3 Biomarkers Exploratory Research Tumor Tissue Collection…….…..25 
4.0 Introduction, Background and Rationale………………………………...25 
    4.0.1 Current Chemotherapy…………………………………………………..25 
    4.0.2 Epothilones………………………………………………………………..26 
    4.0.3 Cetuximab…………………………………………………………………37 
    4.0.4 Biomarkers Rationale Assessments…………………………….……...47 
5.0 Study Design…………………………………………………………………..49 
6.0 Study Population……………………………………………………………...49 
    6.1 Inclusion Criteria…………………………………………………………….49 
    6.2 Exclusion Criteria……………………………………………………………50 
7.0 Treatment Plan/Methods………………………………………………….….51 
    7.1 Treatment Arm 1………………………………………………………...…..51 
    7.2 Treatment Arm 2…………………………………………………………….52 
    7.3 Dose modification …………………………………………………………..52 
       7.3.1 Ixabepilone dose modifications ………………………………….……52 
       7.3.2 Cetuximab dose modifications ……………………………………..… 55 
T    7.4 Discontinuation of Subjects from TreatmentT……………………….….....T56 
    7.5 Surgical Intervention…………………………………………….…………..56 
8.0 Criteria for Response………………………………………………….……..57 
    8.0.1 Pathological Response ……………………….……….……………........57 
    8.0.2 RECIST Criteria……………………………………………………….…..58 
9.0 Study Materials………………………………………………………….….…58 
10. Adverse Events……………………………………………………….…….....65 
    10.1 Common side effects of Ixabepilone…………………………….…..….65 
    10.2 Common side effects of cetuximab ………….……………………….....71 
    10.3 Reporting of SAEs………………………………………………………....73 
11. Data Management…………………………………………………………..…76 
12. Statistical Design and Analyses……….………………………………..….76 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
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Page 11 of 83 
   12.1 Sample size estimate……………………………………………………...76 
   12.2 Statistical analysis………………………………………………………….77 
   12.3 Interim data analysis……………………………………………………….78 
13. Reference/Bibliography……………………………………………….…......79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
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Page 12 of 83 
1.0 Synopsis: 
Ixabepilone and capecitabine combination has demonstrated to be an active 
regimen in patients with metastatic breast cancer (MBC) after failing an 
anthracycline and a taxane regimen. Cetuximab is active in tumors that express 
EGFR with demonstrated activity in head and neck and colorectal tumors. A 
proportion of breast cancers are known to express EGFR. Cetuximab's 
mechanism of action suggests the possibility of efficacy in breast cancer patients 
and several studies show that it may be efficacious in Triple Negative Breast 
Cancer (TNBC). This study seeks to evaluate Ixabepilone alone or in 
combination with cetuximab as a possible way to increase antitumor activity. 
 
This is a randomized open-label phase II trial, one hundred sixteen triple 
negative breast cancer patients will be randomized equally between 1) 
Ixabepilone or 2) Ixabepilone plus Cetuximab. Randomization will be stratified by 
disease stage (T1N1-3M0 or T2-4 N0-3M0).  
At the baseline all patients will receive a physical assessment, imaging, a blood 
draw, and a biopsy prior to the start of treatment.   
 
 
1.1 Primary Objective(s): 
To determine the pathologic complete response rate (pCR) (breast and axilla) of  
Ixabepilone versus Ixabepilone when combined with cetuximab in patients with 
invasive breast adenocarcinoma  T1N1-N3M0 or T2-4 N0-3M0 disease who are 
Triple negative and who are candidates for preoperative chemotherapy. 
 
 
1.2 Secondary Objective(s): 
To evaluate overall objective response rate in both treatment groups. 
To assess safety and toxicity of each regimen. 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                    
 
Date: 08/09/2012 
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Page 13 of 83 
1.3 Exploratory Objective(s): 
To correlate the expression of biomarkers such as PTEN, EGFR and EGFR-
pathway associated genes (including, but not limited to TGF-, CRYAB, NRAS, 
KRAS, AKT3, PTEN, MEK1 and KRAS amplicon genes) with the objective 
clinical and pathologic response.  
For all samples available, the following tests will be conducted: 
 Immunohistochemical detection of EGFR, and the PTEN expression in 
tumor tissue samples.  For those EGFR-pathway associated genes 
(including, but not limited to, TGF-, CRYAB, NRAS, KRAS, AKT3, PTEN, 
MEK1 and KRAS amplicon genes) an mRNA-based assay will be used.   
 Additional exploratory biomarker analysis may be performed on tumor or 
blood samples during or following the study.  Such exploratory analyses 
may include assessments of somatic gene mutation, gene/chromosome 
copy number alteration and gene/protein expression for genes/proteins 
related to sensitivity or resistance to ixabepilone, other micro-tubule 
agents and cetuximab.  These exploratory biomarkers may include, but 
are not limited to, beta tubulin isoforms, ABC transporters, TACC3, 
HCAPG, GTSE1, Kallikreins and gene models associated with ixabepilone 
response. 
 
These analyses will allow for the correlation of biomarkers expression and 
response to treatment.  Tumor tissue samples will be obtained from the original 
paraffin blocks or slides containing tumor tissue from the initial diagnostic work-
up (see section 7.1).  
 
 In addition to the diagnostic core needle biopsy for biomarkers at baseline a 
second search for the same biomarkers will be done at the time of surgery. 
The following tests will be conducted (prioritized in the order below): 
 EGFR expression by IHC 
 PTEN expression by IHC 
 Estrogen receptor expression by IHC (at baseline only)  


Ixabepilone                                              CA163-157                                                         TMHRI 
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 Progesterone receptor expression by IHC (at baseline only)  
 Her2 neu expression by IHC and/or FISH (at baseline only)  
 Ki67 (MIB-1) by IHC (at baseline only) 
 TGF- expression by  mRNA-based assay 
 CRYAB expression by  mRNA-based assay  
 NRAS expression by  mRNA-based assay 
 KRAS expression by  mRNA-based assay 
 AKT3 expression by  mRNA-based assay  
 MEK1 expression by  mRNA-based assay 
 KRAS amplicon genes expression by  mRNA-based assay 
 Beta tubulin isoforms 
 ABC transporters 
 TACC3 
 HCAPG 
 GTSE1 
 Kallikreins and defined gene models associated with ixabepilone 
response. 
 Additional exploratory biomarkers related to ixabepilone, anti-microtubule 
and cetuximab sensitivity or resistance 
  
The goal of this clinical research study is to compare the effectiveness of each 
study group of chemotherapy in triple negative breast cancer patients, and to 
evaluate the pathologic response rate for each group.   We will be collecting 
tissue from the primary tumor for biomarker testing; the procedure will be done at 
baseline, and at the time of surgery. 
 
 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
BMS-247550                                           Clinical Protocol                                         Version:    8                                                                                                           
 
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Page 15 of 83 
 
2.0 Study Flow chart or Schedule of Events 
 
 
 
 
Procedure 
Screening/Baseline Visit 
Prior to Each Cycle 
End-of- Treatment Visit a 
Follow-up 
Eligibility Assessments 
 
 
 
 
Obtain Informed Consent 
X 
 
 
 
Confirm Inclusion/Exclusion Criteria  Met b 
X 
 
 
 
Obtain Medical History 
X 
 
 
 
Safety Assessments 
 
 
 
 
Karnofsky performance scale a b 
X 
X 
X 
 
Record Weight and Height 
X 
X 
X 
 
Document Vital Signs 
X 
X 
X 
 
Assess Signs and Symptoms and Adverse Events c, o 
X 
X 
X 
 
Perform Pregnancy Test in WOCBP d 
X 
 
 
 
Perform mammogram e 
X 
 
X 
 
Perform ultrasound of breast and nodal region e  
X 
 
X 
 
(MRI)* 
 
 
 
 
Perform Laboratory Tests  fghi 
X 
X 
X 
X 
Prepare Paraffin Block/Slides  j 
X 
 
X 
 
Obtain Blood Sample for biomarkers  k **  
X 
 
X 
 
Perform Electrocardiogram  l 
X 
 
X 
 
Perform Echocardiogram  l 
X 
 
 
 
Efficacy Assessments 
 
 
 
 
Evaluate Tumor Response RECIST Criteria  m 
X 
 
X 
 
Clinical Drug Supplies 
 
 
 
 
Premed Before Infusion n 
 
X 
 
 


Ixabepilone                                              CA163-157                                                         TMHRI 
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a. Evaluate subjects who discontinue the protocol for reasons other than disease progression every 4 weeks until progression or until they receive additional anti-cancer 
therapy. 
b. Karnofsky Performance Status of =/> 70% is required for study entry.  
c. Document signs and symptoms and adverse events at least every 4 weeks until all study drug-related toxicities resolve, stabilize, return to baseline, or are deemed 
irreversible. 
d. Pregnancy tests (serum or urine) should be performed within 72 hours of study start, or whenever pregnancy is suspected. 
e. Mammogram and ultrasound should have been performed any time within 90 days prior to beginning of the study treatment and within 3 to 4 weeks of the neoadjuvant 
therapy completion before surgery.  *MRI (magnetic resonance imaging) should be performed only if requested by the physician. 
f. Laboratory tests comprise albumin, alkaline phosphatase, ALT, AST, total bilirubin, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactic dehydrogenase, 
magnesium (at baseline only for the ixabepilone alone arm), potassium, phosphorus, and sodium, as well as complete blood count (Hemoglobin, Hematocrit, RBC, WBC, 
Platelets ) with differential (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils).   CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every 
cycle for patients with an abnormal creatinine.  
g. Perform laboratory tests within 72 hours of beginning each cycle. Perform baseline laboratory tests within four (4) weeks before administration of study drug 
h. Perform complete blood count (Hemoglobin, Hematocrit, RBC, WBC, Platelets) with differential (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils) at week 1 
and week 2 for the first 4 cycles and thereafter at the expected time of nadir (lowest count of any type of blood cell).    
i. Laboratory tests comprise of calcium, magnesium, and potassium before every dose of cetuximab therapy and for at least 8 weeks following the completion of cetuximab. 
Replete electrolytes as necessary.  
j. Send tissue slides to the central laboratory (see lab manual). Collected at baseline, and at the time of surgery [UPTEN, EGFR and EGFR-pathway associated genes 
(TGF-a, CRYAB, NRAS, KRAS, AKT3, PTEN, MEK1 and KRAS amplicon genes).  Additional exploratory biomarkers may include (but are not limited to) beta tubulin 
isoforms, ABC transporters, TACC3, HCAPG, GTSE1, Kallikreins and defined gene models associated with ixabepilone response. Tumor biomarkers will be assessed on a 
formalin-fixed, paraffin-embedded (TFFPET) tumor sample from a previous biopsy (baseline) and from the surgical specimen. A minimum of 15 slides will be collected at 
each time. 
k. Serum sample for biomarkers expression at baseline, and at the time of surgery.      ** Optional (Serum sample for biomarkers expression will be done at later time). 
l. A 12-lead ECG with QT measurement should be performed at screening, at the end of study/early termination, and whenever medically indicated.  An Echocardiogram 
should be performed at screening only and whenever medically indicated.   
m. Evaluate tumor response using RECIST criteria before chemotherapy and before surgery (from randomization to disease progression or until surgery).  
n. Subjects who are to receive ixabepilone are to be premedicated approximately 1 hour before the infusion with both an oral H1 blocker (diphenhydramine 50 mg or 
equivalent) and an oral H2 blocker (eg, ranitidine 150-300 mg or cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 20–40 mg); premedication with steroids is 
indicated in subjects who developed a hypersensitivity reaction to ixabepilone in previous cycles.      Subjects who are to receive cetuximab are to be premedicated with an 
H1 antagonist (e.g., 50 mg of diphenhydramine IV) 
o. Monitor the subject for hypersensitivity reactions during and after all infusions.


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2.1 Study Procedures by Visit and Treatment Cycle 
Laboratory analyses and clinical examinations are to be repeated for a total 
treatment duration time of 4 to 6 months. Radiologic examinations are to be 
performed before chemotherapy and before surgery (from randomization to 
disease progression or until surgery). 
The maximum number of treatment cycles allowed is 4. 
The sequence of events for up to 4 cycles is described below. 
2.2 Screening/Baseline visit 
Informed consent must be obtained before performing any study-related 
procedures. Screening procedures may be done up to 4 weeks prior the start of 
neo-adjuvant therapy. Screening evaluation will include blood work, pregnancy 
testing, medical history, physical exam (including tumor measurements of the 
breast and lymph node, height, weight, blood pressure, heart rate and 
temperature) electrocardiogram, and echocardiogram. Tumor measurements will 
be recorded as the largest dimension in centimeters.  Medical history should 
include relevant underlying conditions and concomitant medications. Baseline 
signs and symptoms are to be recorded and followed throughout the trial. A 
mammography and ultrasound will be performed to assess disease status. 
Prior to initiation of neo-adjuvant therapy, a core tumor breast biopsy and blood 
sample will be obtained for baseline biomarkers expression studies. 
If a patient entered the study (i.e. signed informed consent) prior to histological 
confirmation of breast cancer, this biopsy may serve the dual purpose of 
confirming the diagnosis and obtaining tissue for biomarkers research. 
Following confirmation of eligibility, a blocked randomization will be used to 
randomize patients to either arm 1 or arm 2.  A master sequence of 
randomization numbers for each arm will be generated. 
For those study patients who voluntarily agree to have an optional serum 
samples taken for biomarkers expression; blood samples will be stored and the 
biomarkers expression will be done at later time (see lab manual).  Patients will 
be informed that they will not be excluded from the clinical study if they do not 
wish to participate in the (blood samples) biomarkers study. 


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•The biomarkers blood sample must be collected after a patient number has 
been obtained. (see CA163157 Procedure Manual). 
• A minimum of 15 tissue slides from the tumor breast biopsy or lymph nodes 
(when available) will be collected at baseline and send to the central laboratory.  
Note: please collect all tissue slides (15 at baseline and 15 after surgery) at the 
site before send it out to the central lab (see lab manual) 
2.2.1 Radiological Evaluation Visit 
• Perform mammogram and ultrasound of the breast and nodal region to 
determine baseline tumor status using RECIST criteria. This radiological 
evaluation should be completed within 90 days before study drug administration. 
If more than 90 days have elapsed since the baseline radiological evaluation, the 
mammogram and ultrasound must be repeated before the initial infusion of study 
drug is administered. If, at any time, is suspected progression diseases a 
complete radiological evaluation must be performed.  
MRI (magnetic resonance imaging), only if requested by physician). 
2.3 Cycle 1 Clinic Visit 
• Following confirmation of eligibility, a blocked randomization will be used to 
randomize patients to either arm 1 or arm 2.  A master sequence of 
randomization numbers for each arm will be generated (see CA163157 Protocol 
Manual). Once the subject is randomized, administration of study drug must 
begin within 72 hours. NOTE: If more than 72 hours have elapsed between the 
blood sampling for laboratory analysis and administration of ixabepilone or 
cetuximab, then the analyses must be repeated. (Except for cycle 1 for which 
baseline labs obtained within 2 weeks are accepted.) 
• laboratory tests within 72 hours of beginning each cycle comprise albumin, 
alkaline phosphatase, ALT, AST, total bilirubin, blood urea nitrogen, calcium, 
chloride, creatinine, glucose, lactic dehydrogenase, magnesium (at baseline only 
for the ixabepilone alone arm), potassium, phosphorus, and sodium, as well as 
complete blood count (Hemoglobin, Hematocrit, RBC, WBC, Platelets ) with 
differential (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils).  


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CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every cycle for patients 
with an abnormal creatinine.  
• Laboratory tests comprise of calcium, magnesium, and potassium before every 
dose of cetuximab therapy (before every cycle for the ixabepilone plus cetuximab 
arm). 
• Perform a physical examination; record weight and height, karnofsky 
performance scale, document vital signs. Assess signs and symptoms and 
document baseline adverse events. 
• Subjects who are to receive ixabepilone are to be premedicated approximately 
1 hour before the infusion with either 1)both an oral H1 blocker (diphenhydramine 
50 mg or equivalent) and an oral H2 blocker (eg, ranitidine 150-300 mg or 
cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 20–40 mg); or 2) 
with premedication per institutional standards.  Premedication with steroids is 
indicated in subjects who developed a hypersensitivity reaction to ixabepilone in 
previous cycles.      Subjects who are to receive cetuximab are to be 
premedicated with an HB1 Bantagonist (e.g., 50 mg of diphenhydramine IV or 
equivalent) 
• Infuse ixabepilone or ixabepilone plus cetuximab accordingly with the 
randomization arm. 
2.3.1 Cycle 1 Post-Infusion Laboratory Visits 
• Perform platelet count and complete blood count with differential at week 1 (+/- 
3 days) and week 2(+/- 3 days) for the first 4 cycles and thereafter at the 
expected time of nadir (lowest count of any type of blood cell).    
2.3.2 Cycle 2 Pre-Infusion Laboratory Visit 
• Within 72 hours before beginning the Cycle 2 infusion, obtain blood sample for 
analysis of albumin, alkaline phosphatase, ALT, AST, total bilirubin, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactic dehydrogenase, potassium, 
phosphorus, and sodium, as well as complete blood count (Hemoglobin, 
Hematocrit, RBC, WBC, Platelets ) with differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils).  


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CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every cycle for patients 
with an abnormal creatinine.  
• Laboratory tests comprise of calcium, magnesium, and potassium before every 
dose of cetuximab therapy (before every cycle for the ixabepilone plus cetuximab 
arm). 
2.3.2.1 Cycle 2 Clinic Visit 
• Perform a physical examination to include tumor measurements of the breast 
and lymph node; record weight and height, karnofsky performance scale, 
document vital signs. Assess signs and symptoms and document baseline 
adverse events. 
• Subjects who are to receive ixabepilone are to be premedicated approximately 
1 hour before the infusion with either 1) both an oral H1 blocker 
(diphenhydramine 50 mg or equivalent) and an oral H2 blocker (eg, ranitidine 
150-300 mg or cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 
20–40 mg); or 2) with premedication per institutional standards.  Premedication 
with steroids is indicated in subjects who developed a hypersensitivity reaction to 
ixabepilone in previous cycles.       
•Subjects who are to receive cetuximab are to be premedicated with an H B1 
Bantagonist (e.g., 50 mg of diphenhydramine IV or equivalent). 
• Infuse ixabepilone or ixabepilone plus cetuximab accordingly with the study 
arm. 
2.3.2.2 Cycle 2 Post-Infusion Laboratory Visits 
• Perform platelet count and complete blood count with differential at week 1(+/- 
3 days) and week 2 (+/- 3 days) for the first 4 cycles and thereafter at the 
expected time of nadir (lowest count of any type of blood cell).    
2.3.3 Cycle 3 Pre-Infusion Laboratory Visit 
• Within 72 hours before beginning the Cycle 3 infusion, obtain blood sample for 
analysis of albumin, alkaline phosphatase, ALT, AST, total bilirubin, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactic dehydrogenase, potassium, 
phosphorus, and sodium, as well as complete blood count (Hemoglobin, 


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Hematocrit, RBC, WBC, Platelets ) with differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils).  
CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every cycle for patients 
with an abnormal creatinine.  
• Laboratory tests comprise of calcium, magnesium, and potassium before every 
dose of cetuximab therapy (before every cycle for the ixabepilone plus cetuximab 
arm). 
2.3.3.1 Cycle 3 Clinic Visit 
• Perform a physical examination to include tumor measurements of the breast 
and lymph node; record weight and height, karnofsky performance scale, 
document vital signs. Assess signs and symptoms and document baseline 
adverse events. 
• Subjects who are to receive ixabepilone are to be premedicated approximately 
1 hour before the infusion with either 1) both an oral H1 blocker 
(diphenhydramine 50 mg or equivalent) and an oral H2 blocker (eg, ranitidine 
150-300 mg or cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 
20–40 mg); or 2) with premedication per institutional standards.   Premedication 
with steroids is indicated in subjects who developed a hypersensitivity reaction to 
ixabepilone in previous cycles.       
•Subjects who are to receive cetuximab are to be premedicated with an H B1 
Bantagonist (e.g., 50 mg of diphenhydramine IV or equivalent). 
• Infuse ixabepilone or ixabepilone plus cetuximab accordingly with the study 
arm. 
2.3.3.2 Cycle 3 Post-Infusion Laboratory Visits 
• Perform platelet count and complete blood count with differential at week 1(+/- 
3 days) and week 2 (+/- 3 days) for the first 4 cycles and thereafter at the 
expected time of nadir (lowest count of any type of blood cell).    
2.3.4 Cycle 4 Pre-Infusion Laboratory Visit 
• Within 72 hours before beginning the Cycle 4 infusion, obtain blood sample for 
analysis of albumin, alkaline phosphatase, ALT, AST, total bilirubin, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactic dehydrogenase, potassium, 


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phosphorus, and sodium, as well as complete blood count (Hemoglobin, 
Hematocrit, RBC, WBC, Platelets ) with differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils).  
CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every cycle for patients 
with an abnormal creatinine.  
• Laboratory tests comprise of calcium, magnesium, and potassium before every 
dose of cetuximab therapy (before every cycle for the ixabepilone plus cetuximab 
arm). 
2.3.4.1 Cycle 4 Clinic Visit 
• Perform a physical examination to include tumor measurements of the breast 
and lymph node; record weight and height, karnofsky performance scale, 
document vital signs. Assess signs and symptoms and document baseline 
adverse events. 
• Subjects who are to receive ixabepilone are to be premedicated approximately 
1 hour before the infusion with either 1)both an oral H1 blocker (diphenhydramine 
50 mg or equivalent) and an oral H2 blocker (eg, ranitidine 150-300 mg or 
cimetidine 300–800 mg or nizatidine 150-300 mg or famotidine 20–40 mg); or 2) 
with premedication per institutional standards.  Premedication with steroids is 
indicated in subjects who developed a hypersensitivity reaction to ixabepilone in 
previous cycles.       
•Subjects who are to receive cetuximab are to be premedicated with an H B1 
Bantagonist (e.g., 50 mg of diphenhydramine IV or equivalent). 
• Infuse ixabepilone or ixabepilone plus cetuximab accordingly with the study 
arm. 
2.3.4.2 Cycle 4 Post-Infusion Laboratory Visits 
• Perform platelet count and complete blood count with differential at week 1(+/- 
3 days) and week 2 (+/- 3 days) for the first 4 cycles and thereafter at the 
expected time of nadir (lowest count of any type of blood cell).    
2.4 End-of-Treatment/Early Termination Visit 
Within 3 - 4 weeks of completing cycle 4 or one (1) week after the patient has 
withdrawn from the study for any reason other than completed treatment. 


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 • Obtain blood sample for analysis of albumin, alkaline phosphatase, ALT, AST, 
total bilirubin, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactic 
dehydrogenase, potassium, phosphorus, and sodium, as well as complete blood 
count (Hemoglobin, Hematocrit, RBC, WBC, Platelets ) with differential 
(Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils) .  
CrCL  “CrCl = [(140 - age) x IBW] / (Scr x 72)  (x 0.85 for females)” before every cycle for patients 
with an abnormal creatinine.  
• Laboratory tests comprise of calcium, magnesium, and potassium for at least 8 
weeks following the completion of cetuximab therapy. Replete electrolytes as 
necessary.  
• Perform a physical examination to include tumor measurements of the breast 
and lymph node; record weight and height, karnofsky performance scale, 
document vital signs. Assess signs and symptoms and document baseline 
adverse events. 
• For those study patients who voluntarily agree to have an optional serum 
samples taken for biomarkers expression; blood samples will be stored and the 
biomarkers expression will be done at later time (see lab manual).  Patients will 
be informed that they will not be excluded from the clinical study if they do not 
wish to participate in the (blood samples) biomarkers study. 
• Perform electrocardiogram at the end of the study/early termination visit. 
• Perform mammogram and ultrasound of breast and nodal region to determine 
tumor status using RECIST criteria. 
2.5 Post-neoadjuvant Surgical Intervention 
Within 3 - 4 weeks of completing neoadjuvant therapy, patients will undergo 
surgery of the breast and axilla according to local guidelines. Patients will remain 
in the study throughout the neoadjuvant therapy, regardless of type, until the 
completion of surgical intervention and the collection of the post-neoadjuvant 
therapy biopsy. Portions of tumor tissue from the primary site, or lymph nodes 
(when available), will be obtained for post treatment biomarkers expression 
studies. 


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Note: please collect all tissue slides (15 at baseline and 15 after surgery) at the 
site before send it out to the central lab (see lab manual) 
2.6 End of Study Assessments/ Follow-up 
Vital signs including blood pressure, heart rate and temperature will be 
performed during this visit. Toxicity assessment will be continuous throughout the 
study. CTC Version 3.0 (dated June 10, 2003) will be used to grade toxicities.  
For the patients on the ixabepilone plus cetuximab arm the labs will be done for 
at least 8 weeks and will include calcium, magnesium, and potassium following 
the completion of cetuximab therapy. Replete electrolytes as necessary.  
 
End of study visit will occur approximately 30 days after surgery. The patients on 
the ixabepilone arm with continuing diagnosis of toxicity related to neoadjuvant 
chemotherapy will be seen by the Investigator at least every 4 weeks until all 
study drug related toxicities resolve, stabilize, return to baseline or are deemed 
irreversible as judged by the investigator. The patients on the ixabepilone plus 
cetuximab arm with continuing diagnosis of toxicity related to neoadjuvant 
chemotherapy will be seen by the Investigator at least every week (eight (8) 
weeks total)  until all study drug related toxicities resolve, stabilize, return to 
baseline or are deemed irreversible as judged by the investigator. 
2.7 Details of Procedure 
2.7.1 Safety Assessments 
Medical history will include relevant underlying conditions. Baseline signs and 
symptoms are to be recorded and followed throughout the trial. Toxicity 
assessments will be continuous during treatment and in post-treatment follow-up 
and occur every 4 weeks until all study drug related toxicities resolve, stabilize, 
return to baseline or are deemed irreversible as judged by the investigator. CTC 
Version 3.0 (June 10, 2003) will be used to grade toxicities. Vital signs including 
blood pressure, heart rate and temperature should be performed at each physical 
exam. Perform baseline laboratory tests within two (2) weeks before 
administration of study drug, baseline serum chemistries (lactate dehydrogenase 
(LDH), glucose, electrolytes, albumin, blood urea nitrogen (BUN), creatinine, 


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alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, total bilirubin, magnesium, calcium and phosphorus) and 
hematology (Complete Blood Count (CBC) + differential + platelets) will be done 
at screening. Additionally, CBC + differential and platelets and serum chemistry 
panel must be performed within 72 hours prior to each subsequent 
chemotherapy cycle. 
Laboratory tests may be done more frequently if medically indicated.  
If CTC Grade 4 hematologic toxicity is seen, repeat CBC + differential + platelets 
should be repeated every 3 - 4 days until recovery. 
2.7.2 Efficacy Assessments 
A clinical assessment as well as mammography and ultrasound will be performed 
to assess disease status at baseline. 
Clinical tumor response in the primary site and in the axilla will be assessed after 
each cycle of treatment and prior to the next treatment by physical exam.  Three 
to four weeks after the last treatment with the study drugs patients will be 
assessed for disease status via mammography and ultrasound as well as clinical 
assessment. Disease progression suspected from clinical tumor response 
assessments during any cycle should be confirmed by mammography and 
ultrasound.  
 
3.0 Biomarkers Research Assessment 
3.0.1 Biomarkers Exploratory Research Tumor Tissue Collection 
Two samples of tumor tissue will be collected during the course of the study. The 
first sample will be collected prior to treatment with the study drug and the 
second at the time of the surgery. These samples will be used to obtain mRNA 
for analysis of tumor gene expression. Tumor biomarkers will be assessed on a 
formalin-fixed, paraffin-embedded (TFFPET) tumor sample from a previous biopsy 
(baseline) and from the surgical specimen. A minimum of 15 slides will be 
collected at each time. Details for processing, storing and shipping these 
samples will be provided by BMS in the CA163157 Procedure Manual. 
3.0.2 Biomarkers Exploratory Research Blood Collection  


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This procedure is optional (Serum sample for biomarkers expression will be done 
at later time). 
One venous blood sample of 2 mLs will be collected. The specimen will be 
obtained prior to treatment with the study drugs. This sample will be used to 
obtain mRNA for analysis of gene expression. Details for collection, processing, 
storing and shipping these samples will be provided in the CA163157 Procedure 
Manual. 
 
 
 
3.0.3 Biomarkers Exploratory Research Tumor Tissue Collection 
Any patient, who switches to another neoadjuvant therapy prior to surgery, will be 
asked to undergo an additional breast biopsy. This breast biopsy is optional and 
will require an additional consent. The biopsy must be obtained within 21 days 
after last dose of study drug and prior to next therapeutic regimen. 
Details for processing storing and shipping these samples will be provided by 
BMS in the CA163157 Procedure Manual. 
 
4.0 Introduction, Background and Rationale 
Breast cancer is the most common cancer in women. It kills 376,000 women a 
year worldwide, and there are about 900,000 new cases annually. Estimates for 
2007 indicate that breast cancer will cause 180,510 cases of new cancers in the 
United States, accounting for 26% of new cancer cases in women and 40,460 
cancer deaths. Approximately 50% of women are diagnosed with localized 
disease. Although many of these women will have an initial good response to 
treatment, 50% to 75% of those diagnosed with early disease will eventually 
relapse. Metastatic breast cancer is largely incurable using conventional therapy, 
with a median survival of 2 to 3 years from manifestation of metastases. P1 
4.0.1 Current Chemotherapy 
Many chemotherapeutic agents have been demonstrated to be active in MBC, 
including alkylating agents, anti-metabolites, anthracyclines, vinca alkaloids, 


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podophyllotoxins, and taxanes. Anthracyclines and taxanes are generally 
considered the most active cytotoxic drug classes in breast cancer. As a result, 
both classes of agents are commonly used in the metastatic as well as the 
adjuvant setting. Docetaxel and paclitaxel, alone or in combination with other 
chemotherapeutic agents, have shown significant response rates in first- or 
second-line treatment of MBC. As second-line monotherapy, taxanes have had 
response rates in the range of 28% to 55%.  Despite high activity, however, 
relapse is common and long-term disease control is rare.  Additionally, many 
subjects fail to respond to taxanes and anthracyclines. Options are limited for 
subjects who have failed prior treatment with both an anthracycline and a taxane. 
Capecitabine alone , and in combination with ixabepilone are currently the only 
chemotherapy agents specifically approved in regions around the world for the 
treatment of metastatic breast cancer in subjects who have failed or are resistant 
to both an anthracycline and a taxane.P2,3,4 
4.0.2 Epothilones  
The epothilone are a new class of non-taxane tubulin polymerization agents 
obtained by fermentation of the myxobacterium Sorangium cellulosum.P5 
P The 
chief components of the fermentation process are epothilones A and B. In 1994, 
the National Cancer Institute discovered that the epothilones possess potent 
cytotoxic activity. The cytotoxic activities of the epothilones, like those of the 
taxanes, have been linked to stabilization of microtubules, which results in mitotic 
arrest at the G2/M transition.P6,7
P  Importantly, the epothilones are active against 
various taxane-resistant cell lines, including those with overexpression of the 
multidrug resistance gene and BIII tubulin isoforms, or have tubulin mutations. 
Ixabepilone is a semi-synthetic derivative of the natural product epothilone B 
specifically designed to overcome the metabolic instability of the natural product 
as demonstrated in preclinical models. Similar to paclitaxel, ixabepilone blocks 
cells in the mitotic phase of the cell division cycle and is a highly potent cytotoxic 
agent capable of killing cancer cells at low nanomolar concentrations. 
An important feature of ixabepilone is its antitumor activity in a broad range of 
taxane sensitive and taxane-resistant preclinical human tumor models. Phase 1 


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studies of ixabepilone have demonstrated antitumor activity in cancers of the 
ovary, cervix, colon, stomach, and breast, as well as in melanoma, non-small-cell 
lung carcinoma, and non-Hodgkin’s lymphoma. Phase 2 studies of monotherapy 
ixabepilone have demonstrated notable activity in subjects with both taxane-
sensitive and taxane-resistant breast cancer as well as in other tumor types. A 
Phase 1/2 study of ixabepilone plus capecitabine has established that the 
combination is active in subjects who have failed prior anthracycline and taxane 
and that the two agents can be safely administered together, each at efficacious 
doses. Subset analysis from the recently completed CA163046 study showed 
that subjects with HER2 (ErbB2) positive metastatic breast cancer previously 
treated with a taxane and an anthracycline benefit from ixabepilone plus 
capecitabine over capecitabine alone. 
Preclinical Metabolism and Potential for Drug Interactions 
In vitro studies suggest that CYP3A4 is the CYP isozyme primarily responsible 
for the oxidative metabolism of ixabepilone in humans. Therefore, 
coadministration of inhibitors of CYP3A4 may affect the pharmacokinetics of 
ixabepilone. In vitro studies also suggest that ixabepilone is a weak inhibitor of 
human CYP3A4. Given that ixabepilone is administered on an intermittent 
schedule (q21 days), is a weak inhibitor of CYP3A4 in vitro (IC50 of 
approximately 3700 ng/mL), and typically has peak plasma concentrations 
of less than 400 ng/mL when administered as a 3-hour infusion, there is a low 
likelihood of a clinically important effect on the pharmacokinetics of 
coadministered medications that are dependent on CYP3A4 metabolism. 
Phase 1 Ixabepilone Monotherapy Studies 
To date, approximately 2700 subjects have been treated with ixabepilone in the 
Bristol-Myers Squibb (BMS)-sponsored Phase 1, Phase 2, and Phase 3 studies.P8
P 
Ixabepilone is also being independently evaluated in studies conducted by the 
National Cancer Institute Cancer Therapy Evaluation Program. 
BMS has sponsored two Phase 1 studies of ixabepilone monotherapy, which 
were designed to establish a recommended dose for Phase 2 studies. CA163-
001 evaluated ixabepilone administered intravenously (IV) on Day 1 of a 21-day 


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cycle (q3 weeks). CA163-002 evaluated ixabepilone administered IV on a weekly 
schedule. CA163-001 is summarized below; CA163-002 is summarized in the 
Investigator Brochure.P8
P (Of note, the National Cancer Institute has also 
sponsored Phase 1 monotherapy studies, which evaluated a variety of 
schedules, including a daily x 5 days q21-day schedule). CA163-001 was an 
open-label dose-escalation study of ixabepilone administered once 
every 3 weeks as a 1-hour infusion in subjects with advanced malignancies. 
Sixty-one (61) subjects were treated at dose levels of 7.4, 15, 30, 50, 57, and 65 
mg/mP2
P. At doses below 50 mg/mP2
P, no dose-limiting toxicities (DLT) were 
observed. First-course DLT was experienced by 2 out of 3 subjects at 65 mg/m P2
P 
(Grade 3 neuropathy and prolonged Grade 4 neutropenia; prolonged Grade 4 
neutropenia) and by all 3 subjects at 57 mg/m P2
P (Grade 3 arthralgia and myalgia 
in 2 subjects; Grade 4 neutropenia with pneumococcal sepsis and death in 1 
subject). After the maximum tolerated dose was established as 50 mg/m P2
P, a 
cohort of 10 additional subjects were treated at this dose. Severe toxicity 
requiring a dose reduction was observed in only 1 of these subjects (febrile 
neutropenia). Other toxicities included fatigue, weakness, constipation, diarrhea, 
nausea, vomiting, rash, alopecia, and low-grade neuropathy. Antitumor activity 
seen among 22 subjects treated at 50 mg/m P2
P included a complete response in 
ovarian cancer and partial responses in non-small-cell lung cancer and 
melanoma. Due to cumulative neuropathy observed with the 1-hour schedule, 
this study was expanded at doses of 40 and 50 mg/m P2
P administered as a 3-hour 
infusion. As of July 2002, data were available for 12 subjects treated at 40 mg/m P2
P 
over 3 hours for a total of 35 cycles. The most notable toxicity was neutropenia. 
Grade 4 neutropenia was observed in 2 subjects (17%) but no episodes of febrile 
neutropenia were reported. Sensory or painful peripheral neuropathy of any 
grade was reported in 4 (33%) subjects, all Grade 1.   There were no treatment 
discontinuations due to drug toxicity in this dose cohort. H1 and H2 histamine 
blockers were introduced as routine premedication after hypersensitivity 
reactions (HSRs) were reported early in the Phase 1 program. No subsequent 
HSRs were reported in the study. Other common safety events included 


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myalgias (8%) and stomatitis/pharyngitis (8%). No deaths occurred on-study that 
were deemed related to study drug. One partial response was reported in this 
dose cohort in a patient with ovarian cancer. 
CA163-031: A Combined Phase 1/Phase 2 Study 
CA163-031 was an open-label, multicenter, dose-escalation study of the 
combination of ixabepilone and capecitabine for the treatment of taxane- and 
anthracycline-pretreated MBC. The primary objective of the study was to 
determine the recommended Phase 2 and Phase 3 doses of ixabepilone and 
capecitabine. However, once safety and preliminary efficacy data identified 
ixabepilone 40 mg/mP2
Pplus capecitabine 2000 mg/mP2
P as the recommended dose, 
the protocol was amended to enroll additional subjects at this dose to estimate 
overall response rate.P 9
P 
CA163-031 Efficacy Summary 
No objective responses were observed among the 6 subjects in the ixabepilone 8 
mg/mP2
P + capecitabine 1650 mg/mP2
Pdose cohort. One partial response was 
observed among the 6 subjects in the ixabepilone 10 mg/m P2
P + capecitabine 1650 
mg/mP2
P dose cohort. In the second phase of the study, 62 subjects were treated 
with the doses selected in the first phase: 40 mg/m P2
P ixabepilone, given on Day 1 
of each cycle, and 1000 mg/mP2
P capecitabine, administered twice daily (total daily 
dose: 2000 mg/mP2
P) on Days 1–14 of each cycle. Of these 62 subjects, 50 were 
evaluable for response. The objective response rate was 30% (95% CI: 17.9%, 
44.6%), including 1 complete response (2%) and 14 partial responses (28%). 
Stable disease was observed in 16 (32%) subjects and progressive disease in 14 
(28%). Median time to response was 6.0 weeks; duration of response was 6.9 
months; and progression-free survival was 3.8 months. The overall response rate 
among subjects with ER-/PR-/HER2-negative tumors (n=22) was 23%. P9
P 
CA163-031 Safety Summary (Ixabepilone 40 mg/mP2
P + Capecitabine 2000 
mg/mP2
P Dose Cohort) 
A total of 62 subjects received the recommended Phase 2/Phase 3 dose of 
ixabepilone 40 mg/mP2
P plus capecitabine 2000 mg/mP2
P. Of the 30 subjects who 
received this dose in the Phase 1 segment, 2 developed dose-limiting toxicity of 


Ixabepilone                                              CA163-157                                                         TMHRI 
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Grade 3 hand-foot syndrome.  Two of the 62 subjects (3%) in this dose cohort 
died on study or within 30 days of the last dose of study drug. One death was 
due to disease progression; the other was due to septic shock that was judged to 
be probably related to study drug. Fifteen subjects (24%) in this dose cohort had 
at least 1 serious adverse event (SAE).   SAEs that occurred in more than 1 
subject were nausea (4 subjects), vomiting (4 subjects), neutropenia (2 subjects), 
stomatitis (2 subjects), dehydration (2 subjects), dyspnea (2 subjects), and 
convulsions (2 subjects). Most subjects (95%) in this dose cohort had at least 1 
treatment-related adverse event (TRAE). The most frequently reported TRAEs of 
any grade were fatigue (79%), nausea (74%), hand-foot syndrome (63%), 
alopecia (63%), myalgia (60%), paresthesia (55%), and diarrhea (52%).  
Treatment-related neutropenia was reported in 4 (7%) subjects. P9
P 
CA163-031 Safety Summary (Other Dose Cohorts) 
Of the 6 subjects in the ixabepilone 8 mg/m P2
P+ capecitabine 1650 mg/mP2
P dose 
cohort, none died and 1 subject (17%) developed an SAE of pyrexia. TRAEs that 
occurred in ≥ 16.7% of subjects were these: paresthesia (67%), alopecia (50%), 
erythrodysesthesia syndrome (50%), diarrhea (50%), nausea (50%), vomiting 
(50%), constipation (33%), myalgia (33%), headache (33%), neuropathic pain 
(33%), and rash (33%). The following TRAEs occurred in 16.7% of subjects: 
stomatitis, abdominal discomfort, abdominal pain, upper abdominal pain, 
sensitivity of teeth, fatigue, injection site irritation, pyrexia, hepatic pain, 
pharyngitis, skin infection, anorexia, arthralgia, back pain, muscle spasm, pain in 
extremity, peripheral neuropathy, peripheral sensory neuropathy, cough, 
respiratory tract congestion, palmar-plantar erythrodysesthesia syndrome, 
increased lacrimation, diarrhea, nail disorder, skin discoloration, hot flush, and 
orthostatic hypotension.  Of the 6 subjects in the ixabepilone 10 mg/m P2
P + 
capecitabine 1650 mg/mP2
P dose cohort, none died and 1 subject each (17%) 
developed an SAE of abdominal pain, nausea, or deep-vein thrombosis. TRAEs 
that occurred in ≥ 16.7% of subjects were these: alopecia (83%), fatigue (83%), 
myalgia (83%), diarrhea (83%), nausea (83%), paresthesia (67%), palmar-
plantar erythrodysesthesia syndrome (67%), headache (50%), constipation 


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(50%), dyspepsia (50%), stomatitis (50%), increased lacrimation (50%), 
abdominal pain (33%), upper abdominal pain (33%), and vomiting (33%). The 
following TRAEs occurred in 16.7% of subjects: pyrexia, catheter site infection, 
nasopharyngitis, upper respiratory tract infection, anorexia, decreased appetite, 
vulvovaginal discomfort, blister, nail disorder, rash, and skin exfoliation.  Of the 
30 subjects in the ixabepilone 40 mg/m P2
P + capecitabine 1650 mg/mP2
P dose cohort, 
5 died: 3 of disease progression, 1 of pulmonary embolism, and 1 of pneumonia 
and terminal cardiovascular dysfunction. The SAEs of neutropenia and 
dehydration each occurred in 7% of subjects.  
The following SAEs occurred in 3.3% of subjects: febrile neutropenia, stomatitis, 
vomiting, fatigue, noncardiac chest pain, pyrexia, urinary tract infection, 
increased AST, and decreased platelet count. 
TRAEs that occurred in ≥ 7% of subjects were these: alopecia (70%), nausea 
(70%), paresthesia (67%), palmar-plantar erythrodysesthesia syndrome (67%), 
vomiting (53%), diarrhea (57%), myalgia (53%), constipation (37%), stomatitis 
(37%), peripheral neuropathy (37%), arthralgia (23%), rash (23%), increased 
lacrimation (23%), dyspnea (20%), dizziness (20%), nail disorder (20%), fatigue 
(17%), peripheral sensory neuropathy (17%), dehydration (13%), decreased 
appetite (13%), dysgeusia (13%), neuropathic pain (13%), hypoesthesia (13%), 
anorexia (10%), and cough (10%). The following TRAEs occurred in 7% of 
subjects: neutropenia, oral hypoesthesia, retching, pyrexia, pain, decreased 
weight, joint swelling, shoulder pain, headache, ageusia, pruritus, skin 
discoloration, and hot flush. P9
P 
CA163-009: Phase 2 Study in Taxane-Resistant MBC 
CA163-009 was an international multi-institution study conducted in subjects with 
MBC who were resistant to paclitaxel or docetaxel. Ixabepilone was administered 
on Day 1 of an every-21-day cycle. To be eligible, subjects must have had tumor 
progression within 4 months of their last dose of a taxane-containing regimen if 
administered in the metastatic setting, or within 6 months of taxane therapy if 
administered in the adjuvant setting. The taxane regimen must have been the 
last regimen received by the subject.   Subjects were required to have 


Ixabepilone                                              CA163-157                                                         TMHRI 
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dimensionally measurable disease and Eastern Cooperative Oncology Group 
(ECOG) performance status of 0-1.   At the onset of the study, ixabepilone was 
administered as a 50 mg/mP2
P infusion over 1 hour, repeated every 21 days. Due 
to the severity of peripheral neuropathy observed in the first subjects enrolled in 
this study, as well as in the CA163-010 study, the infusion duration was extended 
to 3 hours. The dose of ixabepilone was then reduced to 40 mg/m P2
Pdue to 
excessive myelosuppression and mucositis observed in another study in subjects 
treated with the 50 mg/mP2
P over 3-hour regimen. 
A total of 49 subjects were treated. Median age was 54 years. Results in 
evaluable subjects were Partial Response: 6 (12%); Stable Disease: 20 (41%); 
and Progressive Disease: 21 (43%).P10 
CA163-010: Phase 2 Study in Taxane-Sensitive MBC 
CA163-010 was a multinational, multicenter, nonrandomized, open-label study of 
ixabepilone in subjects with taxane-sensitive MBC. Ixabepilone was administered 
on Day 1 of an every-21-day cycle. Subjects must have received an 
anthracycline in the adjuvant setting but no prior therapy for metastatic disease. 
Prior taxane therapy in the adjuvant setting was permitted provided treatment 
was greater than 1 year before enrollment. Subjects had to have at least one bi-
dimensionally measurable lesion and an ECOG performance status of 0-1.  At 
the onset of the study, ixabepilone was administered as a 50 mg/m P2
P infusion over 
1 hour, repeated every 21 days. Due to the severity of peripheral neuropathy 
observed in the first subjects enrolled in this study, as well as in CA163-009, the 
infusion duration was extended to 3 hours. The dose of ixabepilone was then 
reduced to 40 mg/mP2
Pdue to excessive myelosuppression and mucositis observed 
in another study in subjects treated with the 50 mg/m P2
P over 3-hour regimen.  A 
total of 65 subjects were treated. Median age was 52 years. Results in evaluable 
subjects were Partial Response: 27 (42%); Stable Disease: 23 (35%); and 
Progressive Disease: 13 (20%).P11
P 
CA163-080: Phase 2 Study in Treatment-Naive MBC 
CA163-080 was a single-arm, open-label, multicenter, multinational study of 
ixabepilone as neoadjuvant therapy in treatment-naive MBC. Ixabepilone was 


Ixabepilone                                              CA163-157                                                         TMHRI 
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given in a dose of 40 mg/mP2
P as a 3-hour IV infusion every 3 weeks. A total of 161 
subjects were treated. Median age was 55 years. Results in evaluable subjects 
were Primary Best Overall Response Rate (Complete Response [CR] or Partial 
Response [PR]): 98/161 (61%); Pathologic Complete Response in Breast [pCR BBB]: 
29/161 (18%); and Pathologic Complete Response in Breast and Lymph Nodes 
[pCRBBLB]: 17/161 (11%). Independent assessment of subject responses yielded 
pCRBBB and pCRBBLB rates of 14% and 9%, respectively. In subjects with ER-
negative, ER-/PR-negative, and triple-negative tumors, as assessed by locally 
read immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), 
investigator-assessed pCRBBB rates were 29%, 33%, and 26%, respectively. The 
pCRBBLB rates were 19%, 23%, and 19%, respectively. 
No deaths were reported. Twelve (8%) subjects reported SAEs. Among these 
subjects, 10 (6%) reported at least 1 SAE assessed as possibly, probably, or 
certainly related to ixabepilone therapy. These SAEs included peripheral or 
sensory neuropathy, febrile neutropenia, neutropenia, vomiting, and 
hypersensitivity, each reported in 2 subjects; and mucositis, constipation, 
diarrhea, stomatitis, lymphopenia, leukopenia, thrombocytopenia, increased ALT, 
and increased AST, each reported in 1 subject. 
Treatment-related adverse events were reported in 97% of subjects. The most 
common (≥ 15% of subjects) were alopecia (86%), myalgia (50%), arthralgia 
(30%), asthenia (27%), neutropenia (21%), peripheral sensory neuropathy 
(20%), nausea (19%), fatigue (19%), and diarrhea (15%). Most were Grade 1 to 
2. Grade 3/4 treatment-related adverse events were reported in 25% of subjects. 
The most common Grade 3/4 event was neutropenia (14%). P12 
CA163-081: Phase 2 Study in Refractory MBC 
CA163-081 was a single-arm, open-label, multicenter, multinational, two-stage 
design study of ixabepilone in MBC that was resistant to an anthracycline, a 
taxane, and capecitabine. A total of 126 subjects were treated. Data from this 
study have been published.  Of the 126 treated subjects, 113 were evaluable for 
response. Subjects were heavily pretreated: 88% had received ≥ 2 lines of prior 
chemotherapy in the metastatic setting. Independent Radiology Facility (IRF)-


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assessed objective response rate (ORR) was 11.5% (95% CI: 6.3%–18.9%) for 
response-evaluable subjects. Investigator-assessed ORR for all treated subjects 
was 18.3% (95% CI: 11.9%–26.1%). Half (50%) of subjects achieved stable 
disease (SD), with 14.3% achieving SD ≥ 6 months. Median duration of response 
and progression-free survival were 5.7 months and 3.1 months, respectively. 
Median overall survival was 8.6 months. Ixabepilone demonstrated activity in 
5/42 IRF response-evaluable subjects (ORR: 12%) with triple-negative tumors 
(tumors that did not express ER, PR, or HER2).  Subjects received a median of 4 
treatment cycles (range 1-16), and 25% of subjects received ≥ 8 cycles. Grade 3-
4 treatment-related events included peripheral sensory neuropathy (14%), 
fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%).   Resolution 
of Grade 3-4 peripheral sensory neuropathy occurred after a median period of 
5.4 weeks. Thus, ixabepilone demonstrated clear activity and a manageable 
safety profile in subjects with MBC resistant to anthracycline, taxane, and 
capecitabine. Responses were durable and notable in subjects who had not 
previously responded to multiple prior therapies. P 13
P 
Phase 3 Metastatic Breast Cancer Studies: CA163-046 P14
Pand CA163-048P15
P 
Two Phase 3 open-label, randomized, multicenter, multinational studies in MBC 
have completed enrollment. CA163-046 has enrolled subjects with taxane-
refractory MBC who have received prior treatment with or are refractory to an 
anthracycline. CA163-048 has enrolled subjects with MBC who have received 
prior treatment with an anthracycline and a taxane. Both studies have two 
treatment arms: ixabepilone plus capecitabine or capecitabine alone. 
These results supported the use of ixabepilone plus capecitabine in two Phase 3 
studies in patients with breast cancer. Studies CA163046 and CA163048 were 
randomized, multicenter, multinational studies comparing ixabepilone plus 
capecitabine versus capecitabine alone in patients with metastatic breast cancer. 
The primary endpoint of CA163046 was progression-free survival in patients 
previously treated with or resistant to an anthracycline and who are taxane 
resistant. The primary endpoint for CA163048 is overall survival in patients 
previously treated with an anthracycline and a taxane. P15 


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Study 046, an international Phase 3 study, was designed to compare ixabepilone 
plus capecitabine with capecitabine alone in anthracycline-pretreated or -
resistant and taxane-resistant locally advanced MBC.P 
PParticipants were required 
to have measurable disease with tumors that progressed rapidly in the adjuvant 
or metastatic setting after receiving both anthracyclines and taxanes. Eight 
percent of patients were receiving first-line treatment, having relapsed within one 
year of prior anthracycline/taxane therapy in the adjuvant setting; treatment for 
the remaining 92% of patients was as either second- or third-line therapy. Of the 
85% of patients with progression in the metastatic setting following prior taxane, 
42% progressed on taxane therapy. A total of 737 patients received ixabepilone 
(40 mg/mP2
P as a 3-hour intravenous (IV) infusion on Day 1 of a 21-day cycle) plus 
capecitabine (2000 mg/mP2
P orally administered in two divided doses each on Days 
1 through 14 of a 21-day cycle) (n=369) or capecitabine alone (2500 mg/m P2
P on 
the same schedule as the same schedule) (n=368). The primary endpoint was 
progression free survival (PFS) evaluated by blinded Independent Radiology 
Review Committee (IRRC). The addition of ixabepilone to capecitabine resulted 
in a clinically meaningful and statistically robust improvement in PFS in patients 
with MBC resistant to anthracyclines and taxanes. The improvement in PFS by 
the addition of ixabepilone to capecitabine was consistent across subpopulations, 
including patients with visceral metastases, >2 sites of metastatic disease, ≥65 
years of age, or with HER2+ breast cancer. P14
P 
CA163048 compared ixabepilone in combination with capecitabine to 
capecitabine alone in patients with metastatic or locally advanced breast cancer 
previously treated with anthracyclines and taxanes. A total of 1198 patients were 
treated: 595 patients received ixabepilone (40 mg/mP2
P as a 3-hour intravenous 
(IV) infusion on Day 1 of a 21-day cycle) plus capecitabine (2000 mg/m P2
P orally 
administered in two divided doses each on Days 1 through 14 of a 21-day cycle) 
and 603 patients received capecitabine alone (2500 mg/m P2
P on the same 
schedule). In this study overall survival (OS) was the primary endpoint. Results 
demonstrated statistically significant and clinically meaningful superiority in PFS 
and improved RR over capecitabine alone that translated into a modest 


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improvement in OS favoring the combination which did not meet statistical 
significance. P15 
Both Phase 3 studies showed a statistically significant and clinically meaningful 
improvement in PFS in favor of the combination of ixabepilone and capecitabine 
over capecitabine alone. Results of these studies showed an improvement in 
median PFS of 1.6 to 1.8 months and a 21 to 25% reduction in the risk of 
progression. The benefit in PFS was supported by significant improvements in 
objective response rate (ORR) in favor of the combination, including a more than 
doubling of the ORR in CA163046 (35% vs 14%) as assessed by the IRRC. The 
analysis of OS in both studies showed a 0.9 hazard ratio (HR) favoring the 
combination that did not reach statistical significance but was consistent with the 
absence of a detrimental effect. No other Phase 3 studies conducted in patients 
with breast cancer previously treated with anthracyclines and a taxane have 
demonstrated a survival benefit.P 14
P 
Peripheral Neuropathy 
Some subjects in these studies have experienced ixabepilone-related sensory 
neuropathy that is most often cumulative and reversible. Less frequently, severe 
motor neuropathy, usually presenting with lower extremity weakness, has been 
observed. In addition, there have been rare reports of autonomic neuropathy. 
Neuropathy may be dose- and time dependent. In the event of severe peripheral 
neuropathy, ixabepilone treatment was to be discontinued and not resumed until 
the neuropathy returned to baseline or to ≤ Grade 1, as defined by the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE). If the neuropathy was greater than Grade 1, dose reductions were 
warranted, provided the subject qualified for additional treatment.  Peripheral 
neuropathy was a dose-limiting toxicity in Phase 1 monotherapy studies of 
ixabepilone at doses above 50 mg/m P2
Pevery 3 weeks, and cumulative neuropathy 
has commonly been reported in the Phase 2 studies. The neuropathy is dose 
dependent and may also be schedule related. The neuropathy is cumulative in 
nature and gradually lessens following the discontinuation of therapy. Subjects 
are typically described as presenting with sensory manifestations (dysesthesias 


Ixabepilone                                              CA163-157                                                         TMHRI 
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and paresthesias, involving hands and feet). Neuropathic pain has also been 
reported, although less frequently 
(Grade 3/4-related in 3% of 439 subjects treated across all BMS Phase 2 
studies). Motor neuropathy has been reported only as a related Grade 3/4 
adverse event in 1% of all Phase 2 subjects, and it has only rarely been 
described in the absence of sensory or painful neuropathy. To date, autonomic 
neuropathy has been reported in only two subjects, both enrolled in Phase 2 
breast cancer studies. One subject developed orthostatic hypotension and 
gastroparesis after 5 cycles of therapy and the other developed gastroparesis 
after 14 cycles of therapy.    When ixabepilone dose reductions were necessary 
due to toxicity, the first reduction was to be to a dose of 32 mg/m P2
P. The use of the 
32 mg/mP2
P dose has been established in at least two other ixabepilone studies: 
the CA163-011 study of subjects with non-small cell lung cancer and the CA163-
116 study of subjects with metastatic pancreatic cancer. A total 
dose per cycle of 30 mg/m P2
P has also been administered in subjects with breast 
cancer (6 mg/m2 daily times 5 every 3 weeks) in studies led by the National 
Cancer Institute. 
Hypersensitivity Reactions 
The diluent used with ixabepilone is a BMS-purified polyoxyethylated castor oil 
(Cremophor®EL) and has the potential for inducing a hypersensitivity reaction. In 
clinical studies of ixabepilone, anaphylaxis and severe hypersensitivity reactions 
(dyspnea requiring bronchodilators, hypotension requiring treatment, syncope, 
bradycardia) that were reported as serious adverse events have occurred in less 
than 1% of subjects. Routine premedication, including H1 and H2 antihistamines 
(not corticosteroids) was instituted after 2 subjects developed severe 
hypersensitivity adverse events (dyspnea and bronchospasm) in the weekly 
Phase 1 monotherapy study. Since premedication was instituted, the incidence of 
the NCI CTCAE term “hypersensitivity” of any grade is < 1% in 439 subjects 
treated in all BMS-sponsored Phase 2 studies. In addition, 17% of subjects had a 
CTCAE term of “allergy/immunology, other” (of any grade) reported; the majority 
of incidents consisted of skin rash. 


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4.0.3 Cetuximab 
Cetuximab is a genetically engineered version of a mouse antibody that contains 
both human and mouse components.   It can be produced in large quantities in 
the laboratory. This new monoclonal antibody is believed to work by targeting a 
natural protein called "epidermal growth factor receptor" (EGFR) on the surface 
of cancer cells, interfering with their growth. Cetuximab is a chimeric monoclonal 
antibody, an epidermal growth factor receptor (EGFR) inhibitor with 
demonstrated activity in colorectal cancer and head and neck cancer. 
Cetuximab is believed to operate by binding to the extra cellular domain of the 
EGFR of cells that express EGFR, which include “cancer cells”, preventing ligand 
binding and activation of the receptor. This blocks the downstream signaling of 
EGFR resulting in impaired cell growth and proliferation. Cetuximab has also 
been shown to mediate antibody dependent cellular cytotoxicity (ADCC).  For 
patients with tumors that express EGFR and who no longer responded to 
treatment with irinotecan alone or in combination with other chemotherapy drugs, 
the combination treatment of cetuximab and irinotecan shrank tumors in 22.9% of 
patients and delayed tumor growth by approximately 4.1 months. For patients 
who received cetuximab alone, the tumor response rate was 10.8% and tumor 
growth was delayed by 1.5 months.  The efficacy and safety of cetuximab alone 
or in combination with irinotecan were studied in a randomized, controlled trial 
with 329 patients and also in combination with irinotecan in 138 patients in which 
all patients received both drugs.    Cetuximab was further evaluated as a single 
agent in a third clinical trial with 57 patients. Safety data from an additional 111 
patients treated only with cetuximab was also evaluated. All of the trials included 
patients with EGFR-expressing metastatic colorectal cancer, whose disease had 
progressed after receiving irinotecan. (Cetuximab) is indicated for the treatment 
of EGFR-expressing, metastatic colorectal carcinoma; In combination with 
irinotecan for patients who are refractory to irinotecan-based chemotherapy, and 
as a single agent for patients who are intolerant to irinotecan-based therapy. 
The effectiveness of cetuximab in EGFR-expressing mCRC is based on objective 
response rates.  Currently, no data are available that demonstrate an 


Ixabepilone                                              CA163-157                                                         TMHRI 
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improvement in disease-related symptoms or increased survival with cetuximab 
in combination with irinotecan for the treatment of EGFR-expressing, metastatic 
colorectal carcinoma. P16, 17
P 
Squamous Cell Carcinoma of the Head and Neck (SCCHN) 
Cetuximab is indicated in combination with radiation therapy for the initial 
treatment of locally or regionally advanced squamous cell carcinoma of the head 
and neck, and as a single agent, is indicated for the treatment of patients with 
recurrent or metastatic squamous cell carcinoma of the head and neck for whom 
prior platinumbased therapy has failed.  
Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally 
or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the 
oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) 
to receive either cetuximab plus radiation therapy or radiation therapy alone. 
Stratification factors were Karnofsky Performance Status (60–80 versus 90–100), 
nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint 
Committee on Cancer 1998 staging criteria), and radiation therapy fractionation 
(concomitant boost versus once-daily versus twice-daily). Radiation therapy was 
administered for 6–7 weeks as once daily, twice daily, or concomitant boost. 
Cetuximab was administered as a 400 mg/m2 initial dose beginning one week 
prior to initiation of radiation therapy, followed by 250 mg/m2 weekly 
administered 1 hour prior to radiation therapy for the duration of radiation therapy 
(6–7 weeks). 
 Of the 424 randomized patients, the median age was 57 years, 80% were male, 
83% were Caucasian, and 90% had baseline Karnofsky Performance Status ≥80. 
There were 258 patients enrolled in US sites (61%). Sixty percent of patients had 
oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% 
had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation 
therapy with concomitant boost, 26% received once-daily regimen, and 18% 
twice-daily regimen.   The main outcome measure of this trial was duration of 
locoregional control. Overall survival was also assessed. Results are presented 
in the following Table. 


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Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN 
 
Cetuximab 
+ 
Radiation 
(n=211) 
Radiation 
Alone 
(n=213) 
 
Hazard Ratio 
(95% CIPa
P) 
Stratified 
Log-rank 
p-value 
 
 
Locoregional control 
 
 
 
 
Median duration (months) 
24.4 
14.9 
0.68 (0.52–0.89) 
0.005 
 
Overall survival 
 
 
 
 
Median duration (months) 
49.0 
29.3 
0.74 (0.57–0.97) 
0.03 
 Pa
P CI = confidence interval 
Study 2 was a single-arm, multicenter clinical trial in 103 patients with recurrent 
or metastatic SCCHN. All patients had documented disease progression within 
30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg 
test dose of cetuximab on Day 1, followed by a 400-mg/m2 initial dose, and 250 
mg/m2 weekly until disease progression or unacceptable toxicity.  The median 
age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky 
Performance Status of ≥80. 
The objective response rate was 13% (95% confidence interval 7%–21%). 
Median duration of response was 5.8 months (range 1.2–5.8 months).P16 
The immunohistochemical expression of epidermal growth factor receptor 
(EGFR) in 241 patients with recurrent breast cancer, out of the 241 patients, 
EGFR expression was positive in 87 (36%) patients and negative in 154 (64%) 


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patients with recurrent breast cancer. EGFR expression was positive in 71 of 170 
(42%) cases of primary tumor samples and in 28 of 103 (27%) biopsy samples of 
recurrent breast cancer. An inverse relationship between EGFR and estrogen 
receptor (ER) status was noted. EGFR expression was positive in 68 of 109 
(62%) cases with negative ER status while EGFR expression was positive in 17 
of 130 (13%) cases with positive ER status (p<0.0001). Patients with positive EGFR expression had a signicantly worse post relapse 
survival (p<0.0001) compared to those with EGFR negative expression. Patients with a negative ER status had a signicantly worse post relapse survival 
(p<0.0001) than those with a positive ER status.   Additionally, patients with positive EGFR expression had a signicantly (p = 0.0021) worse post relapse 
survival compared to those with negative EGFR expression in patients who were 
ER positive. No difference in post relapse survival was observed in patients who 
were ER negative. There was a signicant difference in treatment response (p = 0.0014) and 
objective response rate (p = 0.0075) between patients with positive and negative 
EGFR expression in patients receiving chemotherapies; whereas the objective response in patients receiving hormonal therapy was not statistically signicant. 
However, there was a statistical difference in the treatment response (p = 
0.0209) in hormonal therapies. Additionally, there was a signicant difference in 
the treatment response (p = 0.0196) and the objective response rate (p = 0.0061) 
between cases with positive and negative EGFR expression. EGFR negative/ER 
positive tumors had a better treatment response compared to the EGFR 
positive/ER negative tumors which had a worse treatment response. Patients 
with a positive ER status had a better response to hormonal therapies than those 
with ER negative tumors. 
Response to first line treatment and EGFR expression are both independently signicant (p = 0.0016) factors for post relapse survival. Additionally, in a 
multivariate analysis, ER status was determined to be an independently signicant (p = 0.0104) factor for post relapse survival; however, EGFR expression was not a signicant 
factor for post relapse survival. Patients who 


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responded to first line treatment and who showed positive EGFR expression had a signicantly (p = 0.0008) shorter time to progression and signicantly
      
(p < 0.0001) worse post relapse survival than those with negative EGFR 
expression. P18 
 
 
Cetuximab Pre-Clinical Data 
Howard Hughes Medical Institute researchers have found that four aberrant genes 
work together to promote the growth of primary breast tumors. Cooperation among 
the four genes also enables cancerous cells to escape into the bloodstream and 
penetrate through blood vessels into lung tissues.   Although shutting off these 
genes individually can slow cancer growth and metastasis, the researchers found 
that turning off all four together had a far more dramatic effect on halting cancer 
growth and metastasis.   Metastasis occurs when cells from a primary tumor break 
off and invade another organ. It is the deadliest transformation that a cancer can 
undergo, and therefore researchers have been looking for specific genes that propel 
metastasis.   Massagué et al at the Memorial Sloan-Kettering Cancer Center, also 
found that they could reduce the growth and spread of human breast tumors in mice 
by simultaneously targeting two of the proteins produced by these genes, using 
drugs already on the market. The researchers are exploring clinical testing of 
combination therapy with the drugs – cetuximab (Erbitux®) and celecoxib 
(Celebrex®) – to treat breast cancer metastasis.   In an earlier study, Massagué and 
colleagues had identified 18 genes whose abnormal activity is associated with 
breast cancer’s ability to spread to the lungs. In the new study published in Nature, 
they focused on four of these genes. These genes, which code for proteins called 
epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to 
help regulate growth and remodeling of blood vessels.   The researchers silenced 
various combinations of the four genes in human breast cancer cells that had 
metastasised to the lung, and then tested these cells in mice. To silence the four 
genes, the scientists used a technique called RNA interference, in which RNA 
molecules are tailored to suppress expression of target genes.   The aggressive 


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metastatic tumor cells of these genes decreased both their ability to grow large 
aggressive tumors in the mouse mammary gland and also the ability to release cells 
from these tumors into the circulation.  “The remarkable thing was that while 
silencing these genes individually was effective, silencing the quartet nearly 
completely eliminated tumor growth and spread."   Microscopic analysis of blood 
vessel structure in the tumors revealed that knocking down all four genes greatly 
reduced growth of the tangle of blood vessels typically seen in tumors. Further 
experiments revealed that the tumor blood vessels that did form allowed fewer 
cancer cells to escape into circulation.   The researchers next explored how loss of 
the four abnormal genes affected the metastatic capability of the cells in the lung. 
They injected cells deficient in the four genes directly into the circulatory system of 
mice. "When these cells reached the lung capillaries, they just got stuck there,"   
Cetuximab is an antibody that blocks the action of epiregulin and is used to treat 
advanced colorectal cancer. Celecoxib is an inhibitor of COX2 that is used as an 
anti-inflammatory, and is being tested in clinical trials against many types of cancer. 
The researchers also tested whether cetuximab and celecoxib would work effectively 
in concert to reduce metastasis in mice.  The combination of these two inhibitory 
drugs was effective, even though the drugs individually were not very effective.   
The establishment of distant metastases depends on the capacity of small numbers 
of cancer cells to regenerate a tumor after entering a target tissue. The mechanisms 
that confer this capacity remain to be defined. Here we identify a role for the 
transcriptional inhibitors of differentiation Id1 and Id3 as selective mediators of lung 
metastatic colonization in the triple negative [TN, i.e., lacking expression of estrogen 
receptor and progesterone receptor, and lacking Her2 (human epidermal growth 
factor receptor 2) amplification] subgroup of human breast cancer. Although broad 
expression of Id1 has recently been documented in tumors of the rare metaplastic 
subtype, here we report that rare Id1-expressing cells are also present in the more 
common TN subset of human breast tumors but not in other subtypes. We also 
provide evidence that Id1 expression is enriched in clinically obtained hormone 
receptor negative lung metastases. Functional studies demonstrate that Id1 and its 
closely related family member Id3 are required for tumor initiating functions, both in 


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the context of primary tumor formation and during metastatic colonization of the lung 
microenvironment. In vivo characterization of lung metastatic progression reveals 
that Id1 and Id3 facilitate sustained proliferation during the early stages of metastatic 
colonization, subsequent to extravasation into the lung parenchyma. These results 
shed light on the proliferative mechanisms that initiate metastatic colonization, and 
they implicate Id1 and Id3 as mediators of this malignant function in the TN 
subgroup of breast cancers.P19 
Case Report 
BalticP20
P reported a case of a 39 year old woman who underwent a left breast mastectomy in 1998 due to inltrative ductal carcinoma (T2 N0 M0). No other 
therapy was applied at that time. In 2005, multiple liver metastases in the liver were conrmed by MRI. Hormonal status of the tumor showed ER and PR expression along with EGFR expression dened by immunohistochemistry. The 
CMF regimen along with Cetuximab as initiated. Four months after therapy 
began, MRI finding revealed signicant reduction on the number and size of 
metastases in liver segments 6 and 8, mainly in the subcapsular region of the 
liver.  
TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic 
triple-negative (basal-like) breast cancer. Basal-like breast cancer (BBC) has low 
expression of ER, PR, and HER2, and is thus often called triple negative (TN). 
Preclinical studies suggest that BBC depend on EGFR/HER1 for proliferation. TBCRC 
001 is a multicenter randomized phase II study of cetuximab (C) alone and combined 
with carboplatin (P) in TN metastatic BrCa (MBC). Methods: Eligibility required 
measurable disease, U<U 3 prior chemotherapy, no prior platinum or EGFR inhibitor. 
Patients (pts) in Arm 1 received C alone (400 mg/m P2
P, then 250 mg/mP2
P weekly) with P 
(AUC 2, 3 of 4 weeks) added upon progression (PD). Pts in Arm 2 received C+P 
throughout. Primary endpoint was objective response (RR, CR+PR). Results: 102 TN 
patients were enrolled; Arm 1 = 31 pts (closed in 3/07), Arm 2 = 71 (closed 10/07). 
Mean age 51, 68% white, 26% African American. 87% received prior adjuvant chemo, 
54% prior chemo for MBC (24% > 1 prior). Arm 1: PR 6% (2 pts, > 40 weeks), stable 
disease (SD) 4%, and clinical benefit (CB=PR or SD > 6mos) 10%. Arm 2: RR 18% 


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(13 pts), SD 9% (6), and CB 27% (19). PR did not appear to differ by line of therapy: 
14% 1st-line, 31% 2nd-line, 17% 3rd-line. Most pts progressed rapidly; median PFS 
was 2.0 months. The regimen was tolerable, grade 3 toxicity occurring in > 5% pts 
were: Arm 1 - rash only (10% pts); Arm 2 - rash (6%), fatigue (6%), and N/V (6%). 
Two grade 4 infusion reactions occurred in Arm 2. Biopsies from 16 mets confirmed 
subtype: basal-like (13), claudin-low (2), HER2+/ER- (1). Preliminary 
pharmacodynamics on paired biopsies (before/after 1-2 weeks therapy) in 9 pts reveal 
that 7 had gene expression evidence of activity across the EGFR pathway: 2 
decreased with treatment (1PR, 1SD); 5 had no change or increased activity with 
treatment (1SD, 4 PD). Final response rates and further correlative endpoints will be 
presented. Conclusions: C alone was well tolerated but has low activity in TN MBC. 
C+P has 18% RR and 27% CB. Many pts progressed rapidly, consistent with the 
aggressive behavior of this tumor subtype. Serial biopsies offer insight into EGFR 
pathway modulation by therapy. Translational studies confirming molecular subtype, 
identifying biologic effects of EGFR inhibition and platinum, evaluating circulating 
tumor cells, and studying the BRCA1 pathway are ongoing P21
P. 
A phase II trial of irinotecan plus cetuximab in patients with metastatic 
breast cancer and prior anthracycline and/or taxane-containing therapy 
(N0436). Background: Irinotecan has a 23% response rate (RR) in patients (pts) 
with previously treated metastatic breast cancer (MBC) (Perez, JCO 2004). 
Epidermal growth factor receptor (EGFR) is overexpressed in MBC, especially in 
those with ER-/PR- and HER2-negative tumors (triple-negative, [TNeg]). 
Cetuximab is a monoclonal antibody against EGFR with additive activity to 
irinotecan in colorectal cancer with acceptable toxicity. Methods: This one-stage 
phase II study enrolled pts with MBC, measurable disease, and prior 
anthracycline and/or taxane therapy. Pts received cetuximab 400 mg/m P2
P day 1 
cycle 1 then 250 mg/mP2
P weekly and irinotecan 80 mg/mP2
P days 1, 8 of each 21-
day cycle. Primary endpoint was confirmed RR by RECIST criteria. Planned 
sample size was 36. Genotyping for UGT1A1 polymorphisms was performed. 
Results: 19 eligible pts enrolled from 2/06 to 9/06 with a median age of 49 yrs 
(range: 28-76), 74% had visceral disease, 32% were ER and/or PR positive, 11% 


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were HER2 positive, 58% were TNeg. 79% had prior chemotherapy for MBC. Pts 
received a median of 2 cycles (range: 1-11) of treatment. Confirmed RR was 
11% (95% CI: 1-33%), with 1 PR and 1 CR. One pt had stable disease for 11 
cycles. RR and clinical benefit rate (CBR: RR + stable > 6 months) for Tneg vs 
non- Tneg was 18% vs 0% (p=0.49) and 27% vs 0% (p=0.23). 12 pts progressed 
on therapy within 2 cycles. With low response rate and rapid progression, the 
study closed early. NCI CTC version 3 grade 3-4 adverse events occurred in 10 
pts; only dermatologic toxicity (derm tox) had a > 5% incidence (26%). Patients 
with grade U>U 2 derm tox had a CBR of 21% (3/14) vs 0% in patients with grade 0-
1. 18 pts have progressed with a median time to progression of 1.4 mos (95% CI: 
1.1-2.2 mos). 15 pts have died with a median overall survival of 9.4 mos (95% CI: 
3.3-16.1 mos). UGT1A1 results will be presented. Conclusions: Irinotecan and 
cetuximab has minimal activity in this population. Tolerability is acceptable. There 
was a numerically higher CBR in Tneg pts and patients with grade U>U 2 derm tox, 
but small pt numbers limit conclusions. Better predictive factors for response to 
EGFR inhibition are needed. NCI CA-25224, CA-63848, CA-37404, CA- 60276, 
Bristol-Myers Squibb, Imclone systemsP22
P. 
Preliminary results of a randomized phase II study of weekly Irinotecan 
/carboplatin with or without cetuximab in patients with metastatic breast 
cancer. O'Shaughnessy and colleagues also presented data on the use of 
cetuximab in a randomized phase 2 study of weekly irinotecan (90 mg/m P2
P) and 
carboplatin (AUC 2), with or without cetuximab (250 mg/m P2
P). In the overall 
intention-to-treat study population, response rate improved marginally from 28% 
to 33% with the addition of cetuximab. Approximately half of the study population 
(78 patients) had triple-negative tumors. In that subgroup, cetuximab was 
associated with a response rate of 49% compared with 30% when chemotherapy 
was used alone. No significant differences in PFS or overall survival were 
observed in any subgroup, and significant toxicity led to dose reductions in 
starting doses of the chemotherapy agents. Based on the available evidence, 
there is little reason to believe that either single-agent cetuximab or a small 
molecule tyrosine kinase inhibitor of EGFR will have substantial activity in the 


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triple-negative setting. It remains unknown whether these agents will prove useful 
in this context when combined with chemotherapyP23
P 
 
 
 
 
4.0. 4.  Biomarkers Rationale Assessments:  
EGFR 
Epidermal growth factor receptors (EGFRs) are the prototypic members of a 
family of growth factors derived from membrane-anchored precursors. All 
members of this family are characterized by the presence of at least one EGFR 
structural unit in their extracellular domain. TIncreased expression and activation 
of receptor tyrosine kinasesP 
Poccurs frequently in human breast carcinomas. 
Roughly 35% breast cancers express EGFR as ascertained by IHC and its 
expressed with a 2-fold higher frequency in hormone receptor negative breast 
cancers compared to hormone receptor positive breast cancers .P24,25,26
P  
A wide variety of in vitro and in vivo biological effects have been ascribed to EGF 
and other members of the EGF family. EGF promotes proliferation and 
differentiation of mesenchymal and epithelial cells.   EGF family ligand-receptor 
signaling is implicated in a wide variety of human carcinomas.   Several therapiesP 
Ptargeting these receptors are currently in clinical trials and therapeutic strategies 
including blockage of individual receptorsP 
Pwith monoclonal antibodies and 
inhibition of tyrosine kinaseP 
Pfunction.P  27, 28, 29    
PInsufficient data exists to suggest a 
link between EGFR protein expression and response to EGFR inhibitors in breast 
cancer.P 30 
PTEN  
PTEN is a tumor suppressor that negatively regulates the PI3 kinase pathway, 
which is downstream of EGFR.  Loss of PTEN protein expression, attributed to 
loss of heterozygosity and/or post-transcriptional modification, is exhibited in 16 – 
37% of breast cancersP31, 32
P.  PTEN-loss is significantly associated with HR-


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negative breast cancers. P33, 34, 35 
PStudies has been shown to confer resistance to 
EGFR inhibitors in vitro in breast cancer cells and to predict response to Erbitux 
in metastatic colorectal cancers P36, 37, 38
P. 
 
 
EGFR-associated signature genes 
Hoadley et al showed that the expression of a number of EGFR-pathway related 
genes are associated with the basal-like subtype, including: TGF-, CRYAB, 
NRAS, KRAS, AKT3, PTEN, MEK1 and KRAS amplicon genes.  In addition, this 
group identified three gene signatures that correlated with EGFR activity in vitro 
that could be identified in two breast cancer patient cohorts.  While the genes in 
these signatures do not appear to be directly related to the EGFR pathway, they 
may still have predictive value.P 39 
 
Other exploratory biomarkers 
Additional exploratory biomarkers related to ixabepilone, anti-microtubule and 
cetuximab sensitivity and resistance may be assessed.  Markers shown to have 
an association with paclitaxel resistance, include beta tubulin isoforms, 
specifically beta III tubulin P40
P and ABC transporter expression, specifically MDR1 
and MRP7P41
P.  The capacity of these biomarkers to predict response to 
ixabepilone has not been established, as yet.  Preliminary analyses have 
suggested that several gene models, including TACC3, HCAPG, GTSE1, 
Kallikreins and pre-defined gene sets, may be able to differentiate ixabepilone 
activity from paclitaxel activity.  These models were derived from a comparison of 
gene expression patterns of pathological CR patients in microarray data available 
from two neoadjuvant breast cancer studies, CA163-080 (ixabepilone 
monotherapy) and MDA-133 (paclitaxel-FAC combination therapy) P42
P. 
 
 
 
 


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5.0 Study Design 
IXABEPILONE 40mg/m2 3-hours infusion every 21 days
(including, but not limited to) 
EGFR 
PTEN 
TGF-
CRYAB
NRAS
KRAS
AKT3 
MEK1 
KRAS amplicon genes
beta tubulin isoforms
ABC transporters
TACC3
HCAPG
GTSE1
Kallikreins and defined gene 
models associated with 
ixabepilone response. 
Baseline
STUDY DESIGN AND TREATMENT
RANDOMIZED OPEN-LABEL NEO-ADJUVANT PHASE II STUDY COMPARING 
IXABEPILONE (I) Vs IXABEPILONE PLUS CETUXIMAB (IC) IN  TRIPLE NEGATIVE 
BREAST CANCER PATIENTS  (ICE).
Surgery
IXABEPILONE 40mg/m2 3-hours infusion every 21 days
x   4 cycles
CETUXIMAB 400mg/m2 2-hours infusion initial dose on
Cycle1 day 1 followed by  250mg/m2 over one hour Infusion on a weekly 
basis thereafter. 
PLUS
Additional 
Chemotherapy 
per PI Discretion
x   4 cycles
Biomarkers
Biomarkers
(including, but not limited to) 
EGFR 
PTEN 
TGF-
CRYAB
NRAS
KRAS
AKT3 
MEK1 
KRAS amplicon genes
beta tubulin isoforms
ABC transporters
TACC3
HCAPG
GTSE1
Kallikreins and defined gene 
models associated with 
ixabepilone response. 
 
 
6.0 Study Population 
-Patients with either T1N1-N3M0 or T2-4 N0-3M0 disease who are triple negative 
and who are candidates for preoperative chemotherapy.  
Patients will receive a physical assessment, imaging, a blood draw, and a biopsy 
prior to the start of treatment.    
 
6.1 Inclusion Criteria: 
-Patients with histologic confirmation of invasive breast carcinoma. 
-Patients must have intact primary tumor. 
-Age ≥ 18 years. 


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-Invasive breast carcinoma must be determined to be ER (-), PR (-) and 
HER2Neu (-) prior to study entry. 
-Patients should have T1N1-3M0 or T2-4 N0-3M0. 
-Patients with bilateral breast cancer are eligible. 
-Patients should have a Karnofsky performance scale of ≥ 70%. 
-Patients must have clinically measurable disease by physical exam to be treated 
in the neoadjuvant setting. 
-Patients should have adequate bone marrow function, as defined by peripheral 
granulocyte count of ≥ 1500/mmP3
P, and platelet count ≥ 100000mmP3
P. 
-Patients must have adequate liver function with a bilirubin within normal 
laboratory values. Alkaline phosphatase and transaminases (ALT and AST) may 
be up to 1.5 x upper limit of normal (ULN) of the institution. 
-Patients should have adequate renal function with creatinine levels within 
normal range. 
-Patients should have a normal left ventricular ejection fraction (LVEF) of ≥50%. 
-Negative serum or urine pregnancy test for a woman of childbearing potential 
(WOCBP). 
-WOCBP must use a reliable and appropriate contraceptive method during the 
study and six months after chemotherapy is completed. WOCBP are women who 
are not menopausal for 12 months or had no previous surgical sterilization. 
-Patients must sign an informed consent indicating that they are aware of the 
investigational nature of the study, in keeping with institutional policy. 
 
6.2 Exclusion Criteria: 
-Patients with a history of other invasive malignancies diagnosed and treated 
within the previous 5 years, except non-melanoma skin cancer and non-invasive 
cervical cancer. 
-Her2Neu, ER and PR positive patients should be excluded. 
-Patients with an organ allograft or other history of immune compromise. 
-Prior treatment with any investigational drug within the preceding 4 weeks. 
-Chronic treatment with systemic steroids or another immunosuppressive agent. 


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- Uncontrolled chronic viral infections or patients requiring parenteral antibiotics 
will be excluded. Patients taking highly active anti-viral therapies and with 
controlled disease will be allowed to participate.  
-Patients with an active, bleeding diathesis or on oral anti-vitamin K medication 
(except low dose coumadin defined as 1 mg a day) 
-Other concurrent and/or uncontrolled medical disease which could compromise 
participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension, 
severe infection, severe malnutrition, unstable angina, or congestive heart failure 
- New York Heart Association Class III or IV, ventricular arrhythmias, active 
ischemic heart disease, myocardial infarction within six months, chronic liver or 
renal disease, active upper GI tract ulceration). 
-Patients with a pre-existing peripheral neuropathy > grade 1. 
6.3 Randomization 
Blocked randomization will be used to randomize patients to either arm 1 or arm 
2.  A master sequence of randomization numbers for each arm will be generated. 
 
7.0 Treatment Plan/Methods 
This is a randomized open-label phase II trial; 116 triple negative breast cancer 
patients will be randomized equally between 1) Ixabepilone or 2) Ixabepilone plus 
Cetuximab.   The study population will include patients≥ 18 years of age 
diagnosed with invasive mammary carcinoma.  Patients will be assigned to 
treatment arms using a stratified blocked randomization, with strata based on 
disease stage (T1N1-3M0 or T2-4 N0-3M0). All patients will receive a physical 
assessment, imaging, a blood draw, and a core needle biopsy (CNB) a biopsy 
prior to the start of treatment.   
 
7.1 Treatment Arm 1 
Patients will receive Ixabepilone 40mg/m P2
P given over approximately 3-hours on day 1  
Patients will receive a total of four cycles of this combination with each cycle given 
21(+/- 3) days.  


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Subjects will be premedicated approximately 1 hour before the ixabepilone infusion with 
either 1) both an oral H1 blocker (diphenhydramine 50 mg or equivalent) and an oral H2 
blocker (e.g., ranitidine 150 300 mg or cimetidine 300–800 mg or nizatidine 150-300 mg 
or famotidine 20–40 mg); or 2) with premedication per institutional standards. 
Premedication with steroids is indicated in subjects who developed a hypersensitivity 
reaction to ixabepilone in previous cycles. Patients with severe reaction should not be 
retreated (see dose modification chart below). 
 
7.2 Treatment Arm 2 
Patients will receive Ixabepilone 40mg/m P2
P given over approximately 3-hours on day 1 
followed by Cetuximab given on day 1 at 400 mg/m P
2 
Pas an initial loading dose (first 
infusion) administered as a 120-minute IV infusion (maximum infusion rate 5 mL/min) 
followed by 250 mg/mP
2 
Pinfused over 60 minutes (maximum infusion rate 5 mL/min) as a 
subsequent weekly dose.  Patients will receive a total of 4 cycles of this combination 
with each cycle being 21 (+/-3) days.  
Subjects will be premedicated approximately 1 hour before the ixabepilone infusion with 
either 1)both an oral H1 blocker (diphenhydramine 50 mg or equivalent) and an oral H2 
blocker (e.g., ranitidine 150-300 mg or cimetidine 300–800 mg or nizatidine 150 300 mg 
or famotidine 20–40 mg); or 2) with premedication per institutional standards. 
Premedication with steroids is indicated in subjects who developed a hypersensitivity 
reaction to ixabepilone in previous cycles.  Patients with severe reaction should not be 
retreated.  Subjects who are to receive cetuximab are to be premedicated with an H B1 
Bantagonist (e.g., 50 mg of diphenhydramine IV or equivalent) 
 
7.3 Dose modifications: 
7.3.1 Ixabepilone dose modifications: 
The dose of Ixabepilone may be decreased depending on how well the patient 
tolerates the study treatment.    Subjects should be evaluated during treatment 
by periodic clinical observation and laboratory tests including complete blood cell 
counts. If toxicities are present, treatment should be delayed to allow recovery.  


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If toxicities recur, an additional 20% dose reduction should be made. 
The dose levels of Ixabepilone will be reduced as described in the table below: 
Dose Level                                              Ixabepilone 
      1                                                         (Starting Dose) 40 mg/mP2
P 
     -1                                                         32 mg/mP2
P 
     -2                                                         25 mg/mP2
P 
Patients requiring dose reductions below dose level -2 must discontinue 
Ixabepilone, with the following exception: Patients with responding disease may 
continue treatment on study after consultation with the sponsor, TMHRI. 
No dose re-escalation will be allowed after dose reduction. 
 
Dose Modification - Study Drug Related Non-Hematologic Toxicities 
 
Toxicity 
Ixabepilone 
Grade 2                               
Grade 2 except Gr 2 Neuropathy lasting ≥7 
days Pa  
P                                
No change                          
Grade 2                              
Neuropathy                         
 
Decrease 1 dose level P b,c
P 
 
Dose Modification - Study Drug Related Non-Hematologic Toxicities 
Toxicity 
Ixabepilone  
Grade 3 
 
Grade 3  
NeuropathyP c
P 
Decrease 1 dose 
levelP  a, b 
P 
Grade 3 
Neuropathy 
lasting < 7 days 
Decrease 1 dose 
Level Pa, b 
 


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a. Delay until toxicity resolved to baseline or ≤Grade 1.
 
b. Patients requiring more than two dose reductions will discontinue Ixabepilone 
except those who appear to be benefiting from treatment in which case treatment 
can be continued after consultation with and approval by the Sponsor “The 
Methodist Hospital Research Institute” (TMHRI). 
c. Excludes Grade 3 fatigue/asthenia and transient arthralgia/myalgia for which 
no dose reduction is required. 
d. Responding patients who have sufficiently recovered from toxicity during 
previous cycle may be considered for retreatment after dose reduction only after 
discussion with and agreement by Sponsor (TMHRI). 
Dose Modification - Hematologic Toxicities 
Toxicity 
Ixabepilone 
Grade 3: 
 
Grade 3 Platelets 
with: significant 
bleeding or 
requiring platelet 
Decrease 1 dose 
Level Pa,b
P 
 
Grade 3 
Neuropathy lasting ≥7 days
 
Discontinue 
Ixabepilone Pd
P 
 
Grade 4 
 
Grade 4 toxicity   
Discontinue 
Ixabepilone P d
P 


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transfusion 
Grade 4 
 
Grade 4 Platelets 
Decrease 1 dose 
Level Pa,b
P 
Grade 4 
Neutrophils lasting ≥7 days
 
Decrease 1 dose 
Level Pa,c 
 
Febrile Neutropenia 
any grade 
Decrease 1 dose 
Level Pa,c
P 
 
a. Patients requiring more than 2 dose reductions will discontinue Ixabepilone except those who appear to 
be benefiting from treatment in which case treatment can be continued after consultation with and approval 
by the Sponsor (TMHRI) 
b. Delay until platelet count ≥100,000/mm
P3P  
c. Delay until neutrophil count ≥1,500/mm
 P43, 44
P 
 
 
 
7.3.2. Cetuximab Dose Modifications: 
Infusion Reactions  
Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI 
CTC Grade 3–4 infusion reactions.  
Immediately and permanently discontinue cetuximab for serious infusion 
reactions, requiring medical intervention and/or hospitalization. P45 
Dermatologic Toxicity: Recommended dose modifications for severe (NCI-CTC 
Grade 3 or 4) acneform rash are: 
Cetuximab Dose Modification Guidelines for Rash 
Severe Acneform                     cetuximab                            Outcome                      cetuximab Dose 
Rash Modification  
1st occurrence             Delay infusion 1 to 2 weeks      Improvement             Continue at 250 mg/m P2
P 
                                                                                      No Improvement        Discontinue cetuximab 
 


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2nd occurrence            Delay infusion 1 to 2 weeks     Improvement            Reduce dose to 200 mg/m P2
P 
                                                                                     No Improvement         Discontinue cetuximab 
 
3rd occurrence             Delay infusion 1 to 2 weeks     Improvement            Reduce dose to 150 mg/mP2
P 
                                                                                      No Improvement        Discontinue cetuximab 
4th occurrence                 Discontinue cetuximab 
 
Patients who experience unacceptable cetuximab toxicity or who are determined 
to have progressive disease as defined by RECIST during any cycle will be 
discontinued from the ixabepilone plus cetuximab arm.  However if the toxicity is 
related with cetuximab only; then ixabepilone will be given on a regular basis until 
the neoadjuvant cycles are completed.  
Patients who are deemed not appropriate for further chemotherapy will proceed 
to local therapy (surgical intervention or radiation therapy). 
 
 
 
7.4 Discontinuation of Subjects from Treatment:  
Subjects MUST discontinue study treatment (investigational or noninvestigational 
treatment) for any of the following reasons:  
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness 
which, in the opinion of the investigator, indicates that continued participation in 
the study is not in the best interest of the subject. 
• Pregnancy. 
• Termination of the study by the sponsor, by the local IRB or by the 
supporting/funding organization Bristol-Myers Squibb (BMS) 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious 
disease) illness. 
All subjects who discontinue study treatment should comply with protocol-
specified follow-up procedures.  The only exception to this requirement is when a 


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subject withdraws consent for all study procedures or loses the ability to consent 
freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). 
If a subject was withdrawn before completing the study, the reason for withdrawal 
must be entered on the appropriate case report form (CRF) page. 
 
7.5 Surgical Intervention 
Approximately 3-4 weeks following completion of neoadjuvant chemotherapy a 
clinical assessment and repeat mammography and ultrasound will be performed. 
The patient will then proceed to breast and axillary surgery as judged by the 
treating physician. Surgery should be performed approximately 3 - 4 weeks 
after the last dose of neoadjuvant ixabepilone or Ixabepilone plus 
cetuximab regimen or at resolution of possible hematological or infective 
complication. Reasons for delaying surgery in individual patients must be 
recorded in source documentation. 
 
8.0 CRITERIA FOR RESPONSE 
8.0.1 PATHOLOGICAL RESPONSE: The histologic response after treatment will 
be evaluated in the primary tumor and in the axillary lymph nodes removed by 
axillary dissection. In the primary tumor, cellular modifications will be evaluated in 
both the infiltrating tumoral component and in the possible ductal component, if 
applicable: 
− Analysis of the viable residual infiltrating component (% of total tumoral mass) 
− Analysis of the residual ductal component (% of total tumoral mass) 
− Determination of the mitotic index. 
In the axillary lymph nodes: analysis of the viable residual component. 
The criteria of pathological response will be defined according to the Sataloff 
Classification P46
P.  
The response in the primary tumor site will be graded from A to D. 
Primary site response: 
T-A Total or near total therapeutic effect. 


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T-B Subjectively greater than 50% therapeutic effect but less than total or  
near total. 
T-C Less than 50% therapeutic effect, but effect evident 
T-D No therapeutic effect. 
Axillary lymph node response: 
N-A Evidence of therapeutic effect, no metastatic disease. 
N-B No nodal metastasis or therapeutic effect. 
N-C Evidence of therapeutic effect but nodal metastasis still 
Present. 
N-D Viable metastatic disease, no therapeutic effect 
pCR corresponds to pathological grades T-A; N-A, N-B. 
 
 
8.0.2 RECIST Criteria 
The main endpoint in this study is to determine the pathologic complete response 
rate (pCR) (breast and axilla) of  Ixabepilone versus Ixabepilone when combined 
with cetuximab in patients with invasive breast adenocarcinoma  T1N1-N3M0 or 
T2-4 N0-3M0 disease who are Triple negative and who are candidates for 
preoperative chemotherapy. 
The clinical tumor response will be assessed using RECIST criteria at baseline 
and before surgery.  
RECIST criteria offer a simplified, conservative, extraction of imaging data for 
wide application in clinical trials. They presume that linear measures are an 
adequate substitute for 2-D methods and register four response categories TP47
TP:  
 
CR (complete response) = disappearance of all target lesions  
 
PR (partial response) = 30% decrease in the sum of the longest diameter     
           of target lesions  
 
PD (progressive disease) = 20% increase in the sum of the longest     
           diameter of target lesions  
 
SD (stable disease) = small changes that do not meet above criteria  
9.0 Study Materials:  


Ixabepilone                                              CA163-157                                                         TMHRI 
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 Chemistry 
The epothilones are a class of tubulin polymerization agents obtained from the 
fermentation of Sorangium cellulosum. Ixabepilone is a semisynthetic derivative 
of epothilone B that has improved in vitro metabolic stability when compared with 
its natural precursor.  
Pharmaceutical Properties and Formulation 
Investigational Product Identification 
Ixabepilone for Injection 
Ixabepilone is a 16-membered polyketide macrolide, with a chemically modified 
lactam substitution for the naturally existing lactone. The chemical name for 
ixabepilone 
is 
[1S-[1R*,3R*(E),7R*, 
10S*,11R*,12R*,16S*]]-7,11-dihydroxy-
8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-
azabicyclo[14.1.0]heptadecane-5,9-dione. It has a molecular formula of 
CTB27
TBHTB42
TBNTB2
TBOTB5
TBS, and its molecular weight is 506.71 grams/mole.  
Ixabepilone for Injection is supplied as a lyophilized (freeze dried), white to 
off-white, whole or fragmented cake in a vial. The drug product is available in two 
potencies: 
 Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. 
 Ixabepilone, for injection 45 mg supplied with diluent for ixabepilone, 23.5 mL. 
Vehicle for Constitution of Ixabepilone for Injection 
Vehicle for Constitution of Ixabepilone for Injection is supplied with the drug 
product for use in constitution of the lyophile. Vehicle for Constitution is provided 
in vials containing 8.0 mL/via (15mg) and 23.5mL (45mg) the vehicle is a mixture 
of dehydrated alcohol and cleaned Cremophor (polyoxyethylated castor oil). One 
vial of the 8.0 mL/vial vehicle product is provided whenever a 15 mg/vial of 
Ixabepilone for Injection is supplied.  


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Packaging 
Ixabepilone for Injection and the Vehicle for Constitution are packaged in Type I 
glass vials, stoppered with butyl rubber closures and sealed with aluminum seals. 
A sufficient excess of drug and vehicle is provided in the respective vials to allow 
for withdrawal losses. 
Handling and Dispensing of Investigational Product 
The investigational product should be stored in a secure area according to local 
regulations. It is the responsibility of the investigator to ensure that the 
investigational product is dispensed only to study patients. The investigational 
product must be dispensed only from official study sites by authorized personnel, 
according to local regulations. 
Storage Requirements/Stability 
Ixabepilone for Injection should be stored refrigerated at 2C to 8C (36F to 
46F) and protected from light. Vehicle for Constitution should be stored at 2C to 
25C (36F to 77F). If the vehicle is refrigerated, it must be allowed to warm to 
room temperature before constitution of the lyophile. After initial constitution with 
the accompanying vehicle, the solution may be stored in the vial for a maximum 
of 1 hour at room temperature and room light. The constituted solution should not 
be stored in the syringe. After final dilution with Lactated Ringer’s Injection, USP 
(LRI) to ixabepilone concentrations between 0.2 and 0.6 mg/mL, the solution is 
stable when stored at room temperature and room light for a maximum of 
6 hours. Administration of the entire infusion volume must be completed within 
the 6-hour time period as noted above.  
Lactated Ringer’s Injection, USP is specified because it has a pH range of 6 to 
7.5, which is required to maintain ixabepilone stability. Other diluents should not 
be used with ixabepilone. 


Ixabepilone                                              CA163-157                                                         TMHRI 
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Preparation and Administration 
An ixabepilone kit contains two vials, a vial of ixabepilone for injection which 
contains ixabepilone powder and a vial containing diluent for ixabepilone. Only 
the supplied diluent must be used for constituting ixabepilone for injection. The 
ixabepilone kit must be stored in a refrigerator at 2 C - 8 C (36 F - 46 F) in the 
original package to protect from light. Prior to constituting ixabepilone for 
injection, the kit should be removed from the refrigerator and allowed to stand at 
room temperature for approximately 30 minutes. When the vials are first removed 
from the refrigerator, a white precipitate may be observed in the diluent vial. This 
precipitate will dissolve to form a clear solution once the diluent warms to room 
temperature. To allow for withdrawal losses, the vial labeled as 15 mg 
ixabepilone for injection contains 16 mg of ixabepilone and the vial labeled as 45 
mg ixabepilone for injection contains 47 mg of ixabepilone. The 15-mg 
ixabepilone kit is supplied with a vial providing 8 mL of the diluent and the 45-mg 
ixabepilone kit is supplied with a vial providing 23.5 mL of the diluent. After 
constituting with the diluent, the concentration of ixabepilone is 2 mg/mL. 
A. To constitute: 
1) With a suitable syringe, aseptically withdraw the diluent and slowly inject it 
into the ixabepilone for injection vial. The 15-mg ixabepilone is constituted 
with 8 mL of diluent and the 45-mg ixabepilone is constituted with 23.5 mL of 
diluent. 
2) Gently swirl and invert the vial until the powder in ixabepilone is completely 
dissolved. 
B. To dilute: 
Before administration, the constituted solution must be further diluted only with 
normal saline (NS) or Lactated Ringer’s Injection; USP (LRI) supplied in DEHP 
[di-(2-ethylhexyl) phthalate] free bags. For most doses, a 250 mL bag of LRI is 
sufficient. However, it is necessary to check the final infusion concentration of 
each dose based on the volume of NS or LRI to be used. The final concentration 


Ixabepilone                                              CA163-157                                                         TMHRI 
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for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final 
infusion concentration, use the following formulas: 
Total Infusion Volume = mL of Constituted Solution + mL of LRI 
Final Infusion Concentration = Dose of ixabepilone (mg)/Total Infusion 
Volume (mL)  
1) Aseptically, withdraw the appropriate volume of constituted solution 
containing 2 mg of ixabepilone per mL. 
2) Aseptically, transfer to an intravenous (IV) bag containing an appropriate 
volume of LRI to achieve the final desired concentration of ixabepilone. 
3) Thoroughly mix the infusion bag by manual rotation. 
The infusion solution must be administered through an appropriate in-line filter 
with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion 
containers and administration sets must be used. Any remaining solution should 
be discarded according to institutional procedures for antineoplastics. 
Incompatibilities 
To minimize patient exposure to the plasticizer di-(2-ethylhexyl) phthalate 
(DEHP), which may be leached by Cremophor from some brands of polyvinyl 
chloride (PVC) infusion bags or administration sets, diluted ixabepilone solutions 
should be stored in bottles (glass, polypropylene) or plastic bags (polyethylene, 
polypropylene, polyolefin, ethylene-vinyl-acetate) and administered either 
through polyethylene-lined administration sets or through PVC sets plasticized 
with TOTM (trioctyl trimellitate). Intravenous infusion sets and components 
typically used to administer paclitaxel have been found to be compatible with 
infusions of ixabepilone. 
The following infusion components have been qualified for use with Ixabepilone 
for Injection and Vehicle (Cremophor-containing) for Constitution: 


Ixabepilone                                              CA163-157                                                         TMHRI 
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Intravenous infusion sets containing an in-line 0.22 micron filter 
 Baxter Vented Paclitaxel Set (Catalog #2C7553) 
 Abbott Primary IV Plumset (Catalog #11947) 
 
Intravenous infusion sets not containing an in-line 0.22 micron filter 
 McGaw AccuPro Pump Nitroglycerin IV Set (Catalog #V8333) 
 Clintec IV Fat Emulsion Set (Catalog #2C1105) 
Filter Extension Set (to be used with intravenous infusion sets not 
containing an in-line filter) 
 Braun Filtered Extension Set with 5 Micron Filter (Catalog #FE-5010Y) 
Diluted solutions may also be administered using a syringe pump and 
polyethylene-lined extension sets. 
 
 
Safety Precautions 
Appropriate protective clothing, eye shield, mask, and gloves should be worn and 
Class II vertical-laminar-airflow safety cabinets should be used during the 
preparation and handling of ixabepilone. 
Investigational Product Records at Investigational Site(s) 
The study drug will be kept in the investigational pharmacy at the sponsor site 
(TMHRI).  It is the responsibility of the Investigator to ensure that a current record 
of investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed. Records or logs must comply 
with applicable regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number. 


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 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 
Ixabepilone dispensing record/inventory logs and copies of signed packing lists 
must be maintained at the investigational site. Batch numbers for ixabepilone 
must be recorded in the drug accountability records. 
Destruction of Investigational Product 
Investigational product must be destroyed at the site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the disposal, 
written authorization has been granted by BMS, procedures for proper disposal 
have been established according to applicable regulations and guidelines and 
institutional procedures, and appropriate records of the disposal have been 
documented. 
Drug Ordering and Accountability 
Initial Orders - further information to be provided 
Following submission and approval of the required regulatory documents, a 
supply of ixabepilone may be ordered from BMS. Investigators must complete a 
Drug Request Form and email it to epothilone.supplies@bms.com. Please fax to 
866-227-7229 or 203-677-6489 if you cannot send the form electronically. 
Ixabepilone vials (15mL) are shipped in quantities of 18. Allow 5 business days 
for shipment of drug from BMS receipt of the ixabepilone Clinical Supply Request 
form. Drug is protocol specific, but not patient specific. 
All products will be shipped via Federal Express in a temperature-controlled 
container. Shipments will be made from BMS on Monday through Thursday for 


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delivery onsite Tuesday through Friday. There will be no weekend or holiday 
delivery of drug. It is possible that sites may have more than one ixabepilone 
clinical study ongoing at the same time. 
UIt is imperative that only product 
designated for this protocol number be utilized for thisU 
Ustudy.U To help segregate 
product for this study from other investigational or marketed product, stickers 
bearing the BMS protocol number will be provided and should be affixed to the 
front of the outer carton just above the company names so as not to obscure any 
marking. 
Re-supply 
Reorders 
should 
be 
emailed 
directly 
to 
BMS 
using 
epothilone.supplies@bms.com for shipment within 5 business days. When 
assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 5 business days from 
BMS receipt of request. Ixabepilone vials (15 and 45 mL) are shipped in 
quantities of 18. Drug is not patient specific. Be sure to check with your 
pharmacy regarding existing investigational stock to assure optimal use of drug 
on hand.P48 
CetuximabP49 
SUPPLY AND STORAGE: Injection: supplied as 50 mL, single-use vial 
(preservative free) containing 100 mg of cetuximab at a concentration of 2 
mg/mL by ImClone.P 
SOLUTION PREPARATION AND COMPATIBILITY: PARENTERAL 
ADMINISTRATION: Intermittent infusion via infusion pump or syringe pump run 
loading dose over 2 hours, and maintenance dose over 1 hour infusion rate 
should not exceed 5mL/min use NS to flush line at the end of infusion. DOSAGE 
GUIDELINES: Numerous dosing schedules exist and depend on disease, 
response and concomitant therapy. Guidelines for dosing also include 
consideration of absolute neutrophil count (ANC). Dosage may be reduced, 


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delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities. 
 
10.  Adverse Events  
10.1 Common side effects of ixabepilone:  
Because clinical trials are conducted under widely varying conditions, the 
adverse reaction rates observed in the clinical trials of a drug cannot be directly 
compared to rates in other clinical trials and may not reflect the rates observed in 
clinical practice.   Unless otherwise specified, assessment of adverse reactions is 
based on one randomized study (Study 046) and one single-arm study (Study 
081). In Study 046, 369 patients with metastatic breast cancer were treated with 
Ixabepilone 40 mg/mP2
P administered intravenously over 3 hours every 21 days, 
combined with capecitabine 1000 mg/m P2
Ptwice daily for 2 weeks followed by a 1-
week rest period. Patients treated with  capecitabine as monotherapy (n=368) in 
this study received 1250 mg/mP2
P twice daily for 2  weeks every 21 days. In Study 
081, 126 patients with metastatic or locally advanced breast cancer were treated 
with Ixabepilone 40 mg/m P2
P administered intravenously over 3 hours every 3 
weeks.   The most common adverse reactions (≥20%) reported by patients 
receiving Ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, 
myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and 
musculoskeletal pain.   The following additional reactions occurred in ≥20% in 
combination treatment: palmarplantar  erythrodysesthesia (hand-foot) syndrome, 
anorexia, abdominal pain, nail disorder,  and constipation. The most common 
hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and 
thrombocytopenia.   NCI CTC grading for febrile neutropenia ranges from Grade 
3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other 
neutropenia-related deaths (9) occurred in the absence of reported febrile 
neutropenia.  Peripheral sensory neuropathy (graded with the NCI CTC scale) 
was defined as the occurrence of any of the following: areflexia, burning 
sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, 
neuritis, neuropathy, neuropathy peripheral,  neurotoxicity, painful response to 


Ixabepilone                                              CA163-157                                                         TMHRI 
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normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, 
polyneuropathy, polyneuropathy toxic and sensorimotor disorder.  
Peripheral motor neuropathy was defined as the occurrence of any of the 
following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor 
neuropathy, and peripheral sensorimotor neuropathy.   Palmar-plantar 
erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in 
Study 046.   A G-CSF (granulocyte colony stimulating factor) or GM-CSF 
(granulocyte macrophage stimulating factor) was used in 20% and 17% of 
patients who received Ixabepilone in Study 046 and Study 081, respectively.  
The following serious adverse reactions were also reported in 1323 patients  
treated with Ixabepilone as monotherapy or in combination with other therapies in 
Phase 2 and 3 studies.  
Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, 
urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory 
tract infection. 
Blood and Lymphatic System Disorders: coagulopathy, lymphopenia.  
Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, 
hypokalemia, hypovolemia.    
Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, 
abnormal coordination, lethargy.  
Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left 
ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial 
ischemia.  
Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, 
hypovolemic shock, vasculitis.  
Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, 
respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain  
Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, 
dysphagia, gastritis, gastrointestinal hemorrhage  
Hepatobiliary Disorders: acute hepatic failure, jaundice  
Skin and Subcutaneous Tissue Disorders: erythema multiforme  


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Musculoskeletal, Connective Tissue Disorders, and Bone Disorders: muscular 
weakness, muscle spasms, trismus  
Renal and Urinary Disorders: nephrolithiasis, renal failure  
General Disorders and Administration Site Conditions: chills  
Investigations: increased transaminases, increased blood alkaline phosphatase, 
increased gamma-glutamyltransferase.  
DRUG INTERACTIONS  
Effect of Other Drugs on Ixabepilone Drugs That May Increase Ixabepilone 
Plasma Concentrations CYP3A4 Inhibitors: Co-administration of ixabepilone with 
ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% 
compared to ixabepilone treatment alone. If alternative treatment cannot be 
administered, a dose adjustment should be considered. The effect of mild or 
moderate inhibitors (e.g. erythromycin, fluconazole, or verapamil) on exposure to 
ixabepilone has not been studied. Therefore, caution should be used when 
administering mild or moderate CYP3A4 inhibitors during treatment with  
Ixabepilone, and alternative therapeutic agents that do not inhibit CYP3A4 should 
be considered. Patients receiving CYP3A4 inhibitors during treatment with 
Ixabepilone should be monitored closely for acute toxicities (eg, frequent 
monitoring of peripheral blood counts between cycles of ixabepilone). Drugs That 
May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: 
ixabepilone is a CYP3A4 substrate. Strong CYP3A4 inducers 
(eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin,  
and phenobarbital) may decrease ixabepilone concentrations leading to 
subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction 
potential should be considered for coadministration with ixabepilone. St. John's 
Wort may decrease ixabepilone plasma concentrations unpredictably and should 
be avoided.    Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit 
CYP enzymes at relevant clinical concentrations and is not expected to alter the 
plasma concentrations of other drugs.    In patients with cancer who received 
ixabepilone (40 mg/mP2
P) in combination with capecitabine (1000 mg/m P2
P), 
ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, 


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and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or 
capecitabine administered separately.    The interaction is not clinically significant 
given that the combination treatment is supported by efficacy data. 
USE IN SPECIFIC POPULATION  
Pregnancy Category D: Ixabepilone may cause fetal harm when administered to 
pregnant women. There are no adequate and well-controlled studies with 
Ixabepilone in pregnant women. Women should be advised not to become 
pregnant when taking Ixabepilone. If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised 
of the potential hazard to the fetus. 
Ixabepilone was studied for effects on embryo-fetal development  in pregnant 
rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 
0.11 and 0.3 mg/kg/day, respectively.   There were no teratogenic effects.   In 
rats, an increase in resorptions and post-implantation loss and a decrease in the 
number of live fetuses and fetal weight was observed at the maternally toxic dose 
of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on 
AUC). Abnormalities included a reduced ossification of caudal vertebrae, 
sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity 
(death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately 
one-tenth the human clinical dose based on body surface area). No fetuses were 
available at this dose for evaluation. 
Nursing Mothers: It is not known whether ixabepilone is excreted into human 
milk. Following intravenous administration of radiolabeled ixabepilone to rats on 
days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable 
with those in plasma and declined in parallel with the plasma concentrations. 
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants from ixabepilone, a decision must be 
made whether to discontinue nursing or to discontinue ixabepilone taking into 
account the importance of the drug to the mother.  
Pediatric Use:  The safety and effectiveness of ixabepilone in pediatric patients 
have not been established.  


Ixabepilone                                              CA163-157                                                         TMHRI 
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Geriatric Use:  Clinical studies of ixabepilone did not include sufficient numbers 
of subjects aged sixty five and over to determine whether they respond differently 
from younger subjects. Forty-five of 431 patients treated with ixabepilone in 
combination with capecitabine were ≥65 years of age and 3 patients were ≥75. 
Overall, the incidence of grade 3/4 adverse reactions were higher in patients ≥65 
years of age versus those <65 years of age (82% versus 68%) including grade 
3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar 
erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% 
versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and 
asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 
patients ≥65 years with normal baseline hepatic function or mild impairment.  
Thirty-two of 240 breast cancer patients treated with ixabepilone as monotherapy 
were ≥65 years of age and 6 patients were ≥75. No overall differences in safety 
were observed in these patients compared to those <65 years of age.  
Hepatic Impairment: Ixabepilone was evaluated in 56 patients with mild to severe 
hepatic impairment defined by bilirubin levels and AST levels. Compared to 
patients with normal hepatic function (n=17), the area under the curve (AUC0-
infinity) of ixabepilone increased by:  
• 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin  
<1.5 x ULN; 
• 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and  
• 81% in patients with bilirubin >3 x ULN and any AST level.  
Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with  
severe hepatic impairment (bilirubin >3 x ULN).  Ixabepilone in combination with 
capecitabine must not be given to patients with AST or ALT >2.5 x ULN or 
bilirubin >1 x ULN.  
Dose reduction is recommended when administering Ixabepilone as 
monotherapy to patients with hepatic impairment Because there is a need for 
dosage adjustment based upon hepatic function, assessment of hepatic function 
is recommended before initiation of Ixabepilone and periodically thereafter.  


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Renal Impairment: Ixabepilone is minimally excreted via the kidney. No controlled 
pharmacokinetic studies were conducted with Ixabepilone in patients with renal 
impairment. Ixabepilone in combination with capecitabine has not been evaluated 
in patients with calculated creatinine clearance of <50 mL/min. ixabepilone as 
monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. 
In a population pharmacokinetic analysis of Ixabepilone as monotherapy, there 
was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 
mL/min) on the pharmacokinetics of ixabepilone.  
OVERDOSAGE  
One case of overdose of Ixabepilone has been reported. The patient mistakenly  
received 100 mg/mP2
P (total dose 185 mg) and was admitted to the hospital for 
observation. The patient experienced myalgia (grade 1) and fatigue (grade 1) 
one day after infusion and was treated with a centrally acting analgesic. The 
patient recovered and was discharged without incident.  There is no known 
antidote for overdosage of Ixabepilone. In case of overdosage, the patient should 
be closely monitored, and supportive treatment should be administered.  
Management of overdose should include supportive medical interventions to treat 
the presenting clinical manifestations.P  43, 44 
10.2 Common side effects of cetuximab:  
Dermatologic toxicities, including acneform rash, skin drying and fissuring, 
paronychial inflammation, and infectious sequelae (for example S. aureus sepsis, 
abscess formation, cellulitis, blepharitis, cheilitis) occurred in patients receiving 
cetuximab therapy. Acneform rash occurred in 76–88% of 1373 patients 
receiving cetuximab in clinical trials. Severe acneform rash occurred in 1–17 % of 
patients.     Acneform rash usually developed within the first two weeks of 
therapy and resolved in a majority of the patients after cessation of treatment, 
although in nearly half, the event continued beyond 28 days. Monitor patients 
receiving cetuximab for dermatologic toxicities and infectious sequelae. Instruct 
patients to limit sun exposure during cetuximab therapy.   Acne-like rash (88%), 
nausea, vomiting (55%, 41%) tiredness or weakness (73%), diarrhea (72%), 
abdominal pain (55%) more serious side-effects are rarer, but include: infusion 


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reactions (3%), interstitial lung disease (0.5%), sepsis (3%), kidney dysfunction 
(2%), pulmonary embolism (1%). 
Serious infusion reactions, requiring medical intervention and immediate, 
permanent discontinuation of cetuximab included rapid onset of airway 
obstruction (bronchospasm, stridor, hoarseness), hypotension, and/or cardiac 
arrest. Severe (NCI CTC Grade 3 and 4) infusion reactions occurred in 2–5% of 
1373 patients in clinical trials, with fatal outcome in 1 patient. 
Approximately 90% of severe infusion reactions occurred with the first infusion 
despite premedication with antihistamines.    In patients evaluated during clinical 
trials, hypomagnesemia occurred in 55% of patients (199/365) receiving 
cetuximab and was severe (NCI-CTC Grade 3 and 4) in 6–17%. The onset of 
hypomagnesemia and accompanying electrolyte abnormalities occurred days to 
months after initiation of cetuximab. Periodically monitor patients for 
hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 
weeks following the completion of cetuximab.  
The safety of cetuximab in combination with radiation therapy and cisplatin has 
not been established. Death and serious cardiotoxicity were observed in a single-
arm trial with cetuximab, radiation therapy, and cisplatin (100 mg/mP2
P) in patients 
with locally advanced SCCHN. Two of 21 patients died, one as a result of 
pneumonia and one of an unknown cause. Four patients discontinued treatment 
due to adverse events. Two of these discontinuations were due to cardiac 
events. 
It is not known whether cetuximab, is secreted in human milk since IgG 
antibodies, such as cetuximab, can be excreted in human milk. Because many 
drugs are excreted in human milk and because of the potential for serious 
adverse reactions in nursing infants from cetuximab, a decision should be made 
whether to discontinue nursing or to discontinue the drug, taking into account the 
importance of the drug to the mother. If nursing is interrupted, based on the 
mean half-life of cetuximab, nursing should not be resumed earlier than 60 days 
following the last dose of cetuximab.  P45, 50, 51
P 


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Adverse Event (AE) related to the study is defined as any untoward medical 
occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of ixabepilone whether or not considered 
related to ixabepilone. 
During this clinical trial, adverse events can be spontaneously reported or elicited 
during open-ended questioning, examination, or evaluation of a subject. (In order 
to prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more adverse events.) 
 
 
A serious AE is any untoward medical occurrence that at any dose:   
 results in death,  
 is life-threatening (defined as an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe),  
 requires inpatient hospitalization or causes prolongation of existing 
hospitalization,  
 results in persistent or significant disability/incapacity,  
 is a congenital anomaly/birth defect,  
 results in the development of drug dependency or drug abuse,  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the patient 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed in the definition above.)  Examples of such 
events include, but are not limited to, intensive treatment in an emergency 


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room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) 
     Also is considered the occurrences of pregnancy or overdose (regardless of   
     adverse outcome), and cancer as events which must be reported as  
     important medical events.P 48 
10.3 Reporting of SAEs 
Following the subject’s written consent to participate in the study, all SAEs 
should be collected and reported, including those thought to be associated with 
clinical trial procedures. Following study completion, any SAE thought to be 
related to study drug or clinical trial procedures should also be reported to the 
sponsor: The Methodist Hospital Research Institute and the local IRB. 
SAE terminology and severity grading will be based on (CTCAEv3). 
The following categories and definitions of causal relationship to study drug 
should be considered for use for this clinical study. 
 Certain: There is a known causal relationship between the study drug and the 
SAE. The event responds to withdrawal of study drug (dechallenge), and 
recurs with rechallenge when clinically feasible. (>95% certainty) 
 Probable: There is reasonable causal relationship between the study drug 
and the SAE. The event responds to dechallenge. Rechallenge is not 
required. (65%-95% probability) 
 Possible: There is reasonable causal relationship between the study drug and 
the SAE. Dechallenge information is lacking or unclear. (35%-65% probability 
of relatedness) 
 Not likely: There is temporal relationship to study drug administration, but 
there is not a reasonable causal relationship between the study drug and the 
SAE. (5-35% probability of relatedness) 
 Not related: There is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is known causal 


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relationship between the SAE and another drug, concurrent disease, or other 
circumstance. (<5% chance of relatedness) 
 Adverse events classified as “serious” require expeditious handling and 
reporting to the sponsor (TMHRI) and local IRB to comply with regulatory 
requirements.  
 All serious AEs whether related or unrelated to ixabepilone, must be 
immediately reported to the sponsor (TMHRI) by the investigator or 
designee within 24 hours of becoming aware of the event. If only limited 
information is initially available, follow-up reports are required.  The 
original SAE form must be kept on file at the study site. 
 
 
 
All SAEs should be faxed or emailed to TMHRI at: 
The Methodist Hospital Research Institute 
Fax Number: 713-793-7001 
Email: mnsalazar@tmhs.org and  afroehlich@tmhs.org 
 For studies conducted under an 
UInvestigator INDU, any event that is both 
serious and unexpected must be reported to the FDA as soon as possible 
and, in no event, later than 7 days (death or life-threatening event) or 15 
days (all other SAEs) after the investigator’s or institution’s initial receipt of 
the 
information. 
 
The 
Methodist 
Hospital 
Research 
Institute 
 will be provided with a simultaneous copy via facsimile of all adverse 
events filed with the FDA.  SAEs should be reported on the MedWatch 
Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
MedWatch forms should be mailed or faxed to the FDA at: 
MEDWATCH 
5600 Fishers Lane 


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Rockville, MD  20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178)            
All SAEs are to be simultaneously be faxed to Bristol-Myers Squibb at: 
Global Pharmacovigilance and Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
Email:Worldwide.safety@bms.com 
 
 Collection of complete information concerning SAEs is extremely 
important.  Full descriptions of each event will be followed by the 
sponsor. Thus, follow-up information which becomes available as the 
SAE evolves, as well as supporting documentation (e.g., hospital 
discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
 An overdose is defined as the accidental or intentional ingestion of any 
dose of a product that is considered both excessive and medically 
important.  For reporting purposes, the sponsor considers an 
overdose, regardless of adverse outcome, as an important medical 
event. 
 AEs should be followed to resolution or stabilization, and reported as 
SAEs if they become serious. This also applies to subjects 
experiencing AEs that cause interruption or discontinuation of 
ixabepilone, or those experiencing AEs that are present at the end of 
their participation in the study; such subjects should receive post-
treatment follow-up as appropriate. 
In BMS supported trials, all SAEs must be collected which occur within 30 days 
of discontinuation of dosing or completion of the patient’s participation in the 
study if the last scheduled visit occurs at a later time.  In addition, the Investigator 
should notify BMS of any SAE that may occur after this time period which they 
believe to be certainly, probably or possibly related to ixabepilone. P 48 


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11. Data Management 
An outcome database would be created for this specific project.  
Using Excel (spread sheet) program  
 
12.  Statistical Design and Analyses 
12.1 Sample size estimate 
The published study CA163-080 has shown that the pathological complete 
response (pCR) rate is 18% based on a single agent Ixabepilone data, and is the 
same percentage that we assume for patients that will be treated with 
ixabepilone (Treatment Arm 1). With total 108 patients (54 in each arm), we will 
be able to detect 25% difference in pCR rates between the arm with Ixabelpilone 
plus Cetuximab (Treatment Arm 2) and Arm 1 with 81.9% power and a two-sided 
significance level of 0.05. A total of 116 patients will be enrolled to allow for 6.5% 
dropout before randomization of 108 patients. Table 1 provides power estimates 
to detect hypothesized 25%, 27%, 29%, and 31% difference in pCR rate in the 
treatment am 1 compared to the treatment arm 2 with given sample size of 54 
patients in each arm.  
 
Table 1. Power to detect different differences of pathological complete response 
rates in the two arms with given sample size of 54 patients in each arm.  
Projected pathological complete response rate 
Estimated power (%) 
Treatment Arm 1 
Treatment Arm 2 
18% 
0.43% 
81.9 
 
0.45% 
87.0 
 
0.47% 
91.0 
 
0.49% 
94.0 
 
U12.2 Statistical analysis 
UAll major treatment comparisons between the two randomized groups in this trial 
will be performed according to the principle of “intention-to-treat”, that is, subjects 


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will be analyzed according to the treatment arm to which patients were 
randomized, regardless of compliance to assigned treatment.U USummary statistics 
will be provided for overall response rates and pCR rates by treatment arm. U The 
different rates between treatment arms will be compared by Cochran-Mantel-
Haenszel test. . Logistic regression models will be used to assess the association 
between expression of biomarkers (such as PTEN, EGFR and EGFR-pathway 
associated genes (including, but not limited to TGF-, CRYAB, NRAS, KRAS, 
AKT3, PTEN, MEK1 and KRAS amplicon genes) from the baseline and the 
overall objective or pathologic response, controlled by treatment arm, age, and 
disease stage. The unpaired t-test will be applied to compare the difference of 
expression of biomarkers between the baseline and at surgery in the two arms. 
Benjamini and Hochberg adjustment will be used to adjust multiple comparisons 
in expressions of all marks.  Safety and toxicity of each regimen will be tabulated 
by type and grade at the end of chemotherapy. . Radiographic efficacy 
assessment will be performed on all patients at the end of chemotherapy. 
Statistical significance is defined as 2-tailed p=0.05 level. Stata Version 10 
(College Station, TX) will be used for all statistical analyses. 
12.3 Interim data analysis 
Safety 
Interim data analysis for monitoring safety will be conducted at every cycle for the 
two arms. Severity of adverse effects will be reported to the Data Monitoring 
Committee as part of the interim study reports.  
Interim data analysis for monitoring efficacy is not applicable for this protocol. 
 
 
 
 
 
 
 
 


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