Clinical trial NCT01593020
Conditions: Breast Cancer
Keywords: Breast cancer Early Stage Breast Cancer Not Overexpressing HER-2 Primary invasive adenocarcinoma of the breast Paclitaxel Taxol Eribulin E7389 5-Fluorouracil 5-FU Adrucil Efudex Epirubicin Ellence Cyclophosphamide Cytoxan Neosar Doxorubicin Doxorubicin hydrochloride Adriamycin PFS Adriamycin RDF Adriamycin Rubex
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-08-03; Completion date: 2020-11-04
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if and how well eribulin, given in combination with standard chemotherapy, can treat early-stage breast cancer compared to paclitaxel given in combination with standard chemotherapy. In this study, the standard chemotherapy being given is either 5-fluorouracil, epirubicin, and cyclophosphamide (called FEC) or 5-fluorouracil, doxorubicin, and cyclophosphamide (called FAC).

Eribulin is a changed version of the structure of a natural substance from a sea sponge. It is designed to block cells from dividing, which may cause cancer cells to die.

Paclitaxel is designed to block cancer cells from dividing, which may cause them to die.

5-fluorouracil is designed to block cancer cells from growing and dividing, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Epirubicin is designed to block the way cancer cells grow and divide, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Doxorubicin is designed to stop the growth of cancer cells, which may cause the cells to die.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and/or keep them from spreading throughout the body. This may cause the cancer cells to die.

Detailed description:
Study Groups If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. You will have an equal chance of being assigned to either group.

If you are in Group 1, you will receive paclitaxel for 4 cycles. You also will be treated with FAC or FEC for 4 cycles. Your treating doctor will decide whether you will receive FEC or FAC.

If you are in Group 2, you will receive eribulin for 4 cycles. You will also be treated with FAC or FEC for 4 cycles. Your treating doctor will decide whether you will receive FEC or FAC.

Each cycle is 21 days.

Study Drug Administration for Group 1 You will receive paclitaxel by vein over 1 hour on Days 1, 8, and 15 of each 21-day study cycle.

Before the infusion, you will be given drugs by vein, to help decrease the risk of an allergic reaction.

If you have severe side effects, future treatments may be delayed, the dose may be decreased, or you may be taken off study.

Once you have received 4 cycles of paclitaxel, you will receive either FEC or FAC chemotherapy for 4 cycles. Your treating doctor will decide whether you will receive FEC or FAC.

Study Drug Administration for Group 2 You will receive eribulin by vein over 2-5 minutes on Days 1 and 8 of each 21-day study cycle.

Once you have received 4 cycles of eribulin, you will receive FEC or FAC chemotherapy for 4 cycles. Your treating doctor will decide whether you will receive FEC or FAC.

FEC or FAC Treatment After you have received 4 cycles of either paclitaxel or eribulin, you will receive FEC or FAC.

If you are given FEC chemotherapy, you will receive 5-Fluorouracil by vein over 15 minutes, epirubicin by vein over 30 minutes, and cyclophosphamide by vein over 30-60 minutes on Day 1 of every 21-day cycle.

If you are given FAC chemotherapy, you will receive 5-Fluorouracil by vein over 15 minutes, doxorubicin by vein over 15 minutes, and cyclophosphamide by vein over 30-60 minutes on Day 1 of 21-day cycle.

Before FEC or FAC chemotherapy, you will be given drugs by vein to help decrease the risk of allergic reaction. These drugs will include dexamethasone and zofran.

Study Visits During Paclitaxel or Eribulin On Day 1 of each cycle: If you have had these tests within 10 days before Day 1 of Cycle 1, they may not need to be repeated.

You will have a physical exam, including a measurement of your weight and vital signs.

You will be asked about any side effects you may be having and any drugs you may be taking.

Your performance status will be recorded. Blood (about 1-2 teaspoons) will be drawn for routine tests.

On Days 8 and 15 of Cycle 1-4, blood (about 1 teaspoon) will be drawn for routine tests.

At Week 12, you will have a core biopsy.

At the end of Cycle 4:

You will have an ultrasound of the breast to check the status of the disease. You will have an ECHO or MUGA scan. You will have a core biopsy and fine needle aspiration of the tumor. A small needle will be inserted into the tumor at the safest and easiest location to withdraw cancer cells. This will be used to learn which tumor markers may predict who may best respond to therapy.

Study Visits During FEC or FAC Chemotherapy

On Day 1 of every third week:

You will have a physical exam, including a measurement of your weight and vital signs.

You will be asked about any side effects you may be having and any drugs you may be taking.

Your performance status will be recorded. Blood (about 1-2 teaspoons) will be drawn for routine tests.

After you have finished FEC or FAC treatment, you may have surgery. At the end of the chemotherapy treatment, you will be referred to the breast surgeon to discuss surgery. There is an small possibility (less than 3%) that tumor has gotten worse during treatment, and additional chemotherapy may be necessary.

Length of Study You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Paclitaxel, doxorubicin, epirubicin, and cyclophosphamide are FDA approved and commercially available for the treatment of breast cancer. Eribulin is FDA approved and commercially available to treat metastatic breast cancer in patients who have received at least 2 chemotherapy regimens for the treatment of metastatic disease. The use of eribulin with the FEC/FAC regimens is investigational for neoadjuvant treatment.

Eribulin will be provided at no cost to you while you are on this study. You and/or your insurance provider will be responsible for the cost of paclitaxel, doxorubicin, epirubicin, and cyclophosphamide.

Up to 162 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: ARM 1: Participants receive Paclitaxel 80 mg/m2 by vein over 1 hour weekly for 12 doses of a 21 day cycle.

Participants on both arms receive FEC or FAC for 4 cycles (21 day cycle) at the preference of the treating physicians. arm 2: ARM 2: Participants receive Eribulin 1.4 mg/m2 by vein over 2-5 minutes on days 1 and 8 every 3 weeks for 4 cycles (21 day cycle).

Participants on both arms receive FEC or FAC for 4 cycles (21 day cycle) at the preference of the treating physicians.
Interventions: intervention 1: Paclitaxel intervention 2: Eribulin intervention 3: 5-Fluorouracil intervention 4: Epirubicin intervention 5: Cyclophosphamide intervention 6: Doxorubicin
Intervention descriptions: intervention 1: 80 mg/m2 by vein over 1 hour on Days 1, 8, and 15 of each 21-day cycle. intervention 2: 1.4 mg/m2 by vein over 2-5 minutes on Days 1 and 8 of each 21-day study cycle. intervention 3: 500 mg/m2 by vein on day 1 for 4 cycles (21 day cycle) at preference of treating physicians. intervention 4: 100 mg/m2 by vein on day 1 for 4 cycles (21 day cycle) at preference of treating physicians. intervention 5: 500 mg/m2 by vein on day 1 for 4 cycles (21 day cycle) at preference of treating physicians. intervention 6: 50 mg/m2 by vein on day 1, over 72 hour continuous infusion or intravenous bolus, for 4 cycles (21 day cycle) at preference of treating physicians.

Protocol documents:
Prot_SAP_000.pdf: 
2012-0167 
October 22, 2014 
Page 1 
 
 
A Randomized Phase II Neoadjuvant Study of Sequential 
Eribulin Followed by FAC/FEC-regimen Compared to Sequential 
Paclitaxel Followed by FAC/FEC-regimen in Patients with Early 
Stage Breast Cancer Not Overexpressing HER-2 
 
  
  Study Chair: 
Vicente Valero, MD, F.A.C.P. 
 
 
 
Professor, Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center  
1515 Holcombe Boulevard, Unit 1354  
 
Houston, TX 77030  
 
(713) 792-2817 tel.  
 
(713) 794 4385 fax.  
 
vvalero@mdanderson.org  
 
 
Collaborators: 
 
Savitri Krishnamurthy, MD 
Professor, Department of Pathology 
The University of Texas MD Anderson Cancer Center  
 
James M Reuben, MBA, PhD 
Professor, Department of Hematopathology - Research 
The University of Texas MD Anderson Cancer Center  
 
Joe Ensor, PhD 
Research Statistician, Department of Biostatistics 
The University of Texas MD Anderson Cancer Center  
 
Gary J Whitman, MD 
Professor, Department of Diagnostic Radiology 
The University of Texas MD Anderson Cancer Center  
 
Naoto T Ueno, PhD 
Professor, Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center  
 
Stacy Moulder, MD 
Associate Professor, Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center  


2012-0167 
October 22, 2014 
Page 2 
 
Table of Contents 
 
1. OBJECTIVES AND RESEARCH HYPOTHESIS 
1.1   Primary Objectives……………………………………………… ...………………1 
1.2   Secondary Objectives ....…………………………………………………………...2 
1.3  Exploratory Objectives ...………………………………………………………….3 
1.4  Research Hypothesis ....……………………………………………………………4 
 
2. BACKGROUND  
2.1   Breast Cancer ...........................................................................................................5 
2.2   Primary Systemic Therapy: Historical Perspective .................................................6 
2.3.  Pathological Assessment ..........................................................................................6 
2.4.  Phase II and III Randomized PST Breast Cancer Trials ..........................................7 
2.5.  Current Primary Systemic Chemotherapy Regimens ..............................................9 
2.6.  Primary Systemic Therapy in Operable Breast Cancer .........................................10 
2.7.  Role of the Pathological Complete Response in Breast Cancer ............................11 
2.8.  Primary Systemic Therapy: Sequential versus Alternating Regimens ..................12 
 
3. ERIBULIN (Halaven®) 
3.1  Description………………………………………… …………………………….13 
3.2  Clinical Pharmacology ...........................................................................................14 
 
3.2.1 Mechanisum of Action …………………………… ...………………………13 
 
3.2.2 Pharmacodynamics – Cardiac Electrophysiology.......………………………14 
 
3.2.3 Pharmacokinetics ..……………… .…………………………………………14 
3.3.  Metabolism………………… ……………………………………………………14 
3.4.  Elimination……… ……………………………………………………………….14 
3.5.  Effects of Age, Gender, and Race……… ………………………………………. 15 
3.6.  Non-clinical Toxicology………………… ………………………………………15 
3.7.  Clinical Studies………………………………………… ....……………………..15 
3.8.  Drug Supply, Storage and Handling…………………… ....……………………  17 
3.9.  Indication and Usage……………………………………………………………..17 
3.10. Warning and Precautions………… ....………………………………………...... 17 
3.11. Dosage and Administration....................................................................................18 
3.12. Adverse Reaction ...................................................................................................21 
3.13 Drug Interactions ...................................................................................................23 
 


2012-0167 
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4. TREATMENT PLAN 
4.1 Study Design ....……………………………………………………………………26 
4.2  Eligibility……………… ………………………………………………………….26 
 
4.2.1 Inclusion Criteria...…………………………………………………………..26 
 
4.2.2 Exclusion Criteria ..………………………………………………………….27 
4.3  Drug Administration Plan ....………………………………………………………27 
4.4  Duration of Study ………………………………………………………………….28 
4.5  Dose Modification ………………………………………………………………...29 
4.6  Evaluation During Study ..…………………………………………………………35 
4.7  Concurrent Supportive Care ..……………………………………………………..35 
4.8  Criteria for removal from the study………………… .……………………………36  
4.9  Criteria for Response .……………………………………………………………..36 
 
5. CORRELATIVE STUDIES  
5.1  Hot Spot Mutation Analysis Methodology .....…………………………………….37 
5.2  Molecular Inversion Probes (MIP) Arrays Methodology ....………………………38 
5.3  CTCs Blood Collection ..…………………………………………………………..38 
 
6. STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
6.1 Assessment of Compliance .....…………………………………………………….38 
6.2 Assessment of Accountability ..……………………………………………………38 
 
7. ADVERSE EVENT REPORTING AND DATA COLLECTION 
7.1 Adverse Event Reporting ....……………………………………………………….39 
7.2 Expedited Adverse Event Reporting Guidelines ………………………………….39 
7.3 Serious Adverse Event (SAE) Reporting to Eisai .....……………………………...39 
7.4 SAE definition.…………………………………………………………………… 39 
7.5 Adverse Event Data Collection .…………………………………………………...40 
7.6 AE/SAE Follow up ....……………………………………………………………..40 
 
8. STATISTICAL ANALYSIS………………… ..………………………………………40 
9. PUBLICATION OF TRIAL RESULTS… .....…………………………………………41 
10. STUDY CALENDER ………………… ....……………………………………………42 
11. REFERENCES…………………… ....…………………………………………….......43 


2012-0167 
October 22, 2014 
Page 4 
 
List of Abbreviations 
 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
b.i.d. 
bis in diem/twice a day 
CRF 
Case Report/Record Form 
CS&E 
Clinical Safety and Epidemiology 
CR 
Clinical Research 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
IEC 
Independent Ethics Committee 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
o.d. 
omnia die/once a day 
p.o. 
per os/by mouth/orally 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization 


2012-0167 
October 22, 2014 
Page 5 
 
1. OBJECTIVES AND RESEARCH HYPOTHESIS 
 
1.1 
Primary Objectives  
To estimate the pathological complete response (pCR) rate of eribulin followed by FAC/FEC-
regimen relative to the pCR rate of paclitaxel followed by FAC/FEC-regimen in patients with 
HER-2 negative, operable breast cancer.  
1.2 
Secondary Objectives 
1.2.1 To evaluate the safety of the combination of eribulin followed by FAC/FEC-regimen.  
 
1.2.2 To determine the rate of breast conservation surgery.  
1.3 
Exploratory Objectives 
1.3.1 To explore in this population using Hot Spot Mutation Analysis (HSMA) and Molecular 
Inversion Probes (MIP) arrays and analyze if there are any predictive patterns of expression that 
may be differentially predictive of pCR to eribulin followed by FAC/FEC regimen versus 
paclitaxel followed by FAC/FEC regimen. 
 
1.3.2 To determine the effect of eribulin on the presence of Circulating tumor cells (CTC) and 
CTCs with epithelial and/or EMT gene expression in PB. 
 
1.4 Research Hypothesis 
Sequential administration of eribulin followed by FAC/FEC-regimen (5-Fluorouracil, 
Adriamycin or Epirubicin, and Cyclophosphamide), has greater activity based on pCR rate 
relative to sequential administration of Paclitaxel followed by FAC/FEC-regimen as primary 
systemic therapy for women with early stage breast cancer. 
A biomarker-defined population can be identified in which a higher pCR rate is observed in 
subjects treated with eribulin followed by FAC/FEC-regimen compared with paclitaxel followed 
by FAC/FEC-regimen. 
 
 


2012-0167 
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2. BACKGROUND 
2.1.  Breast Cancer 
Invasive breast cancer is the most common malignancy in women worldwide. In the United 
States, breast cancer is the most common female cancer, the second most common cause of death 
in women (after lung cancer), and is the main cause of death in women between the ages of 45 
and 55. [2]  However, over the last decade the mortality rate has declined in the United States 
and United Kingdom largely because of widespread use of mammography, breast cancer 
screening programs, advances in evaluation technique, and more effective adjuvant 
treatments.[3] 
Studies that compared preoperative (neoadjuvant or primary systemic therapy) and adjuvant 
chemotherapy in patients with early stage breast cancer have shown no difference in overall 
survival or disease free survival. [4] Primary systemic therapy (PST) is increasingly being used 
in the management of patients with early breast cancer. Neoadjuvant chemotherapy allows for 
monitoring of response to chemotherapy and enhances chances of breast conservation surgery 
and/or a better cosmetic outcome following mastectomy in patients with locally advanced breast 
cancer. [5, 6] Additionally, the neoadjuvant setting is ideal for pharmacogenomic studies to 
identify breast cancer patients likely to respond best to therapy. The provision of a surgical 
specimen, at the end of therapy, allows for a more rapid assessment of response (pathological 
responses) than adjuvant trials. Pathological complete response (pCR) is widely accepted as a 
valuable prognostic indicator of long-term outcome after neoadjuvant therapy. [7] 
2.2.  Primary Systemic Therapy: Historical Perspective 
The rationale for considering the evaluation of primary systemic therapy (PST) in patients with 
operable breast cancer began to evolve as clinical observations demonstrated the utility of this 
approach in patients with locally advanced breast cancer (LABC), [8-10]  and inflammatory 
breast cancer (IBC). In addition, preclinical observations, [11, 12] and mathematical models of 
tumor growth, dissemination, and development of resistance to chemotherapy support the use of 
PST rather than adjuvant therapy. These could lead to achieve longer disease-free survival (DFS) 
and overall survival (OS), presumably through early treatment of systemic micromestatatic 
disease.  Since its initial use in the early 1970s, PST has become the standard of care for 
management of LABC and IBC, and increasingly been used for treatment of large operable and 
more recently for early-stage breast cancer.  
Chemo-, hormone-, and recently trastuzumab-base therapy are potential PST options for the 
different sub-types of breast cancer in 2011.  PST provides several advantages, including down-
staging allowing surgery for non-operable breast cancer, and increasing breast-conservative 
surgery rate in patients with large operable breast cancer.  It also provides an early surrogate 
factor, pCR, for long-term outcome and in-vivo model to assess clinical benefit and finally a 
research tool for understanding breast cancer biology and treatment mechanisms of action(s). 
 


2012-0167 
October 22, 2014 
Page 7 
 
2.3.  Pathological Assessment 
A variety of endpoints can be used to measure outcomes of PST for breast cancer other than 
directly measuring survival (DFS, and OS), which requires a large number of patients and long 
term follow-up. These endpoints included clinical response, radiologic response, rate of breast 
conservative surgery (BCS), and pathologic response. The results of several studies have been 
shown that pCR is predictive of long-term survival. [13-16]At present, the achievement of pCR 
has emerged as the primary end point of most interest in the clinical research literature. 
Attainment of pCR is associated with a favorable prognosis; such patients have a far lower risk 
of subsequent recurrence than do patients with residual invasive tumor at the time of surgery, and 
also seem to have improved overall survival. Despite the strong evidence of predictive value of 
pCR in this context, there is no consensus on the measurement of this important endpoint. 
Clinical and pathological responses are both frequently used as objective measurements of 
effectiveness of PST.  Three of the most commonly used criteria in the literature are those by  
Sataloff et al [16], Feldman et al, [13] and most recently Symmans and collaborators from the 
University of Texas, MD Anderson Cancer Center. The first 2 sets of criteria have some overlap 
but, for the most part, differ from each other. 
In general, 60% to 90% of patients with invasive breast cancer show clinical response; however, 
only 3% to 30% of patients achieve pCR. Two large studies using PST, NSABP B-18 and B-27 
defined pCR as no residual invasive cancer in the breast after PST and at the time of surgery, 
whereas other studies also take node status and noninvasive cancer into account. An International 
Expert Panel recently recommended that pCR be defined as no invasive or noninvasive tumors in 
the beast and axillary tissues removed at the time of surgery. [8]  
Symmans et al [17] showed a continuous index combining pathologic measurements of the 
primary tumor (size and cellularity) and nodal metastases (number and size) and tested as an 
independent predictor of distant relapse-free survival. Patients with minimal residual disease 
(RD) (RCB-I) carried the same prognosis as pCR (RCB-0).  On the other hand, patients with 
extensive RD (RCB-III) had poor prognosis.  RCB was independently prognostic in a 
multivariate model that included age, pretreatment clinical stage, hormone receptor status, 
hormone therapy, and pathologic response (pathologic complete response [pCR] vs. RD; hazard 
ratio = 2.50; 95% CI 1.70 to 3.69; P < .001).  Seventeen per cent of patients had minimal RD 
(RCB-I). These patients carried the same prognosis as pCR (RCB-0).  Extensive RD (RCB-III) 
was seen in 13% of patients.  It was associated with poor prognosis, regardless of hormone 
receptor status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer 
stage of residual disease. The calculation formula and detailed description can be found at a 
dedicated Web site: http://www.mdanderson.org/breastcenter_RCB.  
2.4. 
 Phase II and III Randomized PST Breast Cancer Trials 
Several large Phase III trials investigated the efficacy of chemotherapy when is administered as 
PST compared with adjuvant systemic treatment.  
In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a large 
phase III study (NSABP P-18) to compare PST and post-operative chemotherapy.  [7, 18, 19]A 
total of 1,523 patients with T1-3 N0-1 M0 breast cancer were randomized to receive four cycles 
of doxorubicin and cyclophosphamide (AC) either as PST or adjuvant therapy. Breast tumor size 
was reduced in 79% of patient after PST, and 36% had a clinical complete response (cCR) rate, 
43% clinical partial response (cPR), and a 13% pCR. Clinical nodal response was observed in 


2012-0167 
October 22, 2014 
Page 8 
 
89% of patients with node-positive disease; 73% had nodal cCR, and 44% of these patients had 
pCR.  At 9 years, the authors reported no difference in DFS (67% for both groups) or OS (69% 
PST vs. 70% adjuvant groups; P = .80).  However, there was a favor trend in favor of PST in 
women less than 50 years old (HR 0.85, P = .053). The investigators reported that the use of PST 
improved BCS from 60% to 67% (P < .01). Even with improved rates of BCS, there was no 
statistically significant difference in the rate of local recurrence between treatment groups (P = 
.12). A marginal increase in the rate of local recurrence for patients who were converted from 
proposed mastectomy to segmental mastectomy (15.9%) was seen when compared with patients 
who were eligible to undergo segmental mastectomy as per initial plan (9.9%) (P = .04). This 
difference loses statistical significance after controlling for age and initial clinical tumor size.  
NSABP B-27, a large prospective randomized trial, [15, 20] was designed to evaluate whether 
the addition of docetaxel to AC PST would prolong DFS and OS and improve clinical and 
pathologic tumor response rates.  Women with operable breast cancer (n = 2,411) were randomly 
assigned to receive either 4 cycles of PST AC followed by surgery (Group 1), 4 cycles of AC 
followed by 4 cycles of docetaxel, followed by surgery (Group 2), or 4 cycles of AC followed by 
surgery and then 4 cycles of docetaxel (Group 3).  The addition of docetaxel to AC increased 
pCR rate (26.1% vs 13.7%; P < .001).   pCR was a significant predictor of OS (HR 0.33, P < 
.0001).  The pathologic nodal status after chemotherapy was also a significant prognostic factor 
for OS (P < .0001).    However, this study did not prospective assess the role docetaxel in 
patients with residual disease after PST AC.  There was no stratification after AC. The patients 
with all eight cycles of PST administered at front had a trend toward improvement in RFS. [15] 
One caveat with this study is that at the time it was conducted, all patients received tamoxifen, 
which was initiated concurrently with chemotherapy, regardless of hormone-receptor status. The 
simultaneous administration of tamoxifen and chemotherapy may have affect benefit from 
chemotherapy. 
The European Organization for Research and Treatment of Cancer (EORTC) Trial 10902 
randomized 698 patients with stage I to IIIB breast cancer to receive four cycles of PST or 
adjuvant FEC-100. [21] The primary objective of this study was to determine the impact of 
timing of therapy on DFS and OS. After a follow-up of 4-years the OS was 82% for PST group 
compared to 84% for those treated in the adjuvant setting (P = .38). For patient who received 
PST, the overall response rate (ORR) (cCR + cPR) was 49% and cCR 7%. Thirteen of 350 
patients (4%) in the PST group had a pCR. For this study, response was determined by both 
clinical examination and changes with the mammogram, possibly explaining the low overall 
clinical CR. PST was associated with an increased rate of 35% BCS compared to 22% for the 
control group. The rate of locoregional recurrence was equivalent between treatment groups. 
The European Cooperative Trial in Operable (ECTO) Breast Cancer randomly tested the efficacy 
of postoperative chemotherapy doxorubicin followed by cyclophosphamide, methotrexate, and 
5-fluorouracil (CMF) or doxorubicin and paclitaxel (AP) followed by CMF versus PST 
consisting in AP followed by CMF.  [22, 23] A total of 1,355 patients entered the study. Overall, 
PST induced a clinical response in 78% of the patients and pCR 23%. There was no significance 
in RFS when AP/CMF was given before surgery compared with the same regimen given after 
surgery (HR, 1.21; P = .18) However, the rate of breast-conserving surgery was significantly 
higher with preoperative chemotherapy (63% vs. 34%; P < .001) 


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The wide variety of PST clinical trials recently completed or ongoing in early breast cancer 
reflects the pressing need to identify the most effective agents and regiments to optimize both 
surgical and long-term outcomes for these patients. 
Two prospective clinical studies from M.D. Anderson Cancer Center evaluating different 
sequence of taxane followed by anthracycline-based PST have been published. Green et al [24] 
evaluated the role of paclitaxel given at two different schedules in the PST setting. In this study, 
258 patients were randomly assigned to receive weekly paclitaxel or standard every 3-weekly 
paclitaxel to determine if different schedules or dose densities of paclitaxel would achieve 
improved pCR rate. The doses of weekly paclitaxel varied based on clinical status of axillary 
nodes. Weekly paclitaxel was given at a dose of 80 mg/m2 for 12 weeks to those with node-
negative disease or 150 mg/m2 (3 weeks on and 1 week off) for four cycles to those with node-
positive disease. Standard paclitaxel was administered as 24-hour infusion at 225 mg/m2 every 3 
weeks for four cycles. After completion of paclitaxel, all patients received FAC x 4 cycles. 
Clinical responses were similar in both groups (P = .25). The pCR rates were higher in those 
who received weekly paclitaxel than those who received standard paclitaxel (28% vs.15.7%; P = 
.02) with an improved BC rate (47% vs. 38%; P = .05). There are already data supporting the 
superiority of weekly paclitaxel over every 3-weekly paclitaxel in the adjuvant setting reported 
in the Eastern Cooperative Oncology Group (ECOG) 1199 [25] and in the metastatic setting 
reported in the Cancer and Leukemia Group B (CALGB) 9840. [26]  
Lastly, Buzdar el al [27] compared two taxane schedules (weekly paclitaxel [WP] x 12 versus 3-
week docetaxel plus capecitabine (DC) x 4 cycles, followed by: FEC-100 x 4 cycles. Patients 
were randomized 1:1 and stratified by the timing of therapy (PST vs. adjuvant). A total of 216 
patients were treated with PST and 107 were randomized to WP arm and 109 to DC arm. The 
pCR rates were 18.7% and 17.4% on each arm, respectively (P = .81). The DC arm had higher 
incidence of hand foot syndrome, and myelosuppression, and WP treatment higher neurotoxicity. 
The primary endpoint was DFS, and the secondary endpoint pCR. The study was designated to 
include 930 patients to have 80% power. An interim analysis in June 2008 to the data monitoring 
committee the study was closed due to futility. The authors concluded that WP and DC in the 
PST setting had same efficacy and WP was associated with better tolerance and less toxicity. 
2.5. Current Primary Systemic Chemotherapy Regimens 
Pathological complete response rates are generally higher with anthracycline-based combinations 
than with regimens not containing anthracycline (doxorubicin or Epirubicin). Consequently, 
most PST regimens for breast cancer are anthracycline-based combination: AC 
(doxorubicin/Cyclophosphamide); FAC (fluorouracil/doxorubicin/cyclophosphamide); CE 
(cyclophosphamide/epirubicin); and FEC (fluorouracil/epirubicin/cyclophosphamide). However, 
other non-anthracycline based drug combinations, such as CMF 
(cyclophosphamide/methotrexate/fluorouracil) with or without a taxane, are also in common use. 
Increased duration of chemotherapy administration from 12 to 18 weeks or longer improves pCR 
rates. [6] The addition of paclitaxel or docetaxel to anthracyclines based regimes has resulted in 
pCR of up to 28.2%. [24] The Aberdeen study showed that tumors that did not respond to an 
anthracycline-based regimen may respond to docetaxel. Additionally sequential and non-
concomitant addition of taxane to anthracycline-based chemotherapy results in higher pCR rates. 
[28] 


2012-0167 
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Page 10 
 
At present, there is no evidence to suggest that one taxane is superior to the other in the 
neoadjuvant setting.  
Table 1 shows multiple studies in the literature reporting pCR rates 
 
Table 1:   Pathological Response Rates in the Literature 
 
Trial/Reference 
No. of Patients 
Agent(s) 
No. of Cycles 
pCR (%) 
Fisher [7] 
 
1523 
AC 
X 4 
9 
Buzdar  [29] 
 
87 
Paclitaxel 
X 4 
9 
Amat [30] 
 
80 
Docetaxel 
X 6 
20 
NSABP B27  
[20]  
1502 
AC 
X 4 
13 
Aberdeen [31] 
 
47 
CVAP-Docetaxel 
X4 and x4 
34 
Green [24] 
 
258 
T-FAC 
12 w and x 4 
15.7 (q3w Pac) 
28.1 (qw Pac) 
SWOG0012 [32] 
 
265 
AC-Pac 
X 4 and 12 w 
17% 
AC = doxorubicin and cyclophosphamide; CVAP = cyclophosphamide, vincristine, doxorubicin, 
and prednisone; FAC = Fluorouracil, doxorubicin, and cyclophosphamide; T = Paclitaxel. 
2.6. 
Primary Systemic Therapy in Operable Breast Cancer  
The Breast Medical Oncology Department at MD Anderson has been one of the pioneers in the 
use of neoadjuvant chemotherapy for the treatment of breast cancer. The sequential or concurrent 
administration of taxane and anthracycline constitute the backbone of early breast cancer 
treatment. At MD Anderson Cancer Center our current standard of care for the treatment of 
breast cancer is the sequential administration of paclitaxel 80 mg/m2 IV, weekly for 12 cycles 
followed by FAC/FEC-regimen, IV, every 3 weeks for 4 cycles. [15]  This treatment is 
administered for a total of 24 weeks. Several studies randomized trials has been conducted in our 
institution incorporating novel drugs and compared with the standard regimen.  
PST has several potential advantages compared with the traditional strategy of surgery followed 
by adjuvant chemotherapy. In addition, PST reduces the size of the primary tumor and lymph 
node metastasis in greater than 80% of cases, increasing the probability that breast-conserving 
surgery can be performed. [13-16] A second advantage of this sequencing schedule is that it 
permits the assessment of response of the primary tumor to the particular chemotherapy regimen. 
This assessment allows the opportunity to “cross-over” to a different regimen for an individual 
patient if there is minimal or no response to the first regimen. These and other theoretic 
advantages for PST must be balanced carefully with other aspects of individual patient 
management. 
Most of the reports of combined-modality treatment for LABC were based on treatment 
programs that included anthracycline-containing combination of chemotherapy regimens, such as 


2012-0167 
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Page 11 
 
fluorouracil, doxorubicin, and Cyclophosphamide (FAC) or FEC when the anthracycline used 
was Epirubicin. Since the introduction of taxanes over the past decade, there have been several 
reports in which an anthracycline and taxane combination was utilized.  
One of the first considerations for studying PST for breast carcinoma was to investigate whether 
earlier delivery of chemotherapy offered the possibility of improved survival in patients with 
locally advanced breast carcinoma. To test these concepts, the National Surgical Adjuvant Breast 
and Bowel Project (NSABP) began the B-18 trial to test whether sequencing chemotherapy 
before surgery would improve outcomes. [13-15] 
 The trial enrolled 1523 patients with early-
stage, operable breast carcinoma and randomized them to receive four cycles of 
doxorubicin/Cyclophosphamide (AC) either before or after surgical treatment. The primary end 
points of this trial were disease-free survival (DFS) and overall survival (OS). With respect to 
these end points, the trial was a negative study. After 9 years, the OS and DFS were nearly 
identical between the two groups (P = .80, P =0.5, respectively). A second large randomized 
prospective trial that directly compared the sequencing of chemotherapy and surgery was 
performed by the European Organization of Research and Treatment of Cancer (EORTC). [16] 
This trial randomized 698 patients to preoperative or postoperative chemotherapy comprised of 
four cycles of FEC (5-Fluorouracil, Epirubicin, and Cyclophosphamide). Like the NSABP B-18 
trial, the EORTC study demonstrated equivalent survival and rates of distant metastases between 
the two treatment arms.  
Gianni el al, [17] randomized 1,355 patients with breast cancer > 2 cm to three groups: adjuvant 
doxorubicin (A) followed by cyclophosphamide, methotrexate, and 5-FU (CMF) 
(Sx→A→CMF); adjuvant doxorubicin and paclitaxel (AT) followed by CMF (Sx→AT→CMF); 
and neoadjuvant AT followed by CMF (AT→CMF→Sx). pCR rates in the neoadjuvant arm 
were 23% in breast only and 20% in breast plus axilla patients. The breast conservative treatment 
rate was also better in this arm (65% vs. 34%; P <.001). At 5 years of follow up, adjuvant 
chemotherapy was similar to PST in terms of freedom for progression (P =.24) and OS (P = .81)  
A recent meta-analysis addressed directly the question of neoadjuvant versus adjuvant 
chemotherapy. [18]  Nine randomized clinical trials involving 3,946 patients were included. pCR 
rates were highly variables among these trials. Six trials had a higher rate of BCT after PTS. No 
difference was observed between the two arms for death, disease progression, or distant 
recurrence.  Surprisingly, PST was associated with a higher locoregional recurrence (risk ratio, 
[RR] 1.22; P = .15). This greater risk was largely attributed to those trials in which radiation 
alone without surgery was used in patients who achieved a clinical complete response to PST. 
(RR, 1.53; P =.009). 
2.7. 
Role of the Pathological Complete Response in Breast Cancer  
A pathological complete response (pCR) implies the absence of residual invasive disease 
following PST. Pathological complete response is associated with long-term survival, and has 
been adopted as the primary end point for neoadjuvant trials.  While it is generally held that a 
definition of pCR should include patients without residual invasive carcinoma in the breast 
(pT0), the presence of nodal metastasis, minimal residual cellularity, and residual in situ 
carcinoma are not consistently defined as pCR or residual disease (RD). When there is no 
residual invasive cancer in the breast, the number of involved axillary lymph nodes is inversely 
related to survival. [19] Conversely, patients who convert to node-negative status after treatment 
have excellent survival, even if there is RD in the breast. [20] Symmans and collaborators, [33]
 


2012-0167 
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Page 12 
 
recently introduced a residual breast cancer burden (RCB) index as a novel independent new risk 
factor that improves the prediction of distant relapse after PST compared with currently used risk 
factors. RBC can be divided in four categories: patients with minimal residual disease (RCB-I) 
have the same 5-year prognosis as those with pCR (RCB-0), irrespective of the type of 
neoadjuvant chemotherapy administered, adjuvant hormonotherapy, or the pathologic stage of 
RD. Extensive RD (RCB-III) was associated with poor prognosis, irrespective of the type of 
neoadjuvant chemotherapy administered, adjuvant hormontherapy or the pathologic stage of 
RCB. 
2.8. 
 Primary Systemic Therapy: Sequential versus Alternating Regimens 
Several important observation regarding the sequence of anthracycline and taxane-based 
treatment during PST have raised the question which sequence of treatment will be most 
favorable to impact in the pCR rates and outcome (DFS and OS) of breast cancer patients. 
Anthracyclines are usually administered before taxanes (or combined with taxanes), a practice 
which reflects the sequence of administration used in clinical trials rather than research-based 
evidence. 
Miller et al [34] published in 2005 a phase II randomized biomarker discovery study in patients 
with operable breast cancer. Seventy patients were treated with the dose dense sequence 
doxorubicin (75 mg/m2 every 2 weeks, 3 cycles) followed by docetaxel (40 mg/m2 weekly, 6 
cycles) (AD) or the vice versa sequence DA. Patients treated with DA had a pCR rate 17% 
compared with the sequence of AD with a pCR rate of 8.6%. In the sequence DA the 
relative dose intensity (RDI) for A and D were 0.94 and 0.97, respectively. The sequence AD 
resulted in RDI for A and D were 0.95 and 0.85, respectively. 
The Neo-tAnGo is a large randomized phase III study conducted in United Kingdom, comparing 
epirubicin plus cyclophosphamide (E/C) followed by paclitaxel with and without gemcitabine 
compared with paclitaxel with or without gemcitabine followed by epirubicin plus 
cyclophosphamide. (E/C Pac+/-Gem vs. Pac+/-Gem EC). [35]   A total of 831 patients with 
T2 tumors or above, were randomized to a 2-by-2 factorial design, and the primary endpoint of 
the study was the pCR rate in the breast as well in the axillary lymph nodes. Patient 
characteristics were well balanced in both arms. The pCR rates were identical for EC  T (17%) 
compared with the EC  T+Gem sequence (P = .98). However, the sequence T+/- Gem  EC, 
showed a pCR of 20% compared with 15% for the EC then T+/-Gem (P = .03). Adjustment by 
stratification did not alter the results. 
Similarly, Alvarez et al [36]analyzed retrospectively the sequence of chemotherapy with taxanes 
and anthracyclines in 1,414 patients that received PST at MD Anderson Cancer Center between 
1991 and 2009. A total of 1188 patients (84%) received the sequence taxane followed by 
anthracycline. (TA) and 226 patients (16%) received the sequence of anthracycline followed 
by taxane (AT). A total of 249 patients (21%) achieved a pCR in the TA sequence compared 
with 28 patients (12.3%) in the AT sequence. (P = .004). In addition, for all patients that were 
treated with the sequence TA the 5-year and 10-year DFS rates were 78.9% and 61.4%, 
respectively. (P = .0001) For patients treated with the sequence AT, the 5-year and 10-year 
DFS rates were 57.5% and 45.2%, respectively. (P = .0001). 
These three studies demonstrated evidence that dose delivery and efficacy improve when taxane 
is given first with less immediate toxicity. Several ongoing randomized adjuvant trials, such as 
SOLD and NSABP-B40, taxanes are now given before anthracyclines. 


2012-0167 
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3. ERIBULIN (HALAVEN®) 
3.1 Description 
Eribulin mesylate (Halaven®) is a non-taxane microtubule dynamics inhibitor. Eribulin is a 
synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria 
okadai. The chemical name for eribulin mesylate is 11,15:21:24,28-Triepoxy-7,9-ethano-12.15-
methano-9H,15-furo[3,2-i]furo[2’,3’:5,6]pyrano[4,3-b][1,4]dioxacyclopetacosin-5(4H)-one,2-
[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methaylene)-
,(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-
methanesulfonnate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical 
formula is C40 H59NO11.CH4O3S. Eribulin mesylate has the following structural formula: 
 
Eribulin is clear, colorless, sterile solution for intravenous administration. Each vial contains 1 
mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95) 
3.2 Clinical Pharmacology 
3.2.1 Mechanism of Action 
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and 
sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based 
antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and 
ultimately, apoptotic cell death after prolonged mitotic blockage. 
 
3.2.2 Pharmacodynamics - Cardiac Electrophysiology 
The effects of eribulin on the QTc interval was assessed in an open-label, uncontrolled, 
multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 
mg/m2 of eribulin on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed 
on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from 
baseline (95% upper confidence interval) was 11.4 (19.5) ms. 


2012-0167 
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3.2.3 Pharmacokinetics 
The pharmacokinetics of eribulin is linear with a mean elimination half-life of approximately 40 
hours, a mean volume of distribution of 43 L/M2 to 114/m2 and mean clearance of 1.16 L/hr/m2 
to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. The human plasma protein 
binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65% 
eribulin exposure after multiple dosing is comparable to that following a single dose. No 
accumulation of eribulin is observed with weekly administration. 
3.3 Metabolism 
Unchanged eribulin was the major circulating species in plasma following administration of C-
eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, 
confirming that there are no major human metabolites of eribulin. 
Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro. Eribulin inhibits 
CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially 
increase the plasma level of CYP3A4 substrates. Eribulin shows no induction potential for 
CYP1A, CYP2C9, CYP2C19, and CYP3A in primary hepatocytes. No significant inhibition of 
CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations 
up to 5 M in pooled human liver microsomes. In vitro drug interaction studies indicate that 
eribulin does not inhibit drugs that are substrates of these enzymes and it is unlikely that eribulin 
will affect plasma levels of drugs that are substrates of CYP enzymes. Eribulin is a substrate and 
a week inhibitor of the drug efflux transporter P-gp in vitro. 
3.4 Elimination 
Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to 
patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged 
eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively. 
3.5 Effects of Age, Gender, and Race 
Based on a population pharmacokinetic analysis with data collected from 340 patients, gender, 
race, and age do not have a clinically meaningful effect on the PK of eribulin. 
3.6 Nonclinical Toxicology 
Carcinogenicity studies have not been conducted with eribulin mesylate. 
Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). 
Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in 
an in vivo rat bone marrow micronucleus assay. 
The effects of eribulin on human fertility are unknown. Fertility studies have not been conducted 
with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog 
and rat toxicology studies suggest that male fertility may be compromised by treatment with 
eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium 
with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the 
recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the 
recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 
cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human 
dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 


2012-0167 
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3.7 Clinical Studies 
Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast 
cancer who received at least two chemotherapeutic regimens for the treatment of metastatic 
disease and experienced disease progression within 6 months of their last chemotherapeutic 
regimen. [1]  Patients were required to receive prior anthracycline- and taxane- based 
chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive 
eribulin (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). 
Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine 
exposure. Eribulin was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-dayy. 
Eribulin-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. 
Control arm therapy consisted of 97% chemotherapy (25% vinorelbine, 18% gemcitabine, 18% 
capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), or 3% hormonal 
therapy. The main efficacy outcome was overall survival. 
Patients demographic and baseline characteristics were comparable between the treatment arms. 
The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of the 
patients were enrolled in North America/Western Europe/Australia, 25% in Eastern 
Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients have a 
baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including 
estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 
49%, negative 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative 
status (ER-, PR-, HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 
38% lung) and bone disease (61%) and number of sites of metastases (greater than two: 50%), 
were also similar in the eribulin and control arms. Patients received a median of four prior 
chemotherapy regimens in both arms. 
In Study 1, a statistically significant improvement in overall survival was observed in patients 
randomized to the eribulin arm compared to the control arm (see Table 2). An updated unplanned 
survival analysis, conducted when 77% of events had been observed (see Figure 1) was 
consistent with the primary analysis. In patients randomized to eribulin, the objective response 
rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration 
was 4.2 months (95% CI: 3.8, 5.0 months). 
 
 


2012-0167 
October 22, 2014 
Page 16 
 
 
Table 2: Comparison of Overall SURVIVAL in Eribulin and Control arm – Study 1 
Overall Survival 
 
 
 
 
Eribulin 
 
Control arm 
 
 
 
 
 
 
 
(n=508) 
 
(n=254) 
 
 
 
 


2012-0167 
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3.8 Drug Supply, Storage and Handling 
NDC 62856-389-01 Eribulin mesylate injection, 1mg/2 mL, in a single-use vial. One vial per 
carton. 
Store at 25ºC (77ºF); excursions permitted to 15º - 30ºC (59º - 86ºF). Do not freeze. Store the 
vials in their original cartons 
 3.9 Indication and Usage 
Eribulin is a microtubule inhibitor indicated for the treatment of patients with metastatic breast 
cancer who have previously received at least two chemotherapeutic regimens for the treatment of 
metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the 
adjuvant or metastatic setting. 
3.10 Warning and Precautions 
3.10.1 Neutropenia 
Severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of 
patients in Study 1, leading to discontinuation in <1% of patients [see Adverse Reactions (6)]. 
Patients with alanine aminotransferase or aspartate aminotransferase > 3 × ULN (upper limit of 
normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than 
patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a 
higher incidence of Grade 4 neutropenia and febrile neutropenia. Monitor complete blood counts 
prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 
cytopenias. Delay administration of Eribulin and reduce subsequent doses in patients who 
experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies 
of Eribulin did not include patients with baseline neutrophil counts below 1,500/mm3. 
3.10.2 Peripheral Neuropathy 
Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) 
of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to 
discontinuation of Eribulin (5% of patients; 24/503). Neuropathy lasting more than one year 
occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new 
or worsening neuropathy that had not recovered within a median follow-up duration of 269 days 
(range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory 
neuropathy. Withhold Eribulin in patients who experience Grade 3 or 4 peripheral neuropathy 
until resolution to Grade 2 or less. 
3.10.3 Embryo-Fetal Toxicity 
There are no adequate and well-controlled studies of Eribulin in pregnant women. Eribulin is a 
microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a 
pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin 
mesylate at approximately half of the recommended human dose based on body surface area. If 
this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she 
should be apprised of the potential hazard to the fetus. 
 
 


2012-0167 
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3.10.4 QT Prolongation 
In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day, 
independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG 
monitoring is recommended if therapy is initiated in patients with congestive heart failure, 
bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III 
antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to 
initiating Eribulin and monitor these electrolytes periodically during therapy. Avoid Eribulin in 
patients with congenital long QT syndrome.  
3.11 Dosage and Administration 
3.11.1 Recommended Dose 
The recommended dose of Eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes 
on Days 1 and 8 of a 21-day cycle. 
The recommended dose of Eribulin in patients with mild hepatic impairment (Child-Pugh A) is 
1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. 
The recommended dose of Eribulin in patients with moderate hepatic impairment (Child-Pugh B) 
is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. 
The recommended dose of Eribulin in patients with moderate renal impairment (creatinine 
clearance of 30-50 mL/min) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on 
Days 1 and 8 of a 21-day cycle.  
3.11.2 Dose Modification 
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.  
Recommended dose delays 
Do not administer Eribulin on Day 1 or Day 8 for any of the following: 
− ANC < 1,000/mm3 
− Platelets < 75,000/mm3 
− Grade 3 non-hematologic AEs (except constitutional symptoms, such as fatigue, muscle aches, 
insomnia, dry mouth and sweating; and skin changes such as dry skin, pruritus, and nail 
changes; and constipation) should have all study treatment immediately interrupted pending 
investigator determination of whether the AEs are related or not related to study treatment.  
 
- The use of G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–
macrophage colony-stimulating factor) is recommended for patients who receive Eribulin and 
at treating physician discretion. 
If toxicities resolve or improve to ≤ Grade 2 severity by Day 8, resume Eribulin at 1.4 mg/m² 
 
 
 
The Day 8 dose may be delayed for a maximum of 1 week. 
− If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. 
− If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer Eribulin at a 
reduced dose and initiate the next cycle no sooner than ≥ 2 weeks later. 


2012-0167 
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3.11.3 Recommended dose reductions 
If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, 
resume Eribulin at a reduced dose as set out in Table 3. 
Do not re-escalate Eribulin dose after it has been reduced. 
 
Eribulin dose calculation for patients with BSA of > 2.0. The research nurse will notify the 
Principal Investigator who will discuss the appropriate dose with the attending physician prior to 
treatment. 
 
It is well known that obese patients have a high risk to be overdosed using standard BSA 
measures, especially for highly myelotoxic drugs like eribulin. Therefore, for patients that are 
going to be treated with eribulin and their BSA >2.0.  We are rounding down the BSA to 2. This 
will allow us to manage her blood toxicity more efficiently. 
 
Table 3. Recommended Dose Eribulin Reductions 
 
 
 
Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse 
Events (CTCAE) version 4.0. 
3.11.4 Instructions for Preparation and Administration 
Aseptically withdraw the required amount of Eribulin from the single-use vial and administer 
undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Do not dilute in or 
administer through an intravenous line containing solutions with dextrose. Do not administer in 
the same intravenous line concurrent with the other medicinal products. Store undiluted Eribulin 
in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration 


2012-0167 
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(40°F or/ 4°C). Store diluted solutions of Eribulin for up to 4 hours at room temperature or up to 
24 hours under refrigeration. Discard unused portions of the vial. 
3.11.5 Dosage Forms and Strengths 
Eribulin Injection, 1 mg/2 mL (0.5 mg/mL). 
3.11.6 Contraindications 
None. 
 
 


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3.12 Adverse Reactions 
The following adverse reactions are discussed in detail in other sections of the labeling: 
• Neutropenia  
• Peripheral neuropathy  
• QT interval prolongation 
The most common adverse reactions (≥ 25%) reported in patients receiving Eribulin were 
neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. 
The most common serious adverse reactions reported in patients receiving Eribulin were febrile 
neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in 
discontinuation of Eribulin was peripheral neuropathy (5%).  
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. 
In clinical trials, Eribulin has been administered to 1,222 patients with multiple tumor types, 
including 240 patients exposed to Eribulin for 6 months or longer. The majority of the 1,222 
patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial 
and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%). 
The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In 
Study 1, patients were randomized (2:1) to receive either Eribulin (1.4 mg/m2 on Days 1 and 8 
of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 
503 patients received Eribulin, and 247 patients in the control group received therapy consisting 
of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 
15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median 
duration of exposure was 118 days for patients receiving Eribulin and 63 days for patients 
receiving control therapy. Table 2 reports the most common adverse reactions occurring in at 
least 10% of patients in either group. 
 
 


2012-0167 
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Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 
MedDRA ver 10.0 
 
 
Eribulin 
 
 
 
Control Group 
 
 
 
 
 
n=503  
 
 
 
n=247 
 
 
 
 
 
All Grades  
≥ Grade 3  
All Grades  
≥ Grade 3 
Blood and Lymphatic System Disordersa 
 
Neutropenia  
 
 
82%  
 
57%  
 
53%  
 
23% 
 
Anemia  
 
 
58%  
 
2%  
 
55%  
 
4% 
Nervous system disorders 
 
Peripheral neuropathyb   
35%  
 
8%  
 
16%  
 
2% 
 
Headache  
 
 
19%  
 
<1%  
 
12%  
 
<1% 
General disorders and administrative site conditions 
 
Asthenia/Fatigue  
 
54%  
 
10%  
 
40%  
 
11% 
 
Mucosal inflammation   
9%  
 
1%  
 
10%  
 
2% 
 
Pyrexia  
 
 
21%  
 
<1%  
 
13%  
 
<1% 
Gastrointestinal disorders 
 
Constipation  
 
 
25%  
 
1%  
 
21%  
 
1% 
 
Diarrhea  
 
 
18%  
 
0  
 
18%  
 
0 
 
Nausea  
 
 
35%  
 
1%  
 
28%  
 
3% 
 
Vomiting  
 
 
18%  
 
1%  
 
18%  
 
1% 
Musculoskeletal and connective tissue disorders 
 
Arthralgia/Myalgia  
 
22%  
 
<1%  
 
12%  
 
1% 
 
Back pain  
 
 
16%  
 
1%  
 
7%  
 
2% 
 
Bone pain  
 
 
12%  
 
2%  
 
9%  
 
2% 
 
Pain in extremity  
 
11%  
 
1%  
 
10%  
 
1% 
Investigations 
 
Weight decreased  
 
21%  
 
1%  
 
14%  
 
<1% 
Metabolism and nutrition disorders 
 
Anorexia  
 
 
20%  
 
1%  
 
13%  
 
1% 
Respiratory, thoracic, and mediastinal disorders 
 
Cough   
 
 
14%  
 
0  
 
9%  
 
0 
 
Dyspnea  
 
 
16%  
 
4%  
 
13%  
 
4% 
Skin and subcutaneous tissue disorders 
 
Alopecia  
 
 
45%  
 
NAc  
 
10%  
 
NAc 
Infections and Infestations 
 
Urinary Tract Infection   
10%  
 
1% 
 
5%  
 
0 
a based upon laboratory data. 
b includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral 
sensory neuropathy, and paraesthesia. 
c not applicable; (grading system does not specify > Grade 2 for alopecia). Based 
Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received Eribulin in 
Study 1, and 29% (144/503) of patient’s experienced Grade 4 neutropenia. Febrile neutropenia 
occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile 
neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and 
discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the 
mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater 
thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 
factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of 
patients who received Eribulin. 


2012-0167 
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Peripheral Neuropathy: In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy 
and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to 
peripheral neuropathy was required by 3% (14/503) of patients who received Eribulin. Four 
percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% 
(8/503) of patients developed Grade 3 peripheral motor neuropathy. 
Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 
18% of Eribulin-treated patients experienced Grade 2 or greater ALT elevation. One Eribulin-
treated patient without documented liver metastases had concomitant Grade 2 elevations in 
bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to Eribulin. 
Less Common Adverse Reactions: The following additional adverse reactions were reported in  
≥ 5% to <10% of the Eribulin-treated group: 
 
• Eye Disorders: increased lacrimation 
• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth 
• General Disorders and Administration Site Conditions: peripheral edema 
• Infections and Infestations: upper respiratory tract infection 
• Metabolism and Nutrition Disorders: hypokalemia 
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness 
• Nervous System Disorders: dysgeusia, dizziness 
• Psychiatric Disorders: insomnia, depression 
• Skin and Subcutaneous Tissue Disorders: rash 
 
To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or 
contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 
 
3.13 Drug Interactions 
3.13.1 Effects of Other Drugs on Eribulin 
No drug-drug interactions are expected with CYP3A4 inhibitors and P-gp inhibitors. The effect 
of ketoconazole, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and a P-gp inhibitor, on 
the pharmacokinetics (PK) of eribulin was studied in an open-label, two-treatment, two-
sequence, two-way crossover trial in 12 patients with advanced solid tumors. The mean dose-
normalized AUC values were similar when eribulin was administered with or without 
ketoconazole (ratio of the mean AUC: 0.97; 90% CI: 0.83, 1.12). 
3.13.2 Effect of Eribulin on Other Drugs 
Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 
enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical 
concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are 
substrates of these enzymes. 


2012-0167 
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3.13.3 Use in Specific Populations 
3.13.3.1 Pregnancy Category D 
There are no adequate and well-controlled studies with Eribulin in pregnant women. Eribulin is a 
microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a 
pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin 
mesylate at approximately half of the recommended human dose based on body surface area. 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.  
In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin 
mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 
0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). 
Increased abortion and severe external or soft tissue malformations were observed in offspring at 
doses 0.64 times the recommended human dose based on body surface area (mg/m2), including 
the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, 
reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were 
also reported at or above doses of 0.43 times the recommended human dose.  
Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the 
recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain 
and decreased food consumption. 
3.13.3.2 Nursing Mothers 
It is not known whether Eribulin is excreted into human milk. No studies in humans or animals 
were conducted to determine if Eribulin is excreted into milk. Because many drugs are excreted 
into human milk and because of the potential for serious adverse reactions in human milk fed 
infants from Eribulin, a decision should be made whether to discontinue nursing or to 
discontinue Eribulin taking into account the importance of the drug to the mother. 
3.13.3.3 Pediatric Use 
The safety and effectiveness of Eribulin in pediatric patients below the age of 18 years have not 
been established. 
3.13.3.4 Geriatric Use 
Study 1 did not include sufficient numbers of subjects aged 65 years and older to determine 
whether they respond differently from younger subjects. Of the 827 subjects who received the 
recommended dose and schedule of Eribulin in clinical studies, 15% (121/827) were 65 and 
older, and 2% (17/827) patients were 75 and older. No overall differences in safety were 
observed between these subjects and younger subjects. 
3.13.4 Hepatic Impairment 
A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate 
(Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function 
(n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate 
hepatic impairment, respectively. Administration of Eribulin at a dose of 1.1 mg/m2 to patients 
with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment 


2012-0167 
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resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic 
function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic 
impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate 
hepatic impairment (Child-Pugh B). Eribulin was not studied in patients with s severe hepatic 
impairment (Child-Pugh C). 
3.13.5 Renal Impairment 
No formal PK trials were conducted with Eribulin in patients with renal impairment. Available 
data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 
50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), 
the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients 
with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients 
with moderate renal impairment. The safety of Eribulin was not studied in patients with severe 
renal impairment (CrCl < 30 mL/min). 
3.13.6 Overdosage 
Overdosage of Eribulin has been reported at approximately 4 times the recommended dose, 
which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction 
lasting one day.  There is no known antidote for Eribulin overdose. 


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4. TREATMENT PLAN 
4.1 Study Design 
This is a randomized, multi-center, open-label, Phase II study of sequential eribulin followed by 
FAC/FEC-regimen or Paclitaxel followed by FAC/FEC-regimen as neoadjuvant therapy in 
women with operable invasive breast cancer patients whose HER2 is not over-expressed.  
 
Approximately 162 women will be randomly assigned on a 1:1 basis to either arm.  81 
randomized patients per arm.  
4.2 Eligibility 
 
4.2.1 Inclusion Criteria:  
To be included in the study, the subject must have: 
  
 1) Signed written informed consent 
2) Histologically confirmed primary invasive adenocarcinoma of the breast.  
3) Clinical stage breast cancer T2-3, N0-3, M0 
4) Negative HER-2/neu expression as determined by local hospital laboratory using 
Fluorescence In Situ Hybridization (FISH), or is less or equal to 1+ using 
Immunohistochemistry (IHC). 
5) No prior treatment for primary invasive adenocarcinoma of the breast such as 
irradiation, chemotherapy, hormonal therapy, immunotherapy, investigational therapy 
or surgery. Subjects receiving hormone replacement treatment (HRT) are eligible if 
this therapy is discontinued at least 2 weeks before starting study treatment. 
Treatment for DCIS is allowed, such as surgery, hormonal therapy and radiotherapy.  
6) Karnofsky performance status (KPS) of 80 – 100.  
7) The ability and willingness to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
8) Baseline MUGA or echocardiogram scans with LVEF of > 50%.  
9) Normal PTT and either INR or PT < 1.5 x ULN. 
10) Men or women 18 years of age or older. 
11) Women of childbearing potential (WOCBP) must agree to use a medically acceptable 
method of contraception to avoid pregnancy throughout the study and for up to 8 
weeks after the last dose of study drugs. 
12) Willingness to have core biopsies and/or FNA performed before the start of study 
treatment and at the end of 12 week on treatment. 


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4.2.2 Exclusion Criteria: 
 
1) Women who are pregnant (including positive pregnancy test at enrollment or prior to 
study drug administration) or breast-feeding.  
2) Disease free of prior malignancy for < 5 years with the exception of DCIS, curatively 
treated basal carcinoma of the skin, local skin squamous cell carcinoma or carcinoma 
in situ of the cervix.  
3) Absolute neutrophil count (ANC) < 1500/mm3  
4) Total bilirubin > 1.5 times the upper limit of normal (ULN)  
5) AST or ALT > 2.5 times the upper limit of normal (ULN)  
6) Platelets < 100,000/mm3.  
7) Serum creatinine > 1.5 x ULN or creatinine clearance < 60 mL/min (measured or 
calculated by Cockcroft-Galt method)  
8) Evidence of metastatic breast cancer following a standard tumor staging work-up.  
9) Evidence of inflammatory breast cancer.  
10) Evidence of any grade 2 sensory or motor neuropathy.  
11) Known human immunodeficiency viral (HIV) infection  
12) Serious intercurrent infections or non-malignant medical illness that are uncontrolled 
or the control of which may be jeopardized by this therapy.  
13) Psychiatric disorders or other conditions rendering the subject incapable of complying 
with the requirements of the protocols.  
 
 


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4.3 Drug Administration Plan 
 
Randomization will be stratified by tumor size at baseline, estrogen and progesterone expression 
status and Investigator Site.  
 
ARM 1: Patients will receive Paclitaxel 80 mg/m2 IVPB over 1 hour weekly for 12 doses 
followed by FAC/FEC. 
 
ARM 2: Patients will receive eribulin 1.4 mg/m2 IV infusion or per institutional guidelines over 
2-5 minutes on days 1 and 8 every 3 weeks for 4 cycles (21 day cycle) followed by FAC/FEC. 
 
Patients on both arms will receive either FEC or FAC x 4 cycles (21 day cycle) at the 
preference of the treating physicians. 
 
FEC Chemotherapy: 
• 5-Flurouracil 500mg/m2 IV on day 1 
• Epirubicin 100mg/m2 IV on day 1 
• Cyclophosphamide 500mg/m2 IV on day 1 
 
FAC Chemotherapy: (may be given instead of FEC) 
• 5-Flurouracil 500mg/m2 IV on day 1  
• Doxorubicin 50mg/m2 IV on day 1 over 30 minutes continuous infusion or IV 
bolus (as per institutional standard) 
• Cyclophosphamide 500mg/m2 IV on day 1 
 
Treatment Modification 
Patients who progress in the breast while on eribulin or paclitaxel prior to or at completion of 
the first 12 weeks of treatment will discontinue eribulin or paclitaxel and will automatically be 
considered non-responders to eribulin or paclitaxel and then will start the FAC/FEC-regimen.  
 
Patients who progress outside of the breast/present with metastatic disease will be taken off 
study. We will attempt to confirm progression histologically (biopsy). 
 
Patients who discontinue eribulin or paclitaxel prior to 12 weeks due to toxicity will be 
evaluated for response to FAC/FEC-regimen unless the PI believes that proceeding directly to 
surgery would be in the best interest of the patient (e.g., subjects with large tumors that progress 
rapidly on eribulin or paclitaxel.) If progressive disease occurs while on FAC/FEC- treatment, 
chemotherapy will be discontinued and the subjects should remain on the study until after they 
have undergone definitive surgery. 
 
4.3.4 Surgery 
 
All patients will undergo definitive breast surgery 4 -6 weeks from last dose of FAC/FEC-
regimen. It is up to the surgeon’s discretion if tumors must be removed by either lumpectomy 
with axillary dissection (i.e. breast conservation surgery) or modified radical mastectomy (i.e. 
mastectomy with axillary clearance) after discussion with the patient.  The surgical specimens 


2012-0167 
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Page 29 
 
(breast and axillary lymph node tissue) will be evaluated for pathological complete response 
(defined per protocol) by central Pathologists  at M.D. Anderson Cancer Center. 
 
 
 
4.4 Duration of Study 
The study is expected to be completed within 36 months from study initiation. The duration of 
chemotherapy treatment per subject will be approximately 6 months, corresponding to 4 cycles 
of eribulin followed by 4 cycles of FAC/FEC-regimen or 12 cycles of weekly paclitaxel followed 
by 4 cycles of FAC/FEC-regimen.  
 
This study will be conducted at the University of Texas MD Anderson Cancer Center main campus 
and the Regional Care Centers (RCC). 
 
Study Schema 
 
 


2012-0167 
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Page 30 
 
  
 
 
4.5 Dose modification 
 
4.5.1 Eribulin modification: please refer to section 3.11.3 (Table 3) 
 
4.5.2 Weekly Paclitaxel 
Patient on weekly paclitaxel will continue paclitaxel without dose modification if ANC > 
1000/mm3  and Plt ≥100,000/mm3 on day of the next dose. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Paclitaxel Dose Modification 
 
Event 
Paclitaxel Dose Modification 
Neutropenia 
≥ 1000/mm3  
 
No change to paclitaxel. 
 
• 
For ANC ≤ 1500/mm3 consider the use of prophylactic 
myeloid growth factors (filgrastim), Neuopogen® 
• 
Start on day 2 and use for 1-2 days according to 
patient need, at physician discretion, and to avoid dose 
reduction.  
• 
Growth factor should not be given on the same day as 
chemotherapy.  
Note: Pegfilgrastim Neulasta® may not be used with paclitaxel due to 
the weekly dosing in this study.  
 


2012-0167 
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<1000/mm3 
Hold paclitaxel until ANC > 1000/mm3. Resume paclitaxel based on 
timing of recovery:  
• 
≤ 1 week—no change to paclitaxel  
• 
Recheck CBC at Physician discretion 
• 
1 but < 3 weeks—reduce paclitaxel dose by 25% for all 
subsequent cycles  
• 
> 3 weeks—stop paclitaxel. Patient should proceed with 
additional chemotherapy or surgery at the discretion of 
the treating physician. Patient remains on study for 
outcome assessment  
 
 
Neutropenic Fever  
 
ANC ≤ 1000/mm3,  
fever ≥ 38.5°C  
 
• 
Hold paclitaxel until resolved (ANC > 1000/mm3, fever < 
38.5°C). Resume paclitaxel according to number of 
episodes:  
• 
First episode: no change in paclitaxel  
• 
Second episode: 25% dose reduction of paclitaxel for all 
subsequent cycles  
• 
Third episode: stop paclitaxel. Patient should proceed 
with additional chemotherapy or surgery at the discretion 
of the treating physician. Patient remains on study for 
outcome assessment.  
 
 
Event 
Paclitaxel Dose Modification 


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Page 32 
 
 
 
If paclitaxel is held for 3 weeks in a row, stop paclitaxel. Patients should 
proceed with additional chemotherapy or surgery at the discretion of the 
treating physician. Patient remains on study for outcome assessment.  
 
 
Note: GCSF may be used between days 2–6 according to patient need, 
at physician discretion, and to avoid dose reduction. Pegfilgrastim 
Neulasta®   may not be used with paclitaxel due to the weekly dosing in 
this study.  
Thrombocytopenia  
 
>100,000/mm3 
No change to paclitaxel. 
75–99,999/mm3  
 
Hold paclitaxel until ≥ 100,000/mm3, resume paclitaxel based on timing 
of recovery:  
• 
≤ 1 week—no change to paclitaxel.  
• 
1 but < 3 weeks—reduce paclitaxel dose by 25% for all 
subsequent cycles.  
• 
> 3 weeks—stop paclitaxel. Patient should proceed with 
additional chemotherapy or surgery at the discretion of the 
treating physician. Patient remains on study for outcome 
assessment.  
 
< 75,000/mm3  
 
 
Hold paclitaxel until ≥ 100,000/mm3. Resume paclitaxel with a 25% 
dose reduction for all subsequent cycles.  
 
If paclitaxel is held for 3 weeks in a row, stop paclitaxel. Patient should 
proceed with additional chemotherapy or surgery at the discretion of the 
treating physician. Patient remains on study for outcome assessment.  
Anemia 
All Grades 
No change in paclitaxel. 
 
For all anemia events related to paclitaxel regardless of grade, iron 
studies should be checked and iron should be replaced as indicated. 
 
• 
Red blood cell transfusions can be given at the investigators’ 
discretion as needed for symptom control. 
 
 
 
Hepatic 
Grade 0 or 1 
No change in paclitaxel 


2012-0167 
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Page 33 
 
 
Grade 2  
 
Grade 2 bilirubin:  
 
Hold paclitaxel until bilirubin resolves to ≤ grade 1. Resume 
paclitaxel based on time of recovery.  
• 
If bilirubin resolves to ≤ grade 1 in < 2 weeks, resume 
paclitaxel at previous dose.  
• 
If bilirubin remains at grade 2 after holding two consecutive 
doses of paclitaxel (2 weeks), resume paclitaxel with a 25% 
reduction in dose for all subsequent doses.  
• 
If paclitaxel is held for 3 weeks in a row, stop paclitaxel. 
Patient should proceed with additional chemotherapy or 
surgery at the discretion of the treating physician. Patient 
remains on study for outcome assessment. 
 
A rise in indirect bilirubin with a normal direct bilirubin believed to be 
attributable to Gilbert’s disease does not require change in dose or a 
drug hold. A note to file should be created.  
 
Grade 2 AST or ALT:  
Hold paclitaxel until AST/ALT resolve to ≤ grade 1.  
• 
If AST/ALT resolve to ≤ grade 1 in < 3 weeks, resume 
paclitaxel at previous dose.  
• 
If paclitaxel is held for 3 weeks in a row, stop paclitaxel. 
Patient should proceed with additional chemotherapy or 
surgery at the discretion of the treating physician. Patient 
remains on study for outcome assessment  
Grade 3  
 
Grade 3 bilirubin (not due to Gilbert’s disease):  
 
Stop paclitaxel. Patient should proceed with additional chemotherapy 
or surgery at the discretion of the treating physician. Patient remains 
on study for outcome assessment.  
 
Grade 3 AST or ALT:  
 
Hold paclitaxel until AST/ALT resolve to ≤ grade 3. Resume 
paclitaxel at the previous dose.  
• 
If AST/ALT remains at grade 3 after holding two 
consecutive doses of paclitaxel, resume paclitaxel with a 
25% dose reduction for all subsequent doses.  
• 
If paclitaxel is held for 3 weeks in a row, stop paclitaxel. 
Patient should proceed with additional chemotherapy or 
surgery at the discretion of the treating physician. Patient 
remains on study for outcome assessment.  
 
 


2012-0167 
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Page 34 
 
 
 
Grade 4 
 
  
Grade 4 bilirubin, AST or ALT:  
 
Stop paclitaxel. Patient should proceed with additional chemotherapy 
or surgery at the discretion of the treating physician. Patient remains 
on study for outcome assessment.  
Nausea/Vomiting  
 
Grade 0–2  
 
No change to paclitaxel. 
≥ Grade 3  
 
Hold paclitaxel until resolved to < grade 1.  
• 
Resume paclitaxel at previous dose with modification of pre-
medications.  
• 
For second episode > grade 3 despite maximal supportive care:  
➢ Resume paclitaxel with a 25% dose reduction for all 
subsequent doses  
 
 
 
 
Mucositis 
Grade 0-2 
No change in paclitaxel. 
> Grade 3 
Hold paclitaxel until resolved to < grade 1.  
• 
Resume paclitaxel at the previous dose, with modification of 
premedications.  
• 
For second episode > grade 3 despite maximal supportive care:  
 
➢ Resume paclitaxel with a 25% dose reduction for all 
subsequent cycles.  
 
Neurotoxicity 
Grade 0–1 
 
No change to paclitaxel. 
Grade 2-3  
 
 
Hold paclitaxel until neuropathy improves to ≤ grade 1.  
 
• 
Resume paclitaxel with a 25% dose reduction for all 
subsequent cycles.  
 
If paclitaxel is held for 3 weeks in a row for neuropathy, stop 
paclitaxel. Patient should proceed with additional chemotherapy or 
surgery at the discretion of the treating physician. Patient remains on 
study for outcome assessment.  
Grade 4 
Stop paclitaxel. Patient should proceed with additional chemotherapy or 
surgery at the discretion of the treating physician. Patient remains on 
study for outcome assessment  
 
 
 
 
 
 
 
 
Anaphylaxis/Hypersensitivity 


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Page 35 
 
Mild (e.g., mild flushing, rash, 
pruritis)  
 
Complete paclitaxel infusion.  
• 
No treatment required, but observe patient at least until 
symptoms have resolved.  
 
Moderate (e.g., moderate 
flushing, rash, mild dyspnea, 
chest discomfort)  
 
Stop paclitaxel infusion.  
• 
Give intravenous diphenhydramine 20–25 mg and intravenous 
dexamethasone 10 mg.  
 
If symptoms resolve:  
• 
Resume paclitaxel infusion after recovery of symptoms at half 
the previous rate for 15 minutes. If no recurrence of symptoms, 
the planned rate may be resumed.  
 
If symptoms recur after paclitaxel re-challenge:  
• 
Stop paclitaxel infusion and stop all subsequent paclitaxel 
therapy. Patient should proceed with additional chemotherapy 
or surgery at the discretion of the treating physician. Patient 
remains on study for outcome assessment.  
Severe (e.g., hypotension 
requiring pressors, 
angioedema, respiratory 
distress requiring 
bronchodilators)  
 
Stop paclitaxel infusion.  
• 
Administer diphenhydramine 25 mg and dexamethasone 10 mg 
IV. Add epinephrine or bronchodilators as needed per 
institutional guidelines.  
• 
Stop all subsequent paclitaxel therapy. Patient should proceed 
with additional chemotherapy or surgery at the discretion of the 
treating physician. Patient remains on study for outcome 
assessment.  
 
Other Clinically Significant Toxicity Excluding Fatigue, Alopecia, and Leukopenia at Physician 
Discretion  
 
Grade 0 or 1  
 
No change to paclitaxel.  
 
Grade 2  
 
Hold paclitaxel until resolved to ≤ grade 1. Resume paclitaxel at 
previous dose.  
• 
Increase supportive care measures if possible.  
 
≥ Grade 3  
 
Hold paclitaxel and contact the DCC for further instruction (1-877-303-
0226).  
If ≥ grade 3toxicity recurs,  
• 
Stop paclitaxel and contact the DCC for further instruction (1-
877-303-0226).  
 
 
 
 
 
 
 
 
 
 
 


2012-0167 
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Page 36 
 
 
 
 
 
Dose modification for FEC/FAC is based on standard practice per treating physician.  
4.5.4 Dose adjustments in hepatic impairment  
Alkaline Phosphatase 
 
AST +/or ALT 
 
Dose 
 
<2.5 x ULN 
 
and 
 
<1.5 x ULN 
 
 
100% 
2.5 – 5 x ULN  
and 
 
1.6 – 5 x ULN  
 
 75% 
>5 x ULN 
 
and 
 
>5 ULN 
 
Hold Treatment 
 
4.5.5 Dosage in grade 3/4 cutaneous reactions 
Reduce by 20%; further reduce by 20% if reactions continue. 
4.5.6  Dose adjustments in myelosuppression 
No dose adjustment necessary. Up to 7 days therapy delay allowed if ANC < 1,000. The use of 
G-CSF support is permitted after the first cycle of therapy. If a delay of therapy > 7days  occurs, 
G-CSF will be used with the next cycle with peg-filgrastin 6 mg SC 24 hours after FEC (or 
FAC). 
4.5.7 Dose adjustments in renal impairment 
         No dose adjustment necessary. 
 
4.6 Evaluation during Study  
See Study Calendar for evaluations during Study. 
 
4.7 Concurrent and supportive care  
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient are allowed, including drugs given prophylactically (eg, Antiemetics +/- steroids, colony 
stimulating factors), with the following exceptions:  
• No other investigational therapy should be given to patients. 
• No anticancer agents other than the study medications administered as part of this study 
protocol should be given to patients. 
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies 
including herbal supplements, specifically, St. John’s Wort must be documented in the medical 
record  
4.7.1 Eribulin: No premedication needed.   
Medications to avoid with eribulin therapy that may cause QTc prolongation: Appendix D. 
 
4.7.2 Paclitaxel Premedication:  
Dexamethasone 10 mg in NS 50 mL IV, 30 minutes prior to weekly paclitaxel infusion. Taper 
dexamethasone to 4 mg IV after the 3rd dose if no infusion related reaction was noted 
previously.  


2012-0167 
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Page 37 
 
Compazine 10 mg PO every 6 hours PRN per nausea is recommended. 
 
4.7.3. FAC or FEC-regimen Premedication:  
 
On Day 1 of each Cycle 30 minutes prior to chemotherapy: 
a) Ondansetron 8 mg IV,  
b) Lorazepam 1 mg IV,  
c) Dexamethasone 20 mg IV.  
 
After chemotherapy infusion: 
a) Ondansetron 8 mg PO every 8 hours during first 48 hours,  
b) Compazine 10 mg PO every 6 hours PRN per nausea. 
4.8 Criteria for removal from the study 
 
Treatment will continue until one of the following criteria is met:  
• 
Patient withdrew consent 
• 
Completion of all prescribed protocol therapy.  
• 
In the judgment of the investigator the continuation of study treatment is not in the best 
interests of the patients. 
 
4.9 Criteria for Response  
The primary endpoint of this study is to assess pathologic complete response (pCR) will be 
determined based on the routine clinical pathology report. Response categories will be assigned 
as follows:  
Pathologic complete response (pCR) is defined in this study as complete absence of any viable 
invasive cancer cells in the resected breast and lymph nodes.  
 
 


2012-0167 
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4.9.1 Definition of Residual Cancer Burden  
We will measure the residual cancer burden (RCB) as a continuous variable derived from the 
primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. RCB can also 
divided in four classes (RCB-0 to RCB-III) 
RCB-0 (pCR), Minimal RCB (RCB-I), Moderate RCB (RCB-II), and Extensive RCB (RCB-III) 
The following parameters are required from pathologic examination in order to calculate 
Residual Cancer Burden (RCB) after neoadjuvant treatment:  
 
1. 
The largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor bed 
if multicentric disease)   
2. 
Submission of the entire largest cross-sectional area of the residual tumor bed for histologic 
mapping, with specific identification of those slides in the pathology report (e.g. "the largest 
cross-sectional area of primary tumor bed was submitted in cassettes A5 - A9")  
• If the residual tumor is large (i.e. largest diameter > 5 cm), then at least 5 representative 
cassettes from the largest cross-sectional area are sufficient, but should be identified in 
the original pathology report (e.g. "representative sections from the largest cross-
sectional area of primary tumor bed were submitted in cassettes A5 - A9")  
3. 
Histologic assessment of the percentage of the tumor bed area that contains carcinoma (all 
carcinoma, i.e. invasive and in situ), select one of the following:   
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%  
• To assess cellularity it is helpful to scan across the sections of tumor bed and then 
estimate the average cellularity from the different microscopic fields.   
• When estimating percentage cancer cellularity in any microscopic field, compare the 
involved area with obvious standards, e.g. more or less than half, one quarter, one fifth, 
one tenth, one twentieth, etc.   
• Expect there to be variable cellularity within the cross section of any tumor bed, but 
estimate the overall cellularity from the average of the estimates in different microscopic 
fields of the tumor bed.   
• e.g. if cellularity in different fields of the tumor bed were estimated as 20%, 10%, 20%, 
0%, 20%, 30%, then an average estimate of overall cellularity would be 20%.  
4. 
Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, select 
one of the following:   
 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%  
5. 
The number of positive (metastatic) lymph nodes  
6. 
The largest diameter (mm) of the largest nodal metastasis  
The RCB can be access online: www.mdanderson.org/breastcancer_RCB   
 
 


2012-0167 
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5. CORRELATIVE STUDIES  
Research Hypothesis: Sequential administration of eribulin followed by FAC/FEC-regimen, has 
greater activity based on pCR rate to the historical sequential administration of paclitaxel 
followed by FAC/FEC-regimen as neoadjuvant therapy for women with early breast cancer with 
tumors that do not overexpress HER-2.  
5.1 Hot Spot Mutation Analysis Methodology: DNA will be extracted using the QiaAMP 
microkit (Qiagen Inc. Valencia, CA) according to manufacturer’s instructions.  A mass 
spectroscopy-based approach evaluating single nucleotide polymorphisms (SNPs) will be used to 
detect known mutations in PIK3CA, AKT1, AKT2, AKT3, PHLPP2, mTOR, Rictor, PDPK1, 
MC1R, BRAF, HRAS, KRAS, MEK1, MEK2, NRAS, RAF1, PRKAG1, GNAC, EGFR, FGFR1, 
FGFR2, FGFR3, KIT, VGFR, ER, MET, ALK, GNAS, CDK4, CDKN2A, CTNNB1, FBXW7, 
JAK2, RET, FLT3. Polymerase chain reaction (PCR) and extension primers for each gene will be 
designed using Sequenom, Inc. (San Diego, CA) Assay Design. PCR-amplified DNA will be 
cleaned using EXO-SAP (Sequenom) primer extended by IPLEX chemistry, desalted using 
Clean Resin (Sequenom) and spotted onto Spectrochip matrix chips using a nanodispenser 
(Samsung).  Chips will be run in duplicate on a Sequenom MassArray MALDI-TOF MassArray 
system. Sequenom Typer Software and visual inspection will be used to interpret mass spectra.  
Reactions where more than 15% of the resultant mass runs in the mutant site in both reactions 
will be scored as positive.  
5.2 Molecular Inversion Probes (MIP) Arrays Methodology: The MIP assay has been described, 
[37] including a study conducted by our group on samples from the SPORE population. DNA is 
extracted from tumor material that has at least 80% tumor cells based on review by a dedicated 
breast cancer pathologist by repeat lysis using a Qiagen cocktail (Qiagen, Valencia, CA). MIP 
probes are oligonucleotides with two complementary end sequences to two adjacent genomic 
sequences, such that the ends anneal to the DNA in an inverted fashion with a single ‘detector’ 
base between. The ‘detector’ can be either the site of a germline SNP or a somatic mutation that 
occurs as a single nucleotide change. The MIP probe is hybridized to genomic DNA and split 
into two tubes that contain paired fluorescent nucleotide mixes (triphosphates of A+T or C+G). 
In the presence of polymerase and ligase, the MIP probe circularizes with the complementary 
nucleotide. An important advantage of the MIP technology is that allelic discrimination is 
enzymatically derived, fluorescent, and highly specific, allowing for multiplexed assays 
(presently 330,000 probes) with very precise quantization of signals. There is no “bleed through” 
of a second allele, as often happens with the differential hybridization in standard SNP arrays. 
Critical for small samples such as biopsies and FFPE (where it is challenging if not impossible to 
perform robust whole genome amplification), MIP arrays provide accurate results with only 37 
ng of input DNA, which is an order of magnitude lower than that required for SNP arrays.  
5.3 CTCs blood collection: Cytokines and Micro RNA.A 10-mL red-top Vaccutainer tube will 
be collected to measure serum levels of soluble markers using Millipore 37-Plex Luminex 
multiplex assay. Additionally, we will isolate total mRNA for the detection of micro RNAs by 
RT-PCR. The miRNA to be assessed are miR-221, miR-222, miR-17-5p, miR-17-3p, miR-18a, 
miR-19a, miR-20a, miR-19b, miR-92-1, let-7f and miR-27b, U6 (control). 
CTC measurement:  5 ml of peripheral blood will be collected in AdnaCollect tubes and 
transported to the lab on ice for processing.  We will measure CTC using the PCR based 
AdnaTest Breast Detect assay. 
EMT CTC: 7 ml of peripheral blood in EDTA (purple top Vaccutainer) will be collected for the 
isolation of peripheral blood mononuclear cells and subsequently depletion of 


2012-0167 
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Page 40 
 
CD326+/EpCAM+ cells and peripheral blood CD45+ leukocytes, isolation of RNA and 
detection of EMT-inducing transcription factor transcripts by RT-PCR.    
Patients agreeing to participate in optional procedures will have the correlative samples 
obtained when logistically feasible. Optional procedures not obtained will not be 
considered protocol deviations. 
 
 
 
6. STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
 
 
6.1 Assessment of Accountability  
The investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area, under recommended storage conditions and 
in accordance with applicable regulatory requirements.  All study drug supplies must be kept in a 
locked limited access room.  The study drug must not be used outside the context of the protocol.  
Under no circumstances should the investigator or other site personnel supply study drug to other 
investigators, patients, or clinics, or allow supplies to be used other than directed by this 
protocol.  
7. Adverse Event Reporting and data collection 
7.1 Adverse Event Reporting 
An adverse event (AE) is any condition that appears or worsens after the subject is enrolled in an 
investigational study.  AE’s will be graded by numerical score according to the NCI Common 
Terminology Criteria Adverse Events (CTCAE) version 4.0 (http://ctep.cancer. 
gov/forms/CTCAEv4. pdf). Adverse Events not included in the defined NCI CTCAE should be 
scored according to their impact on the subject’s ability to perform daily activities as follows:  
• Mild: no limitations to normal activities  
• Moderate: causes some limitations to normal activities  
• Severe: causes inability to carry out usual activities of daily living Reporting 
Requirements for Baseline Adverse Events  
Although a pertinent positive finding identified on baseline assessment is not an AE, when 
possible it is to be documented as ‘Course Zero’ using CTC/CTCAE terminology and grade. An 
expedited AE report is not required if a patient is entered on a protocol with a pre-existing 
condition (e.g., elevated laboratory value, diarrhea). The baseline AE must be re-assessed 
throughout the trial and reported if it fulfills expedited AE reporting guidelines.  
• If the pre-existing condition worsens in severity, the investigator must reassess the event 
to determine if an expedited report is required.  
• If the AE resolves and then recurs, the investigator must re-assess the event to determine 
if an expedited report is required. No modification in grading is to be made to account for 
abnormalities existing at baseline.  
7.2 Expedited Adverse Event Reporting Guidelines 
Any AE falling under the definition of serious requires submission of a written report to the 
Institutional Review Board (IRB) via the Office of Protocol Research (OPR). SAEs will be 
required to be reported from the time that consent is signed, during the course of treatment and 


2012-0167 
October 22, 2014 
Page 41 
 
within 30 days after the last day of active treatment. Beyond 30 days of treatment, completion of 
only those SAEs that, in the judgment of the investigator, are definitely, possibly or probably 
related to the study treatment will required to be reported.  All SAEs should be reported:  
Within 24 hours from the time the PI becomes aware of the event: All events resulting in a 
participant’s death.  
Within 5 working days from the time the PI becomes aware of the event: All serious AEs other 
than that stated in point #1. 
7.3 Serious Adverse Event (SAE) Reporting to Eisai  
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-
threatening), Principal Investigator will report to the Eisai by facsimile any Serious Adverse 
Event (“SAE,” as defined below) that occurs during the SAE reporting period (as defined below) 
in a Study subject assigned to receive the Eisai Product.  Principal Investigator will report such 
SAEs using an FDA MEDWATCH form and the Serious Adverse Event Fax Cover Sheet 
provided by Eisai.  SAEs should be reported as soon as they are determined to meet the 
definition, even if complete information is not yet available.   
7.4 SAE Definition 
A serious adverse event is defined by ICH Guideline E2A and Federal Regulation 62, Oct. 7, 
1997 as those events, occurring at any dose, which meets any of the following criteria:  
• Results in death, 
• Is immediately life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, 
• Is a congenital abnormality/birth defect 
• Any other medical event that, in the medical judgment of the Principal Investigator, 
may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above is also considered an SAE. A planned medical or 
surgical procedure is not, in itself, an SAE.  
• In addition, events that may not meet these criteria, but which the investigator finds 
very unusual and/or potentially serious, will also be reported in the same manner. All 
SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient’s participation in the study, must be followed until 
either:  
• The event resolves, or 
• The event stabilizes, or 
• The event returned to baseline if a baseline value is available, or 
• The event can be attributed to other than the study drug or other than study conduct. 
7.5 Adverse Event Data Collection 
The following information will be collected for all adverse events:  
• Start and stop dates  
• Severity (grade)  
• Relationship to study drug (attribution)  
Whether or not the subject discontinued treatment due to the AE  
Note all AEs on the Adverse Event Case Report Form (CRF) whether or not related to study 
drug.  


2012-0167 
October 22, 2014 
Page 42 
 
AE grading and assignment of attribution require documentation by medical personnel who are 
directly involved in the clinical care of protocol subjects.  
7.6 AE/SAE Follow up  
All AEs/SAEs, including laboratory abnormalities, that in the opinion of the investigator are 
clinically significant, will be followed up according to good medical practices.  
 
NOTE: If a subject begins a new anticancer therapy, the adverse event reporting period for non-
serious adverse events ends at the time the new treatment is started.  Death must be reported if it 
occurs during the serious adverse event reporting period after the last dose of investigational 
product, irrespective of any intervening treatment.  
 
 


2012-0167 
October 22, 2014 
Page 43 
 
8. STATISTICAL ANALYSIS 
Demographic and baseline characteristics will be summarized by treatment arm for all 
randomized patients using descriptive statistics.   
All patients who receive at least one dose of eribulin or paclitaxel will be included in the analysis 
for safety. The safety analysis will report the frequency of all adverse events and the laboratory 
abnormalities, as well as the frequency of dose interruptions, dose reductions and treatment 
discontinuation for toxicity in each treatment arm. Toxicity rates will be presented using the 
worst NCI-CTCA grade per patient.  
 
The efficacy endpoint of this randomized phase II neoadjuvant study in women with early stage 
breast cancer not overexpressing HER-2 is pathologic complete response (pCR).  Patients will be 
randomized in a 1:1 ratio electronically into two groups by the University Of Texas MD 
Anderson Cancer Center’s Clinical Oncology Research System (CORe).   
Group 2 will receive sequential Eribulin followed by FAC/FEC-regimen chemotherapy and 
Group 1 will receive sequential paclitaxel followed by FAC/FEC-regimen chemotherapy 
(MDACC standard of care).   
The primary objective is to compare the pCR rate of eribulin followed by FAC/FEC-regimen to 
the pCR rate of paclitaxel followed by FAC/FEC-regimen in HER-2 negative women with 
operable breast cancer.  A binomial superiority two-sample test for population proportions will 
be used to compare the pCR rates of the two groups.   
An interim futility analysis is planned for this two-stage trial after the endpoint has been 
evaluated for the first 46 surgically evaluable patients.  If the test statistic at the end of the first 
stage is less than -0.876, the trial will stop for futility; else, the trial will continue until 152 
surgically evaluable patients are accrued.  A test statistic greater than 1.272 at the end of the 
second stage implies that the pCR rate for Group 2 is significantly better.   
 
These calculations assume:  
1. 
A one-sided z-test based on a pooled estimate of the variance,  
2. 
An alpha error of 0.10,  
3. 
80% power,  
4. 
A treatment arm assignment fraction of 50%, and  
5. 
An alpha spending function based on the O’Brien-Fleming boundary.   
 
The pCR rate of Group 1 is assumed to be 18% and the trial is powered to detect an 
improvement of the 15 percentage points for the pCR rate (i.e., a pCR rate of 33% for Group 2).  
We expect accrual to be approximately 6 patients per month.  As a secondary objective, the rate 
of breast conservation surgery will be estimated for each group and a 95% confidence interval 
for the rate of breast conservation surgery for each group will be reported.   
 We expect accrual to be approximately 6 patients per month.    
As a secondary objective, the rate of breast conservation surgery will be estimated for each group 
and a 95% confidence interval for the rate of breast conservation surgery for each group will be 
reported. 
Death occurring prior to surgery is considered a treatment failure. 
 
 


2012-0167 
October 22, 2014 
Page 44 
 
 
 
 
 
9. PUBLICATION OF TRIAL RESULTS  
Publications resulting from this trial may be developed by the investigator who will provide Eisai 
an opportunity (within 60 days before submission or other public disclosure) to prospectively 
review any proposed publication, abstract or other type of disclosure that reports the results of 
the study.  
 


2012-0167 
October 22, 2014 
Page 45 
 
9.0 STUDY CALENDAR  
STUDY WEEK 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
26 
28 
STUDY DAY 
-14 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
 
 
Eribulin(+/- 2) 5 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Paclitaxel(+/- 2) 5 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
FAC/FEC 
Regimen(+/-3) 5 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
General Physical 
X 
X* 
  
  
x 
  
  
X 
  
  
x 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Vitals Signs, 
Weight 
X 
X* 
  
  
x 
  
  
X 
  
  
x 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Performance 
Status 
X 
X* 
  
  
x 
  
  
X 
  
  
x 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Baseline 
Symptoms / 
Toxicities 
X 
X* 
  
  
X 
  
  
X 
  
  
x 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
CBC 
X 
X* 
X 
X1 
X 
X 
X1 
X 
X 
X1 
X 
X 
X1 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Chemistries2 
X 
X* 
  
  
x 
  
  
x 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
 
Pregnancy Test 
(Serum) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Cardiac Scan 
(MUGA or 
2DEcho) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Breast Ultrasound 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
Core and FNA 
Biopsy and 
Correlative 
studies 
x 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
CTC Optional3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
Surgery/RCB4  
See 
footnote  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
*If performed  > 10 days before start the treatment 
 
1  CBC only for Paclitaxel group 
2 Chemistries: Albumin, BUN, Calcium, Creatinine, Total Bilirubin, Alk. Phosphatase, ALT (SGPT), AST (SGOT), Electrolytes (Sodium, Potassium, Chloride, CO2,) Magnesium, 
Glucose 
3 Will follow patients toxicities 2 weeks after surgery when follow-up scheduled with surgeon and collect third CTC at this time. 
4 Surgery/RCB performed during Weeks 26-28 
5 Add allowable +/- days in the treatment schedule 


2012-0167 
October 22, 2014 
Page 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2012-0167 
October 22, 2014 
Page 47 
 
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