Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response (pCR) Following Neoadjuvant Chemotherapy
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: SCRI Development Innovations, LLC

 
 
 
 
 
 
 
 
BRE 186 
 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic 
Complete Response (pCR) Following Neoadjuvant Chemotherapy 
SCRI PROTOCOL NUMBER: 
BRE 186 
TRIAL DRUGS: 
 
Eribulin 
SPONSOR: 
SCRI Oncology Research Consortium 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
STUDY CHAIR/COORDINATING 
INVESTIGATOR 
Denise A. Yardley, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Ave., Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
MEDICAL MONITOR: 
John D. Hainsworth, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Ave., Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
 
DATE FINAL: 
26 MAY 2011 
 
 
Amendment Number: 
1 
Amendment Date: 
25 JAN 2012 
Amendment Number: 
2 
Amendment Date: 
20 MAR 2013 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 2 of 68 
Clinical Trial Protocol Statement of Compliance 
 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
 
International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
 
Ethical principles that have their origins in the Declaration of Helsinki  
 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the <Study Chair> / <Coordinating Investigator>/ <Principal Investigator>, I 
understand that my signature on the protocol constitutes my agreement and understanding 
of Principal Investigator responsibilities to conduct the clinical trial in accordance to the 
protocol and applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in writing from 
the Sponsor, shall be defined as a deviation from the protocol, and shall be formally 
documented as such. 
 
 
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted sponsor responsibilities to the 
CRO and the <Study Chair> / <Coordinating Investigator>/ <Principal Investigator> as 
defined by the protocol, applicable clinical trial agreements (CTA), and/or business 
contracts, but does not in any capacity relieve me of my responsibilities as the Sponsor.  
Additionally, my signature constitutes my understanding and agreement that any changes 
to the protocol, CTA, or contracts shall be implemented timely with my review and 
approval prior to implementation. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 4 of 68 
Clinical Trial Protocol Acceptance Form 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic 
Complete Response (pCR) Following Neoadjuvant Chemotherapy 
SCRI PROTOCOL NUMBER: 
BRE 186 
TRIAL DRUG: 
 
Eribulin 
DATE FINAL: 
26 MAY 2011 
Amendment Number: 
1 
Amendment Date: 
25 JAN 2012 
Amendment Number: 
2 
Amendment Date: 
20 MAR 2013 
 
 
 
 
 
 
 
 
 
 
_________________________________ 
 
____________________________  
_____________ 
Principal Investigator Name 
 
 
Principal Investigator Signature  
Date 
(Name Printed or Typed) 
 
 
<Insert Site Name and ID info as applicable> 
 
 
 
 
 
 
<Insert Site Location> 
 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 5 of 68 
BRE 186 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy 
 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
1 
 
 
 
25 JAN 2012 
 
 
 
Inclusion Criteria were clarified as follows: 
2.  Histologically confirmed breast cancer prior to surgery with the 
following staging criteria: T1-T3, N1N0-N2, and M0 (T1N0M0 patients 
are excluded). 
4.  At least 3 weeks Patients must be ≥21 days and ≤ 84 days from 
breast surgery and fully recovered.  Patients may have had mastectomy 
or breast conservation surgery with axillary node dissection. 
5.  Pathologic CR (pCR) not achieved following neoadjuvant treatment 
(i.e., residual invasive breast cancer (>5 mm) in the breast or presence of 
nodal disease at surgery [ypT0, N1-N3a, M0 or ypT1b-T4, N1N0-
N3aN2, M0]. 
14.  Female patients who are not of child-bearing potential (see 
Appendix D), and female patients of child-bearing potential who agree 
to use adequate contraceptive measures (see Appendix D), who are not 
breastfeeding, and who have a negative serum pregnancy test performed 
within 48 hours7 days prior to start of trial treatment. 
Exclusion Criterion #2 was clarified as follows: 
2.  Radiotherapy prior to the start of study treatment. 
Section 5 Trial Design and Figure 1: 
Patients may undergo locoregional radiation therapy either during or 
following chemotherapy according to institutional guidelines 
(Section 7.8).  Radiotherapy prior to the start of study treatment is not 
permitted.  Patients in Cohort B (hormone-receptor-positive) and 
Cohort C (HER2-positive) may receive adjuvant therapy according to 
institutional guidelines. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 6 of 68 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
1 
 
 
 
25 JAN 2012 
 
 
 
7.2  Baseline Assessments 
Note:  baseline laboratory assessments will be allowed up to 7 days 
outside of the 7-day specified window, provided that critical laboratory 
assessments (CBC, CMP, pregnancy test, and PT/INR and PTT [for 
patients receiving warfarin only]) are repeated on Cycle 1, Day 1 prior 
to study treatment. 
 
Complete blood count (CBC) including 3-part differential and 
platelets (may be done up to 72 hours prior to treatment) 
 
Coagulation analysis:  prothrombin time (PT)/International 
Normalization Ratio (INR) and partial thromboplastin time 
(PTT) (may be done up to 72 hours prior to treatment) 
 
Serum pregnancy test within 48 hours 7 days of first dose of 
trial drug (Section 7.5.3) 
7.5.4  Pregnancy Test 
All females of childbearing potential must complete a serum pregnancy 
test within 48 hours 7 days prior to the initiation of eribulin therapy. 
Minor typographical errors were corrected. 
ICF modifications were made. 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 7 of 68 
BRE 186 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy 
 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
2 
 
 
 
20 MAR 2013 
 
 
 
Inclusion Criteria were clarified as follows: 
2.  Histologically confirmed breast cancer prior to surgery with the 
following staging criteria: T1-T3, T4a, T4b, N0-N2, N3a and M0 
(T1N0M0 patients are excluded).  Inflammatory disease is excluded. 
5.  Pathologic CR (pCR) not achieved following neoadjuvant treatment 
(i.e., residual invasive breast cancer (>5 mm) in the breast or presence of 
nodal disease at surgery [ypT0/T1a, N1-N3a, M0 or ypT1b-T4, N0-N3a, 
M0]. 
Section 6.2 Dose Modifications for Eribulin: 
For patients who experience toxicities during the trial, one or more doses 
of eribulin may need to be reduced, delayed, or withheld.  Patients can 
either have trastuzumab delayed or continue to receive trastuzumab on 
an every-3-week schedule even if administration of eribulin is delayed 
or withheld on Day 11per the treating physician’s discretion. 
Section 6.2.1 Recommended Dose Delays of Eribulin 
For ANC <1500/µL on Day 1, delay dose of Eribulin until ANC 
>1500/µL, then: 
 
Initiate treatment with prophylactic granulocyte-CSFs, with 
no dose reductions.  
 
If patient is already receiving granulocyte-CSF treatment, 
reduce dose by 1 dose level. 
Section 7.2 Baseline Assessments and Appendix C 
Patients must have the following assessments performed ≤7 days before 
receiving their first dose of study drug.  Note:  baseline laboratory 
assessments (except the serum pregnancy test) will be allowed up to 7 
days outside of the 7-day specified window, provided that critical 
laboratory assessments (CBC, CMP, pregnancy test, and PT/INR and 
PTT [for patients receiving warfarin only]) are repeated on Cycle 1, Day 
1 prior to study treatment. 
Section 7.3.1 Day 1 of each cycle 
The following assessments will be performed at each of these visits: 
 
CBC, including 3-part differential and platelets (may be done 
up to 72 hours prior to treatment) 
 
CMP plus magnesium (may be done up to 72 hours prior to 
treatment)

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 8 of 68 
BRE 186 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy 
 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
2 
 
 
 
20 MAR 2013 
 
 
 
Section 7.5.1 Follow-Up After Completion of Eribulin Treatment 
Patients will be followed every 3 months during years 1 and 2, every 6 
months during years 3 through 5, and annually thereafter for toxicity, 
and disease progression, and survival.  At each visit, patients will have a 
physical examination, complete blood counts, chemistry profile, and 
evaluation of any new symptoms.  After disease progression is 
documented, patients will be followed until they initiate new treatment 
as specified in Section Error! Reference source not found..  
Assessments at these visits will be performed as described in 
Appendix C. 
Section 7.5.2. Follow-Up After Disease Progression 
After disease progression is documented, patients will be followed to 
document any new anti-cancer therapies received after discontinuation 
of study treatment.  Patients may be contacted during outpatient visits or 
by telephone. 
Section 7.8 Radiation Therapy 
Experience with concurrent eribulin and radiation therapy is limited and 
hence safety will be evaluated after the first 10 patients on each cohort 
have been treated with concurrent eribulin and radiotherapy. 
Section 8.1.1 Eribulin, Labeling, Packaging, Storage 
Eribulin mesylate (HALAVEN™) is a clear, colorless, and sterile 
solution for injection that contains 1.0 mg eribulin drug substance in 
2.0 mL of solution.  Eribulin clinical supply is packaged in single-use 
glass vials. 
Clinical supplies of eribulin should be stored at room temperature.  
Storage at temperatures between 2°C and 8°C, however, are acceptable 
and provide an extended provisional shelf life. 
The supply for this study may be provided with one of two labeled 
storage requirements (see 1. and 2. below).  The storage conditions are 
not interchangeable and the supply must be stored as detailed on the 
supply labels.      
1.  Refrigerated:  Store in a refrigerator, between 2°C - 8°C 
(36°F - 46°F).  Do not freeze.  Store the vials in their original 
cartons.    
2.  Controlled room temperature:  Store at controlled room 
temperature of 25°C (77°F); excursions permitted to 15°C - 
30°C (59°F - 86°F).  Do not freeze.  Store the vials in their 
original cartons.

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 9 of 68 
BRE 186 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy 
 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
2 
 
 
 
20 MAR 2013 
 
 
 
Section 8.1.3 Precautions and Risks with Eribulin 
For a complete discussion of risk information including precautions and 
adverse reactions for Eribulin, please refer to the current Eribulin 
Investigator’s Brochure. 
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%). 
8.1.3.1 Neutropenia 
If patients develop severe neutropenia lasting longer than five days or 
neutropenia with a fever, their next dose of erlibulin should be delayed 
and reduced.  Severe neutropenia (ANC <500/mm3) lasting more than 
one week occurred in 12% (62/503) of patients in the recently completed 
Phase 3 trial, leading to discontinuation in <1% of patients.  Patients 
with ALT or AST >3 × ULN 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 five days. 
8.1.3.2 Peripheral Neuropathy 
In the Phase 3 trial with eribulin, Grade 3 peripheral neuropathy 
occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of 
patients.  Peripheral neuropathy was the most common toxicity leading 
to discontinuation of erlibulin (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 to 662 days).  Monitor patients closely for signs of 
peripheral motor and sensory neuropathy.  Withhold erlibulin in patients 
who experience Grade 3 or 4 peripheral neuropathy until resolution to 
Grade 2 or less. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 10 of 68 
BRE 186 
 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy 
 
History of Amendments 
Amendment # 
Amendment Date 
Revision(s) Made 
2 
 
 
 
20 MAR 2013 
 
 
 
8.1.3.3 QTc Interval Prolongation 
In an uncontrolled open-label ECG study in 26 patients, QT 
prolongation was observed on Day 8, independent of eribulin 
concentration, with no QT prolongation observed on Day 1.  
Electrocardiogram 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, 
(Appendix E) 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. 
Appendix C Schedule of Assessments 
Footnote g: 
Complete staging work-up to confirm localized disease should include 
computed tomography (CT) scans of the chest and abdomen/pelvis 
(abdomen/pelvis preferred; abdomen accepted), a CT scan of the head or 
MRI of the brain (if symptomatic), and either a positron emission 
tomography (PET) scan or a bone scan.  (Note:  a PET/CT is acceptable 
for baseline imaging in lieu of CT examinations or bone scan).  Negative 
scans performed prior to the initiation of neoadjuvant therapy, or at any 
subsequent time, are acceptable and do not need to be repeated. 
Footnote l: 
After completion of eribulin treatment, patients will be followed every 3 
months during years 1 and 2, every 6 months during years 3-5, and annually 
thereafter for toxicity and disease progresson survival. 
Footnote m: 
CBC, including 3 part differential and platelets and CMP plus magnesium 
may be done up to 72 hours prior to treatment. After disease progression is 
documented, patients will be followed every 3 months until they initiate new 
treatment. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 11 of 68 
CLINICAL PROTOCOL BRE 186 SYNOPSIS 
Title of Trial: 
Phase II Trial of Eribulin in Patients Who Do Not Achieve Pathologic Complete Response 
(pCR) Following Neoadjuvant Chemotherapy (BRE 186) 
SCRI Protocol 
Number: 
BRE 186 
Sponsor: 
Sarah Cannon Research Institute (SCRI) Oncology Research Consortium 
Trial Duration: 
The duration of the trial from first enrollment to last patient last 
visit (LPLV) is 18 to 24 months. 
Phase of Trial:  II 
Trial Centers: 
This is a multicenter trial to be conducted in the United States at approximately 20 sites. 
Objectives: 
Primary objective 
The primary objective of this trial is to: 
 
Assess the efficacy of eribulin when administered to patients who do not achieve 
pCR following standard neoadjuvant chemotherapy (+/- trastuzumab).  The primary 
endpoint will be 2-year disease-free survival (DFS) rate. 
 
Secondary objective 
The secondary objectives of this trial are to: 
 
Assess the feasibility of administering 6 cycles of eribulin following standard 
neoadjuvant chemotherapy and primary surgical therapy. 
 
Assess the toxicity of eribulin in this patient population. 
Trial Design: 
This is a nonrandomized, open-label trial that will evaluate 6 cycles of eribulin administered 
postoperatively in patients who do not achieve pCR following a standard neoadjuvant 
chemotherapy regimen.  There will be three cohorts of patients based on tumor type: triple-
negative (A), hormone-receptor-positive/HER2-negative (B), and HER2-positive (C).  
Patients who are HER2-positive will receive trastuzumab as part of neoadjuvant treatment 
and concurrently with postoperative eribulin treatment. 
Trial Population: 
The trial population will consist of consenting female patients who do not achieve pCR (i.e., 
have residual invasive disease in breast or lymph node tissue) after treatment with a standard 
neoadjuvant chemotherapy regimen and surgery. 
Number of 
Patients: 
One-hundred forty-eight patients will be enrolled in this trial (54 in Cohort A, 42 in Cohort B, 
and 52 in Cohort C). 
Drug Supply 
The pharmaceutical company, Eisai, will provide eribulin (HALAVEN™) for this trial.  
Trastuzumab (Herceptin®) is commercially available and will be obtained from commercial 
sources.  Eribulin will be dispensed to the sites by the SCRI Oncology Research Consortium. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 12 of 68 
CLINICAL PROTOCOL BRE 186 SYNOPSIS (continued) 
Trial Drugs, 
Dose, and Mode 
of 
Administration: 
All patients will receive eribulin 1.4 mg/m2 IV Days 1 and 8 every 21 days for 6 cycles.  
Patients with HER2-positive tumors will also receive trastuzumab 6 mg/kg IV Day 1 every 
21 days to complete a total of 1 year (52 weeks) of treatment from the start of neoadjuvant 
administration.  If the last dose of trastuzumab was given >28 days from trial treatment start, 
the loading dose should be 8 mg/kg. 
Patients will receive either eribulin alone (Cohorts A & B) or eribulin + trastuzumab (Cohort C) 
based on their HER2 status and/or hormone receptor status. 
Cohort 
Trial Drugs & Mode of Administration 
Cohort A:  Triple-negative 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
Cohort B:  Hormone-receptor-
positive/HER2-negative 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
Cohort C:  HER2-positive 
Eribulin:  1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
 
Trastuzumab:  6 mg/kg IV (Day 1 every 21 days) 
 
Inclusion 
Criteria: 
Patients must meet the following criteria in order to be included in this clinical trial: 
1. Female patients ≥18 years-of-age. 
2. Histologically confirmed breast cancer prior to surgery with the following staging 
criteria: T1-T3, T4a, T4b, N0-N2, N3a and M0 (T1N0M0 patients are excluded).  
Inflammatory disease is excluded. 
3. Previous treatment with a minimum of 4 cycles of neoadjuvant anthracycline and/or 
taxane containing chemotherapy (+trastuzumab in HER2-positive patients). 
4. Patients must be ≥21 days and ≤ 84 days from breast surgery and fully recovered.  
Patients may have had mastectomy or breast conservation surgery with axillary node 
dissection. 
5. Pathologic CR (pCR) not achieved following neoadjuvant treatment (i.e., residual 
invasive breast cancer (>5 mm) in the breast or presence of nodal disease at surgery 
[ypT0/T1a, N1-N3a, M0 or ypT1b-T4, N0-N3a, M0]. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (see 
Appendix A). 
7. Recovery from any toxic effects of prior therapy to ≤ Grade 1 per the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0) except 
fatigue or alopecia. 
8. Peripheral neuropathy Grade ≤2 per NCI CTCAE v4.0 at trial entry. 
9. Normal left ventricular ejection fraction (LVEF), within the institutional limits of 
normal, as measured by echocardiography (ECHO) or multi-gated (MUGA) scan in 
patients to receive trastuzumab with eribulin (Cohort C). 
 
10. Adequate hematologic function defined as: 
 
Absolute neutrophil count (ANC) ≥1500/μL 
 
Hemoglobin (Hgb) ≥9 g/dL 
 
Platelets ≥100,000/uL 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 13 of 68 
CLINICAL PROTOCOL BRE 186 SYNOPSIS (continued) 
Inclusion 
Criteria 
(continued): 
11. Adequate liver function defined as: 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
the upper limit of normal (ULN) 
 
Total bilirubin ≤1.5 x ULN (unless the patient has grade 1 bilirubin elevation 
due to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin). 
12. Adequate renal function defined as: 
 
Serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated 24-hour creatinine 
clearance ≥45 mL/min. 
13. Complete staging work-up to confirm localized disease should include computed 
tomography (CT) scans of the chest and abdomen/pelvis (abdomen/pelvis preferred; 
abdomen accepted), a CT scan of the head or MRI of the brain (if symptomatic), and 
either a positron emission tomography (PET) scan or a bone scan.  (Note:  a PET/CT is 
acceptable for baseline imaging in lieu of CT examinations or bone scan).  Negative 
scans performed prior to the initiation of neoadjuvant therapy, or at any subsequent 
time, are acceptable and do not need to be repeated. 
14. Female patients who are not of child-bearing potential (see Appendix D), and female 
patients of child-bearing potential who agree to use adequate contraceptive measures 
(see Appendix D), who are not breastfeeding, and who have a negative serum 
pregnancy test performed within 7 days prior to start of trial treatment. 
15. Willingness and ability to comply with trial and follow-up procedures. 
16. Ability to understand the investigative nature of this trial and give written informed 
consent. 
17. Agree to delay in reconstruction in terms of implants placed in setting of expanders 
until chemotherapy is completed and the patient has recovered.  Expansion of 
expanders may continue during trial treatment. 
Exclusion 
Criteria: 
Patients who meet any of the following criteria will be excluded from entry into this trial: 
1. Presence of other active cancers, or history of treatment for invasive cancer <3 years prior 
to trial entry (except thyroid, cervical cancer).  Patients with Stage I cancer who have 
received definitive local treatment at least 3 years previously, and are considered unlikely 
to recur are eligible.  All patients with previously treated in situ carcinoma (i.e., non-
invasive) are eligible, as are patients with history of non-melanoma skin cancer. 
2. Radiotherapy prior to the start of study treatment. 
3. History or clinical evidence of central nervous system metastases or other metastatic 
disease. 
4. Non-healed surgical wound. 
5. Known or suspected allergy/hypersensitivity to eribulin. 
 
6. Cardiac disease, including:  congestive heart failure Class II-IV per New York Heart 
Association classification (Appendix B); cardiac ventricular arrhythmias requiring anti-
arrhythmic therapy; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., 
began within the last 3 months), or myocardial infarction within the past 6 months. 
7. Chronic use of drugs that cause QTc prolongation (see Appendix E).  Patients must 
discontinue use of these drugs 7 days prior to the start of study treatment. 
8. Women who are pregnant or lactating.  All females of child-bearing potential must have 
negative serum or urine pregnancy tests within 48 hours prior to trial treatment (see 
Appendix D). 
 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 14 of 68 
CLINICAL PROTOCOL BRE 186 SYNOPSIS (continued) 
Exclusion 
Criteria 
(continued): 
9. Patients with known diagnosis of human immunodeficiency virus (HIV), hepatitis C virus, 
or acute or chronic hepatitis B infection. 
10. Prolongation of heart rate-corrected QT interval (QTc) >480 msecs (using Bazett’s 
formula). 
11. Minor surgical procedures (with the exception of the placement of port-a-cath or other 
central venous access) performed less than 7 days prior to beginning protocol treatment. 
12. History of cerebrovascular accident including transient ischemic attack (TIA), or untreated 
deep venous thrombosis (DVT)/ pulmonary embolism (PE) within the past 6 months.  
Note: Patients with recent DVT/PE receiving treatment with a stable dose of therapeutic 
anti-coagulating agents are eligible. 
13. Patients may not receive any other investigational or anti-cancer treatments while 
participating in this trial. 
14. History of any medical or psychiatric condition or laboratory abnormality that in the 
opinion of the investigator may increase the risks associated with the trial participation or 
investigational product(s) administration or may interfere with the interpretation of the 
results. 
15. Inability or unwillingness to comply with trial and/or follow-up procedures outlined in the 
protocol. 
Statistical 
Methodology: 
 
The efficacy and safety analysis populations will consist of all patients who received at least 
1 dose of protocol treatment. 
 
Three cohorts of patients with residual disease following neoadjuvant therapy (triple-negative 
[A], hormone-receptor-positive (ER+ and/or PR+)/HER2-negative [B], and HER2-positive [C]) 
will be evaluated separately to obtain preliminary efficacy information.  With standard 
neoadjuvant therapy, the approximate 2-year DFS of patients who do not achieve pCR are as 
follows:  triple-negative, 40%; hormone-receptor-positive/HER2-negative, 80%; and HER2-
positive, 60%.  Treatment capable of providing relative improvement in these results by 40% in 
the triple-negative cohort, 15% in the hormone-receptor-positive/HER2-negative cohort, or 
25% in the HER2-positive cohort would be worthy of further development.  For a one-sided test 
of hypothesis at alpha = 0.10 and power = 0.80, the required sample sizes are 49, 38 and 47, 
respectively.  In order to adjust for potential non-evaluable patients, this preliminary study will 
treat 54, 42, and 52 patients, respectively, in the three cohorts.  This will allow determination of 
a 2-year DFS within 95% confidence intervals for each subgroup, as follows: 
Cohort A  Triple-negative:  42.0% - 67.9% 
Cohort B  Hormone-receptor-positive (and HER2-negative) cohort: 78.7% - 96.9%  
Cohort C  HER2-positive cohort: 61.0% - 84.5% 
Evaluation of safety among patients in each cohort will also provide sufficient experience to 
determine the tolerability and toxicity of this regimen.  Safety data will be tabulated for patients 
who receive any amount of trial medication.  Adverse events (AEs) will be tabulated by body 
system, preferred term, severity, and relation to treatment.  Worst toxicity grades per patient 
will be tabulated for selected AE and laboratory measurements by using NCI CTCAE criteria 
V4.0. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 15 of 68 
 
CLINICAL TRIAL BRE 186 CONTACT INFORMATION: 
SCRI Contact Information: 
SCRI Oncology Research Consortium 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Principal Investigator: 
Denise A. Yardley, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Ave., Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Medical Monitor: 
John D. Hainsworth, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Ave., Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
 
 
Safety Dept. Phone # / Fax #: 
(615) 329-7358 / (866) 807-4325 
 
Regulatory Phone # / Fax #: 
(615) 329-7274 / (615) 297-2793 
 
Enrollment Phone # / Fax #: 
(877) MY-1-SCRI / (866) 699-0258 
 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 16 of 68 
List of Abbreviations 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CMP 
comprehensive metabolic profile 
CRF 
Case Report Form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
disease-free survival 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HalB 
halichondrin B 
HER2 
human epidermal growth factor receptor 2 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MUGA 
multigated (radionuclide) angiogram 
NCI 
National Cancer Institute 
OS 
overall survival 
pCR 
pathologic complete response 
PET 
positron emission tomography 
PR 
progesterone receptor 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QA 
quality assurance 
SAE 
serious adverse event 
SCRI 
Sarah Cannon Research Institute 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of normal 
VACP 
vincristine, doxorubicin, cyclophosphamide, and prednisone 
VbMP 
vinblastine, methotrexate, and prednisone 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 17 of 68 
  
Table of Contents 
 
1. 
INTRODUCTION ............................................................................................................... 22 
1.1. 
Background ........................................................................................................ 22 
1.2. 
Eribulin .............................................................................................................. 22 
1.2.1. 
Clinical experience with eribulin ....................................................... 23 
1.3. 
Rationale for the Trial ........................................................................................ 24 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ........................................................................ 24 
2.1. 
Primary objective ............................................................................................... 24 
2.2. 
Secondary objectives ......................................................................................... 24 
3. 
TRIAL POPULATION ........................................................................................................ 24 
3.1. 
Inclusion Criteria ............................................................................................... 25 
3.2. 
Exclusion Criteria .............................................................................................. 26 
3.3. 
Discontinuation from Trial Treatment ............................................................... 27 
3.3.1. 
Pregnancy ........................................................................................... 28 
4. 
TRIAL REGISTRATION .................................................................................................... 28 
5. 
TRIAL DESIGN .................................................................................................................. 29 
Figure 1: 
Treatment Schema for BRE 186 ........................................................................ 30 
5.1. 
End of Trial ........................................................................................................ 31 
5.2. 
Method of Treatment Assignment and Blinding ............................................... 31 
5.3. 
Concomitant Medications .................................................................................. 31 
6. 
DOSE MODIFICATIONS................................................................................................... 31 
6.1. 
Dose Reductions ................................................................................................ 32 
6.2. 
Dose Modifications for Eribulin ........................................................................ 32 
6.2.1. 
Recommended Dose Delays of Eribulin ............................................ 32 
6.2.2. 
Recommended Dose Reductions of Eribulin ..................................... 33 
6.2.3. 
Interruption of Eribulin Infusion ........................................................ 33 
6.3. 
Dose Modifications for Trastuzumab ................................................................ 34 
6.3.1. 
Interruption of Trastuzumab Infusion ................................................ 34 
6.3.2. 
Trastuzumab Dosage Adjustments..................................................... 34 
6.3.3. 
Criteria for Withholding a Dose of Trastuzumab .............................. 34 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
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6.3.4. 
Trastuzumab Delayed- or Missed-Doses ........................................... 34 
6.3.5. 
Criteria for Re-treatment with Trastuzumab ...................................... 35 
7. 
TRIAL ASSESSMENTS AND TREATMENT .................................................................. 35 
7.1. 
Overview ............................................................................................................ 35 
7.2. 
Baseline Assessments ........................................................................................ 35 
7.3. 
Trial Treatment Assessments ............................................................................. 36 
7.3.1. 
Day 1 of each cycle ............................................................................ 36 
7.3.2. 
Day 8 of each cycle ............................................................................ 36 
7.4. 
Post-Treatment and End of Study Treatment ..................................................... 37 
7.5. 
Follow-Up .......................................................................................................... 37 
7.5.1. 
Follow-Up After Completion of Eribulin Treatment ......................... 37 
7.5.2. 
Follow-Up After Disease Progression Error! Bookmark not defined. 
7.5.3. 
Comprehensive Metabolic Profile ..................................................... 38 
7.5.4. 
Pregnancy test .................................................................................... 38 
7.6. 
Echocardiograms and Multi-gated Angiograms ................................................ 38 
7.7. 
12-Lead Electrocardiograms .............................................................................. 38 
7.8. 
Radiation Therapy .............................................................................................. 39 
8. 
INVESTIGATIONAL PRODUCTS ................................................................................... 39 
8.1. 
Eribulin .............................................................................................................. 39 
8.1.1. 
Labeling, Packaging, and Storage ...................................................... 39 
8.1.2. 
Preparation and Administration of Eribulin ....................................... 40 
8.1.3. 
Precautions and Risks Associated with Eribulin................................ 40 
8.2. 
Trastuzumab ....................................................................................................... 40 
8.2.1. 
Labeling, Packaging, Supply, and Storage ........................................ 41 
8.2.2. 
Preparation and Administration ......................................................... 41 
8.2.3. 
Precautions and Risks Associated with Trastuzumab ........................ 41 
8.3. 
Accountability of Investigational Products ........................................................ 43 
9. 
STATISTICAL CONSIDERATIONS................................................................................. 43 
9.1. 
Trial Population ................................................................................................. 43 
9.2. 
Planned Interim Analyses .................................................................................. 43 
9.3. 
Final Analysis Plan ............................................................................................ 43 
9.4. 
Data and Safety Monitoring Board .................................................................... 44 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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9.5. 
Steering Committee ........................................................................................... 44 
10. SAFETY REPORTING AND ANALYSES ....................................................................... 44 
10.1. 
Safety Analyses .................................................................................................. 44 
10.2. 
Adverse Events .................................................................................................. 44 
10.2.1. 
Definitions of Adverse Events ........................................................... 45 
10.2.2. 
Recording of Adverse Events ............................................................ 45 
10.2.3. 
Abnormal Laboratory Values and Vital Signs ................................... 45 
10.2.4. 
Handling of Adverse Events .............................................................. 45 
10.3. 
Serious Adverse Events ..................................................................................... 46 
10.3.1. 
Definitions of Serious Adverse Events .............................................. 46 
10.3.2. 
Serious Adverse Event Reporting by Investigators ........................... 46 
10.3.3. 
Sponsor Serious Adverse Event Reporting Requirements ................. 47 
10.4. 
Recording of Adverse Events and Serious Adverse Events .............................. 48 
10.4.1. 
Diagnosis vs. Signs and Symptoms ................................................... 48 
10.4.2. 
Persistent or Recurrent Adverse Events ............................................. 48 
10.4.3. 
Abnormal Laboratory Values............................................................. 48 
10.4.4. 
Deaths................................................................................................. 49 
10.4.5. 
Hospitalization, Prolonged Hospitalization, or Surgery .................... 49 
10.4.6. 
Pre-Existing Medical Conditions ....................................................... 49 
10.4.7. 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies .............. 49 
10.5. 
Protocol-Defined Events of Special Interest ...................................................... 49 
10.5.1. 
Pregnancy, Abortion, Birth Defects/Congenital Abnormalities ........ 49 
10.5.2. 
Trial Drug Overdose .......................................................................... 50 
11. ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......................... 50 
11.1. 
Institutional Review Board Approval ................................................................ 50 
11.2. 
Regulatory Approval .......................................................................................... 50 
11.3. 
Insurance and Indemnity .................................................................................... 51 
11.4. 
Informed Consent............................................................................................... 51 
11.5. 
Confidentiality ................................................................................................... 51 
11.5.1. 
Patient Confidentiality ....................................................................... 51 
11.5.2. 
Investigator and Staff Information ..................................................... 52 
11.6. 
Financial Information......................................................................................... 52 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 20 of 68 
12. RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ............................ 53 
12.1. 
Amendments to the Protocol .............................................................................. 53 
12.2. 
Documentation Required to Initiate the Trial .................................................... 53 
12.3. 
Trial Documentation and Storage ...................................................................... 54 
12.4. 
Data Collection .................................................................................................. 55 
12.5. 
Trial Monitoring, Auditing, and Inspecting ....................................................... 56 
12.6. 
Quality Assurance and Quality Control ............................................................. 56 
12.7. 
Disclosure and Publication Policy ..................................................................... 56 
13. REFERENCES .................................................................................................................... 58 
14. APPENDICES ..................................................................................................................... 60 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 21 of 68 
 
List of Tables 
Table 1: 
Description of Dosing by Cohort ....................................................................... 29 
Table 2: 
Recommended Eribulin Dose Reductions - Applies to Day 1 and Day 8 ......... 33 
 
List of Figures 
Figure 1: 
Treatment Schema for BRE 186 ........................................................................ 30 
 
 
List of Appendices 
Appendix A: 
ECOG Performance Status Criteria ................................................................... 60 
Appendix B: 
New York Heart Association Classifications .................................................... 61 
Appendix C 
Schedule of Assessments for BRE 186 (Residual Breast Cancer) .................... 62 
Appendix D: 
Guidelines Regarding Women of Childbearing Potential ................................. 64 
Appendix E 
Prohibited Drugs That Prolong QT Interval and/or Induce Torsades De Pointes 
and Class IA and III Antiarrhythmics ........................................................................................... 66 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 22 of 68 
1. 
INTRODUCTION 
1.1. 
Background 
Neoadjuvant chemotherapy has become the standard of care for patients with locally advanced 
breast cancer.  Patients achieving a pathologic complete response (pCR) to their neoadjuvant 
therapy have experienced better disease-free survival (DFS) and overall survival (OS).  
Unfortunately, the approximately 20% to 25% rate of pathologic complete response reported 
with standard non trastuzumab containing regimens leaves the majority of patients at increased 
risk of recurrence with inferior DFS and OS. 
In a review of neoadjuvant patients treated at MD Anderson, recurrence and death rates were 
higher in the first 3 years for triple-negative breast cancer (TNBC) compared with non-TNBC 
(1).  In another study examining breast cancer subtypes and outcome to neoadjuvant 
chemotherapy, patients with basal-like and human epidermal growth factor receptor 2 (HER2)-
positive /estrogen-receptor-(ER)-negative subtypes with residual disease experienced more 
frequent early relapses and death.  While it was easier to achieve a pathologic complete response 
in patients with basal-like or HER2-positive /ER-negative subtypes, the patients who did not 
achieve a pCR had a relatively poor prognosis, with most relapses occurring during the first 2 
years following surgery (2). 
Currently, there is little evidence to support the use of further adjuvant chemotherapy for patients 
who do not achieve pCR after treatment with a neoadjuvant chemotherapy regimen.  Since 
residual disease reflects resistance to neoadjuvant chemotherapy, pilot trials have attempted to 
offer further non-cross-resistant chemotherapy.  In a trial from MD Anderson, 110 patients who 
had received neoadjuvant VACP (vincristine, doxorubicin, cyclophosphamide, and prednisone) 
and had residual disease were randomized to receive further treatment with VACP or vinblastine, 
methotrexate, and prednisone (VbMP) (3).  Results demonstrated that adjuvant treatment was 
tolerable, with a suggestion of improved outcomes with VbMP (OS 65% versus 47%, p=0.06).  
Additional data from small pilot trials administering various postoperative chemotherapies have 
also supported this approach, as have pilots with novel biological therapies such as bevacizumab.  
Treatments were generally well tolerated and extended follow-up continues. 
1.2. 
Eribulin 
Eribulin mesylate (Halaven™) is a synthetic analog of halichondrin B (HalB), a natural product 
isolated from the marine sponge, Halichondria okadai (4).  HalB is a large polyether macrolide 
that exerts potent anticancer effects in cell-based and animal models of cancer (4, 5, 6).  The 
structurally simplified synthetic analog, eribulin, encompasses the biologically active 
macrocyclic portion of HalB, and shows similar or identical anticancer properties in preclinical 
models (7). 
Following discovery of the potent anticancer activity of HalB in 1986 (4) it was tested in the US 
National Cancer Institute (NCI) 60-cell line screen using known antimitotic agents and other 
anticancer drugs as comparators (5).  While antiproliferative patterns of HalB in the NCI cell line 
screen were similar to those of other antitubulin drugs, the biochemical mechanism of HalB's 
interaction with tubulin was distinct (5, 8, 9).  HalB noncompetitively inhibited vinblastine 
binding to tubulin, enhanced bis-5,5'-[8-(N-phenyl)-amino-naphthalene-1-sulfonic acid] binding 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 23 of 68 
to tubulin, and had no effect on iodoacetamide alkylation of tubulin sulfhydryl groups; yet HalB 
did not stabilize or inhibit colchicine binding to tubulin.  Therefore, it was concluded that HalB’s 
tubulin-based mechanism is distinct from all other known classes of antitubulin agents (5, 8, 9). 
 
Eribulin exerts its antiproliferative effects via a tubulin-based antimitotic mechanism.  Currently-
available data indicate that its mechanism of action is similar or identical to that of HalB (7, 8).  
Like HalB, eribulin was shown to be a potent inhibitor of tubulin polymerization into 
microtubules as well as microtubule dynamics in vitro and in whole cells (7, 10).  Nonclinical 
data show that sub- to low-nmol/L levels of eribulin inhibit cancer cell proliferation via induction 
of irreversible cell cycle blocks at G2/M, disruption of mitotic spindles, and initiation of 
apoptosis (7, 11). 
 
Human tumor xenograft studies in mice (ovary, lung, breast, colon, melanoma, pancreatic, and 
fibrosarcoma) demonstrate tumor regressions, remissions, and an increased lifespan at dose 
levels below the maximum tolerated dose (7, 12).  In vivo animal model data predict that eribulin 
will have greater efficacy than the taxanes and that increased antitumor activity can be achieved 
with fewer adverse effects. In addition, the potential for common side effects and drug-drug 
interactions with eribulin are less than or equal to existing therapies.  Currently, there is no 
evidence for taxol-like hypersensitivity with eribulin.  Although eribulin is a PgP drug efflux 
pump substrate (13), it retains full in vitro activity against cancer cells that are taxane-resistant 
due to β-tubulin mutations (14), suggesting that eribulin may show clinical effectiveness in 
subjects with refractory tumors that are taxane resistant based on β-tubulin mutations. 
 
In summary, eribulin kills cancer cells via apoptosis secondary to inhibition of cellular 
microtubule dynamics, disruption of mitotic spindle formation and induction of irreversible cell 
cycle arrest at G2/M. When tested in a variety of animal models of human cancer, these 
molecular- and cell-based anticancer activities of eribulin result in significant antitumor effects 
including tumor growth inhibition, regressions, remissions and increased life span. Current 
nonclinical data predict anticancer efficacy greater than the taxanes, achieved with fewer adverse 
effects. 
 
Eribulin was approved by the U.S. Food and Drug Administration (FDA) on 15 November 2010 
to treat patients with metastatic breast cancer who had received at least two prior chemotherapy 
regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies. 
1.2.1. 
Clinical experience with eribulin 
Eleven Phase 1 and 5 Phase 2 trials of eribulin have been conducted worldwide (USA, Europe, 
and Japan).  In addition, one Phase 3 study in patients with advanced breast cancer has been 
completed. 
 
The pharmacokinetic profile of eribulin was established in the early phase studies.  In general, 
the pharmakokinetics of eribulin are characterized by a rapid distribution phase, with a prolonged 
elimination phase after intravenous infusion.  The disposition of E7389 follows linear kinetics 
over the dose range studied, as shown by consistent dose-independent pharmacokinetic 
parameters and similar dose-normalized parameters. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 24 of 68 
 
Eribulin’s safety and effectiveness were established in the single Phase 3 study in 762 women 
with metastatic breast cancer who had received at least two prior chemotherapy regimens for 
late-stage disease (15, 16).  Patients were randomly assigned to receive treatment with either 
eribulin or a different single-agent therapy chosen by their oncologist in a 2:1 ratio. 
The study was designed with OS as the primary endpoint.  The median OS for patients receiving 
eribulin was 13.1 months compared with 10.6 months for those who received a different single-
agent therapy and was considered to demonstrate a clear survival benefit. 
The most common side effects reported by women treated with eribulin include neutropenia/ 
leukopenia, asthenia/fatigue, nausea, constipation, alopecia, arthralgia/myalgia, pyrexia, and 
peripheral neuropathy. 
1.3. 
Rationale for the Trial 
Eribulin, a novel chemotherapeutic agent with efficacy in patients with refractory metastatic 
breast cancer, may be effective in the treatment of patients with locally advanced breast cancer 
who do not achieve pCR following neoadjuvant therapy.  We propose to evaluate eribulin as 
adjuvant therapy in patients who do not achieve pCR following standard neoadjuvant 
chemotherapy.  Three cohorts of patients will be evaluated separately: triple-negative, hormone-
receptor-positive/HER2-negative, and HER2-positive.  Hormone-receptor-positive patients may 
be ER and /or PR positive. 
2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1. 
Primary objective 
The primary objective of this trial is to: 
 Assess the efficacy of eribulin when administered to patients who do not achieve pCR 
following standard neoadjuvant chemotherapy (+/-trastuzumab).  The primary endpoint 
will be 2-year DFS rate. 
2.2. 
Secondary objectives 
The secondary objectives of the trial are to: 
 Assess the feasibility of administering 6 cycles of eribulin following standard 
neoadjuvant chemotherapy and primary surgical therapy. 
 Assess the toxicity of eribulin in this patient population. 
3. 
TRIAL POPULATION 
Patients must have baseline evaluations performed prior to the first dose of trial drug and must 
meet all inclusion and exclusion criteria.  The Principal Investigator or his/her designee must 
review the results of all baseline evaluations that assure that all inclusion and exclusion criteria 
have been satisfied prior to enrollment of that patient. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 25 of 68 
3.1. 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in this clinical trial: 
1. Female patients ≥18 years-of-age. 
2. Histologically confirmed breast cancer prior to surgery with the following 
staging criteria: T1-T3, T4a, T4b N0-N2, N3a and M0 (T1N0M0 patients are 
excluded).  Inflammatory disease is excluded. 
3. Previous treatment with a minimum of 4 cycles of neoadjuvant anthracycline 
and/or taxane containing chemotherapy regimen (+trastuzumab in HER2-
positive patients). 
4. Patients must be ≥21days and ≤ 84 days from breast surgery and fully 
recovered.  Patients may have had mastectomy or breast conservation surgery 
with axillary node dissection. 
5. Pathologic CR (pCR) not achieved following neoadjuvant treatment (i.e., 
residual invasive breast cancer (>5 mm) in the breast or presence of nodal 
disease at surgery [ypT0/T1a, N1-N3a, M0 or ypT1b-T4, N0-N3a, M0]. 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-
1 (see Appendix A). 
7. Recovery from any toxic effects of prior therapy to ≤ Grade 1 per the NCI 
Common Terminology Criteria for Adverse Events (CTCAE v4.0) except 
fatigue or alopecia. 
8. Peripheral neuropathy Grade ≤2 per NCI CTCAE v4.0 at trial entry. 
9. Normal left ventricular ejection fraction (LVEF), within the institutional limits of 
normal, as measured by an echocardiogram (ECHO) or multi-gated angiogram 
(MUGA) in patients to receive trastuzumab with eribulin (HER2-positive). 
10. Adequate hematologic function defined as: 
• 
Absolute neutrophil count (ANC) ≥1500/μL 
• 
Hemoglobin (Hgb) ≥9 g/dL 
• 
Platelets ≥100,000/uL 
11. Adequate liver function defined as: 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
the upper limit of normal (ULN) 
• 
Total bilirubin ≤1.5 x ULN (unless the patient has grade 1 bilirubin elevation 
due to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin). 
12. Adequate renal function defined as: 
• 
Serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated 24-hour creatinine 
clearance ≥45 mL/min. 
13. Complete staging work-up to confirm localized disease should include computed 
tomography (CT) scans of the chest and abdomen/pelvis (abdomen/pelvis 
preferred; abdomen accepted), a CT scan of the head or MRI of the brain (if 
symptomatic), and either a positron emission tomography (PET) scan or a bone 
scan.  (Note:  a PET/CT is acceptable for baseline imaging in lieu of CT 
examinations or bone scan).  Negative scans performed prior to the initiation of 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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Page 26 of 68 
neoadjuvant therapy, or at any subsequent time, are acceptable and do not need to 
be repeated. 
14. Female patients who are not of child-bearing potential (see Appendix D), and 
female patients of child-bearing potential who agree to use adequate contraceptive 
measures (see Appendix D), who are not breastfeeding, and who have a negative 
serum pregnancy test performed within 7 days prior to start of trial treatment. 
15. Willingness and ability to comply with trial and follow-up procedures. 
16. Ability to understand the investigative nature of this trial and give written 
informed consent. 
17. Agree to delay in reconstruction in terms of implants placed in setting of 
expanders until chemotherapy is completed and the patient has recovered.  
Expansion of expanders may continue during trial treatment. 
3.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from entry into the trial: 
1. Presence of other active cancers, or history of treatment for invasive cancer 
<3 years prior to trial entry (except thyroid, cervical cancer).  Patients with 
Stage I cancer who have received definitive local treatment at least 3 years 
previously, and are considered unlikely to recur are eligible.  All patients with 
previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are 
patients with history of non-melanoma skin cancer. 
2. Radiotherapy prior to the start of study treatment. 
3. History or clinical evidence of central nervous system metastases or other 
metastatic disease. 
4. Non-healed surgical wound. 
5. Known or suspected allergy/hypersensitivity to eribulin. 
6. Cardiac disease, including:  congestive heart failure Class II-IV per New York 
Heart Association classification (Appendix B); cardiac ventricular 
arrhythmias requiring anti-arrhythmic therapy; unstable angina (anginal 
symptoms at rest) or new-onset angina (i.e., began within the last 3 months), 
or myocardial infarction within the past 6 months. 
7. Chronic use of drugs that cause QTc prolongation (see Appendix E).  Patients 
must discontinue use of these drugs 7 days prior to the start of study 
treatment. 
8. Women who are pregnant or lactating.  All females of child-bearing potential 
must have negative serum pregnancy test within 48 hours prior to trial 
treatment (see Appendix D). 
9. Patients with known diagnosis of human immunodeficiency virus (HIV), 
hepatitis C virus, or acute or chronic hepatitis B infection. 
10. Prolongation of heart rate-corrected QT interval (QTc) >480 msecs (using 
Bazett’s formula). 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
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11. Minor surgical procedures (with the exception of the placement of port-a-cath 
or other central venous access) performed less than 7 days prior to beginning 
protocol treatment. 
12. History of cerebrovascular accident including transient ischemic attack (TIA), 
or untreated deep venous thrombosis (DVT)/ pulmonary embolism (PE) 
within the past 6 months.  Note: Patients with recent DVT/PE receiving 
treatment with a stable dose of therapeutic anti-coagulating agents are eligible. 
13. Patients may not receive any other investigational or anti-cancer treatments 
while participating in this trial. 
14. History of any medical or psychiatric condition or laboratory abnormality that 
in the opinion of the investigator may increase the risks associated with the 
trial participation or investigational product(s) administration or may interfere 
with the interpretation of the results. 
15. Inability or unwillingness to comply with trial and/or follow-up procedures 
outlined in the protocol. 
3.3. 
Discontinuation from Trial Treatment 
Patients will be discontinued from trial treatment for any of the following reasons: 
 Disease progression 
 Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
 Patient requests to withdraw from the trial and discontinue treatment 
 Patient requests to discontinue treatment 
 Pregnancy (see Section 3.3.1) 
 Inability of the patient to comply with trial requirements 
 Conditions requiring therapeutic intervention not permitted by the protocol 
 Intercurrent illness (this will be at the Investigator’s discretion) 
 Non-compliance/lost to follow-up 
Patients who have been discontinued from trial treatment will not be replaced.  After withdrawal 
from protocol treatment, patients must be followed for AEs for 30 calendar days after their last 
dose of trial drug.  All new AEs occurring during this period must be reported and followed until 
resolution, unless, in the opinion of the Investigator, these values are not likely to improve 
because of the underlying disease.  In this case, the Investigators must record his or her reasoning 
for this decision in the patients’ medical records and as a comment on the Case Report Form 
(CRF). 
All patients who have CTCAE Grade 3 or 4 laboratory abnormalities at the time of withdrawal 
must be followed until the laboratory values have returned to Grade 1 or 2, unless it is, in the 
opinion of the Investigator, not likely that these values are to improve because of the underlying 
disease.  In this case, the Investigator must record his or her reasoning for making this decision 
in the patients’ medical records and as a comment on the CRF. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 28 of 68 
3.3.1. Pregnancy 
During the course of the trial, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix D) must contact the treating 
Investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating Investigator). 
If an Investigator suspects that a patient may be pregnant prior to administration of trial drugs, 
the trial drugs must be withheld until the result of the pregnancy test is confirmed.  If a 
pregnancy is confirmed, the patient must not receive any trial drugs, and must be discontinued 
from the trial. 
If an Investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drugs, the trial drugs must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the trial drugs must be permanently stopped, the patient 
must be discontinued from the trial, and the Investigator must notify the SCRI Study Chair as 
soon as possible.  If a patient becomes pregnant while enrolled in the trial, a Pregnancy Form 
should be completed and faxed to the SCRI Safety Department.  For more details regarding 
handling and reporting of pregnancies that occur during treatment, see Section 10.5.1. 
4. 
TRIAL REGISTRATION 
Each patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, and risks and 
discomforts.  Human protection committee (Institutional Review Board [IRB]) approvals of this 
protocol and consent form are required prior to patient enrollment.  Registration must occur prior 
to the initiation of protocol therapy. 
Patients eligible to participate in the trial may enroll through the Sarah Cannon Research Institute 
(SCRI) Oncology Research Consortium (ORC) Central Enrollment Desk at 1-877-MY-1-SCRI.  
Registration may be done via fax (866) 699-0258 Monday through Friday, 8:30 a.m. to 
4:30 p.m., Central Standard Time.  Patient registration will be confirmed via fax within 24 hours, 
or by the next business day. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 29 of 68 
5. 
TRIAL DESIGN 
All patients will receive eribulin 1.4 mg/m2 on Days 1 and 8 every 21 days for 6 cycles via the 
intravenous (IV) route.  Patients with HER2-positive tumors will also receive trastuzumab 
6 mg/kg IV Day 1 every 21 days to complete a total of 1 year (52 weeks) of treatment from the 
start of neoadjuvant administration.  If the last dose of trastuzumab was given >28 days from 
trial treatment start, the loading dose should be 8 mg/kg. 
Patients will receive either eribulin alone (Cohorts A & B) or eribulin + trastuzumab (Cohort C) 
based on their HER2 status and/or hormone-receptor status (Table 1). 
Table 1: 
Description of Dosing by Cohort 
Cohort 
Trial Drugs & Mode of Administration 
Cohort A:  Triple-negative 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
Cohort B:  Hormone-receptor-
positive/HER2-negative 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
Cohort C:  HER2-positive 
Eribulin:  1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
 
Trastuzumab:  6 mg/kg IV (Day 1 every 21 days) 
Patients may undergo locoregional radiation therapy either during or following chemotherapy 
according to institutional guidelines (Section 7.8).  Radiotherapy prior to the start of study 
treatment is not permitted.  Patients in Cohort B (hormone-receptor-positive) and Cohort C 
(HER2-positive) may receive adjuvant hormonal therapy according to institutional guidelines. 
The treatment schema is presented in Figure 1. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 30 of 68 
 
 
Figure 1: 
Treatment Schema for BRE 186 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Patients may receive radiation therapy either during or following chemotherapy per institutional guidelines. 
 
 
 
E
N
R
O
L
L
M
E
N
T 
 
Treatment cycles will be repeated every 21 days (3 weeks). 
 
Cohort A (Triple-negative): 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
 
Cohort B (Hormone-receptor-positive/HER2-negative): 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
 
Cohort C (HER2-positive): 
Eribulin 1.4 mg/m2 IV (Days 1 & 8 every 21 days) 
Trastuzumab 6 mg/kg IV (Day 1 every 21 days) 
Treatment 
will 
continue 
for 
6 cycles. 
F
O
L
L
O
W
U
P 
Breast and/or chest 
wall radiotherapy*, if 
appropriate 
(institutional 
guidelines) 
 
Adjuvant hormonal 
therapy (Cohort B and 
C, per institutional 
guidelines) 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 31 of 68 
5.1. 
End of Trial 
The primary endpoint of this trial is 2-year DFS.  Therefore, patients will be followed for at least 
2 years after last treatment. 
5.2. 
Method of Treatment Assignment and Blinding 
This is a non-randomized trial in which patients will be assigned to treatment based on their 
tumor type. 
 
This is an open-label trial and so blinding is not necessary. 
5.3. 
Concomitant Medications 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the trial without prior consultation with the Investigator.  At each 
visit, the Investigator will ask the patient about any new medications he/she has taken after the 
start of the trial drug. 
Growth factor support:  Routine prophylactic use of colony-stimulating factor (CSF) is not 
recommended during this study.  Myeloid or granulocyte-specific colony-stimulating factor (G-
CSF) may be used, according to standard guidelines (e.g., American Society of Clinical 
Oncology [ASCO] guidelines) or at the discretion of the treating investigator, after discussion 
with the Study Chair.  Colony-stimulating agents must be held at least the day before 
chemotherapy, and initiated at least 1 day after chemotherapy is administered.  Use of colony-
stimulating agents should not substitute for protocol-mandated dose reductions due to 
neutropenia and/or neutropenic fever (Section Error! Reference source not found.).  Use of 
erythropoietin is allowed.  Use of stimulators of thrombopoiesis is not allowed. 
Anti-emetics:  Prophylactic anti-emetic therapy should follow standard guidelines for 
moderately emetogenic chemotherapy. 
Drugs that cause QTc prolongation:  Drugs that cause QTc prolongation are prohibited.  
Please see Appendix E for a list of prohibited drugs. 
The use of any herbal/natural products or other "folk remedies" should be discouraged, but use of 
those products, as well as the use of vitamins, nutritional supplements, and all other concomitant 
medications, is not cause for discontinuation but must be recorded in the CRF. 
All medications (prescriptions or over-the-counter medications) continued at the start of the trial 
or started during the trial or up to 30 days after the last dose of protocol treatment must be 
documented. 
6. 
DOSE MODIFICATIONS 
Treatment-related toxicities will be evaluated utilizing the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE).   If toxicity occurs, the toxicity will be graded, and 
appropriate supportive care treatment will be administered to decrease the signs and symptoms 
thereof.  Dose adjustments will be based on the organ system exhibiting the greatest degree of 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 32 of 68 
toxicity.  If trial medication is held for over 3 weeks due to toxicity, that medication will be 
discontinued. 
6.1. 
Dose Reductions 
Patients who have toxicity related to treatment may have their dose(s) reduced. 
All dose reductions will be made from the planned dosages.  Patients who require dose 
reductions must be evaluated at least weekly until the toxicity stabilizes or improves.  Once 
stable, patients can resume evaluations according to the protocol-specified visit schedule.  If 
toxicity remains unresolved for 3 weeks, the patient will discontinue treatment with that drug.  
Patients in Cohort C who discontinue chemotherapy prior to completing 6 cycles can remain on 
study and continue to receive trastuzumab.  Patients should be evaluated weekly (at a minimum), 
if therapy is on hold. 
There is clinical evidence of QTc prolongation with both eribulin and trastuzumab.  During the 
treatment period, if an ECG indicates a QTc interval 500 msec, then two additional ECGs 
should be obtained within 5 minutes to confirm the abnormality.  The average QTc will be 
determined from the three ECG tracings by manual evaluation, and will be used to determine 
continued eligibility.  If the average QTc is <500 msec, the patient may continue therapy.  If the 
average QTc is ≥500 msec, the study treatment should be discontinued immediately.  The patient 
should be treated appropriately for QTc interval prolongation, and monitored until resolution is 
documented by a repeat ECG, with QTc intervals returning to <480 msec. 
6.2. 
Dose Modifications for Eribulin 
For patients who experience toxicities during the trial, one or more doses of eribulin may need to 
be reduced, delayed, or withheld.  Patients can either have trastuzumab delayed or continue to 
receive trastuzumab on an every-3-week schedule even if administration of eribulin is delayed or 
withheld on Day 1 per the treating physician’s discretion. 
6.2.1. Recommended Dose Delays of Eribulin 
Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. 
 
Do not administer eribulin on Day 1 or Day 8 if any of the following are present: 
 ANC < 1,000/mm3 
 Platelets < 75,000/mm3 
 Grade 3 or 4 non-hematological toxicities 
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. 
For ANC <1500/µL on Day 1, delay dose of Eribulin until ANC >1500/µL, then: 
 Initiate treatment with prophylactic granulocyte-CSFs, with no dose reductions.  
 If patient is already receiving granulocyte-CSF treatment, reduce dose by 1 dose level.  

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 33 of 68 
 
6.2.2. Recommended Dose Reductions of Eribulin 
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 presented in Table 2. 
Do not re-escalate the dosage of eribulin after it has been reduced. 
 
Table 2: 
Recommended Eribulin Dose Reductions - Applies to Day 1 and Day 8 
Event Description 
Recommended Eribulin Dose 
Permanently reduce the 1.4 mg/m2 dose for any of the 
following: 
- 
ANC <500/mm3 for >5 days 
- 
ANC <1,000 /mm3 with fever or infection 
- 
Platelets <25,000/mm3 
- 
Platelets <50,000/mm3 requiring transfusion or 
associated with bleeding 
- 
Grade 2 neuropathy 
- 
Non-hematologic Grade 3 or 4 toxicities 
- 
Omission or delay of Day 8 eribulin dose in 
previous cycle for toxicity 
1.1 mg/m2 (Days 1 & 8 every 21 days) 
Occurrence of any event requiring permanent dose 
reduction while receiving 1.1 mg/m2 
0.7 mg/m2 (Days 1 & 8 every 21 days) 
Occurrence of any event requiring permanent dose 
reduction while receiving 0.7 mg/m2 
Discontinue eribulin 
ANC = absolute neutrophil count 
Toxicities graded in accordance with NCI CTCAE, Version 4.0. 
 
6.2.3. 
Interruption of Eribulin Infusion 
Clinical experience to date does not indicate adverse reactions to infusion with eribulin.  Patients 
who experience any serious infusion reaction during eribulin administration will have the 
infusion stopped.  Continuation of dosing will be based on the severity and resolution of the 
event and will be at the discretion of the Investigator.  Suspected infusion reactions should be 
reported as an adverse event.  All patients who experience such an event will be followed for 
safety. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 34 of 68 
6.3. 
Dose Modifications for Trastuzumab 
6.3.1. 
Interruption of Trastuzumab Infusion 
Patients with pulmonary disease or pre-existing respiratory compromise may be at increased risk 
from serious infusion symptoms, therefore careful consideration must be made before enrolling 
patients with chronic lung disease into this clinical trial.  Patients who experience a life-
threatening infusion reaction (eg, tachypnea, bronchospasm, hypotension, hypoxia) should be 
withdrawn from trastuzumab. 
Patients who experience severe or moderate infusion symptoms may be managed by: 
 Slowing or stopping the trastuzumab infusion 
 Supportive care may include supplemental oxygen, beta agonists, 
antihistamines, or corticosteroids.  Patients who experience mild or 
moderate infusion symptoms may be treated with antipyretics and 
antihistamines. 
Patients who experience mild, moderate, or severe infusion reactions on the first dose may be 
retreated with trastuzumab.  Premedication with corticosteroids, antihistamines, and antipyretics 
may be used before subsequent trastuzumab infusions. 
6.3.2. 
Trastuzumab Dosage Adjustments 
The dose of trastuzumab is 6 mg/kg every 3 weeks.  If the dosing of trastuzumab is interrupted 
for >28 days, however, the loading dose upon resumption should be 8 mg/kg.  There is no 
planned dose modification schedule for trastuzumab.  In case of any need of dose or schedule 
modification this should be discussed with the Sponsor. 
6.3.3. 
Criteria for Withholding a Dose of Trastuzumab 
Cardiac toxicities: 
Use of trastuzumab is contraindicated in patients with a LVEF of less than 45% and those with 
symptomatic heart failure.  In an asymptomatic patient, if LVEF drops 10 percentage points from 
baseline (and to below 50% in patients with a normal baseline measurement) trastuzumab should 
be withheld and a repeat LVEF assessment performed within approximately 3 weeks.  If LVEF 
has not improved, or declined further, discontinuation of trastuzumab should be strongly 
considered, unless the benefits for the individual patient are deemed to outweigh the risks. 
Non-Cardiac related toxicities: 
In any trastuzumab-related case of Grade 3/4 non-cardiac toxicity, the drug should be withheld 
until resolution to Grade 1 toxicity. 
6.3.4. 
Trastuzumab Delayed- or Missed-Doses 
Trastuzumab should be given on Day 1 of each 21-day cycle.  Missed trastuzumab doses will not 
be made up.  Patients who miss more than 4 consecutive weeks of trastuzumab due to toxicity 
will be considered unable to tolerate trastuzumab and will not be retreated with trastuzumab. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 35 of 68 
If trastuzumab treatment cannot be continued due to unresolved trastuzumab-related toxicities, 
eribulin can be continued at the Investigator’s discretion. 
6.3.5. 
Criteria for Re-treatment with Trastuzumab 
Patients should be assessed for toxicity before each dose. 
Patients who develop a toxicity that does not meet the criteria for withholding a dose of 
trastuzumab should continue to receive trastuzumab and their symptoms should be treated.  
Trastuzumab-related toxicity will be considered resolved if it improves to a degree that allows 
for re-treatment with trastuzumab. 
7. 
TRIAL ASSESSMENTS AND TREATMENT 
7.1. 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete schedule of assessments is presented in Appendix C. 
7.2. 
Baseline Assessments 
Patients must have the following assessments performed ≤7 days before receiving their first dose 
of study drug.  Note:  baseline laboratory assessments (except the serum pregnancy test) will be 
allowed up to 7 days outside of the 7-day specified window, provided that critical laboratory 
assessments (CBC, CMP, and PT/INR and PTT [for patients receiving warfarin only]) are 
repeated on Cycle 1, Day 1 prior to study treatment.  Negative scans performed prior to the 
initiation of neoadjuvant therapy, or at any subsequent time prior to trial entry, do not need to be 
repeated.  If not performed previously, scans should be performed <4 weeks prior to trial entry 
(±7 days). 
 Informed consent form prior to any other trial-related procedures 
 Medical history (including assessment of baseline signs and symptoms) 
 Physical examination including measurements of height (body surface area), 
weight, vital signs (resting heart rate, blood pressure, respiratory rate, and oral 
temperature), and assessment of peripheral neuropathy 
 Complete blood count (CBC) including 3-part differential and platelets (may be 
done up to 72 hours prior to treatment) 
 Comprehensive metabolic profile (CMP) plus magnesium (Section 7.5.2) (may be 
done up to 72 hours prior to treatment) 
 Coagulation analysis:  prothrombin time (PT)/International Normalization Ratio 
(INR) and partial thromboplastin time (PTT) (may be done up to 72 hours prior to 
treatment) 
 Serum pregnancy test within 48 hours of first dose of trial drug (Section 7.5.3) 
 ECOG performance status (Appendix A) 
 12-lead electrocardiogram (ECG) 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 36 of 68 
 Baseline LVEF measurement by MUGA/ECHO (Cohort C patients only) 
 Concomitant medication review 
7.3. 
Trial Treatment Assessments 
The treatment regimens for all treatment arms in this study will be given in 3-week (21-day) 
cycles (±5 days).  Patients without evidence of undue toxicity will complete 6 cycles of therapy.   
All patients will visit the trial center on Days 1 and 8 of each 3-week (21-day) treatment cycle 
(±5 days) during trial treatment.  For specific information about the administration of each drug, 
see Sections 8.1.2 and 8.2.2, respectively. 
7.3.1. 
Day 1 of each cycle 
The following assessments will be performed at each of these visits: 
 Update of medical history 
 Physical examination including measurements of weight, vital signs (resting heart 
rate, blood pressure, respiratory rate, and oral temperature), and assessment of 
peripheral neuropathy 
 CBC, including 3-part differential and platelets (may be done up to 72 hours prior 
to treatment) 
 CMP plus magnesium (may be done up to 72 hours prior to treatment) 
 ECOG performance status 
 ECG (this test is required on Day 1 of each cycle; however, ECGs may be 
performed at any time during the study, at the discretion of the treating physician, 
if clinically indicated [see Section 7.7]) 
 ECHO or MUGA for LVEF (after Cycle 3, before start of Cycle 4 for Cohort C 
patients only) 
 PT/INR and PTT will be checked for patients who are receiving warfarin. 
 Adverse event assessment 
 Concomitant medication review 
 Administration of eribulin (Cohorts A & B) or eribulin and trastuzumab 
(Cohort C) 
7.3.2. 
Day 8 of each cycle 
The following assessments will be performed at each of these visits: 
 CBC, including 3-part differential and platelets 
 Adverse event assessment 
 Administration of eribulin (all cohorts) 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 37 of 68 
7.4. 
Post-Treatment and End of Study Treatment 
Patients will return to the study center ≤30 days after treatment ends either due to completion of 
eribulin treatment, or discontinuation from treatment due to unacceptable toxicity or a decision to 
discontinue treatment by the patient or the trial physician. 
 Update of medical history 
 Physical examination including measurement of weight, vital signs, and 
assessment of peripheral neuropathy 
 CBC, including 3-part differentials and platelets 
 CMP plus magnesium 
 ECG 
 ECOG performance status 
 ECHO or MUGA for LVEF (Cohort C patients only) 
 Adverse event assessment 
 Concomitant medication review 
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
trial treatment is administered, that visit may fulfill the End of Treatment Visit. 
After withdrawal from or completion of protocol treatment, patients must be followed for 
adverse events for 30 calendar days after the last dose of trial drug. 
7.5. 
Follow-Up 
7.5.1. 
Follow-Up After Completion of Eribulin Treatment 
Patients will be followed every 3 months during years 1 and 2 for toxicity and disease 
progression.  At each visit, patients will have a physical examination, complete blood counts, 
chemistry profile, and evaluation of any new symptoms.  Assessments at these visits will be 
performed as described in Appendix C. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 38 of 68 
7.5.2. Comprehensive Metabolic Profile 
The following laboratory tests should be performed for each patient for assessment of CMP: 
 
glucose 
 
blood urea nitrogen (BUN) 
 
creatinine 
 
sodium 
 
potassium 
 
chloride 
 
calcium 
 
carbon dioxide (CO2) 
 
alkaline phosphatase 
 
AST (SGOT) 
 
ALT (SGPT) 
 
total bilirubin 
 
total protein 
 
albumin, and 
and 
 
magnesium 
7.5.3. Pregnancy test 
All females of childbearing potential must complete a serum pregnancy test within 7 days prior 
to the initiation of eribulin therapy.  Women of childbearing potential must use effective birth 
control measures during treatment and during the 6 months following completion of trial 
treatment.  Postmenopausal women must have been amenorrheic for ≥12 months in order to be 
considered “of non-childbearing potential” (Appendix D). 
7.6. 
Echocardiograms and Multi-gated Angiograms 
Patients in Cohort C (eribulin + trastuzumab) will have an ECHO or MUGA for LVEF at 
baseline and after Cycle 3 (prior to receiving Cycle 4 treatment).  In addition, an end-of-
treatment ECHO/MUGA is required. 
7.7. 
12-Lead Electrocardiograms 
There is clinical evidence of QTc prolongation with both eribulin and trastuzumab.  Therefore, a 
12-lead ECG will be taken at the pre-treatment visit, and will be repeated on Day 1 of each cycle.  
Electrocardiograms may also be performed at any time during the study, at the discretion of the 
treating physician, if clinically indicated.  Patients should rest at least 10 minutes before ECG 
testing.  Patients should be in the semi-recumbent or supine position when tested; the same 
position must be used for all subsequent ECGs. 
All ECGs must include QTc measurements, either manually or machine-calculated using 
Bazett’s formula, and recorded in the CRF. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 39 of 68 
Bazett’s formula:  QTcB = QT/RR½ 
At screening, if there is significant QTc interval prolongation (defined as a QTc interval 
≥480 msec), the patient will NOT be eligible for the study. 
During the treatment period, if an ECG indicates a QTc interval 500 msec, then two additional 
ECGs should be obtained within 5 minutes to confirm the abnormality.  The average QTc will be 
determined from the three ECG tracings by manual evaluation, and will be used to determine 
continued eligibility.  If the average QTc is <500 msec, the patient may continue therapy.  If the 
average QTc is ≥500 msec, the study treatment should be discontinued immediately.  The patient 
should be treated appropriately for QTc interval prolongation, and monitored until resolution is 
documented by a repeat ECG, with QTc intervals returning to <480 msec. 
7.8. 
Radiation Therapy 
Patients may be treated with breast and or chest wall radiation therapy either during or following 
chemotherapy on this study, according to the institutional or practice standards.  Experience with 
concurrent eribulin and radiation therapy is limited and hence safety will be evaluated after the 
first 10 patients have been treated with concurrent eribulin and radiotherapy.  In MBC patients 
who have received concurrent eribulin with radiation, no adverse safety signals or skin toxicity 
has been noted (personal communication). 
8. 
INVESTIGATIONAL PRODUCTS 
All trial drugs must be kept in a secure place under appropriate storage conditions. 
The Sponsor or its representatives must be granted assess on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
8.1. 
Eribulin 
8.1.1. Labeling, Packaging, and Storage 
Eribulin mesylate (HALAVEN™) is a clear, colorless, and sterile solution for injection that 
contains 1.0 mg eribulin drug substance in 2.0 mL of solution.  Eribulin clinical supply is 
packaged in single-use glass vials. 
Eribulin clinical supply must be stored only as detailed on the clinical supply labeling (carton 
and vial labels).    
The supply for this study may be provided with one of two labeled storage requirements (see 1. 
and 2. below).  The storage conditions are not interchangeable and the supply must be stored as 
detailed on the supply labels.      
1.  Refrigerated:  Store in a refrigerator, between 2°C - 8°C (36°F - 46°F).  Do not 
freeze.  Store the vials in their original cartons.    
2.  Controlled room temperature:  Store at controlled room temperature of 25°C (77°F); 
excursions permitted to 15°C - 30°C (59°F - 86°F).  Do not freeze.  Store the vials in 
their original cartons.  

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 40 of 68 
 
 
Photostability studies have demonstrated that protection from light is not necessary. 
 
The Sponsor, SCRI Oncology Research Consortium, will provide eribulin to the sites 
participating in the trial. 
8.1.2. Preparation and Administration of Eribulin 
Aseptically withdraw the required amount of eribulin from the single-use vial and administer 
undiluted or diluted in 0.9% Sodium Chloride Injection, USP, to concentrations between 0.005 
and 0.2 mg/mL mL over 2 to 5 minutes.  Alternatively, the drug may be administered undiluted 
by slow IV push. 
 
Do not dilute in or administer through an IV line containing solutions with dextrose.  Do 
not administer in the same IV 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 (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. 
8.1.3. Precautions and Risks Associated with Eribulin 
For a complete discussion of risk information including precautions and adverse reactions for 
Eribulin, please refer to the current Eribulin Investigator’s Brochure. 
. 
8.2. 
Trastuzumab 
Trastuzumab (Herceptin®) is a recombinant humanized IgG1 monoclonal antibody that binds to 
domain four of the extracellular segment of the HER2 receptor.  Cells treated with trastuzumab 
undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation.  It has been 
suggested that trastuzumab induces some of its effect by down regulation of HER2 leading to 
disruption of receptor dimerization and signaling through the downstream PI3K cascade.  
P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, 
causing cell cycle arrest.  Also, trastuzumab suppresses angiogenesis by both induction of 
antiangiogenic factors and repression of pro-angiogenic factors.  It is thought that a contribution 
to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2 that 
results in the release of the extracellular domain.  Trastuzumab has been shown to inhibit HER2 
ectodomain cleavage in breast cancer cells.  In addition, trastuzumab is a potent mediator of 
antibody-dependent cell-mediated cytotoxicity.  In vitro, trastuzumab-mediated ADCC has been 
shown to be preferentially exerted on HER2-overexpressing cancer cells compared with cancer 
cells that do not over express HER2 (15). 
Trastuzumab will be administered IV at 6 mg/kg on Day 1 of each 21-day cycle. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
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8.2.1. 
Labeling, Packaging, Supply, and Storage 
Labeling 
Herceptin® is the brand name for trastuzumab. 
Packaging and Formulation 
Trastuzumab is a sterile, white to pale yellow, preservative free lyophilized powder for IV 
administration.  Each vial of trastuzumab contains 400 mg of trastuzumab, 9.9 mg of L histidine 
HCl, 6.4 mg of L histadine, 400 mg of α,α trehalose dihydrate, and 1.8 mg of polysorbate 20, 
USP.  Reconstitution with 20 mL of the supplied Bacteriostatic Water for Injection USP, 
containing 1.1% benzyl alcohol as a preservative, yields 21 mL of a multidose solution 
containing 21 mg/mL trastuzumab, at a pH of ~6. 
Supply 
Trastuzumab will be obtained from commercial sources. 
Storage 
From a microbiological point of view, the trastuzumab infusion solution should be used 
immediately.  If diluted aseptically, it may be stored for 24 hours when refrigerated at 2 to 8°C. 
8.2.2. 
Preparation and Administration 
Trastuzumab will be administered as an IV infusion in accordance with the Herceptin package 
insert. 
8.2.3. Precautions and Risks Associated with Trastuzumab 
For a complete discussion of risk information including precautions and adverse reactions for 
trastuzumab, please refer to the Herceptin package insert and the Investigator Brochure. 
8.2.3.1. 
Cardiac Dysfunction 
Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, cardiac failure, 
hypertension, cardiomyopathy, and cardiac death. 
Signs and symptoms of cardiac dysfunction were observed in a number of women who received 
trastuzumab alone or in combination with chemotherapy, most often anthracycline-based 
treatment.  Cardiac dysfunction was observed most frequently among patients who received 
trastuzumab plus anthracycline (doxorubicin/cyclophosphamide) chemotherapy (28%), 
compared with those who received anthracycline alone (7%), trastuzumab plus paclitaxel (11%), 
paclitaxel alone (1%), or trastuzumab alone (7%).  Severe disability or fatal outcome due to 
cardiac dysfunction was observed in ~1% of all patients. 
The nature of the observed cardiac dysfunction was similar to the syndrome of anthracycline-
induced cardiomyopathy.  The signs and symptoms of cardiac dysfunction usually responded to 
treatment.  Complete and partial responses were observed among patients with cardiac 
dysfunction.  The risk appears to be independent of tumor response to therapy.  Analysis of the 
clinical database for predictors of cardiac dysfunction revealed only advanced age and exposure 

 
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to an anthracycline as possible risk factors.  In the clinical trials, most patients with cardiac 
dysfunction responded to appropriate medical therapy, often including discontinuation of 
trastuzumab.  In many cases, patients were able to resume treatment with trastuzumab.  In a 
subsequent study using weekly paclitaxel and trastuzumab as first-line treatment for MBC, the 
observed incidence of serious cardiac dysfunction was 3% (N=95) (18).  Since the occurrence of 
cardiac dysfunction in the trastuzumab plus chemotherapy trial was an unexpected observation, 
no information is available regarding the most appropriate method for monitoring cardiac 
function in patients receiving trastuzumab.  Significant advances in the understanding and 
treatment of congestive heart failure have been made in the past several years, with many of the 
new drugs demonstrating the ability to normalize cardiac function.  Patients who develop 
symptoms of congestive heart failure while on trastuzumab should be treated according to 
standard guidelines. 
Management of Cardiac Safety 
All patients must have an ECHO or MUGA scan at baseline, and on a regular schedule 
throughout the course of the study.  Investigators are strongly urged to schedule MUGA scans or 
ECHOs at the same radiology facility where the patient’s baseline was done, whenever possible.  
MUGA scans or ECHO are required at protocol-specified time points and after any patient has 
any develops symptoms of congestive heart failure or discontinues protocol treatment. 
8.2.3.2. 
Infusion Associated Symptoms 
During the first infusion with trastuzumab, a symptom complex consisting of chills and/or fever 
is observed in approximately 40% of patients.  Other signs and/or symptoms may include nausea, 
vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia.  These symptoms are 
usually mild to moderate in severity, and occur infrequently with subsequent trastuzumab 
infusions.  These symptoms can be treated with an analgesic/antipyretic such as meperidine or 
paracetamol, or an antihistamine such as diphenhydramine. 
8.2.3.3. 
Serious Infusion Associated Events 
Serious adverse reactions to trastuzumab infusion including dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress have been 
reported infrequently.  In rare cases (4 per 10,000), these events were associated with a clinical 
course culminating in a fatal outcome.  Serious reactions have been treated with supportive 
therapy such as oxygen, beta-agonists, corticosteroids and withdrawal of trastuzumab as 
indicated. 
8.2.3.4. 
Hematologic Toxicity and Neutropenic Infections 
In the clinical trials, an increased incidence of anemia was observed in patients receiving 
trastuzumab plus chemotherapy compared with patients receiving chemotherapy alone.  The 
majority of these anemia events were mild or moderate in intensity and reversible; none resulted 
in discontinuation of trastuzumab therapy. 
In the clinical trials, the per-patient incidences of moderate to severe neutropenia and of febrile 
neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive 

 
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chemotherapy as compared to those who received chemotherapy alone.  In the post marketing 
setting, deaths due to sepsis in patients with severe neutropenia have been reported in patients 
receiving trastuzumab and myelosuppressive chemotherapy, although in controlled clinical trials 
(pre- and post-marketing), the incidence of septic deaths was not significantly increased.  The 
pathophysiologic basis for exacerbation of neutropenia has not been determined; the effect of 
trastuzumab on the pharmacokinetics of chemotherapeutic agents has not been fully evaluated.  
Secondary acute leukemia or myelodysplastic syndrome has been reported in 4 of approximately 
1200 patients who participated in trastuzumab clinical trials.  Patients treated with 
chemotherapeutic agents are known to be at increased risk for secondary leukemia.  The 
observed incidence of leukemia among trastuzumab-treated patients appears to be consistent 
with the expected incidence of leukemia among patients treated with chemotherapy for 
metastatic breast cancer.  Therefore, the contribution of trastuzumab to the etiology of acute 
leukemia or myelodysplastic syndrome in these cases is unclear. 
8.2.3.5. 
Pulmonary Toxicity 
Trastuzumab can cause fatal pulmonary toxicity which includes dyspnea, interstitial 
pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, 
pulmonary insufficiency, and hypoxia, acute respiratory distress syndrome, and pulmonary 
fibrosis.  Events like these may result from infusion reactions. 
8.3. 
Accountability of Investigational Products 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
trial drug supplies at the site.  The sites should destroy any unused product at the end of the study 
(or expired product, if any, during the study), per the site's SOPs for doing so.  A certificate of 
destruction that includes a description of the supplies, quantity destroyed, and method of 
destruction should be returned to the Sponsor. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Trial Population 
The efficacy and safety analysis populations will consist of all patients who received at least one 
dose of protocol treatment. 
9.2. 
Planned Interim Analyses 
No interim analyses are planned. 
9.3. 
Final Analysis Plan 
Three cohorts of patients with residual disease following neoadjuvant therapy (triple-negative 
[A], hormone-receptor-positive (ER and/or PR+) /HER2negative [B], and HER2-positive [C]) 
will be evaluated separately to obtain preliminary efficacy information.  With standard 
neoadjuvant therapy, the approximate 2-year DFS of patients who do not achieve pCR are as 
follows:  triple-negative, 40%; hormone-receptor-positive/HER2-negative, 80%; and HER2-
positive, 60%.  Treatment capable of providing relative improvement in these results by 40% in 

 
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the triple-negative cohort, 15% in the hormone-receptor-positive /HER2-negative cohort, or 25% 
in the HER2-positive cohort would be worthy of further development.  For a one-sided test of 
hypothesis at alpha = 0.10 and power = 0.80, the required sample sizes are 49, 38, and 47, 
respectively.  In order to adjust for potential non-evaluable patients, this preliminary study will 
treat 54, 42, and 52 patients, respectively, in the three cohorts.  This will allow determination of a 
2-year DFS within 95% confidence intervals for each subgroup, as follows:  
Cohort A  Triple-negative:  42.0% - 67.9% 
Cohort B  Hormone-receptor-positive (and HER2-negative) cohort: 78.7% - 96.9% 
Cohort C  HER2-positive cohort: 61.0% - 84.5% 
Evaluation of safety among patients in each cohort will also provide sufficient experience to 
determine the tolerability and toxicity of this regimen.  Safety data will be tabulated for patients 
who receive any amount of trial medication.  Adverse events will be tabulated by body system, 
preferred term, severity, and relation to treatment. Worst toxicity grades per patient will be 
tabulated for selected adverse event and laboratory measurements by using NCI CTCAE criteria 
V4.0. 
9.4. 
Data and Safety Monitoring Board 
The trial will not utilize the services of a Data and Safety Monitoring Board. 
9.5. 
Steering Committee 
The trial will not utilize the services of a Steering Committee. 
10. 
SAFETY REPORTING AND ANALYSES 
10.1. 
Safety Analyses 
Safety assessments will consist of monitoring and recording protocol-defined adverse events 
(AEs) and serious adverse events (SAEs); measurement of protocol specified hematology, 
clinical chemistry, and urinalysis variables; measurement of protocol-specified vital signs; and 
other protocol-specified tests that are deemed critical to the safety evaluation of the trial drug. 
10.2. 
Adverse Events 
The Principal Investigator is responsible for recognizing and reporting AEs and SAEs in the CRF 
and for notifying the SCRI Safety Department of SAEs within 1 day of initial awareness.  It is 
the Sponsor’s responsibility to report relevant SAEs to the applicable local, national, or 
international regulatory body. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 

 
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10.2.1. Definitions of Adverse Events 
An adverse event is the development of an undesirable medical condition, or the deterioration of 
a pre-existing medical condition following or during exposure to a medicinal product, whether or 
not considered causally related to the product. 
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory 
findings). 
10.2.2. Recording of Adverse Events 
All AEs of any patient during the course of the trial will be reported in the case report form, and 
the Investigator will give his or her opinion as to the relationship of the adverse event to trial 
drug treatment (i.e., whether the event is related or unrelated to trial drug administration).  If the 
adverse event is serious, it should be reported immediately (within 1 day of initial awareness) to 
the SCRI Safety Department. 
All AEs, regardless of seriousness or relationship to the trial drugs, spanning from initiation of 
treatment until 30 calendar days after discontinuation or completion of protocol-specific 
treatment as defined by the protocol for that patient, are to be recorded in the CRF. 
10.2.3. Abnormal Laboratory Values and Vital Signs 
The reporting of abnormalities of vital signs as adverse events should be avoided.  Abnormalities 
of vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the patient to discontinue trial treatment, or the Investigator insists that the 
abnormality should be reported as an adverse event (AE).  Any Grade 3 or 4 laboratory 
abnormalities or any clinically significant Grade 1 or 2 hematology or biochemistry laboratory 
values should be recorded as an AE.  If an abnormal laboratory value or vital sign is associated 
with clinical signs and/or symptoms, the sign or symptom should be reported as an AE, and the 
associated laboratory value or vital sign should be considered additional information that must be 
collected on the relevant CRF. 
10.2.4. Handling of Adverse Events 
All AEs resulting in discontinuation from the trial should be followed until resolution or 
stabilization.  Patients must be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment (e.g., chemotherapy, radiation, oral medications, 
targeted therapy, and surgery).  All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the Investigator, these values are not likely to 
improve because of the underlying disease.  In this case, the Investigators must record his or her 
reasoning for this decision in the patient’s medical record and as a comment on the CRF or EDC.  
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the Investigator as treatment related are to be reported. 

 
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10.3. 
Serious Adverse Events 
10.3.1. Definitions of Serious Adverse Events 
The definitions of SAEs are presented below.  The Principal Investigator is responsible for 
ensuring that each staff member involved in the trial is familiar with the content of this section. 
An SAE or reaction is defined as any untoward medical occurrence that: results in death, is 
immediately life-threatening, requires at least a 24-hour in-patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect. 
The definition of SAE also includes any important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the previous definition.  These should also usually be 
considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.  Progression of malignancy 
(including fatal outcomes), if documented by use of appropriate method, should not be reported 
as a serious AE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“in-patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 
 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one that was 
planned prior to entry in the trial), does not require reporting as a SAE to the SCRI Safety 
Department. 
10.3.2. Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs on the CRF and SAEs on the SAE Report Form. 

 
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Adverse events classified by the treating Investigator as serious require expeditious handling and 
reporting to the SCRI Safety Department in order to comply with regulatory requirements.  
Serious AEs may occur at any time from the start of trial treatment through the 30-day follow-up 
period after the last trial treatment.  The SCRI Safety Department must be notified of all SAEs, 
regardless of causality, within 1 day of the first knowledge of the event by the treating physician 
or research personnel. 
To report a SAE, the SAE Report Form should be completed with the necessary information.  
All SAEs and medically confirmed deaths (regardless of causality assessment) occurring on trial 
treatment or within 30 days of last trial treatment must be reported to the Sponsor as SAEs on the 
SAE Report Form and followed until resolution (with autopsy report, if applicable). 
Deaths occurring within 30 days after last trial treatment that are deemed ‘possibly’ or ‘probably’ 
related to trial drug must be reported as SAEs on the SAE Report Form within 1 day of first 
knowledge of the event by the treating physician or research personnel (with an autopsy report, if 
available). 
Deaths occurring 30 days after last trial treatment and not attributed to trial treatment 
(e.g., disease progression) need not be reported as SAEs, but simply captured on the appropriate 
CRF. 
The SAE report should be sent to the SCRI Safety Department via fax or e-mail using the contact 
information listed below: 
SCRI Safety Department  
Fax #:  866-807-4325 
Safety Dept. Email:  CANN.SAE@scresearch.net 
 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the SCRI Safety Department as soon as it is available; these reports should be 
submitted using the SCRI SAE Report Form. 
Investigators must report SAEs and follow-up information to their responsible IRBs according to 
the policies of the responsible IRB. 
10.3.3. Sponsor Serious Adverse Event Reporting Requirements 
Sarah Cannon Research Institute will forward all serious adverse event information, where 
eribulin is the suspected product, to Eisai (Fax # 732-791-1111) within 1 business day of SCRI 
Safety Department personnel becoming aware of the SAE. 
The Sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Conference on Harmonisation (ICH) guidelines, FDA regulations, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements. 

 
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The Sponsor is responsible for reporting unexpected fatal or life-threatening events associated 
with the use of the trial drugs to the regulatory agencies and competent authorities via telephone 
or fax within 7 calendar days after being notified of the event.  The Sponsor will report all 
related but unexpected SAEs including non-death/non-life-threatening related but unexpected 
SAEs associated with the use of the trial medications to the appropriate competent authorities 
(according to local guidelines), Investigators, and central IRBs/IECs (except in the United States 
where Investigators are responsible for reporting to their IRBs per local requirements) by a 
written safety report within 15 calendar days of notification. 
10.4. 
Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SCRI SAE Report Forms and AE CRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE CRF.  
Adverse events that meet the definition of an SAE should additionally be reported following the 
procedures noted in Section 10.3.2. 
10.4.1. Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Coordinating Investigator or designated physician, the AEs constitute components 
of a recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SCRI SAE Report Form and/or AE CRF).  If a diagnosis is subsequently 
established, it should be reported as follow-up information is available.  If a diagnosis is 
determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms 
should be updated to reflect the diagnosis. 
10.4.2. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
CRF.  If a persistent AE becomes more severe or lessens in severity, it should be recorded on a 
separate SAE Report Form and/or AE CRF. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
CRF. 
10.4.3. Abnormal Laboratory Values 
Any Grade 3 or 4 laboratory abnormalities or any clinically significant Grade 1 or 2 hematology 
or biochemistry laboratory values should be recorded as an AE.  If an abnormal laboratory value 
or vital sign is associated with clinical signs and/or symptoms, the sign or symptom should be 
reported as an AE, and the associated laboratory value or vital sign should be considered 

 
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additional information that must be collected on the relevant CRF.  If the laboratory abnormality 
is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report 
Form or AE CRF. 
10.4.4. Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Trial Discontinuation” 
CRF.  All other on-trial deaths, regardless of attribution, will be recorded on an SAE Report 
Form and expeditiously reported to the SCRI Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and AE page of the CRF.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the CRF AE page.  During post-trial 
survival follow-up, deaths attributed to progression of disease will be recorded only on the 
“After Progressive Disease Follow-Up” CRF. 
10.4.5. Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of preexisting hospitalization 
should be documented and reported as an SAE unless specifically instructed otherwise in this 
protocol.  There are some hospitalizations that do not require reporting as an SAE when there is 
no occurrence of an AE (refer to Section 10.3.1). 
10.4.6. Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the trial.  Such conditions 
should be recorded on the General Medical History CRF.  A pre-existing medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the trial.  When recording such events on an SAE Report Form and/or AE CRF, 
it is important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors. 
10.4.7. Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  
Please refer to Section 10.5 for specific instructions. 
10.5. 
Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously (see 
Section 10.2.1). 
10.5.1. Pregnancy, Abortion, Birth Defects/Congenital Abnormalities 
If a patient becomes pregnant while enrolled in the trial, a Pregnancy Form should be completed 
and faxed to the SCRI Safety Department expeditiously, irrespective of whether or not it meets 

 
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the criteria for expedited reporting.  Abortions (spontaneous, accidental, or therapeutic) must 
also be reported to the SCRI Safety Department. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
10.5.2. Trial Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or 
intentional overdose with the trial treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the SCRI Safety Department within one day using the 
corresponding screens in the CRF, and following the same process described for SAE reporting 
(Section 10.3.2), if the overdose is symptomatic. 
An overdose is defined as a dose of eribulin or trastuzumab administered to a patient that is 
greater than the protocol-defined dose for the patient.  For information on how to manage an 
overdose, see the respective Investigator Brochures. 
11. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline and Code of Federal Regulations (CFR) Title 21 part 312, 
applicable government regulations, institutional research policies and procedures and any other 
local applicable regulatory requirement(s). 
11.1. 
Institutional Review Board Approval 
The trial protocol, ICF, IB, available safety information, patient documents (e.g., trial diary), 
patient recruitment procedures (e.g., advertisements), information about payments (i.e., Principal 
Investigator payments) and compensation available to the patients and documentation evidencing 
the Principal Investigator’s qualifications should be submitted to the IRB for ethical review and 
approval if required by local regulations, prior to the trial start. 
The Sponsor and/or designee will follow all necessary regulations to ensure appropriate, initial, 
and ongoing, IRB trial review.  The Sponsor (as appropriate) must submit and, where necessary, 
obtain approval from the IRB for all subsequent protocol amendments and changes to the ICF.  
Investigators will be advised by the Sponsor or designee whether an amendment is considered 
substantial or non-substantial and whether it requires submission for approval or notification 
only to an IRB. 
11.2. 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to trial initiation. If required, the 
Sponsor will also ensure that the implementation of substantial amendment to the protocol and 
other relevant trial documents happen only after approval by the relevant regulatory authorities. 

 
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11.3. 
Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between 
the Principal Investigator or site and the Sponsor. 
11.4. 
Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form. 
The informed consent form (ICF) will be submitted for approval to the IRB that is responsible 
for review and approval of the trial.  Each consent form must include all of the relevant elements 
currently required by the FDA, as well as local county authority or state regulations. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial.  Once the essential information has been provided to the prospective 
candidate, and the Investigator is sure that the individual candidate understands the implications 
of participating in this trial, the candidate will be asked to give consent to participate in the trial 
by signing an informed consent form.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the informed consent form, to 
include the patient’s signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
patients, the patient’s consent to continue participation in the trial should be obtained. 
11.5. 
Confidentiality 
11.5.1. Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPPA) and national data protection laws, 
as applicable.  HIPPA regulations require that, in order to participate in the trial, a patient must 
sign an authorization from the trial that he or she has been informed of following:  
 

 
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 What protected health information (PHI) will be collected from patients in this trial; 
 Who will have access to that information and why; 
 Who will use or disclose that information;  
 That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws; 
 The information collected about the research trial will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the trial; 
 Whether the authorization contains an expiration date; and 
 The rights of a research patient to revoke his or her authorization. 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled trial period. 
In compliance with ICH Good Clinical Practice (GCP) guidelines and applicable parts of 21 CFR 
it is a requirement that the Investigator and institution permit authorised representatives of 
Sponsor, the regulatory authorities, and the IRB direct access to review the patient’s original 
medical records at the site for verification of trial-related procedures and data. 
Measures to protect confidentiality include: only a unique trial number and initials will identify 
patients on the CRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the CRF or database.  No material bearing a patient’s 
name will be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
11.5.2. Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the SCRI database, 
and shall be treated in compliance with all applicable laws and regulations.  When archiving or 
processing personal data pertaining to the Investigator or sub-Investigator, SCRI shall take all 
appropriate measures to safeguard and prevent assess to this data by any unauthorized party. 
11.6. 
Financial Information 
SCRI Oncology Research Consortium is sponsoring this trial.  Eisai will provide funding to 
SCRI Oncology Research Consortium for this trial and will also provide the trial drug, eribulin, 
for all trial participants for the duration of the trial.  The physicians participating in this trial will 
receive compensation from SCRI Oncology Research Consortium. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 53 of 68 
12. 
RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
12.1. 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor.  All amendments require review and approval of all pharmaceutical companies 
and the Principal Investigator supporting the trial.  The written amendment must be reviewed and 
approved by the Sponsor, and submitted to the IRB at the Investigator’s facility for the board’s 
approval. 
Amendments specifically involving change to trial design, risk to patient, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor after IRB approval and specifically when an increase to dosing or patient exposure 
and/or subject number has been proposed; or, when the addition or removal of an Investigator is 
necessitated. 
Items requiring a protocol amendment with IRB and/or FDA approval include, but are not 
limited to, the following: 
 
Change to trial design  
 
Risk to patient 
 
Increase to dose or patient exposure to drug 
 
Subject number increase 
 
Addition or removal of tests and / or procedures 
 
Addition/removal of a new Investigator 
It should be further noted that, if an amendment to the protocol substantially alters the trial 
design or the potential risks to the patients, their consent to continue participation in the trial 
should be obtained. 
12.2. 
Documentation Required to Initiate the Trial 
Before the trial may begin, certain documentation required by FDA regulations must be provided 
by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Research Institute 
SCRI Oncology Research Consortium 
Network Regulatory Affairs 
3322 West End Avenue, Suite 900 
Nashville, Tennessee  37203 
Tel. #:  (615) 329-7274 
Fax #:  (615) 297-2793 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 54 of 68 
Documents at a minimum required to begin a trial in the US include, but are not limited to, the 
following: 
 A signature-authorized protocol and contract 
 A copy of the official IRB approval of the trial and the IRB members list 
 Current Curricula Vita for the principal Investigator and any associate Investigator(s) 
who will be involved in the trial 
 Indication of appropriate accreditation for any laboratories to be used in the trial and a 
copy of the normal ranges for tests to be performed by that laboratory 
 Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
 A copy of the IRB-approved consent form containing permission for audit by 
representatives of the Sponsor, SCRI Oncology Research Consortium, the IRB, and the 
FDA 
 Financial disclosure forms for all Investigators listed on Form FDA 1572 
 GCP Certificate for trial training 
 Site qualification reports, where applicable 
 Verification of Principal Investigator acceptability from local and/or national debarment 
lists 
12.3. 
Trial Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated trial duties and should ensure that all persons assisting in the conduct of the trial 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the CRFs are to be included on this document. All entries in the patient’s CRF are to be 
supported by source documentation, where appropriate. 
Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient’s CRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Principal Investigator and trial staff are responsible for maintaining a comprehensive and 
centralised filing system (Site Trial File/SSF or ISF) of all trial-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  The ISF/SSF must consist of those documents that individually 
or collectively permit evaluation of the conduct of the trial and the quality of the data produced.  
The ISF/SSF should contain as a minimum all relevant documents and correspondence as 
outlined in ICH GCP Section 8 and 21 CFR Part 312.57, including key documents such as the IB 
and any amendments, protocol and any amendments, signed ICFs, copies of completed CRFs, 
IRB approval documents, patient identification lists, enrollment logs, delegation of authority log, 
staff qualification documents, laboratory normal ranges, records relating to the trial drug 
including accountability records.  Drug accountability records should, at a minimum, contain 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 55 of 68 
information regarding receipt, shipment, and disposition.  Each form of drug accountability 
record, at a minimum, should contain Principal Investigator name, date drug shipped/received, 
date, quantity and batch/code, or lot number for identity of each shipment.  In addition, all 
original source documents supporting entries in the CRF must be maintained and be readily 
available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR 
Part 56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment / delivery of the 
drug for investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., CRFs and medical records), all 
original, signed informed consent forms, and copies of all CRFs, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the Investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  The Sponsor will notify the 
Investigators/institutions when the trial-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the trial, both the Sponsor 
and/or its representative should be prospectively notified.  The trial records must be transferred 
to an acceptable designee, such as another Investigator, another institution, or to Sponsor.  The 
Investigator must obtain the Sponsor’s written permission before disposing of any records, even 
if retention requirements have been met. 
12.4. 
Data Collection 
The trial CRF is the primary data collection instrument for the trial. CRFs will be completed 
using the English language and should be kept current to enable the monitor to review the 
patients’ status throughout the course of the trial. 
In order to maintain confidentiality, only trial number, patient number, initials and date of birth 
will identify the patient in the CRF.  If the patient’s name appears on any other document 
(e.g., laboratory report), it must be obliterated on the copy of the document to be supplied to 
SCRI and replaced instead with the patient number and patient’s initials.  The Investigator will 
maintain a personal patient identification list (patient numbers with corresponding patient 
identifiers) to enable records to be identified and verified as authentic.  Patient data/information 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 56 of 68 
will be kept confidential, and will be managed according to applicable local, state, and federal 
regulations. 
All data requested on the CRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the CRF, a 
note should be created verifying that the field was “Not Done” or “Unknown”.  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
12.5. 
Trial Monitoring, Auditing, and Inspecting 
The Investigator will permit trial-related monitoring, quality audits, and inspections by the 
Sponsor, government regulatory authorities, the Sponsor or its representative(s) of all trial-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The Investigator will ensure the capability for inspections of applicable trial-
related facilities.  The Investigator will ensure that the trial monitor or any other compliance or 
QA reviewer is given access to all trial-related documents and trial-related facilities. 
Participation as an Investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor or its representative(s). 
At the Sponsor’s discretion, Source Document Verification may be performed on all data items 
or a percentage thereof. 
12.6. 
Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for trial conduct, data generation & collection, 
recording of data/documentation and reporting according to the protocol, GCP and any 
applicable local, national or international regulations. 
12.7. 
Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential.  The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as per the Sponsor’s publication strategy. 
The financial disclosure information will be provided to the Sponsor prior to trial participation 
from all Principal Investigators and Sub-Investigators who are involved in the trial and named on 
the FDA 1572 form. 
The SCRI Oncology Research Consortium will register the trial on www.clinicaltrials.gov.  In 
addition, the SCRI Oncology Research Consortium will publish the results of the trial.  
Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial.  The Investigator acknowledges that the trial is 
part of a multi-center trial and agrees that any publication by the Investigator of the results of the 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 57 of 68 
trial conducted at research site shall not be made before the first multi-center publication.  In the 
event there is no multi-center publication within 15 months after the trial has been completed or 
terminated at all trial sites, and all data has been received, the Investigator shall have the right to 
publish its results from the trial, subject to the notice requirements described herein and subject 
to acknowledgement of SCRI Oncology Research Consortium as appropriate. Investigator shall 
provide SCRI Oncology Research Consortium thirty (30) days to review a manuscript or any 
poster presentation, abstract or other written or oral material which describes the results of the 
trial for the purpose only of determining if any confidential or patentable information is disclosed 
thereby. If SCRI Oncology Research Consortium requests in writing, the Investigator shall 
withhold any publication or presentation an additional sixty (60) days solely to permit SCRI 
Oncology Research Consortium to seek patent protection and to remove any SCRI Confidential 
Information from all publications. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 58 of 68 
13. 
REFERENCES 
1. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long –term 
survival in patients with triple-negative breast cancer. J Clin Oncol 2008; 26: 1275-1281. 
2. Carey L, Dees C, Sawyer L, et al. The triple negative paradox: primary tumor 
chemosensitivity of breast cancer subtypes. 2007;13: 2329-2334. 
3. Thomas E, Holmes FA, Smith TL, et al. The use of alternate, non-cross-resistant adjuvant 
chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based 
regimen in women with operable breast cancer: long-term results from a prospective 
randomized trial. J Clin Oncol 2004; 22:2294-2302. 
4. Hirata Y, Uemura D. Halichondrins: antitumor polyether macrolides from a marine 
sponge. Pure Appl. Chem., 1986;58:701-710. 
5. Bai R, Paull KD, Herald CL, et al. Halichondrin B and homohalichondrin B, marine 
natural products binding in the vinca domain of tubulin. Discovery of tubulin-based 
mechanism of action by analysis of differential cytotoxicity data. J Biol Chem. 
1991;266:15882-15889. 
6. Fodstad O, Breistol K, Pettit GR, et al. Comparative antitumor activities of halichondrins 
and vinblastine against human tumor xenografts. J Exp Ther Oncol. 1996;1:119-125. 
7. Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, et al. In vitro and 
in vivo anticancer activities of synthetic macrocyclic ketone analogues of Halichondrin 
B. Cancer Res. 2001;61:1013-1021. 
8. Hamel E. Natural products which interact with tubulin in the vinca domain: maytansine, 
rhizoxin, phomopsin A, dolastatins 10 and 15 and Halichondrin B. Pharmacol Ther. 
1992;55:31-51. 
9. Luduena RF, Roach MC, Prasad V, Pettit GR. Interaction of Halichondrin B and 
homohalichondrin B with bovine brain tubulin. Biochem Pharmacol. 1993;45:421-427. 
10. Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, 
Wilson L. The primary antimitotic mechanism of action of the synthetic halichondrin 
E7389 is suppression of microtubule growth. Mol Cancer Ther., 2005;4:1086-1095. 
11. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, 
Littlefield BA. Induction of morphological and biochemical apoptosis following 
prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer 
Res. 2004;64:5760-5766. 
12. Towle MJ, Littlefield BA. Unpublished observations, Eisai Research Institute, 2003. 
13. Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, et al. 
Structure-activity relationships of synthetic halichondrin B analog E7389: in vitro 
susceptibility to PgP-mediated drug effflux [abstract]. Proc Amer Assoc Cancer Res. 
2003;44. Abstract 2751. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 59 of 68 
14. Kuznetsov G, TenDyke K, Littlefield BA. Unpublished observations, Eisai Research 
Institute, 2003. 
15. Cortes J, O’Shaughnessy, Loesch D, et al. Eribulin monotherapy versus treatment of 
physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 
open-label randomised study Lancet 2011; 377-914-923. 
16. E7389 Investigator’s Brochure Oct 22, 2010 
17. Gong SJ, Jin CJ, Rha SY, et al.  Growth inhibitory effects of trastuzumab and 
chemotherapeutic drugs in gastric cancer cell lines. Cancer Letter 2004; 214(2):215-24. 
18. Seidmen AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, et al. Weekly 
Trastuzumab and Paclitaxel Therapy for Metastatic Breast Cancer With Analysis of 
Efficacy by HER2 Immunophenotype and Gene Amplification. J Clin Oncol 2001; 
19(10):2587-95. 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 60 of 68 
14. 
APPENDICES 
Appendix A: 
ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry on 
all pre-disease performance without restriction. 
 
100 
Normal, no complaints, no evidence of disease. 
 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, office 
work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed < 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 
50% of waking hours. 
 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs. 
 
50 
Requires considerable assistance and frequent 
medical care. 
3 
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
40 
Disabled, requires special care and assistance 
 
30 
Severely disabled, hospitalization indicated.  
Death no imminent. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed 
or chair. 
 
20 
Very sick, hospitalization indicated.  Death not 
imminent. 
 
10 
Moribund, fatal processes progressing rapidly. 
5 
Dead 
0 
Dead 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 61 of 68 
Appendix B: 
New York Heart Association Classifications 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
event at rest.  If any physical activity is undertaken, discomfort is increased. 
This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 
2228. 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 62 of 68 
Appendix C Schedule of Assessments for BRE 186 (Residual Breast Cancer) 
Procedures 
Pre-
Treatment 
Trial Treatments (6 Cycles) 
End of Study 
Treatmentk 
Follow-up 
Baselinee 
Day 1 of Every 
Cycleh 
 
Day 8 of Every 
Cycle 
 
Post Cycle 3j 
After 
Completion of 
Treatmentl 
TESTS & OBSERVATIONS 
 
 
 
 
 
 
Medical history (including baseline 
signs/symptoms) 
X 
X 
 
 
X 
X 
Physical examination, vital signs, height, 
weighta 
X 
X 
 
 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
X 
ECG 
X 
Xi 
 
 
X 
 
ECHO or MUGA 
Xf 
 
 
Xf 
Xf 
 
Adverse event evaluation 
 
X 
X 
 
X 
 
Concomitant medication review 
X 
X 
 
 
X 
X 
Survival status 
 
 
 
 
 
X 
LABORATORY TESTS 
 
 
 
 
 
 
CBC, including 3-part differential and 
platelets 
X 
Xm 
X 
 
X 
X 
CMP plus magnesiumb 
X 
Xm 
 
 
X 
X 
PT/INR and PTTc 
X 
Xc 
 
 
 
 
Serum pregnancy testd 
X 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
CT scans of the chest and abdomen 
Xg 
 
 
 
 
 
CT scan or MRI of the brain 
Xg 
 
 
 
 
 
PET scan or Bone scan (PET scan is 
preferred) 
Xg 
 
 
 
 
 
 

 
Trial Drug:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number: BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 63 of 68 
Appendix C: 
Schedule of Assessments for BRE 186 (continued) 
a 
Physical examinations will include measurements of weight, vital signs (resting heart rate, blood pressure, respiratory rate, oral temperature), and assessment of peripheral neuropathy.  
At the baseline visit, height will also be recorded. 
b 
CMP assessment includes the following laboratory tests:  glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, total bilirubin, total 
protein, albumin, plus magnesium. 
c 
After the baseline visit, PT/INR and PTT will be checked for any patients (in all treatment arms) who are receiving warfarin. 
d 
A serum pregnancy test will be performed only for women of childbearing potential (see Section 3.3.1). 
e 
The physical examination, ECOG performance status, CBC, CMP, PT/INR and PTT, ECG, concomitant medication review, and pregnancy test should be done ≤7 days prior to 
initiation of treatment.  Baseline laboratory assessments will be allowed up to 7 days outside of the 7-day specified window, provided that critical laboratory assessments (CBC, CMP, 
pregnancy test, and PT/INR and PTT [for patients receiving warfarin only]) are repeated on Cycle 1, Day 1 prior to study treatment. 
f 
ECHO or MUGA for patients in Cohort C only (eribulin plus trastuzumab) 
g 
Complete staging work-up to confirm localized disease should include computed tomography (CT) scans of the chest and abdomen/pelvis (abdomen/pelvis preferred; abdomen 
accepted), a CT scan of the head or MRI of the brain (if symptomatic), and either a positron emission tomography (PET) scan or a bone scan.  (Note:  a PET/CT is acceptable for 
baseline imaging in lieu of CT examinations or bone scan).  Negative scans performed prior to the initiation of neoadjuvant therapy, or at any subsequent time, are acceptable and do 
not need to be repeated. 
h 
For the Day 1 visits of each treatment cycle, a window for variations from the protocol-specified treatment of up to ± 7 days is allowed, provided that the laboratory value criteria for 
treatment and other protocol requirements are met. 
i 
ECGs are required at the Pre-Treatment visit and on Day 1 of each cycle.  During the treatment period, if an ECG indicates a QTc interval 500 msec, then two additional ECGs should 
be obtained within 5 minutes to confirm the abnormality.  The average QTc will be determined from the three ECG tracings by manual evaluation, and will be used to determine 
continued eligibility.  If the average QTc is <500 msec, the patient may continue therapy.  If the average QTc is ≥500 msec, the study treatment should be discontinued immediately.  
The patient should be treated appropriately for QTc prolongation, and monitored until resolution is documented by a repeat ECG, with QTc intervals returning to <480 msec (see 
Section 7.7). 
j 
Post Cycle 3 prior to the start of Cycle 4 treatment 
k 
All patients will undergo the end-of-treatment assessments listed within 30 days after the last dose of eribulin treatment due to completion of the planned study treatment period, disease 
progression, or once a patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or the study physician.  If treatment is discontinued 
because of toxicity or any other reason(s) at a treatment visit and no study treatment is administered, that visit may fulfill the End-of-Treatment Visit. 
l 
After completion of eribulin treatment, patients will be followed every 3 months during years 1 and 2, for toxicity and disease progression. 
m 
CBC, including 3 part differential and platelets and CMP plus magnesium may be done up to 72 hours prior to treatment. 
 

 
Trial Drugs:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number:  BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 64 of 68 
 
Appendix D: 
Guidelines Regarding Women of Childbearing Potential 
 
Women of Child-Bearing Potential are Defined as Follows: 
 Any female who has experienced menarche and does not meet the criteria for 
“Women Not of Childbearing Potential”. 
  
Women Not of Childbearing Potential are Defined as Follows: 
 
Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) 
 
Women who are >45 years of age, not using hormone replacement therapy and 
who have experienced total cessation of menses for at least 1 year OR who have 
a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value 
<40pg/mL (140 pmol/L) 
 
Women who are >45 years of age, using hormone replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have had 
documented evidence of menopause based on FSH >40 mIU/mL and estradiol 
<40 pg/mL prior to initiation of hormone replacement therapy 
   
Acceptable Contraception Methods: 
Male patients with female partners of child-bearing potential and women patients of childbearing 
potential are required to use two forms of acceptable contraception, including one barrier 
method, during their participation in the trial and for 3 months (women) or 6 months (men) 
following discontinuation of the trial drugs.  Male patients must also refrain from donating sperm 
for 6 months following discontinuation of the trial drugs. 
The following are acceptable forms of barrier contraception:  
 
Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
 
The following are acceptable forms of secondary contraception, when used with a barrier method 
and spermicide:  
 
True abstinence.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception 
 
Male sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate)  
 
Placement of an intrauterine device (IUD) or intrauterine system (IUS), with the 
exception of IUD progesterone T 

 
Trial Drugs:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number:  BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 65 of 68 
Appendix D: 
Guidelines Regarding Women of Childbearing Potential (continued) 
 
The following are unacceptable forms of contraception for women of childbearing potential:  
 
IUD progesterone T  
 
Female condom  
 
Natural family planning (rhythm method) or breastfeeding  
 
Fertility awareness  
 
Withdrawal  
 
Cervical shield 
 
 

 
Trial Drugs:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number:  BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 66 of 68 
Appendix E Prohibited Drugs That Prolong QT Interval and/or Induce Torsades De 
Pointes and Class IA and III Antiarrhythmics 
 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males,TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given IV or at higher-than- recommended doses, 
risk of sudden death, QT prolongation and torsades 
increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 sibstrate with 
narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme. 

 
Trial Drugs:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number:  BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 67 of 68 
Appendix E  Prohibited Drugs That Prolong QT Interval and/or Induce Torsades De 
Pointes and Class IA and III Antiarrhythmics (continued) 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
 
Amantadine 
possible risk for Torsades de Pointes 
 
Amitriptyline 
conditional risk for Torsades de Pointes 
 
Azithromycin 
possible risk for Torsades de Pointes 
 
Chloral hydrate 
possible risk for Torsades de Pointes 
 
Citalopram 
conditional risk for Torsades de Pointes 
 
Clomipramine 
conditional risk for Torsades de Pointes 
 
Clozapine 
possible risk for Torsades de Pointes 
 
Desipramine 
conditional risk for Torsades de Pointes 
 
Diphenhydramine 
conditional risk for Torsades de Pointes 
 
Dolasetron 
possible risk for Torsades de Pointes 
 
Doxepin 
conditional risk for Torsades de Pointes 
 
Dronedarone 
possible risk for Torsades de Pointes 
 
Felbamate 
possible risk for Torsades de Pointes 
 
Flecainide 
possible risk for Torsades de Pointes 
 
Fluoxetine 
conditional risk for Torsades de Pointes 
 
Foscarnet 
possible risk for Torsades de Pointes 
 
Fosphenytoin 
possible risk for Torsades de Pointes 
 
Galantamine 
conditional risk for Torsades de Pointes 
 
Gatifloxacin 
possible risk for Torsades de Pointes 
 
Gemifloxacin 
possible risk for Torsades de Pointes 
 
Granisetron 
possible risk for Torsades de Pointes 
 
Imipramine 
conditional risk for Torsades de Pointes 
 
Indapamide 
possible risk for Torsades de Pointes 
 
Isradipine 
possible risk for Torsades de Pointes 
 
Levofloxacin 
possible risk for Torsades de Pointes 
 
Lithium 
possible risk for Torsades de Pointes 
 
Mexiletine 
conditional risk for Torsades de Pointes 
 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
 
Moxifloxacin 
possible risk for Torsades de Pointes 
 
Nicardipine 
possible risk for Torsades de Pointes 
 
Nortriptyline 
conditional risk for Torsades de Pointes 
 
Octreotide 
possible risk for Torsades de Pointes 
 
Ofloxacin 
possible risk for Torsades de Pointes 
 
 
 

 
Trial Drugs:  Eribulin, SCRI (Sponsor) Clinical Trial Protocol Number:  BRE 186 
Date of Original Protocol:  26MAY2011 
Date of this Version:  20MAR2013, Amendment 2 
CONFIDENTIAL 
Page 68 of 68 
Appendix E  Prohibited Drugs That Prolong QT Interval and/or Induce Torsades De 
Pointes and Class IA and III Antiarrhythmics (continued) 
 
Drug 
QT risk 
Comment 
Ondansetron 
possible risk for Torsades de Pointes 
 
Oxytocin 
possible risk for Torsades de Pointes 
 
Paliperidone 
possible risk for Torsades de Pointes 
 
Paroxetine 
conditional risk for Torsades de Pointes 
 
Perflutren lipid 
microspheres 
possible risk for Torsades de Pointes 
 
Protriptyline 
conditional risk for Torsades de Pointes 
 
Ranolazine 
possible risk for Torsades de Pointes 
 
Risperidone 
possible risk for Torsades de Pointes 
 
Roxithromycin* 
possible risk for Torsades de Pointes 
*not available in the United 
States 
Sertindole 
possible risk for Torsades de Pointes 
 
Sertraline 
conditional risk for Torsades de Pointes 
 
Solifenacin 
conditional risk for Torsades de Pointes 
 
Tizanidine 
possible risk for Torsades de Pointes 
 
Trazodone 
conditional risk for Torsades de Pointes 
 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
 
Trimipramine 
conditional risk for Torsades de Pointes 
 
Venlafaxine 
possible risk for Torsades de Pointes 
 
Ziprasidone 
possible risk for Torsades de Pointes 
 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
  Class IA and III Antiarrhythmics 
 
Class IA antiarrhythmics include: 
 
Disopyramide (Norpace) 
 
Procainimide (Procainimide HCI, Procan, Procanabid, Pronestyl) 
 
Quinidine (Quinidine sulfate, Quinaglute, Quinidex, Cardioquin) 
Class III antiarrhythmics include: 
 
Amiodarone (Cordarone®) 
 
Azimilide (Stedicor®) 
 
Bepridil 
 
Dofetilide (Tikosyn®) 
 
Ibutilide (Corvert®) 
 
Sotalol (Betapace®) 
 
Tedisamil