Clinical trial NCT01827787
Conditions: Breast Cancer
Keywords: metastatic breast cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2013-05-01; Completion date: 2016-05-01
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Improvements in outcomes with metastatic breast cancer (MBC) have been observed in the last 30 years, however, overall prognosis remains poor with median survival of 2 to 3 years. Long term complete responses are observed only for a minority of MBC patients (2-5%) and MBC remains an incurable disease for most patients. Eribulin is a chemotherapy approved by the US FDA in November of 2010 to treat patients with MBC who have received at least two prior chemotherapy regimens. In this research study, the investigators are looking to see how well eribulin helps participants with MBC in an earlier-line setting. Eribulin works by interfering with cancer cell division, growth and spread.

Detailed description:
Based on positive results in heavily pre-treated MBC patients, eribulin is being studied as first-line or second-line chemotherapy treatment. This is a non-randomized, open label study with participants enrolled in one of two cohorts: Cohort 1. Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) or Cohort 2: Triple negative breast cancer (TNBC) meaning HR-negative/HER2-negative (HR-/HER2-). HR- means progesterone receptor-negative (PR-) and estrogen receptor-negative (ER-). Beyond efficacy as measured primarily by response to treatment, investigators will evaluate safety, tolerability and quality of life. In particular, it is hypothesized that eribulin may have lower rates of neuropathy, a common side effect of many of the major chemotherapeutics with activity in MBC. The investigators will study the effect eribulin has on the nerves through regular questionnaires that ask about any nerve-related symptoms. The investigators also plan to send blood samples to explore if gene markers may indicate increased sensitivity to the nerve effects of eribulin.

Arms: arm 1: Eribulin: 1.4 mg/m2 administered intravenously over 2-5 minutes on days 1 and 8 of each 21 day cycle

Participants remained on single agent eribulin until disease progression or withdrawal for other reasons. arm 2: Eribulin: 1.4 mg/m2 administered intravenously over 2-5 minutes on days 1 and 8 of each 21 day cycle

Participants remained on single agent eribulin until disease progression or withdrawal for other reasons.
Interventions: intervention 1: Eribulin
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol number: 13-077 
 
 
Official Title of the study: A Phase 2 Study of Eribulin in Patients with HER2-
negative, Metastatic Breast Cancer: Evaluation of Efficacy, Toxicity, and Patient-
Reported Outcomes 
 
NCT number: NCT01827787 
 
Date of the document: February 23, 2016 


Status Page 
 
 
 
PROTOCOL 13-077 
 
 
 
 
 
 
 
                                                            
Closed To New Accrual  
 
              
 
 
 
 
 
 
 
 
 
Closure Effective Date:  04/15/2016 
No new subjects may be enrolled in the study as described above.  
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 
 
 
 


Page 1 of 1 
Date Submitted: [09/04/13] 
Date Posted: [09/09/13] 
Alert Page  
DF/HCC Protocol #:  [13-077] 
 
Revised: 07.01.13 
Protocol Clarifications (non-drug related e.g. eligibility criteria, study 
assessments) 
 
Protocol 5.5.2, Assessments in the Treatment Phase, page 22: Provider 
Reported CTCAE Form should be completed by MD, NP /PA or Research Nurse 
the same day patients complete the QOL surveys (C1D1, C2D1, C3D1, and then 
day 1 of every other cycle). Please note: 
1. Please include the following information when completing the Provider 
Reported CTCAE Form: Subject MRN, subject initials, date, visit #, and 
provider name and signature. This information is missing from the form on 
page 34 (table 2) and page 80 (Appendix 8). [Amendment forthcoming] 
2. Provider reported CTCAE assessment is missing from Section 9, Table 3: 
Study Calendar. [Amendment forthcoming] 
 
Protocol Section 9, Table 3: Study Calendar, page 37: Tumor assessment 
must be performed every 9 weeks (within 1 week prior to C4D1, C7D1, C10D1, 
etc) during study treatment until PD is documented. That is, Cycle 3 Day 15-21, 
Cycle 6 Day 15-21, Cycle 9 Day 15-21, etc. Study Calendar currently indicates 
tumor assessment should be done prior to C3D1, which is incorrect. [Amendment 
forthcoming]   


DFCI Protocol No: 13-077
Front Sheet
11/10/2017 09:23 AM
Report Generated:
A Phase 2 Study of Eribulin in Patients with HER2-Negative, Metastatic Breast Cancer: Evaluation of Efficacy,
Toxicity and Patient-Reported Outcomes
Title:
Overall Principal Investigator
Email
Institution
Mayer, Erica L
EMAYER@PARTNERS.ORG
Dana-Farber Cancer Institute
Overall Institution:
Dana-Farber Cancer Institute
Primary Contact(s) for Questions
Email
Phone
Andrews, Chelsea
ChelseaP_Andrews@dfci.harvard.e
du
617-632-6210
Kelley, Cassidy Elizabeth
ckelley14@partners.org
2-3548
Site Responsible PI(s)
Email
Institution
Briccetti, Frederick
fbriccetti@partners.org
Dana-Farber Cancer Institute at NHOH
Constantine, Michael
michael_constantine@dfci.harvard.
edu
Dana-Farber Cancer Institute at Milford
Faggen, Meredith G
Meredith_Faggen@dfci.harvard.ed
u
Dana-Farber Cancer Institute at South
Shore
Tung, Nadine
ntung@bidmc.harvard.edu
Beth Israel Deaconess Medical Center
Total Study-Wide Enrollment Goal:
90
Total DF/HCC Estimated Enrollment Goal:
90
Phase: II
Age:
Adults
Age Ranges:
18+
Will all subjects be recruited from pediatric clinics?
CTEP Study:
No
Management Group(s):
Primary Management Group:
DF/HCC Breast Cancer
BIDMC Breast Cancer
DF/HCC Affiliate Site
DF/HCC Breast Cancer
DF/HCC Satellite Site
DFCI/BWH Breast Oncology
OTHER Registering Site
Sponsor Name
Sponsor Protocol No
Roles
Grant Number(s)
DF/HCC Investigator
Regulatory
Dana-Farber/Harvard Cancer Center
Funding
Eisai
Funding
Investigational Drug?
Yes
Drug(s), Biologic(s):
E7389
IND #:
IND Holder Type:
IND Holder Name:
117840
DF/HCC Investigator
Erica Mayer, MD, MPH
Investigational Device?
This study does not use an Investigational Device.
Risk Category:
Greater Than Minimal Risk
Chemotherapy; Human Material Collection; Questionnaires/Surveys/Interviews; Radiological
Protocol Involves:
IRB of Record:


11/10/2017 09:23 AM
Report Generated:
Exams
Date Range: (Medical Record Review and Specimen Collection studies)
Participating Sites under the DFCI IRB
Institution:
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute at Milford
Dana-Farber Cancer Institute at NHOH
Dana-Farber Cancer Institute at South Shore
Participating Institutions Under Other IRB
Institution:
Eastern Maine Medical Center
Location: BANGOR, ME


Page 1 of 1 
 
Protocol Number: 13-077 
 
Approval Date:    04/02/13  (IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:    05/14/13  (Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
 
Date 
Posted 
Revised Sections 
IRB 
Approval 
Date 
OHRS 
Version 
Date 
05/17/13 
Delayed Activation: BIDMC ready. All sites now active. 
N/A 
N/A 
06/27/13 
Front Sheet replaced due to Amendment # 3 
06/20/13 
N/A 
08/06/13 
Front Sheet replaced due to Amendment # 4 
08/05/13 
N/A 
09/09/13 
Alert Page added due to Amendment #5 
09/04/13 
N/A 
10/03/13 
Protocol and Front Sheet replaced due to Amendment 
#6 
09/26/13 
N/A 
03/05/14 
DF/BWCC at DFCI@Milford, DF/BWCC at DFCI 
@SSH, DFCI @NHOH sites added; DFCI @ FH 
removed; Consent Form and Front Sheet replaced due 
to Amendment #7 
03/04/14 
03/05/14 
03/20/14 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #1 
03/13/14 
n/a 
04/14/14 
Front Sheet replaced due to Amendment #8 
04/14/14 
n/a 
07/21/14 
Protocol and Front Sheet replaced due to Amendment 
#9 
07/21/14 
N/A 
03/03/15 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #2 
02/26/15 
N/A 
03/03/15 
Partial Closure: Cohort 1 closed to New Accrual: 
accrual goal met (effective date: 02/27/15; Amendment 
#10; Cohort 2 remains open)  
02/27/15 
N/A 
04/14/15 
Protocol and Front Sheet replaced due to Amendment 
#11 
04/03/15 
N/A 
Date 
Posted 
Revised Sections 
IRB Approval 
Date 
OnCore 
Version Date 
12/09/15 
Front Sheet replaced due to Amendment #12 
12/08/15 
N/A 
02/25/16 
Study renewal/ Consent Form footer replaced due to 
Continuing Review #3 
02/25/16 
02/25/16 
04/13/16 
Eligibility Checklist replaced due to Amendment #13 
02/25/16 
n/a 
04/13/16 
Protocol, Eligibility Checklist and Front Sheet replaced 
due to Amendment #14 
02/26/16 
n/a 
04/22/16 
Permanent Closure to New Accrual: slow accrual 
(effective date: 04/15/16; Amendment #18) 
04/14/16 
N/A 
01/19/17 
Study renewal, Consent Form removed due to Data 
Analysis Only per Continuing Review #4 
12/29/16 
N/A 
11/14/2017 
Front Sheet replaced per Amendment #19 
11/07/2017 
N/A 
11/16/2017 
Study Renewal per Continuing Review #5 
11/09/2017 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1 
 
Protocol Version Date: February 23, 2016 
 
 
Local Protocol #:13-077 
 
 
Title: A Phase 2 Study of Eribulin in Patients with HER2-negative, Metastatic Breast Cancer: 
Evaluation of Efficacy, Toxicity, and Patient-Reported Outcomes 
 
Coordinating Center: Dana-Farber Cancer Institute 
 
Principal Investigator 
Erica L. Mayer MD MPH 
Dana-Farber Cancer Institute 
Breast Oncology Center 
450 Brookline Ave 
Boston, MA 02215 
P 617-632-2335 
F 617-632-1930 
 
Co-Investigators 
Nancy U. Lin MD 
Breast Oncology Center 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
P 617-632-3800 
F 617-632-1930 
 
Otto Metzger Filho MD 
Breast Oncology Center 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
P 617-632-3800 
F 617-632-1930 
 
Harold J. Burstein MD PhD 
Breast Oncology Center 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 


2 
 
P 617-632-3800 
F 617-632-1930 
 
Biostatistician 
Anita Giobbie-Hurder 
Department of Biostatistics and Computational Biology 
Dana-Farber Cancer Institute 
450 Brookline Ave. (CLS 11007) 
Boston, MA 02215 
Ph: 617-632-2193 
Fax: 617-632-5444 
 
Study Coordinator 
Danielle Gore 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
P 617-632-4870 
F 617-632-3550 
 
Director of DF/HCC Survey Core 
Carol Lowenstein 
DFCI LW601 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
P 617.582.9063 
 
Responsible Research Nurse:  
Elizabeth Kasparian, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
P 617-632-5046 
F 617-632-3380 
 
Agent(s): Eribulin mesylate (E7389)  


Protocol #:13-077 
Version Date: 2/23/2016 
 
3 
 
 
STUDY SCHEMA 
 
Abbreviations: CR, complete response; CT, chemotherapy; MBC, metastatic breast cancer; PD, 
progressive disease; PR, partial response; SD, stable disease.  
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
OBJECTIVES .................................................................................................................................................... 8 
1.1. 
Study Design ............................................................................................................................................... 8 
1.2. 
Primary Objectives ..................................................................................................................................... 8 
1.3. 
Secondary Objectives ................................................................................................................................. 8 
2. 
BACKGROUND ................................................................................................................................................ 9 
2.1. 
Study Agent - Eribulin ................................................................................................................................ 9 
2.2. 
Study Disease............................................................................................................................................ 10 
2.3. 
Rationale for Correlative Studies – Patient Reported Outcomes ............................................................. 11 
2.4. 
Rationale for Correlative Studies – Single Nucleotide Polymorphisms and Neurotoxicity ...................... 13 
2.5. 
Rationale for Study ................................................................................................................................... 14 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 15 
3.1. 
Eligibility Criteria .................................................................................................................................... 15 
3.2. 
Exclusion Criteria .................................................................................................................................... 16 
3.3. 
Inclusion of Minorities and Other Underrepresented Populations .......................................................... 17 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 18 
4.1. 
General Guidelines for DF/HCC and DF/PCC Institutions ..................................................................... 18 
4.2. 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................... 18 
4.3. 
Registration Process for Other Investigative Sites ................................................................................... 19 
5. 
TREATMENT PLAN ...................................................................................................................................... 19 
5.1. 
Overall Study Design and Plan ................................................................................................................ 19 
5.2. 
Pretreatment Criteria ............................................................................................................................... 21 
5.3. 
Treatment Phase ....................................................................................................................................... 22 
5.4. 
Agent Administration ................................................................................................................................ 22 
5.5. 
Schedule of Visits and Procedures ........................................................................................................... 23 
5.6. 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 27 
5.7. 
Duration of Therapy ................................................................................................................................. 29 
5.8. 
Duration of Follow Up ............................................................................................................................. 29 
5.9. 
Criteria for Removal from Study .............................................................................................................. 29 
6. 
EXPECTED TOXICITIES AND DOSE/DELAYS MODIFICATION ....................................................... 30 
6.1. 
Eribulin – Expected toxicities ................................................................................................................... 30 
6.2. 
Eribulin - Toxicity Management ............................................................................................................... 31 


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7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 33 
7.1. 
Eribulin ..................................................................................................................................................... 33 
8. 
CORRELATIVE STUDIES ............................................................................................................................ 36 
8.1. 
Patient-Reported Outcomes Assessment ................................................................................................... 36 
8.2. 
Correlative Neurotoxicity Analysis ........................................................................................................... 37 
9. 
STUDY CALENDAR ...................................................................................................................................... 38 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 41 
10.1. 
Efficacy Assessments (Antitumor Activity) ............................................................................................... 41 
10.2. 
Baseline Identification of Target and Nontarget Lesions ......................................................................... 42 
10.3. 
Primary efficacy variable/endpoint .......................................................................................................... 43 
10.4. 
Secondary efficacy variables .................................................................................................................... 43 
10.5. 
Laboratory measurements ........................................................................................................................ 43 
10.6. 
Vital signs and weight measurements ....................................................................................................... 44 
10.7. 
Electrocardiograms .................................................................................................................................. 44 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 45 
11.1. 
Definitions ................................................................................................................................................ 45 
11.2. 
Reporting to the Institutional Review Board (IRB) ................................................................................... 48 
11.3. 
Reporting to Hospital Risk Management .................................................................................................. 49 
11.4. 
Reporting SAEs to EISAI .......................................................................................................................... 49 
11.5. 
Monitoring of Adverse Events and Period of Observation ....................................................................... 49 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 50 
12.1. 
Data Reporting ......................................................................................................................................... 50 
12.2. 
Safety Meetings ......................................................................................................................................... 50 
12.3. 
Monitoring ................................................................................................................................................ 51 
12.4. 
Multicenter Guidelines ............................................................................................................................. 51 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 52 
13.1. 
Protocol Review and Amendments ........................................................................................................... 52 
13.2. 
Informed Consent ..................................................................................................................................... 52 
13.3. 
Ethics ........................................................................................................................................................ 52 
13.4. 
Study Documentation ................................................................................................................................ 53 
13.5. 
Records Retention ..................................................................................................................................... 53 
14. 
STATISTICAL METHODS ........................................................................................................................... 54 
14.1. 
Statistical and Analytical Plans ................................................................................................................ 54 
14.2. 
Determination of sample size ................................................................................................................... 54 
14.3. 
Safety analysis .......................................................................................................................................... 56 


Protocol #:13-077 
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6 
 
14.4. 
Analysis of Secondary Efficacy Variables ................................................................................................ 56 
14.5. 
Analysis of Quality of Life Assessments .................................................................................................... 56 
14.6. 
Neuropathy Analysis ................................................................................................................................. 57 
15. 
PUBLICATION PLAN .................................................................................................................................... 57 
16. 
REFERENCES ................................................................................................................................................. 59 
17. 
APPENDICES .................................................................................................................................................. 61 
17.1. 
Appendix 1 - Overview of RECIST v 1.1 for Evaluation of Tumor Response ........................................... 61 
17.2. 
Appendix 2 - ECOG Performance Status Scale ........................................................................................ 67 
17.3. 
Appendix 3 - Cockcroft and Gault Formula ............................................................................................. 68 
17.4. 
Appendix 4 - New York Heart Association Cardiac Disease Classification ............................................. 69 
17.5. 
Appendix 5 - Common Terminology Criteria for Adverse Events (version 4.0) ....................................... 70 
17.6. 
Appendix 6 – Quality of Life Surveys ....................................................................................................... 71 
17.7. 
Appendix 7 - Blood Sampling for Pharmacogenomics Analysis ............................................................... 80 
17.8. 
Appendix 8: Provider-Reported CTCAE Form......................................................................................... 82 
APPENDIX 9: DF/HCC Multi-Center Data and Safety Monitoring Plan .............................................................. 83 
1. 
INTRODUCTION ............................................................................................................................................ 85 
1.1. 
Purpose ..................................................................................................................................................... 85 
1.2. 
Multi-Center Data and Safety Monitoring Plan Definitions .................................................................... 85 
2. 
GENERAL ROLES AND RESPONSIBILITIES.......................................................................................... 86 
2.1. 
DF/HCC Sponsor ..................................................................................................................................... 86 
2.2. 
Coordinating Center ................................................................................................................................. 87 
2.3. 
DF/HCC Quality Assurance Office for Clinical Trials (QACT) ............................................................... 87 
2.4. 
Participating Institution ........................................................................................................................... 87 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ....................................................... 88 
3.1. 
Protocol Distribution ................................................................................................................................ 88 
3.2. 
Protocol Revisions and Closures .............................................................................................................. 88 
3.3. 
Informed Consent Requirements ............................................................................................................... 89 
3.4. 
IRB Documentation .................................................................................................................................. 89 
3.5. 
IRB Re-Approval ...................................................................................................................................... 90 
3.6. 
Participant Confidentiality and Authorization Statement ......................................................................... 90 
3.7. 
DF/HCC Multi-Center Protocol Registration Policy ............................................................................... 90 
3.8. 
DF/HCC Protocol Case Number .............................................................................................................. 92 
3.9. 
Protocol Deviations, Exceptions and Violations ...................................................................................... 92 
3.10. 
Safety Assessments and Toxicity Monitoring ............................................................................................ 93 
3.11. 
Data Management .................................................................................................................................... 94 


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4. 
REQUISITIONING DRUG ............................................................................................................................ 95 
5. 
MONITORING: QUALITY CONTROL ...................................................................................................... 95 
5.1. 
Ongoing Monitoring of Protocol Compliance .......................................................................................... 95 
5.2. 
Evaluation of Participating Institution Performance ............................................................................... 95 
6. 
AUDITING: QUALITY ASSURANCE ......................................................................................................... 96 
6.1. 
DF/HCC Sponsored Trials ....................................................................................................................... 96 
6.2. 
Participating Institution ........................................................................................................................... 96 
6.3. 
DF/HCC Sponsor and Coordinating Center ............................................................................................ 96 
6.4. 
Sub-Standard Performance ...................................................................................................................... 97 
 
 


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8 
 
 
1. 
OBJECTIVES 
1.1. Study Design 
This is a non-randomized, open label study of eribulin monotherapy in the first or second line 
setting for metastatic HER2-negative breast cancer. Patients will be enrolled in 2 parallel 
cohorts. Cohort 1: Hormone receptor (HR)-positive /HER2-negative (HR+/HER2-). Cohort 2: 
HR-negative/HER2-negative (triple negative breast cancer [TNBC]). A total of 45 patients will 
be included in the HR-positive cohort and 45 in the TNBC cohort.  
1.2. Primary Objectives 
 To evaluate the antitumor activity of first-line treatment with single-agent eribulin mesylate 
in subjects with locally recurrent or metastatic HER2-negative breast cancer by 
determining overall response rate (ORR) (RECIST version 1.1). ORR will be estimated 
separately for the HR+/HER2- and the TNBC monotherapy cohorts. 
1.3. Secondary Objectives 
Efficacy Endpoints:  
 Progression-free survival  
 Time to first response  
 Duration of response  
 Time to first response and duration of response  
Safety Endpoints  
 To assess the safety and tolerability of single-agent eribulin mesylate (Both cohorts will be 
combined for these analyses) 
Quality of Life (QOL) Analyses (Both cohorts will be combined for these analyses) 
 To describe the adverse event (AE) profile of eribulin, according to provider-rated 
CTCAE v.4.0.  
 To describe QOL at baseline and over time using the Functional Assessment of Cancer 
Therapy-Breast (FACT-B).  
 To describe the impact of neurotoxicity on QOL at baseline and over time using the 
FACT-Neurotoxicity Subscale (FACT-Ntx). 
 To describe the profile of patient-reported symptomatic toxicities experienced by patients 
receiving treatment with eribulin using the Patient Reported Outcome (PRO) Version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE).  


Protocol #:13-077 
Version Date: 2/23/2016 
 
9 
 
 To compare FACT-B, FACT-Ntx and PRO-CTCAE toxicity data with provider-reported 
CTCAE toxicity to determine degree of concordance or divergence for each class of 
toxicity.  
Correlative Science: 
 To explore the association between Single Nucleotide Polymorphisms (SNPs) and 
neurotoxicity. For this analysis, the two cohorts will be combined. 
 To collect a repository of blood samples at baseline for future research. 
 
2. 
BACKGROUND 
2.1. Study Agent - Eribulin 
Eribulin mesylate is a synthetic derivative of the natural product halichondrin B, a large 
polyether macrolide isolated from a marine sponge (Halichondria okadai). Halichondrin B 
exhibits anti-cancer activity through a microtubule-destabilizing anti-mitotic mechanism of 
action.1,2 Eribulin exerts its effects by binding to the plus end of microtubules, leading to tubulin 
sequestration into nonproductive aggregates, preventing tubulin polymerization and microtubule 
dynamics. Suppression of microtubule growth interferes with normal mitotic spindle formation, 
and blocks the prometaphase portion of mitosis,3 leading to irreversible cell cycle blockade at 
G2/M, disruption of mitotic spindles, and cell death via apoptosis after prolonged mitotic 
blockage.4 In vitro studies demonstrate that analogues of halichondrin B inhibit cell growth at 
nanomolar concentrations in a wide variety of cancer cell types, including breast, ovary, colon 
and melanoma.5 
The dosing regimen for eribulin selected based on results of Phase 1 studies is 1.4 mg/m2 
administered i.v. on Days 1 and 8 of a 3-week cycle. In an early Phase 2 trial, E7389-A001-201, 
the response rate (RR) in patients with breast cancer previously treated with anthracycline and 
taxanes was 11.5%. 6 Based on these results, the effectiveness and safety of eribulin were further 
explored in Study E7389-A001-211, which included patients with locally advanced or metastatic 
breast cancer who had received between two to five prior chemotherapy regimens, including an 
anthracycline, taxane, and capecitabine, and who had progression on or within 6 months of their 
last chemotherapy regimen. The response rate for eribulin was 9.3% in these heavily pretreated 
subjects.7 
In a Phase 3 trial, E7389-G000-305 (“EMBRACE”), eribulin (1.4 mg/m2 on Days 1 and 8 of a 3-
week cycle) was compared with treatment of the physician’s choice (TPC; any cytotoxic or 
hormonal agent) in subjects heavily pre-treated for locally advanced or metastatic breast cancer 
(MBC). 8 In the analysis of the primary endpoint of overall survival, patients receiving eribulin 
had a longer median overall survival of 13.1 months compared with 10.7 months for TPC 
(P = 0.04, stratified log-rank test; hazard ratio = 0.81). Objective RR was 12% for eribulin 
mesylate and 5% for TPC (P = 0.005). Grade 3 or 4 eribulin-related adverse events (AEs) 
included asthenia/fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). Twelve 


Protocol #:13-077 
Version Date: 2/23/2016 
 
10 
 
percent of eribulin-treated subjects and 7% of TPC-treated subjects experienced treatment-
related serious AEs. Based on the results of this Phase 3 trial, eribulin was approved by the FDA 
in November 2010 for metastatic breast cancer pre-treated with at least 2 prior regimens 
including anthracycline and taxane. 
The tolerability of eribulin and its ease of use suggest possible treatment advantages in 
comparison to other available agents for advanced disease (i.e. taxanes). Preclinical and clinical 
data suggest that eribulin mesylate may exhibit less neurotoxicity, myalgia/arthralgia, and 
hypersensitivity than other chemotherapeutic agents. The most common AEs with single-agent 
eribulin mesylate are asthenia/fatigue and neutropenia. In addition, eribulin requires minimal 
preparation, can be administered quickly, and does not require premedication to prevent 
hypersensitivity. 
The current study will evaluate the safety and efficacy of eribulin for the treatment of HER2-
negative advanced breast cancer in the first- or second-line settings. 
 
2.2. Study Disease 
Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an 
estimated 1.38 million new cases and 458,000 deaths in 2008 alone.9 The American National 
Cancer Institute estimates that approximately 2.4 million women with a history of breast cancer 
were alive in 2004.10 Approximately 10% of patients with breast cancer have de novo metastatic 
disease from diagnosis, and another 10 to 20% present with locally advanced breast cancer. 
Additionally, up to one third of patients with early stage breast cancer cases will develop 
metastatic disease in the course of their lives.11  
Improvements in outcomes with MBC have been observed in the last 30 years, however overall 
prognosis remains poor with a median survival of 2 to 3 years.12 Long term complete responses 
are observed only for a minority of MBC patients (2% to 5%), and MBC remains an incurable 
disease for most of patients.13 The possibility of offering multiple lines of treatment to a 
particular patient makes the treatment decision process a difficult task. A balance between 
treatment response and quality of life should be pursued, as the great majority of MBC patients 
remain incurable. Response rate to first-line chemotherapy ranges from 30% to 60%, with an 
associated time to progression (TTP) of 7 to 10 months. 14 Treatment of MBC after progression 
on first-line treatment is associated with a lower response rate (20% to 30%) and subsequent 
shorter TTP in the range of 6 months. 14  
Despite significant advances in the field of targeted therapies for the treatment of advanced 
breast cancer, there has been little improvement in the development of novel cytotoxics. Eribulin 
is a novel chemotherapeutic agent with proven activity in advanced breast cancer patients 
previously treated with at least two regimens in the advanced setting. The present study aims to 
evaluate the ORR and safety profile of eribulin in the first and second-line treatment of advanced 
breast cancer.  
 


Protocol #:13-077 
Version Date: 2/23/2016 
 
11 
 
2.3. Rationale for Correlative Studies – Patient Reported Outcomes 
When treating metastatic breast cancer, the dual goals of care are prolonging survival and 
optimizing QOL. Treatment selection requires consideration not only of potential anti-neoplastic 
activity, but also of possible toxicities. Neuropathy is a common side effect of many of the major 
chemotherapeutics with activity in MBC, including taxanes, vinorelbine, ixabepilone, and 
eribulin. This toxicity is of particular interest, as it can be cumulative and, if severe, preclude 
further administration of potential active therapy. Although ongoing studies will provide initial 
description of the activity of eribulin in less heavily pretreated patients, these trials are not 
designed to capture the full effect of treatment on the patient aside from response rate. In the 
present study, recommended instruments based on the available evidence supporting their 
psychometric properties and past use in cancer research will be evaluated at baseline, during 
treatment and upon treatment completion.15  
Patient-reported outcomes (PRO) are an important part of new drug evaluation, and may play a 
role in regulatory approval of novel agents in oncology.16 PROs are the consequences of disease 
and/or its treatment as reported by the patient. PROs are evaluated through the use of 
questionnaires developed to assess topics a patient can report about his or her own health. This 
includes symptoms (i.e. nausea, fatigue, diarrhea), physical functioning (difficulty climbing 
stairs or fastening buttons), and mental health (i.e. anxiety, fear or worry).  
Previous studies have demonstrated that patient and clinician reports of symptoms during cancer 
treatment provide discrepant but complimentary information. 17-19 The current standard 
mechanism for reporting toxicities in cancer research is clinician-only reporting using items from 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE). In a retrospective analysis of 14 randomized clinical trials, PRO measures improved 
the predictive accuracy of clinician CTCAE reporting.20 In a prospective study including lung 
cancer patients PRO measurements of toxicities better reflected patients’ underlying state and 
functional status than clinician’s evaluation.18 
In the current study, we will assess quality of life through validated questionnaires (FACT-B and 
FACT-Ntx) and the newly developed items of the Patient-Reported Outcomes Version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE).15  
The FACT-B is a 44-item self-report questionnaire designed to measure multidimensional 
quality of life in patients with breast cancer.21 The FACT-B consists of the FACT-General 
(FACT-G) plus the Breast Cancer Subscale (BCS), which adds items specific to QOL in breast 
cancer. Reliability and validity have been demonstrated in multiple patient samples. The Physical 
Well-Being (PWB), Functional Well-Being (FWB) subscales are sensitive to change in 
performance status rating. Sensitivity to change has also been demonstrated compared to the 
Functional Living Index-Cancer (FLIC) on the FACT-B total score, PWB, FWB, and Emotional 
Well-Being subscales. Internal consistency is high (alpha = 0.90) for the total score, with 
subscale alpha ranging from 0.63 to 0.86. QOL analyses using the Functional Assessment of 


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Cancer Therapy-Breast (FACT-B) have been presented from E2100, and are available as 
comparison data reflecting paclitaxel monotherapy.22  
FACT-Neurotoxicity Subscale (FACT-Ntx) is aimed at the evaluation of quality of life of cancer 
patients suffering from neurotoxicity. 23 FACT -Ntx is a reliable and valid instrument for 
assessing the impact of neuropathy on health-related quality of life and has the sensitivity to 
detect meaningful clinical distinctions and change over time. 
The PRO-CTCAE items have been developed under a contract between the National Cancer 
Institute (NCI) and clinical investigators with the intention that they will be available in future 
studies to allow patients to self-report their own adverse symptoms. The PRO-CTCAE item bank 
(i.e., lexicon of available questions) consists of five “types” of items (present/not present, 
frequency, severity, interference with usual or daily activities, and amount) which can be 
associated with any given symptom. The wording and response options for each type of item are 
as follows (“XXXX” represents the given symptom): 
 
PRESENT/NOT PRESENT: In the last 7 days, did you have any XXXX: 
• Yes / No 
 
FREQUENCY: 
In the last 7 days, how OFTEN did you have XXXX: 
• Never / Rarely / Occasionally / Frequently / Almost constantly 
 
SEVERITY: 
In the last 7 days, what was the SEVERITY of your XXXX at its worst: 
• None / Mild / Moderate / Severe / Very severe 
 
INTERFERENCE: 
In the last 7 days, how much did XXXX INTERFERE with your usual or daily activities: 
• Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
AMOUNT: 
In the last 7 days, did you have any XXX: 
• Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
For each symptom, the types of items used to assess the symptom were previously agreed in the 
development process of the National Cancer Institute’s PRO-CTCAE project. For example, for 
the symptom of “pain”, the PRO-CTCAE includes three items: 
 
In the last 7 days, how OFTEN did you have PAIN: 
• Never / Rarely / Occasionally / Frequently / Almost constantly 
 


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In the last 7 days, what was the SEVERITY of your PAIN at its worst: 
• None / Mild / Moderate / Severe / Very severe 
 
In the last 7 days, how much did PAIN INTERFERE with your usual or daily 
activities: 
• Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
Whereas, for the symptom of “shortness of breath”, the PRO-CTCAE includes only two items: 
 
 In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its worst: 
• None / Mild / Moderate / Severe / Very severe 
 
In the last 7 days, how much did SHORTNESS OF BREATH INTERFERE with your usual or 
daily activities: 
• Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
and for the symptom of “constipation”, the PRO-CTCAE includes only one item: 
 
In the last 7 days, what was the SEVERITY of your CONSTIPATION at its worst: 
• None / Mild / Moderate / Severe / Very severe 
 
In total, the current version of the PRO-CTCAE has 126 items to assess 81 symptoms (Appendix 
6). There are 45 symptoms which are assessed using one item, 27 symptoms which are assessed 
using two items, and 9 symptoms which are assessed using three items. The types of items in 
order of prevalence include severity (used to assess 52 symptoms), frequency (used to assess 26 
symptoms), interference (used to assess 25 symptoms), present/not present (used to assess 
21symptoms), and amount (used to assess 2 symptoms).  
There are 20 symptoms (39 items in total) which were identified as “core” symptoms by the 
PRO-CTCAE development team in collaboration with NCI and FDA advisors based on their 
frequency in cancer patients and prior NCI trials, importance in monitoring, and/or inherent 
patient-reported nature. These symptoms include: Anxiety; arm or leg swelling; constipation; 
decreased appetite; loose or watery stools (diarrhea); dry mouth; fatigue, tiredness, or lack of 
energy; hair loss; headache; insomnia; mouth or throat sores; nausea; numbness or tingling in 
your hands or feet; pain; problems with concentration; problems with tasting food or drink; rash; 
sad or unhappy feelings; shortness of breath; and vomiting. 
 
2.4. Rationale for Correlative Studies – Single Nucleotide Polymorphisms and 
Neurotoxicity 


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Both preclinical and clinical data suggest eribulin may lead to less neuropathy than other 
commonly used breast cancer chemotherapeutics. In mouse models, exposure to eribulin appears 
to cause less neuropathy in comparison to exposure to paclitaxel or ixabepilone.24 In the clinical 
setting, rates of significant neuropathy have only been described in heavily pretreated patients. In 
the EMBRACE study, with a median duration of drug exposure of 4 months, 8% of the 
pretreated population experienced grade 3/4 neuropathy.8 In contrast, in E2100, which included 
an arm evaluating first line weekly paclitaxel, the rate of grade 3/4 sensory neuropathy was 18%, 
with a median duration of therapy of 5.1 months.25 In CALGB 40502, which also included an 
arm evaluating first-line weekly paclitaxel, the rate of grade 3/4 sensory neuropathy was 16%.26 
Additionally, in RIBBON-2, which enrolled patients in the second line setting, the rate of grade 
3-4 sensory neuropathy was 13% in the chemotherapy alone arm (which included paclitaxel, 
gemcitabine, capecitabine, or vinorelbine).27 It is possible that rates of significant neuropathy and 
subsequent detrimental effect on QOL with eribulin may be lower than those observed with other 
agents, especially in less heavily pretreated patients. 
There is increasing interest in host factors, for example genetic polymorphisms that may be 
associated with neurotoxicity and other adverse effects. In the E2100 trial (paclitaxel 
chemotherapy backbone), genome wide association studies led by Dr. Bryan Schneider have 
identified 6 single nucleotide polymorphisms (SNPs) with minor allele frequency > 5% which 
were associated with neuropathy.28 The strongest association was found for RWDD3, where the 
incidence of grade 2-4 neuropathy at any time point was 27% in homozygous wild-type patients 
versus 40% in heterozygous and 60% in homozygous variant patients. It would be of interest to 
explore whether the same SNPs are predictive of toxicity of other potentially neurotoxic agents. 
In addition, capturing neurotoxicity with both traditional physician-rated CTCAE grading and 
with PROs may explore associations between host factors and toxicity in a more comprehensive 
fashion. 
In this study we will evaluate whether previously described SNPs are able to predict the 
observed neurotoxicity reported by patients in a specific PRO assessment of neurotoxicity, but 
also physicians’ reported toxicity.  
 
2.5. Rationale for Study 
Eribulin has a well-demonstrated and approved role in the treatment of pretreated patients with 
metastatic HER2- breast cancer. In this setting, the phase 3 EMBRACE study demonstrated 
improved survival outcomes with eribulin monotherapy in comparison to treatment of physician 
choice, and the toxicity profile was predictable and manageable.8 However, in view of its activity 
in the challenging setting of late-line treatment, eribulin merits assessment in this earlier-line 
setting, as greater clinical activity may be observed in a less heavily pretreated population. 
We propose to expand the experience with eribulin in the first and second line MBC settings 
through a phase 2 trial designed to better define drug activity, with a focus on HR-positive and 
TNBC. An additional goal of the trial is to provide novel PRO-CTCAE data describing the effect 


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of eribulin on patient quality of life (QOL), compare toxicity evaluation by PRO-CTCAE versus 
provider-reported symptoms and validated QOL surveys (FACT-B, FACT-Ntx), and provide 
samples for exploration of host polymorphisms on the development of chemotherapy-related 
toxicity. 
 
3. 
PARTICIPANT SELECTION 
3.1. Eligibility Criteria 
Subjects who meet all of the following criteria may be included in this study: 
 Female or male age 18 years or older at the time of informed consent 
 Have histologically or cytologically proven invasive breast cancer, locally recurrent or 
metastatic, with at least one measurable lesion according to RECIST v 1.1 (Appendix 1). 
Measurable disease is defined as: At least one lesion of 10 mm in the longest diameter 
for a non-lymph node or 15 mm in the short-axis diameter for a lymph node which is 
serially measurable according to RECIST criteria, using CT or MRI 
 Patients may have hormone receptor positive or hormone receptor negative HER2-
negative disease. Hormone receptor positivity (ER and/or PR) is defined by at least 1% of 
positive tumor cells in the sample by immunohistochemistry (IHC). “Triple negative” is 
defined by the lack of estrogen and progesterone receptor and by HER2-negative status. 
HER2-negative disease can be determined by FISH or IHC. Negativity by IHC is defined 
as scores of 0 or 1+. Borderline IHC results (i.e., 2+) should undergo FISH testing; 
subjects with an HER2 FISH ratio < 2.0 are eligible. 
 Prior therapies 
 Up to one prior line of chemotherapy for advanced disease is allowed. If received, 
prior chemotherapy must be discontinued at least 14 days prior to initiation of 
protocol therapy. 
 Prior bevacizumab in the neo/adjuvant or metastatic setting is acceptable. 
 No limit on prior lines of endocrine therapy or biologic therapy. Endocrine 
therapy and biologic thearpy must be discontinued at least 7 days prior to 
initiation of protocol therapy. 
 Patients must have completed any prior radiotherapy at least 2 weeks prior to 
initiation of protocol therapy. 
 Patients must have recovered from any reversible effects of prior therapies to no 
more than Grade 1 toxicity, with the exception of alopecia. 
 ECOG PS score of 0, 1 or 2 (see Appendix 2) 
 Participants must have normal organ and marrow function as defined below 


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 
Creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥40 mL/min per the 
Cockcroft and Gault formula (Appendix 3)  
 
Absolute neutrophil count ≥1.5 x 109/L 
 
Hemoglobin ≥9 g/dL  
 
Platelet count ≥100 x 109/L 
 
Bilirubin ≤1.5 times (x) the institutional ULN 
 
ALT and AST ≤3 x ULN, or < 5 x institutional ULN in subjects with liver 
metastasis. 
 
ECG QTC interval < 470ms  
 The effects of eribulin on the developing human fetus are unknown. For this reason, 
women of child-bearing potential or men must agree to use adequate contraception (barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
 Subjects willing and able to comply with all aspects of the protocol for the duration of the 
study and provide written informed consent before any study-specific screening 
procedures are performed, with the understanding that the subject may withdraw consent 
at any time without prejudice 
 
3.2. Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 Prior treatment with eribulin 
 Subjects who have had a prior malignancy other than carcinoma in situ of the cervix or 
nonmelanoma skin cancer, unless the prior malignancy was diagnosed and definitively 
treated 1.5 or more years before enrollment in this study, with no subsequent evidence of 
recurrence 
 Clinically significant cardiovascular impairment (history of congestive heart failure 
greater or equal to NYHA Class II (Appendix 4); unstable/active angina or MI ≤6 months 
before Day 1 of this study, or serious cardiac arrhythmia) 
 Active brain metastases or unevaluated neurologic symptoms suggestive of brain 
metastases. Subjects with brain metastasis and documented stable disease for > 6 weeks 
may be included in this study. Brain metastases will not be considered measureable 
lesions for the purposes of this trial. 


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 Subjects with metastatic disease limited to bone are ineligible unless at least one lytic 
lesion with identifiable soft tissue components that can be evaluated by MRI or CT, that 
is measurable (≥15 mm at Baseline) and can be followed serially by RECIST v 1.1 
(Appendix 1).  
 Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring the 
use of oxygen  
 Currently pregnant or breast-feeding. All females must have a negative serum or urine 
pregnancy test at the Baseline visit. Females of childbearing potential must agree to use a 
medically acceptable method of contraception (e.g., abstinence, an intrauterine device, a 
double-barrier method such as condom + spermicidal or condom + diaphragm with 
spermicidal, a contraceptive implant, an oral contraceptive or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 30 days 
after discontinuation of study treatment. Subjects who will be exempt from this 
requirement are postmenopausal women (defined as women who have been amenorrheic 
for at least 12 consecutive months, in the appropriate age group, without other known or 
suspected primary cause) or subjects who have been sterilized surgically or who are 
otherwise proven sterile (i.e., bilateral tubal ligation, hysterectomy, or bilateral 
oopherectomy) 
 Subjects with organ allograft requiring immunosuppression 
 HIV-positive individuals on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with eribulin. In addition, these 
individuals are at increased risk of lethal infections when treated with marrow-
suppressive therapy. Appropriate studies will be undertaken in participants receiving 
combination antiretroviral therapy when indicated 
 Subjects with pre-existing Grade 3 or 4 neuropathy. Any peripheral neuropathy must 
recover to Grade ≤1 before enrollment 
 Subjects with a hypersensitivity to halichondrin B or halichondrin B chemical derivative 
 Uncontrolled intercurrent illness including, but not limited, to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study 
requirements  
 Inability to read in English  
 
3.3. Inclusion of Minorities and Other Underrepresented Populations 
Both men and women are eligible for this protocol. Every effort will be made to include patients 
from minority populations. Because breast cancer predominantly affects females, it is anticipated 
that male enrollment will be < 5% of the overall study population.  


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4. 
REGISTRATION PROCEDURES  
4.1. General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registration must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment begins 
will be considered ineligible and registration will be denied.  
A member of the study team will confirm eligibility criteria and complete the protocol-
specific eligibility checklist. 
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator(PI). If a 
participant does not receive protocol therapy following registration, the participant’s registration 
on the study may be cancelled. Notify the QACT Registrar of registration cancellation as soon 
as possible. 
4.2. Registration Process for DF/HCC and DF/PCC Institutions 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time.  
 The registration procedures are as follows: 
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
2. 
Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research 
chart. To be eligible for registration to the protocol, the participant must 
meet all inclusion and exclusion criterion as described in the protocol, and 
reflected on the eligibility checklist. 
 Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295.  
4. 
The QACT Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable.  
5. 
An email confirmation of the registration and/or randomization will be sent to 
the Overall PI, study coordinator(s) from the lead site, treating investigator 


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and registering person immediately following the registration and/or 
randomization. 
 
4.3. Registration Process for Other Investigative Sites 
 
To register a participant, the appropriate documents should be completed by the research nurse 
or data manager and faxed [Fax 617-632-5152] or e-mailed [CTOPM@dfci.harvard.edu] to the 
Study Project Managers. 
 
Please refer to Appendix 9: Section 3.7.1 for a complete list of appropriate documents. 
 
The research nurse or data manager at the participating site will then e-mail 
[CTOPM@dfci.harvard.edu] the Project Manager to verify eligibility.  To complete the 
registration process, the Project Manager will 
 register the participant on the protocol with the QACT 
 fax or e-mail the participant study number, and if applicable the dose treatment level 
to the participating site 
 call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
NOTE: Registration and randomization with the QACT can only be conducted during 
the business hours of 8:00 AM and 5:00 PM Eastern Standard Time Monday through 
Friday. Same day treatment registrations will only be accepted with prior notice and 
discussion with the DF/HCC Lead Institution. 
 
5. 
TREATMENT PLAN  
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications for eribulin are described in Section 6 (Expected Toxicities and 
Dosing Delays/Dose Modification). No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant’s 
malignancy. 
 
5.1. Overall Study Design and Plan 
This is a non-randomized, open label study of eribulin monotherapy in the first or second line 
setting for metastatic HER2-negative breast cancer. Each subject will be assigned a unique 
identification number during screening, which will be used on all CRFs and correspondence 
regarding the subject. 
Patients receiving monotherapy will be enrolled in 2 parallel cohorts: 
 Cohort 1: HR+/HER2-negative (n = 45 pts)  


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 Cohort 2: TNBC (n= 45 pts) 


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Treatment Description 
Agent 
Pre-medications 
Dose 
Route 
Schedule 
Cycle 
Length 
Eribulin 
none 
1.4 mg/m2  
IV over 2 to 5 
minutes  
Days 1, 8 
21 days 
(3 weeks) 
 
The starting dosage of eribulin mesylate in this study, 1.4 mg/m2 administered as an i.v. infusion 
over approximately 2 to 5 minutes on Days 1 and 8 of a 3-week cycle, is based on results of four 
Phase 1 and four Phase 2 clinical studies. Four Phase 1 dose-finding studies were conducted to 
evaluate escalating doses of eribulin mesylate and determine the maximum tolerated dose (MTD) 
of eribulin mesylate as: (1) a 1-hour i.v. infusion on Days 1, 8 and 15 of a 28-day cycle (E7389-
A001-101); (2) a 1-hour i.v. infusion on Day 1 of a 21-day cycle (E7389-A001-102); (3) an i.v. 
bolus on Days 1, 8 and 15 of a 28-day cycle (National Cancer Institute [NCI] Study 5730); and 
(4) a bolus infusion on Days 1 and 8 of a 21-day cycle (E7389-J081-105). The MTD was 
determined to be 1.4 mg/m2 for the bolus injection and 1.0 to 2.0 mg/m2 for the infusion. 
Eribulin mesylate 1.4 mg/m2 i.v. bolus was tested as the starting dose in four Phase 2 studies. In 
the first two Phase 2 studies, subjects initially received eribulin mesylate on Days 1, 8 and 15 in 
28-day cycles. Because the majority of subjects receiving the 28-day dosing schedule 
experienced dose delays, reductions, or omissions due to neutropenia on Day 15 of the cycle, an 
additional cohort of subjects who received eribulin mesylate 1.4mg/m2 on Days 1 and 8 in 
21-day cycles was added. This schedule appeared to be better tolerated than the 28-day schedule 
and demonstrated antitumor activity in all four Phase 2 studies. Thus, the optimal schedule of 
eribulin mesylate based on the four studies appears to be 1.4 mg/m2 administered on Days 1 and 
8 in 21-day (3-week) cycles. 
 
5.2. Pretreatment Criteria 
Pretreatment criteria will be assessed within 21 days of the first dose of study treatment to 
establish eligibility and baseline values. 
Informed consent will be obtained after the study has been fully explained to the subject and 
before the conduct of any screening procedures or assessments. If screening assessments occur 
within 3 days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 
visit and screening tests do not need to be repeated. 
Demographic information and baseline characteristics will be collected at the Screening Visit. 
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance 
with prevailing regulations). Baseline characteristics will include ECOG PS (Appendix 2), 
NYHA cardiac disease classification (Appendix 4), disease status, medical histories, prior and 
concomitant medications, and PE findings. Relevant hormone receptor status will be collected. 


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Within the 21 days prior to therapy initiation patients will undergo baseline clinical evaluation 
(including history, physical evaluation, vital signs, and performance status). Subsequent changes 
from screening PE findings that meet the definition of an AE will be recorded on the AE page of 
the eCRF. 
Additional pre-treatment evaluations include: CBC with differential, chemistries, pregnancy test (if 
indicated), tumor measurements by staging studies and concomitant medication assessmentIf 
eligible and registered, blood collection for correlative studies will occur at Cycle 1 Day 1. 
 
5.3. Treatment Phase 
Treatment cycles will begin with the first dose of administration of study treatment on Cycle 1, 
Day 1 and continue in 3-week (21-day) cycles. Subjects will continue to receive study treatment 
until the development of Progressive Disease (PD) or the subject meets another withdrawal 
criterion as described in Section 15. All subjects will receive eribulin mesylate 1.4 mg/m2 on Day 1 
and Day 8 of each cycle. Subjects will undergo tumor response assessments every 9 weeks.  
After PD is documented or if subject is withdrawn from study, study treatment must be 
discontinued; all enrolled subjects will then be treated according to prevailing local standards at the 
investigator's discretion. Subjects who discontinue study therapy without PD will continue to 
undergo tumor response assessments every 9 weeks (from the date of the last tumor assessment) 
until PD is documented. All subjects will undergo an End-of-Treatment visit within 21 days after 
the final dose of study treatment.  
 
5.4. Agent Administration 
Eribulin Mesylate 
Eribulin mesylate 1.4 mg/m2 will be administered on an outpatient basis via i.v. infusion over 
approximately 2 to 5 minutes on Days 1 and 8 of each 3-week cycle. Therapy will continue until 
PD is documented or another withdrawal criterion is met as specified in Section 5.9. All subjects 
will receive the same starting dosage of eribulin mesylate, based on BSA.  
Please note that minor variations in treatment dates (+/-3 days) may occur depending on 
physician and patient scheduling, observed holidays, inclement weather, etc. Regardless of the 
time of administration, toxicity from previous treatment must be within acceptable ranges as 
described below:  
Criteria for Eribulin administration 
 Absolute Neutrophil Count >1,000/mm3 or >1.0×109/L 
 Platelet Count >75,000/ mm3 or >75×109/L 
 Non-hematologic toxicity CTCAE < Grade 3 or 4 
 


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Before dose administration, the amount of eribulin mesylate needed for each subject must be 
calculated in the following manner: 
1. Scheduled dose (mg/m2) x body surface area (m2) = Dose (mg) 
2. Dose (mg) x 2 = the number of mL of eribulin mesylate to withdraw from vials for 
administration 
Body surface area (BSA) will be calculated using any method that is accepted and customarily 
used by the investigational site, such as the Mosteller formula: 
BSA (m2) = ([Height ([cm) x Weight (kg)]) ÷ 3600)½ 
Height and body weight will be recorded at the screening visit. Thereafter, body weight will be 
recorded on each treatment day and dosing BSA will be calculated accordingly.  
The amount of eribulin mesylate required (as calculated above) will be withdrawn from the 
appropriate number of vials into a syringe. This may be injected directly as an i.v. infusion over 
approximately 2 to 5 minutes or diluted in up to 100 mL 0.9% saline for i.v. infusion over 
approximately 2 to 5 minutes. No special tubing is required for the i.v. administration of eribulin 
mesylate. 
 
5.5. Schedule of Visits and Procedures 
5.5.1. Pre-treatment phase 
Day -21 to Day 0 
Before performing any procedures or assessments, the investigator’s staff will explain the nature 
of the study and the potential risks associated with the study to all subject candidates and their 
respective partners where applicable, and obtain written informed consent from both if required. 
Once the IRB/IEC-approved ICF has been signed, the following procedures and evaluations will 
be performed: 
 
Determination of eligibility (inclusion/exclusion criteria, Section 3): 
 
Record demographic data 
 
Evaluate ECOG PS score (must be 0, 1 or 2 for subject to be eligible) (Appendix 
2) and cardiovascular status per NYHA criteria (Appendix 4)  
 
Record medical and surgical history 
 
Record all prior and concomitant medication use (prescription and nonprescription 
medications as well as transfusions) beginning 30 days before the start of study treatment 
(except record all previous breast cancer treatments) 
 
Perform physical examination 


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 
Obtain vital signs (BP, HR, respiratory rate, and body temperature), weight, and 
height. 
 
Perform tumor assessments to identify target and nontarget lesions. Computed tomography 
or MRIs are to be obtained between Day -21 and Day 1. Confirm the presence of at least 
one measurable lesion 10 mm in the longest diameter for a non-lymph node or 15 mm in 
the short-axis diameter for a lymph node 
 
Obtain bone scan within 6 weeks before start of study treatment.  
 
Perform a 12-lead ECG 
 
Collect serum or urine sample for β-hCG pregnancy testing from all premenopausal and 
any postmenopausal women who have been amenorrheic for <12 months 
 
Collect blood samples for clinical chemistry and hematology analyses (see Table 4) for a 
list of tests to be performed). 
 
Collect blood samples for whole blood for germline DNA SNP analysis  
 
Record any AEs (from the time of the first dose of study treatment) 
 
Schedule Cycle 1 Day 1 Visit: Screening assessments may serve as baseline 
assessments if they are performed within 3 days before the first dose of study treatment. 
 
5.5.2. Assessments in the Treatment Phase  
Reasonable effort should be made to conduct study visits on the day scheduled (3 days). The 
Study Calendar is provided in Table 3.  
Day 1 of Treatment  
 
Record ECOG PS score (for Cycle 1: record if not done at Baseline visit) 
 
Record weight (for Cycle 1: record if not done at Baseline visit) 
 
Record vital signs (BP, HR, respiratory rate, body temperature) before administration of 
eribulin mesylate. 
 
Perform one post baseline 12-lead ECG on Day 1 of Cycle 2 before administration of 
study treatment 
 
Perform physical exam  
 
Collect blood samples for clinical chemistry and hematology analyses within 3 days 
before the scheduled visit (see Table 4 for a list of tests to be performed). Laboratory 
assessments are not required on Day 1 of Cycle 1 if already performed at Baseline (within 3 
days before study administration) 
 
Review all laboratory results before administering study treatment 


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 
Record all concomitant medication use 
 
Cycle 1 D1, cycle 2 D1, cycle 3 D1, and every other cycle (i.e., cycles 5, 7, 9 until 
treatment discontinuation) - Administer QOL surveys (FACT-B, FACT-Ntx, and PRO-
CTCAE) and complete physicians reported CTCAE as detailed below:  
 Administer the QOL surveys (FACT-B, FACT-Ntx, and PRO-CTCAE). Assessments 
may be performed within 3 days before the scheduled 
 Record selected provider-reported CTCAE (detailed in Table 3). Adverse events should 
be graded as the worst grade in the last 7 days, which is different from standard CTCAE 
grading which typically spans the duration of time since the prior clinical assessment or 
treatment. Attempts should be made to have provider-reported CTCAE and QOL surveys 
performed on the same day. 
 
Administer study treatment: 
 
Eribulin mesylate 1.4 mg/m2 as an i.v. infusion over approximately 2 to 5 
minutes 
 
Record any AEs or SAEs 
Day 8 of Treatment  
 
Record weight  
 
Record vital signs (BP, HR, respiratory rate, body temperature) before the 
administration of eribulin mesylate 
 
Collect blood samples for hematology and chemistry analyses within 24 hours before the 
scheduled visit (see Table 4 for the tests to be performed).  
 
Review all laboratory results before administering study treatment. 
 
Administer study treatment: 
 
Eribulin mesylate 1.4 mg/m2 as an i.v. infusion over approximately 2 to 5 
minutes 
 
Tumor Assessments Interval 
Tumor assessments will be performed every 9 weeks, up to 1 week before the administration of 
the first dose of study treatment in the next treatment cycle as indicated in the Study Calendar 
(Table 3): 


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 
Confirm Complete Response (CR) or Partial Response (PR) a minimum of 4 weeks after 
initial response assessmentBone scan and brain CT/MRI at treating physician discretion. 
Scans can also occur as clinically indicated for new symptoms or to confirm disease 
response. Radiological scans that were negative at baseline do not have to be repeated unless 
clinically indicated.  
End-of-Treatment Visit in the Treatment Phase 
Subjects will continue to receive study treatment until PD or another withdrawal criterion is met, 
as described in Section 5.9. If a subject develops PD study treatment must be discontinued and 
end-of-treatment assessments be performed within 21 days of discontinuation of study treatment. 
If study treatment is discontinued without the subject having PD, the subject will undergo end-
of-treatment assessments and enter the posttreatment Follow-up Period for tumor response 
assessment. 
 
5.5.3. End-of-Treatment Procedures 
All subjects will be asked to return to the site for a final, End-of-Treatment visit, if possible. The 
End-of-Treatment visit must be performed within 21 days of final administration of study 
treatment. End-of-treatment assessments will not have to be repeated if the same assessments 
were performed within 7 days of this visit. 
End-of-Treatment Visit 
 
Perform tumor assessments as indicated in the Study Calendar (Table 3). If study 
treatment is discontinued due to PD, then tumor assessments are not required for that subject. 
 
Evaluate ECOG PS 
 
Perform physical exam 
 
Record vital signs (BP, HR, respiratory rate, body temperature) and weight 
 
Collect blood samples for hematology and serum chemistry analyses (see Table 4 for a 
list of tests to be performed) 
 
Record all concomitant medication use. Concomitant medications should be collected 
for 30 days after the last dose of study treatment. 
 
End of treatment visit - Administer QOL surveys (FACT-B, FACT-Ntx, and PRO-
CTCAE)and complete physicians reported CTCAE as detailed below:  
 Administer the QOL surveys (FACT-B, FACT-Ntx, and PRO-CTCAE) survey. 
Assessments may be performed within 3 days before the scheduled clinic visit. 
 Record selected physicians reported CTCAE (detailed in table 2). Adverse events should be 
graded as the worst grade in the last 7 days, which is different from standard CTCAE 
grading which typically spans the duration of time since the prior clinical assessment or 


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treatment. Physicians reported CTCAE and QOL surveys should be performed in the same 
day. 
 
Record any AEs or SAEs 
All AEs, regardless of relationship to study treatment or procedure or grade, will be collected 
from the time the subject signs the study ICF until 30 days after discontinuation of study 
treatment. Any AEs must be followed until resolution or for 30 days after the subject’s last 
study visit, whichever comes first. However, treatment-emergent peripheral neuropathy and 
alopecia will be followed until resolution or another anticancer agent is started, whichever 
occurs first. Serious AEs will be collected for 30 days posttreatment and followed until 
resolution or, if resolution is unlikely, until the event or sequelae stabilize or returns to 
baseline levels.  
5.5.4. Follow-up Period Procedures 
Subjects who do not have PD upon discontinuation of study treatment are to have tumor 
assessments during the post treatment Follow-up Period (using the same methodology and 
acquisition techniques as were used for previous assessments) every 9 weeks from the date of the 
last tumor assessment until PD is documented (see the Study Calendar in Table 3. During the 
Follow-up Period, subjects who have treatment-emergent peripheral neuropathy during the study 
will be followed until resolution of the neuropathy, or until another anticancer therapy is started, 
whichever occurs first. 
 
5.6. General Concomitant Medication and Supportive Care Guidelines 
All diagnostic, therapeutic, or surgical procedures relating to malignancy should be recorded in 
the electronic case report form (eCRF), including the date, indication, description of the 
procedure(s), and any clinical findings. All previous treatments for breast cancer should be 
included. 
All prior treatment or medication administered during the 30 days preceding the first dose of 
study treatment and any concomitant therapy administered to the subject throughout the study 
until 30 days after the final dose of study treatment must be recorded on the Prior and 
Concomitant Therapy page of the eCRF. The generic name of the drug (or trade name for 
combination drugs) must be specified along with the duration of treatment and indication for 
use. If concomitant medication/therapy is administered for an adverse event (AE), investigators 
will record that AE on the AE page of the eCRF. 
Any medication that is considered necessary for the subject’s welfare and that is not expected to 
interfere with the evaluation of study treatment may be given at the discretion of the 
investigator. Ancillary treatments will be given as medically indicated. 
Any changes in documented, permitted concomitant treatment already being taken at the start of 
the clinical study must be recorded on the eCRF, noting the type of medication, duration of use, 
and indication.  


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5.6.1. Premedication 
Premedications (anti-emetics) may be administered before eribulin mesylate administration, but 
are not required. Premedication with steroids or antihistamines to prevent hypersensitivity 
reactions is not required. 
5.6.2. Permitted concomitant Therapies and Medications  
The following agents are permitted, except as noted: 
 
Antiemetics  
 
Antidiarrheal therapy 
 
Antiallergic measures such as corticosteroids and antihistamines 
 
Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-
stimulating factor (GM-CSF), and erythropoietin in accordance with American Society of 
Clinical Oncology guidelines and local standard practice.  
 
Bisphosphonates: Subjects being treated with bisphosphonates when they enter the study 
may continue the medication as long as the dose is stable. Subjects may also initiate 
bisphosphonate therapy while on protocol therapy if it is thought to be medically 
necessary. 
 
Palliative radiotherapy may be given for bone pain or for other reasons (i.e., bronchial 
obstruction, ulcerating skin lesions). The irradiated area should be limited and should not 
involve more than 10% of the bone marrow. The irradiated area cannot be used for tumor 
response assessment.  
 
During palliative radiotherapy, treatment with study treatment should be held. Treatment 
with study treatment may be resumed within 14 days after completion of radiotherapy if 
the subject has recovered from any radiation-associated toxicity.  
 
Ovarian suppression with goserelin or leuprolide are allowed on study. 
5.6.3. Prohibited Concomitant Therapies and Drugs 
The use of investigational or other antitumor therapies, other than eribulin mesylate is 
prohibited during this study. If subjects receive additional antitumor therapies such as 
chemotherapy, hormone therapy (tamoxifen, aromatase inhibitors, fulvestrant), radiation 
therapy other than required for palliation, gene therapy, biologics, or immunotherapy, 
irrespective of the reason for which they are being given, this will be judged to represent 
evidence of progressive disease (PD) and study treatment will be discontinued. These subjects 
will complete all end-of-treatment assessments. 
5.6.4. Drug-Drug Interactions 
The weak inhibitory effect on cytochrome P450 enzymes exhibited by eribulin mesylate in vitro 
suggests a low risk of eribulin mesylate interaction with the pharmacokinetics of other drugs 
coadministered in usual clinic practice. Eribulin mesylate exposure (area under the curve and 


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maximal concentration) was bioequivalent when administered in combination with ketoconazole, 
a potent CYP3A4 inhibitor, compared with administration of eribulin mesylate alone. 
 
5.6.5. Treatment Compliance 
Eribulin mesylate will be administered by trained medical personnel at the investigational site. 
Treatment compliance will be monitored through documentation of study treatment 
administration in the subject’s medical record.  
 
5.7. Duration of Therapy 
Duration of therapy with eribulin will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, treatment 
may continue until one of the following criteria applies: 
 Development of progressive disease by clinical evaluation or as documented by RECIST 
v 1.1 (Appendix 1) 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements 
 
 Participant decides to withdraw from the study, or 
 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.8. Duration of Follow Up 
Participants will be followed for 30 days after removal from study or until death, 
whichever occurs first. Participants removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
5.9. Criteria for Removal from Study 
 
The investigator may withdraw a subject from the study at any time for safety or administrative 
reasons. A subject may stop study treatment at any time for safety or personal reasons. 
Subjects who withdraw after signing the informed consent form (ICF) but before receiving study 
treatment will be replaced.  
 


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Participants will be removed from study when any of the criteria listed in Section 5.7 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with and, if necessary, provided for the participant. 
 
All subjects who withdraw from the study will be required to complete protocol-specified end-
of-treatment assessments within 21 days after the last dose of study treatment (end-of-treatment 
assessments will not have to be repeated if same assessments were done within 7 days of last 
dose). Subjects who do not have progression upon discontinuation of study treatment will have 
tumor assessments every 9 weeks from the date of the last tumor assessment until PD is 
documented. A subject who has ceased to return for visits will be followed up by mail, phone, or 
other means as much as possible to gather information such as the reason for failure to return and 
the status of treatment compliance, presence or absence of AEs, the clinical course of signs and 
symptoms, and survival. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Erica L. Mayer MD MPH at 617-632-2335. 
 
6. 
EXPECTED TOXICITIES AND DOSE/DELAYS MODIFICATION 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
6.1. Eribulin – Expected toxicities 
In a completed Phase 3 trial, E7389-G000-305, eribulin (1.4 mg/m2 on Days 1 and 8 of a 3-week 
cycle) was compared with treatment of the physician’s choice (TPC; any cytotoxic or hormonal 
agent) in subjects heavily pre-treated for locally advanced or metastatic breast cancer. Grade 3 or 
4 eribulin-related AEs were asthenia/fatigue (7.6%), neutropenia (44%), and peripheral 
neuropathy (8.4%). Twelve percent of eribulin-treated subjects and 7% of TPC-treated subjects 
experienced treatment-related SAEs. 


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Refer to Section 5.2 of the Investigator's Brochure for complete details on toxicity in previous 
clinical trials conducted with eribulin. 
6.2. Eribulin - Toxicity Management  
Subjects should be carefully monitored for toxicity. If Grade 3 or 4 toxicities are present, then 
treatment should be delayed to allow for recovery (see instructions for dose delay below). If 
toxicities recur, the dose of eribulin should be reduced. In the setting of neutropenia, growth factor 
support may be added instead of a dose reduction at time of first occurrence of neutropenia at the 
discretion of the investigator. Once the dose of eribulin is reduced, it may not be increased at a 
later date. Dose adjustment recommendations for eribulin are shown in Table 1.  
Eribulin Dose Levels 
Starting dose 
1.4 mg/m2 
1st dose reduction 
1.1 mg/m2 
2nd dose reduction 
0.7 mg/m2 
 
Table 1: Dose adjustment recommendations for eribulin  
 
Adverse reaction/Toxicitya 
Grade/Details 
Eribulin dose modification 
ANC 
< 500 cells/mm3 lasting > 7 days in 
the previous cycle without use of 
growth factors 
Hold eribulin until recovery to grade 
< 2. Eribulin may be resumed at the 
same dose with growth factor 
support, or it may be reduced by one 
dose 
level, 
per 
investigator 
discretion. 
< 500 cells/mm3 lasting > 7 days in 
the previous cycle despite use of 
growth factors 
Hold eribulin until recovery to grade 
< 2, and reduce by 1 dose level. 
<1000 /mm3 with fever or infection 
without use of growth factors 
Hold eribulin until recovery to grade 
< 2. Eribulin may be resumed at the 
same dose with growth factor 
support, or it may be reduced by one 
dose 
level, 
per 
investigator 
discretion. 
<1000 /mm3 with fever or infection 
despite use of growth factors 
Hold eribulin until recovery to grade 
< 2, and reduce by 1 dose level. 
<1000 /mm3 without fever or 
infection without use of growth 
factors 
Hold eribulin until recovery to grade 
< 2 then resume at the same dose 
with growth factor support.  
 
If 
uncomplicated 
neutropenia  
lasting < 1 week (<1000 /mm3 
without 
fever 
or 
infection) 
occurs/recurs despite growth factor 
support, then hold eribulin until 
recovery to grade < 2 . Eribulin may 
be then be resumed at the same dose 
with growth factor support, or it may 
be reduced by one dose level, per 
investigator discretion. 


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32 
 
 
If 
uncomplicated 
neutropenia  
lasting > 1 week (<1000 /mm3 
without 
fever 
or 
infection) 
occurs/recurs despite growth factor 
support, then hold eribulin until 
recovery to grade < 2 and reduce by 
1 dose level.  
  
Platelets 
Grade 2 
Hold eribulin until recovery to grade 
1 
Grade 3 
Hold eribulin until recovery to grade 
1 then reduce by 1 dose level. 
Grade 4 
Hold eribulin until recovery to grade 
1 then reduce by 1 dose level. 
Anemia 
Grade 4 
Hold eribulin until recovery to grade 
< 2 then reduce by 1 dose level. 
PRBC transfusions are permitted to 
treat anemia. 
 Peripheral neuropathy 
Grade 2 
For intolerable (as determined by 
physician and patient) grade 2, 
decrease chemotherapy by one dose 
level.  
Grade 3 
Hold eribulin until recovery to grade 
< 2 then reduce by 1 dose level.  
Grade 4 
Treatment discontinuation.   
Non-hematologic toxicity 
Grade 3, first occurrence 
Hold eribulin until recovery to grade 
< 2. Maximize supportive care 
measures.  If symptom recovery 
occurs within 1 week, then eribulin 
may be resumed at the same dose if 
deemed 
appropriate 
by 
the 
investigator, otherwise, reduce by 1 
dose level. 
Recurrent grade 3, or any grade 4 
toxicity 
Hold eribulin until recovery to grade 
< 2 then reduce by 1 dose level. 
Recurrence of any Grade 3 or 4 event despite reduction to 0.7 mg/m2, or 
persistent grade 3 or 4 toxicity lasting more than 3 weeks despite maximal 
supportive measures 
Treatment discontinuation 
ANC = absolute neutrophil count 
a: Toxicities graded in accordance with National Cancer Institute Common Toxicity Criteria for Adverse Events, 
version 4.0, Appendix 5 
 


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Instructions for Dose Delay 
 
Criteria to continue treatment 
 Absolute Neutrophil Count > 1000/mm3 or >1.0×109/L 
 Platelet Count > 75,000/mm3 or >75×109/L 
 Non-hematologic toxicity <  grade 2 
 
Eribulin will NOT be administered if any of the following values are present on Day 1 or 8 prior 
to treatment administration: 
 Absolute Neutrophil Count <1,000/mm3 or <1.0×109/L 
 Platelet Count <75,000/ mm3 or <75×109/L 
 Non-hematologic toxicity CTCAE Grade 3 or 4 
 
If the dose of eribulin cannot be administered as planned due to treatment-related toxicity, the 
dose should be delayed according to the following instructions: 
 
Day 1 of each cycle: If eribulin cannot be administered on Day 1, the dose should be delayed 
until recovery to above mentioned values (criteria for eribulin administration). The Day 1 dose 
will be rescheduled for when the criteria for eribulin administration are being met. The dose of 
eribulin may have to be reduced following a dose delay in accordance to the instructions for dose 
reduction (Table 1). A maximum of 3 weeks are allowed for a delay in therapy. If the patient 
fails to meet the criteria to continue treatment within 3 weeks, they will be removed from the 
protocol. 
 
Day 8 of each cycle: If eribulin cannot be administered on Day 8, the dose should be delayed 
until recovery to above mentioned values (criteria for eribulin administration). The Day 8 dose 
will be delayed for a maximum of 7 days and as follows: 
 
If the criteria for eribulin administration are met on, or before Day 15 of a cycle, administer 
eribulin as recommended inTable 1; this dose is still called Day 8. 
 Eribulin administration on Day 1 of the next cycle should be no sooner than 14 days later. 
If the criteria for eribulin administration are NOT being met by Day 15 of a cycle, omit the 
Day 8 dose of eribulin for that cycle. Eribulin should be administered as recommended in 
Table 1 on Day 1 of the next scheduled cycle assuming criteria to continue treatment are met 
within a maximum 3 week delay in therapy from originally planned day 8. 
 
7. 
DRUG FORMULATION AND ADMINISTRATION  
7.1. Eribulin 


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Refer to the Investigator’s Brochure for detailed agent information and Havalen® FDA 
approved package for more information. 
 
Description 
Chemical name: 11,15:18,21:24,28- Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-
i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one,2-[(2S)-3-amino-2-
hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-
bis(methylene)(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29a
S)-, methanesulfonate (salt) 
Empirical formula: C40H59NO11•CH4O3S 
Molecular weight: 826.0 (729.9 for free base). 
Structural formula: 
 
 
 
 
Other name: E7389, Halaven® 
Mode of action: Eribulin injection is a non-taxane microtubule dynamics inhibitor.  
Manufacturer: Eisai 
Molecular weight: 826.0 (729.9 for free base). 
Distribution: Vd: 43-114 L/m2 
Protein binding: 49% to 65% 
Metabolism: Negligible 
Half-life, elimination: ~40 hours 
Excretion: Feces (82%; predominantly as unchanged drug); urine (9%, primarily as unchanged 
drug) 
Form 


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Eribulin is clear, colorless, sterile solution for intravenous administration. Each vial contains 1 
mg of eribulin as a 0.5 mg/mL solution in ethanol: water (5:95).Eribulin is manufactured by 
Eisai. 
Storage and Stability 
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. 
Compatibility 
Eribulin is compatible with saline (0.9% Sodium Chloride Injection). It is not compatible with 
solutions with dextrose. 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
Availability 
Eribulin is a commercially available agent but will be supplied free-of-charge from Eisai.  
Preparation 
The amount of eribulin required will be withdrawn from the appropriate number of vials into a 
syringe. This may be injected directly as an i.v. infusion over approximately 2 to 5 minutes or 
diluted in up to 100 mL 0.9% saline for i.v. infusion over approximately 2 to 5 minutes. Do not 
dilute in or administer through an intravenous line containing solutions with dextrose. Do not 
administer in the same intravenous line concurrent with the other medicinal products. 
Administration 
It will be administered over approximately 2-5 minutes. Do not administer in the same 
intravenous line concurrent with the other medicinal products. 
Ordering 
Eribulin will be provided by Eisai and stored in the site research pharmacy. Under no 
circumstances will the investigator allow the study treatment(s) to be used other than as directed 
by this protocol. Clinical supplies will not be dispensed to any individual who is not enrolled in 
the study. Please refer to Appendix 9: Section 4.0 for additional ordering information. 
Accountability 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug accountability form.  
Destruction and Return 
At the end of the study, unused supplies of eribulin should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
 


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8. 
CORRELATIVE STUDIES 
8.1. Patient-Reported Outcomes Assessment  
QOL surveys (PRO-CTCAE, FACT-B, FACT-Ntx) surveys will be administered at cycles 1, 2 
and 3, every other cycle in subsequent cycles, and End-of-Treatment visit (detailed in Table 3 
and Appendix 6).  
In order to minimize incomplete data, which can be a major issue in survey research, surveys 
will be administered using electronic tablets at the specified study visits listed above. This will 
be performed via wireless tablet computers brought to patients by study staff. This is a well-
established method of administering electronic questionnaires to patients. No data will be stored 
on these tablets, and data will be transmitted securely and in de-identified form in real-time to a 
server at the DFCI, where the data will be stored on highly secure servers. As a backup, paper 
copies of QOL surveys will be available at all sites. The PRO-CTCAE Software System will be 
used in this study to administer PRO-CTCAE items to enrolled patients at designated clinic 
visits. Items of the PRO-CTCAE system defined as core symptoms will be used in the present 
study (Appendix 6). 
If a participant is unable to fill out the survey using the electronic tablet, the survey may be filled 
out on paper with the patient ID, date, and timepoint clearly recorded. These paper surveys 
should be returned to the participating site, and a copy stored in the patient research record.   The 
original survey should be mailed to:Survey and Data Management Core 
RE: Eribulin Trial 
Dana-Farber Cancer Institute 
450 Brookline Avenue, LW 601 
Boston, MA 02215 
Selected provider-reported CTCAE (detailed in Table 2, also attached as Appendix 8) will be 
collected on day 1 of cycles 1, 2 and 3, every other cycle in subsequent cycles, and off study visit 
for the purpose of assessing agreement between PRO-CTCAE and provider reported CTCAE. 
Data collection will occur using a form (Appendix 8) to be completed by the provider after the 
patient encounter. Adverse events will be graded as the worst grade in the last 7 days, which is 
different from standard CTCAE grading which typically spans the duration of time since the 
prior clinical assessment or treatment. This adverse event data collection is in addition to routine 
comprehensive adverse event reporting performed at every encounter and detailed in Table 3, the 
Study Calendar. 
 
Table 2: Selected provider-reported CTCAE adverse events to be collected at cycles 1, 2 and 3, 
every other cycle in subsequent cycles, and off study visit. 


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System Organ Class (SOC) 
Adverse event 
None 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Gastrointestinal Disorders 
Constipation 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
Dry mouth 
 
 
 
 
 
Mucositis 
 
 
 
 
 
Nausea 
 
 
 
 
 
Vomiting 
 
 
 
 
 
General disorders and 
administration site conditions 
Hair Loss 
 
 
 
NA 
NA 
Edema limbs 
 
 
 
 
 
Fatigue 
 
 
 
 
 
Pain 
 
 
 
 
 
Metabolism and nutrition 
disorders 
Anorexia 
 
 
 
 
 
Nervous system disorders 
Concentration 
impairment 
 
 
 
 
 
Dysgeusia 
 
 
 
 
 
Headache 
 
 
 
 
 
Peripheral sensory 
neuropathy 
 
 
 
 
 
Psychiatric disorders 
Anxiety 
 
 
 
 
 
Depression  
 
 
 
 
 
Insomnia 
 
 
 
 
 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea 
 
 
 
 
 
 
Abbreviations: Not applicable  
 
We expect that this study will provide supportive data as part of an accumulating body of 
evidence for the psychometric integrity of the PRO-CTCAE. 
8.2.  Correlative Neurotoxicity Analysis 
Previous analysis has identified single nucleotide polymorphisms (SNPs) that predicted 
likelihood of experiencing taxane-induced peripheral neuropathy in the adjuvant breast cancer 
trial; E5103.29 In this study, we plan to explore whether these SNPs also predispose patients to 
peripheral neuropathy from eribulin. 
DNA sample preparation from whole blood 
Whole blood samples (10 ml) are collected in a tube containing a standard anticoagulant, such as 
ACD, EDTA, or heparin. Samples are then stored in a -70°C freezer until they are ready to be 
shipped. The frozen blood samples are shipped on dry ice to Schneider`s lab at Indiana 
University.  
The blood samples are thawed in a water bath at 37°C and gently agitated. Buffy coat samples 
are prepared by centrifuging the blood sample at 3300 g for 10 minutes at room temperature and 
the intermediate clear layer of sample are collected for DNA extraction. QIAamp DNA Blood 


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Mini Kit is used to isolate DNA from the buffy coat samples. Steps in this process include lysis 
and digestion of the sample with a protease, a simple bind-wash-elute procedure, and finally 
precipitation of the DNA for future use. 
Methods:  
DNA from buffy coat will be used to genotype candidate SNPs. The candidates will include 
those SNPs that had a provocative association with peripheral neuropathy from prior work with 
paclitaxel in E5103. We will compare candidate genotypes with the likelihood of developing 
clinically significant peripheral neuropathy in this trial. 
Shipping address for Schneider lab  
Schneider Lab  
980 W. Walnut Street 
Walther Hall C246 
Indianapolis, IN 46202 
Tel: (317)274-4646 
Fax: (317)274-0396 
 
9. 
STUDY CALENDAR 
Table 3 summarizes the Study Calendar. Visits should occur within +/- 3 days of the scheduled 
day. If a subject fails to appear for a scheduled study visit, the investigator will make every 
attempt to contact the subject and determine the reason(s) for the missed visit as completely and 
accurately as possible. Subjects will only be judged as lost to follow-up if they cannot be reached 
after three documented attempts (1 week apart) by the site to contact them.  


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Table 3: 
 
Pre-Tx 
Treatment Phase (cycles 1 to 3 and subsequent 
cycles) 
End of tx. 
Follow-up 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 b 
 
 
Day(D) 
Assessments 
D –21 to 
D 0 
D1 
D8 
D1 
D8 
D1 
D8 
D1 
D8 
Within 21 days 
of final dose c 
Every 
9 weeks d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Medical /  
Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior Medications / 
Procedures 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
Xe 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
Xe 
 
Vital Signs 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
Tumor Assessments 
Xa 
 
 
 
 
 
 
Xa 
 
Xa 
Xa 
12-Lead ECGg 
Xg 
 
 
Xg 
 
 
 
 
 
 
 
Pregnancy Test  
(if applicable) 
Xh 
 
 
 
 
 
 
 
 
 
 
Hematology 
Xi 
Xi 
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi 
 
Blood Sampling 
 
Xj 
 
 
 
 
 
 
 
 
 
Chemistry 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
 
QOL assessments 
 
Xl 
 
Xl 
 
Xl 
 
 
 
Xl 
 
Eribulin mesylate  
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
Xn 
Xn
Xn
Xn
Xn 
Xn
Provider CTCAE 
form 
 
Xo 
 
Xo 
 
Xo 
 
 
 
Xo 
 
 
 Footnotes 
Clinical chemistry and hematology analyses screening assessment may serve as the baseline assessment if performed 
within 3 days (72 hours) before the first dose of study treatment. Assessments on Day 1 of each cycle may be performed 
within 3 days of administration of study treatment, except vital signs (which are measured before administration of 
eribulin mesylate).  
a:  Screening: Baseline tumor assessments of the chest, abdomen, pelvis and other areas of known or newly suspected 
disease should be performed within 21 days before start of treatment. Scans of the abdomen, pelvis, and other areas of 
the body may be done with MRI instead of CT, but evaluation of the chest should be done with CT (Chest x-ray not 
permitted for tumor assessment). CT scans should be performed with oral and iodinated i.v. contrast and MRI scans 
with i.v. gadolinium chelate unless there is a medical contraindication to contrast. If i.v. contrast is contraindicated, 
chest CT should be done without i.v. contrast. Skin lesions should be clinically assessed using a metric ruler to calibrate 


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lesion size. A bone scan should be performed on all subjects within 6 weeks before start of treatment. 
Treatment Phase: Tumor assessments of the chest, abdomen and other areas of known disease that were scanned at 
Baseline, or newly suspected disease, must be performed every 9 weeks during study treatment until PD is documented. 
If treatment is delayed due to toxicity, tumor assessments will remain on a 9 week schedule. Tumor assessment must be 
performed within 1 wk of administration of the first dose of study treatment in the next treatment cycle, and should use 
the same methodology (CT/MRI) and scan acquisition techniques (including use or nonuse of i.v. contrast) as was used 
for the baseline assessments. Possible PR and CR (according to RECIST v 1.1,Appendix ) must be confirmed at no less 
than 4 weeks after the initial response assessment. If a subject withdraws from the study for radiographic evidence of 
PD, tumor assessments are not required at the End-of-Treatment visit.  
Posttreatment Follow-up Period: Subjects without PD at the time study treatment is discontinued should have tumor 
assessments every 9 wks from the date of last tumor assessment until PD is documented.  
Brain scans are at treating physician discretion. Scans can also occur as clinically indicated for new symptoms or to 
confirm disease response. Radiological scans that were negative at baseline do not have to be repeated unless clinically 
indicated.  
Bone Scans: Screening bone scans will be performed within 6 weeks before the start of treatment. Post screening bone 
scans are at treating physician discretion. Scans can also occur as clinically indicated for new symptoms or to confirm 
disease response. Radiological scans that were negative at baseline do not have to be repeated unless clinically 
indicated.  
The same methodology and scan acquisition techniques used at screening should be used throughout the study.  
b:  Assessments in the subsequent treatment cycles should follow assessments specified in cycles 1 to 4. 
c: These assessments will also be conducted upon early discontinuation from the study. 
d: Subjects who discontinue study treatment without having PD will return to the clinic for disease evaluation every 9 
weeks until PD is documented.  
e: Physical examination to be done at Screening, Day 1 of each cycle, and End-of-Treatment visit. PE on Day 1 of each 
cycle may be done within 3 days before the scheduled visit. 
f: Height recorded at Screening. Weight to be recorded on Days 1 and 8 of each cycle and End of Treatment. Other vital 
signs (BP, HR, respiratory rate, and body temperature) will be recorded before administration of eribulin mesylate on 
Days 1 and 8 of each cycle.  
g: ECG evaluations will be performed for all subjects at Screening and during the Treatment Phase before starting the 
second cycle of eribulin mesylate (recommended to be on Day 1 of Cycle 2 before administration of eribulin mesylate).  
h:  Females of childbearing potential must undergo a urine or serum β-hCG pregnancy test at screening. 
i: Hematology will be measured on Day 1 and Day 8 of each cycle. Hematology assessments are not required on Day 1 of 
Cycle 1 if performed within 3 days before study administration. Hematology assessments must be reviewed before 
administration of study treatment.  
j: Collection of whole blood for germline DNA and SNP analysis. If for any reason this sample is missed at baseline, or 
sample is insufficient; this may be redrawn at any timepoint before participant is removed from the study. Refer to 
Appendix 7 for additional information.  
k: Serum chemistry parameters will be measured on Day 1 and day 8 of each cycle. Assessments are not required on Day 1 
of Cycle 1 if performed within 3 days before study administration. Serum chemistry assessments must be reviewed 
before administration of study treatment. 
l: FACT-B, FACT-Ntx and PRO-CTCAE questionnaires to be recorded at Day 1 Cycles 1, 2 and 3, every other cycle in 
subsequent Cycles, and End-of-Treatment visit. Assessments may be performed within 3 days before the scheduled 
visit. 
m: Eribulin mesylate 1.4 mg/m2 given via i.v. infusion over 2 to 5 minutes on Days 1 and 8 of each 3-week cycle. 
n: All AEs, regardless of relationship to study treatment or procedure or grade, will be collected from the time the subject 
initiated therapy until 30 days after discontinuation of study treatment. All AEs must be followed until resolution or for 
30 days after the subject’s last study visit, whichever comes first. However, treatment-emergent peripheral neuropathy 


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of any grade will be followed until resolution or until another anticancer therapy is started, whichever occurs first. 
Serious AEs will be collected for 30 days post treatment and followed until resolution or, if resolution is unlikely, until 
the event or sequelae stabilize. 
O: Adverse event assessments will be graded as the worst grade in the last 7 days and recorded on Day 1 of Cycles 1, 2 and 
3, every other cycle in subsequent Cycles, and End-of-Treatment visit.. Complete form in Appendix 8. 
 
Abbreviations: BP = blood pressure; CBC = complete blood count; CNS = central nervous system; CR = complete 
response; CT = computed tomography; ECG = electrocardiogram; HR = heart rate; i.v. = intravenous; MRI = magnetic 
resonance imaging; PD = disease progression; PE = physical exam; PR = partial response; PS = performance status; QoL = 
quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; Tx = treatment 
 
 
10. 
MEASUREMENT OF EFFECT 
10.1. Efficacy Assessments (Antitumor Activity) 
Tumor response assessments 
All tumor assessments will be performed and analyzed based on RECIST v 1.1 (refer to 
Appendix 1 for details). Eligible subjects for this study must have measurable disease at 
Baseline, determined by the presence of at least one measurable target lesion. To assess best 
response (CR, PR, stable disease [SD], PD, not evaluable [NE]), each subject’s overall tumor 
burden at Baseline will be compared with subsequent measurements of lesions. Tumor response 
is to be assessed every 9 weeks. The same modality and contrast agent should be used for each 
measurement. 
Timing and Method of Tumor Assessments 
Baseline tumor assessments must be performed within 21 days before the first infusion of study 
treatment during the Pretreatment Phase to confirm subject eligibility and to identify target and 
nontarget lesions to be followed during the study. Baseline tumor assessments will consist of 
radiographic evaluation (CT or MRI scans) of the chest, abdomen, pelvis, and any other areas of 
known or suspected disease, along with clinical assessment of skin lesions, if applicable, using a 
metric ruler in the field and measured using calipers. A bone scan should also be performed on 
all subjects within 6 weeks before the first infusion of study treatment. 
Radiologic tumor assessments of the chest, abdomen, pelvis and other areas of known disease 
that are scanned at screening, or areas of newly suspected disease, must be performed every 9 
weeks. During treatment, tumor assessments should be performed any time within 1 week of 
administration of the first dose of study treatment in the next treatment cycle. Tumor assessments 
may be performed sooner than every 9 weeks if there is symptomatic evidence of PD upon 
clinical examination of the subject.  


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For subjects with a possible PR or CR (according to RECIST v 1.1), changes in tumor 
measurements must be confirmed by repeat evaluations, to be performed not less than 4 weeks 
after the response criteria are first met. The same imaging modality and image-acquisition 
protocol (including use or nonuse of i.v. contrast) should be used across all time points to 
allow consistent comparison of lesions.  
The preferred type of CT scan is a diagnostic quality spiral or multi-detector CT with i.v. and 
oral contrast. If iodinated i.v. contrast is contraindicated, it is recommended that the chest 
evaluation be done with noncontrast CT and the abdomen and pelvis evaluation be performed 
using either CT with oral contrast (without i.v. contrast) or MRI with gadolinium chelate i.v. 
contrast. Low-dose noncontract CT transmission scans from a positron-emission tomography 
(PET)-CT combination scanner are not acceptable. Spiral/multidetector CT and MRI body scans 
should be performed using ≤5 mm contiguous slices. Skin lesions should be clinically assessed 
using a ruler with millimeter subdivisions in the field and measurement performed using calipers. 
Ultrasound and low-dose noncontract CT transmission scans from a positron emission 
tomography-CT (PET-CT) combination scanner are not acceptable methods of radiographic 
tumor assessment. However, a fluorodeoxyglucose positron emission tomography (FDG-PET) 
scan, chest x-ray or skeletal x-ray that clearly demonstrates a new metastatic lesion may be used 
to document PD in lieu of the CT/MRI scans. 
Post screening bone scans will be performed at treating physician discretion. Scans can also 
occur as clinically indicated for new symptoms or to confirm disease response. Radiological 
scans that were negative at baseline do not have to be repeated unless clinically indicated.  
The recommended bone scan technique is 99m-technetium-labeled methylene diphosphonate 
(99m-Tc-MDP) scintigraphy or whole-body bone MRI. If an alternative scanning method is 
used, it should be continued throughout the rest of the study.  
The same methodology and scan acquisition techniques used at screening should be used 
throughout the study to ensure comparability. 
A brain scan by CT or MRI will only be performed at treating physician discretion. Scans can 
also occur as clinically indicated for new symptoms or to confirm disease response. Radiological 
scans that were negative at baseline do not have to be repeated unless clinically indicated. Brain 
scans should be performed with contrast-enhanced CT or MRI with ≤5-mm contiguous slices. 
Skin lesions should be clinically assessed using a metric ruler in the field and measured using 
calipers. If subcutaneous masses or nodes are palpable (e.g., bulky) and are assessable by both 
clinical and radiographic techniques, the radiographic (CT/MRI) technique should be used for 
the assessment of these lesions, whether target or nontarget. 
If study treatment is discontinued due to radiographic evidence of PD, the subject does not have 
to undergo tumor assessments at the End-of-Treatment visit. Follow-up disease evaluation is not 
required for subjects who have radiographic evidence of PD at the time of discontinuation of 
treatment or for those subjects who withdraw consent before developing PD. 
10.2. Baseline Identification of Target and Nontarget Lesions 


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At Baseline, the investigator is to select up to a total of five measurable lesions (two per organ) 
that are representative of all involved organs as target lesions. Target lesions are to be selected 
on the basis of their size (the lesion with the longest diameter) and suitability for accurate 
repeated measurements (either by imaging techniques or clinically). To be considered a target 
lesion at Baseline, the lesion must be measurable and have a minimum size of 10 mm in the 
longest diameter for non-lymph node lesions or 15 mm in the short-axis for a lymph node. 
All other lesions (or sites of disease), both measurable and nonmeasurable, will be identified as 
nontarget lesions and will be recorded at Baseline. Nontarget lesions will be evaluated at the 
same assessment time points as target lesions. However, measurements will not be required, and 
these lesions will be followed as “present” or “absent.” 
Refer to Appendix 1 for further details on the evaluation of target and nontarget lesions. 
10.3. Primary efficacy variable/endpoint 
The antitumor activity of eribulin mesylate monotherapy will be assessed by determining ORR 
based on RECIST v 1.1 (Appendix 1). For analysis purposes, ORR is defined as the proportion 
of subjects who achieve a CR plus those who achieve a PR. To be assigned a status of PR or CR, 
changes in tumor measurements must be confirmed by repeat evaluations, to be performed not 
less than 4 weeks after the response criteria are first met. 
10.4. Secondary efficacy variables 
The secondary efficacy endpoints for this study are time to first response, duration of response 
and PFS, defined as follows: 
 Time to first response will be defined for subjects whose best overall response (OR) is a 
CR or PR. The time to first response will be measured from the date of first dose of 
study treatment until the earliest date that CR or PR is objectively documented.  
 Duration of overall response will be defined for subjects whose best OR is CR or PR. 
The duration of OR will be measured from the time that response criteria for CR or PR 
(whichever is recorded first) are first met until the date that PD or death from any cause 
is first objectively documented). Subjects who do not have PD will be censored on the 
day of their last tumor assessment. 
 Progression-free survival will be defined as the time from the date of the first dose of 
study treatment until the date of first documentation of PD or date of death from any 
cause (whichever occurs first). Subjects who die without reported PD are considered to 
have progressed on the day of their death. Subjects who are alive at the end of study 
without reported PD will be censored on the date of their last tumor assessment. 
10.5. Laboratory measurements 
Clinical laboratory tests will be performed at the investigational sites. Screening assessments of 
laboratory parameters may be used as Baseline assessments if they are performed within 3 days 
before the start of study treatment.  


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Table 4 presents the clinical laboratory tests to be performed at various time points during the 
study. All results from laboratory assessments obtained at a scheduled visit must be 
reviewed before administration of study treatment. 
The Study Calendar (Table 3) shows the visits at which blood will be collected for clinical 
laboratory tests.  
Hematology assessments will be performed at Screening, Day 1 and Day 8 of each treatment 
cycle, and the End-of-Treatment visit.  
Clinical chemistry assessments will be performed at Screening, Day 1 and Day 8 of each 
treatment cycle, and the End-of-Treatment visit. 
 
Table 4: 
Clinical Laboratory Tests 
Category 
Tests 
Hematologya  
1. Hematocrit, hemoglobin, RBC, platelet count, WBC with differential 
(bands, basophils, eosinophils, lymphocytes, monocytes, neutrophils), 
ANC 
Clinical Chemistryb 
 
Screening/Baseline Panel 
2. Pregnancy test (serum or urine β-hCG), chloride, potassium, sodium, 
BUN, serum creatinine, calcium, albumin, total protein, alkaline 
phosphatase, ALT, AST, total bilirubin, magnesium 
Treatment Panel  
3. Chloride, potassium, sodium, BUN, serum creatinine, calcium, 
albumin, total protein, alkaline phosphatase, ALT, AST, total bilirubin, 
magnesium 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; β-hCG = 
beta-human chorionic gonadotropin; BUN = blood urea nitrogen; RBC = red blood cells; WBC = white blood 
cells 
a: Hematology assessments obtained at Screening/Baseline, Days 1 and 8 of each treatment cycle  
b: Chemistry assessments obtained at Screening/Baseline, and Day 1 and Day 8 of each treatment cycle  
 
10.6. Vital signs and weight measurements 
Vital sign measurements (blood pressure [BP], heart rate [HR], respiratory rate, oral body 
temperature [C]) and weight will be obtained at the time points designated on the Study 
Calendar. Height will be measured at the Screening Visit only. Weight will be recorded on Day 1 
and 8 of each cycle, before the subject receives study treatment, for calculation of BSA.  
10.7. Electrocardiograms 
Standardized, 12-lead ECGs will be performed at Screening, Baseline, once during Cycles 1 or 2 
(preferably on Day 1 of Cycle 2 before administration of study treatment), and at the End-of-
Treatment visit. The Screening assessment may be used as the Baseline assessment if the ECG is 
performed within 3 days before the start of study treatment.  


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An ECG abnormality may meet AE criteria as described in Section 11 of this protocol and the 
CRF completion guidelines. In these instances, the AE corresponding to the ECG abnormality 
will be recorded on the Adverse Event page of the eCRF. For ECG abnormalities meeting SAE 
criteria, the study site must fax the SAE report, including the ECG report, to the Eisai Drug 
Safety Department using the SAE reporting form. 
 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1. Definitions 
11.1.1. Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
11.1.2. Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at least a 
24-hour hospitalization or prolonged a hospitalization beyond the expected length 
of stay). Hospitalization admissions and/or surgical operations scheduled to occur 
during the study period, but planned prior to study entry are not considered SAEs 
if the illness or disease existed before the person was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the trial (e.g., 
surgery performed earlier than planned). 
 Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 


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Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 respite care 
 
11.1.3. Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a description of expected adverse events associated with eribulin. 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk. 
  11.1.4  Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment.  
 
Unlikely - The AE is doubtfully related to the study treatment. 
 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
 
Procedures for AE and SAE Recording and Reporting 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  


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All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded 
in the participant’s medical record and on the appropriate study-specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Reporting Requirements 
Each investigative site will be responsible to report SAEs that occur at that institution to the 
Overall Primary Investigator , Dr Erica Mayer and to their own Institutional IRB. DF/HCC sites 
will report to Dr Erica Mayer, and the DFCI/HCC IRB. Complete reporting instructions are 
described below.  
 
Reporting to the Study Sponsor 
Serious Adverse Event Reporting 
 
Serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on the local institutional SAE form. This includes events meeting the following 
criteria: 
 
 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
 
 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
 
All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last study 
intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 


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Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 business hours of learning of the occurrence. In the event that 
the participating investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is to report the event 
within 24 business hours after learning of it and document the time of his or her first awareness 
of the adverse event. Report serious adverse events by telephone, email or facsimile to: 
 
 
 
Erica L. Mayer, MD MPH 
 
 
Telephone: 617-632-2335 
 
 
Fax: 617-632-1930 
 
 
emayer@partners.org 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms.  
 
11.2. Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 


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49 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
 
11.3. Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
 
11.4.  Reporting SAEs to EISAI 
All SAEs, as defined in Section 11.1.2, will be reported to EISAI on a Medwatch 3500A form 
within one business dayof the event. The reports will be sent to EISAI at the number listed 
below: 
 
EISAI safety fax number (732-791-1111)  Email: ESI_Safety@eisai.com 
 
External participating sites will send Medwatch 3500A reports directly to EISAI, and a copy will 
be sent to the DFCI project manager:  CTOPM@dfci.harvard.edu 
 
DF/HCC sites will send the Medwatch 3500A reports directly to EISAI and file a copy in the 
study regulatory documents. 
 
11.5. Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study intervention 
should be followed to their resolution, or until the participating investigator assesses them as 
stable, or the participating investigator determines the event to be irreversible, or the participant 
is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should be 
documented on the appropriate case report form and recorded in the participant’s medical record 
to facilitate source data verification.  
 
For some SAEs, the investigator or designee may follow-up by telephone, fax, and/or monitoring 
visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator and their respective IRB of any unanticipated death or adverse 


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event occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.  
 
12. 
DATA AND SAFETY MONITORING 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating practices, working practice documents, and applicable regulations and guidelines. Site 
visit audits may be made periodically by a qualified compliance auditing team, which is an 
independent function from the study conduct team. 
12.1. Data Reporting 
Method 
 
The QACT will collect, manage, and monitor data for this study.  
 
 
Data Submission 
 
The schedule for completion and submission of case report forms (paper or electronic) to the 
QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within approximately 14 days of registration 
Baseline Assessment Form 
Within approximately 14 days of registration 
Treatment Form 
Within approximately 10 days of the last day of 
the cycle 
Adverse Event Report Form 
Within approximately 10 days of the last day of 
the cycle 
Response Assessment Form 
Within approximately 10 days of the completion 
of the cycle required for response evaluation 
Off Treatment/Off Study Form 
Within approximately 14 days of completing 
treatment or being taken off study for any reason 
Follow up/Survival Form 
Within approximately 14 days of the protocol 
defined follow up visit date or call 
 
 
12.2. Safety Meetings 
 


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The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator and 
study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data. 
Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring within 30 days for Phase I or II protocols; 
for gene transfer protocols, summary of all deaths while being treated and during active follow-
up; any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
12.3. Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, and any applicable regulatory requirements. Please refer to 
Appendix 9: Section 5.0 for additional information. 
 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion.  
 
12.4. Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix F. 
 
The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports to all participating institutions for submission to their individual IRBs for action 
as required. 
 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse event 
reporting at each site. 
 


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Except in very unusual circumstances, each participating institution will order the study agent(s) 
directly from supplier.  A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center. 
 
 
13. 
REGULATORY CONSIDERATIONS 
13.1. Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.2. Informed Consent 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
13.3. Ethics 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
 Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  


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 Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
 Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
 
State laws 
 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy. 
 
13.4. Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.  
 
13.5. Records Retention 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  


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14. 
STATISTICAL METHODS 
14.1. Statistical and Analytical Plans 
Statistical programming and analyses will be performed using SAS and other validated statistical 
software as required. 
The primary analyses of efficacy endpoints that are related to tumor assessment will be 
performed using investigator-assessed data. 
The full analysis dataset will include all subjects who receive at least one dose of study 
treatment. Objective response will be assessed according to RECIST 1.1. All patients who 
receive at least one dose of therapy will be included in the calculation of objective response rate. 
Patients who, in retrospect, do not have measurable disease, and patients with no follow up 
evaluation of response, will be considered non-responders for the purpose of analysis of the 
primary endpoint. Confirmation of response is required to assign a status of best overall response 
of CR or PR. 
 
Patients who have developed metastatic disease within 12 months of last dose of (neo) adjuvant 
chemotherapy who enroll on protocol will be considered in the analysis as a second-line patient, 
even if no prior chemotherapy was received in the metastatic setting. 
 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be listed, and summarized for the full 
analysis dataset. For continuous demographic/baseline variables such as age, weight, and vital 
signs, results will be summarized and presented as number (N), mean, median, and range. For 
categorical variables such as race/ethnicity, the number and percentage of subjects will be used. 
Subject Disposition 
The number and percentage of subjects, who complete or prematurely withdraw from the study, 
as well as the reason for discontinuation, will be summarized.  
14.2. Determination of sample size 
The historical ORR data for chemotherapy in the first-line metastatic setting indicated a 33% 
ORR for anthracycline and 38% ORR for taxanes. For patients treated beyond first-line, the 
historical data indicate an approximate 20% ORR. This trial will be open for treatment in either 
the first- or second-line setting. The study primary endpoint is the ORR of eribulin given as 
monotherapy. ORR defined as the proportion of subjects who achieve a confirmed CR or PR 
(RECIST 1.1), will be evaluated for each cohort separately using investigator-assessed data 
(Appendix 1). 
Statistical considerations for eribulin monotherapy cohorts (cohort 1 and 2)  


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ORR will be estimated separately for the HR+/HER2- and the TNBC monotherapy cohorts. For 
the TNBC cohort, it is assumed there will be a 50-50 allocation between first- and second-line 
patients. For the HR-positive cohort, it is assumed there will be a 40-60 allocation between first- 
and second-line patients. The primary objective is to estimate the response rate (by RECIST 1.1) to 
eribulin.  
From the meta-analysis of O’Shaughnessy et al, the ORR in TNBC in the first-line setting was 
approximately 23%, and was 18% in the second-line setting based on the results of the TNBC 
subgroup of patients in the RIBBON-2 trial. With a 50-50 allocation between first- and second-line 
patients, we would assume a response rate of approximately 21-22% in the cohort of TNBC.  For 
patients with HR-positive disease, the estimated ORR from RIBBON-2 was 29.6% in the second-
line setting and has been reported to be between 33-38% for first-line therapy.  We assume a 40-60 
allocation between first- and second-line patients in the HR-positive cohort, and conservatively 
estimate a response rate of 30% in this protocol. 
Our response rate assumptions for this protocol are 22% in the TNBC cohort and 30% in HR-
positive cohort. Because eribulin has already demonstrated activity, including an overall survival 
advantage in the refractory setting, this study will utilize a single-stage design. The sample sizes 
of each cohort were based on the lower bounds of the 90% exact confidence intervals (CI) 
around possible observed response rates, as shown in the Table 5. 
Table 5: Eribulin Sample Size Table  
*Confidence intervals estimated using exact binomial methods. 
Sample 
Size (per 
cohort) 
Number 
responses 
Observed 
response 
rate 
Lower 
end 
90% CI* 
Upper end 
90% CI* 
Width 90% 
CI 
45 
9 
.200 
.109 
.323 
.215 
11 
.244 
.144 
.372 
.228 
13 
.289 
.180 
.420 
.239 
14 
.311 
.199 
.443 
.244 
15 
.333 
.218 
.466 
.248 
16 
.356 
.237 
.489 
.252 
17 
.378 
.257 
.511 
.254 
18 
.400 
.277 
.534 
.257 
19 
.422 
.297 
.555 
.258 
20 
.444 
.317 
.578 
.261 
21 
.467 
.338 
.599 
.261 
For TNBC (orange) cohort, if 16 or more women of 45 have a response, then the lower bound of 
the 90% exact confidence interval of the observed response rate exceeds 22%.  
For ER+ (yellow) cohort, if 20 or more women of 45 have a response, the lower bound of the 
90% exact confidence interval of the observed response rate exceeds 30%, which is the historical 
response rate of the combined 1st and 2nd line groups. 
 


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In the TNBC cohort, there will be 90% power to detect a 22% percent improvement in response 
(22% vs. 44%) assuming an equal allocation of first- and second-line patients.  In the HR-
positive cohort, there will be 90% power to detect a 23 percent improvement in response (30% 
vs. 53%) assuming first- and second-line patients are allocated approximately 40-60.  Both 
calculations assume a two-sided, 0.1 type-1 error and an exact binomial test. 
 
14.3. Safety analysis  
All patients who receive at least one dose of the study regimens will be included in the 
assessment of adverse events (full analysis population). Adverse event information for the two 
cohorts will be combined. Safety data that will be evaluated include AEs, clinical laboratory 
results, vital signs, and ECGs. Abnormal laboratory values will be flagged.  
Adverse event information will be collected from the time the subject signs the ICF until 
resolution or for 30 days after the subject’s last study visit, whichever comes first. Treatment-
emergent AEs (TEAEs) will be analyzed. Adverse events will be regarded as TEAEs if they 
started on or after the date and time of administration of the first dose of study treatment or if 
they were present before the administration of the first dose of study treatment and increased in 
severity during the study. Treatment-emergent peripheral neuropathy will be followed until 
resolution or until the start of another anticancer therapy post treatment, whichever occurs first.  
Adverse events will be graded using CTCAE v 4.0 (Appendix 5). Investigators will collect all 
CTCAE grades for all AEs (to assess both increasing and decreasing severity). Events will be 
summarized by frequency and percentage. 
The incidence of TEAEs and relatedness to study treatment will be summarized. Although an 
adverse event may be reported more than once for a subject, that subject will be counted only 
one time in the incidence count for that adverse event term by the highest CTCAE grade (in the 
summary by CTCAE grade) and by the closest causal relationship to study treatment (in the 
summary by relatedness to study treatment). 
14.4. Analysis of Secondary Efficacy Variables 
Progression-free survival (PFS) will be analyzed using Kaplan-Meier product-limit estimates and 
presented separately for each cohort. Median PFS and the cumulative probability of PFS at 6 and 
12 months will be presented with two sided 90% CIs derived using log(-log(survival)) 
methodology. Time to first response and duration of response will be summarized for the 
responders using the Kaplan-Meier method. The cumulative PFS, time to first response, and 
duration of response probabilities will be plotted over time. Median and first and third quartiles 
from Kaplan-Meier estimation for PFS, time to first response, and duration of response will be 
provided with 90% CIs. 
14.5. Analysis of Quality of Life Assessments 
Patient reported outcome data will be combined for the monotherapy cohorts. QOL surveys 
(FACT-B, FACT-Ntx, and PRO-CTCAE) questionnaires will be obtained at baseline, C2D1, 


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C4D1, C7D1, and at the off-study visit. Quality of life (QoL) data will be combined for the 
monotherapy cohorts (Cohorts 1 and 2). 
 
FACT-B: At each assessment time, subscale scores for physical well-being, emotional well-
being, social well-being, functional well-being, and relationship with doctor will be scored per 
standardized scoring algorithms and will be presented individually and combined to obtain the 
FACT-G total score. In addition, the breast cancer subscale score will be summarized separately 
and combined with the FACT-G to obtain the summary score of the FACT-B. For all subscales 
and total scores, a higher score reflects better QoL. Descriptive statistics will be presented for 
each subscale and total score. We will also summarize changes in scores between baseline and 
C2D1 to assess the effect of treatment upon QoL. Change scores will be compared with zero 
using the Wilcoxon signed-rank test. For the combined monotherapy cohort, a sample of size 90 
will have 80% power to detect a mean change score that is 0.28 times the common standard 
deviation (i.e., effect size of 0.28), when tested at a two-sided 10% significance level. Scores will 
also be summarized graphically over the repeated assessment times to derive a QoL response 
profile over the course of treatment.  
FACT-NTX: The effect of peripheral neuropathy upon QoL will be summarized using the 11-
item FACT-NTX assessment. At each assessment time, scores will be summarized descriptively. 
Changes in score between baseline and C2D1 will also be summarized descriptively on a 
continuous scale, in addition to the proportion of patients who have clinically meaningful 
changes in score of 3 points or greater. The proportion will be presented with a 90% confidence 
interval estimated using exact binomial methods. For a sample of size 90, the confidence interval 
will be no wider than 0.18.  
The primary purpose of the inclusion of PRO-CTCAE is to evaluate the performance of an 
electronic-based system for patient self-reporting of AEs, and assess whether PRO data 
collection improves the accuracy and description of each class of AEs. PRO-CTCAE data will 
also be compared with provider-reported CTCAE toxicity data to estimate the degree of 
concordance or divergence for each class of toxicity. The PRO-CTCAE data evaluation will also 
focus on accurate description of incidence and severity of neuropathy in this patient population. 
The PRO-CTCAE data presentation and analysis will be descriptive and exploratory in nature.  
14.6. Neuropathy Analysis 
Comparison of candidate genotypes with the likelihood of developing clinically significant 
peripheral neuropathy in this trial will be exploratory in nature. 
 
15. PUBLICATION PLAN 


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It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. The 
Primary Investigator will be the final arbiter of the manuscript content.   
The outcome results of this trial will be made public within 24 months of the end of data 
collection. Interim accrual and toxicity results of this trial may also be periodically presented at 
meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer 
Symposium. A full report of the outcomes will be made public no later than two (2) years after 
the end of data collection.  
 


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16. REFERENCES  
 
 
1. 
Hirata Y, Uemura D: Halichondrins: antitumor plyether macrolides from a marine 
sponge. Pure Appl Chem:701-10, 1986 
 
2. 
Bai RL, 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 266:15882-9, 
1991 
 
3. 
Jordan MA, Kamath K, Manna T, et al: The primary antimitotic mechanism of 
action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer 
Ther 4:1086-95, 2005 
 
4. 
Kuznetsov G, Towle MJ, Cheng H, et al: Induction of morphological and 
biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic 
ketone analog E7389. Cancer Res 64:5760-6, 2004 
 
5. 
Towle MJ, Salvato KA, Budrow J, et al: In vitro and in vivo anticancer activities 
of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61:1013-21, 2001 
 
6. 
Vahdat LT, Pruitt B, Fabian CJ, et al: Phase II study of eribulin mesylate, a 
halichondrin B analog, in patients with metastatic breast cancer previously treated with an 
anthracycline and a taxane. J Clin Oncol 27:2954-61, 2009 
 
7. 
Cortes J, Vahdat L, Blum JL, et al: Phase II study of the halichondrin B analog 
eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated 
with an anthracycline, a taxane, and capecitabine. J Clin Oncol 28:3922-8, 2010 
 
8. 
Cortes J, O'Shaughnessy J, 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 377:914-23, 2011 
 
9. 
Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin 
61:69-90, 2011 
 
10. 
American Cancer Society Breast Cancer Facts and Figures 2007-2008 and 
Surveillance Research 2007 
 
11. 
Bernard-Marty C, Cardoso F, Piccart MJ: Facts and controversies in systemic 
treatment of metastatic breast cancer. Oncologist 9:617-32, 2004 
 
12. 
Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic 
complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin 
chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-
positive operable breast cancer. J Clin Oncol 23:3676-85, 2005 
 
13. 
Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients 
with complete remission following combination chemotherapy for metastatic breast cancer. J 
Clin Oncol 14:2197-205, 1996 
 
14. 
Porkka K, Blomqvist C, Rissanen P, et al: Salvage therapies in women who fail to 
respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced 
breast cancer. J Clin Oncol 12:1639-47, 1994 
 
15. 
Dueck AC, Mendoza TR, Mitchell SA, et al: Validity and reliability of the 
patient-reported outcomes version of the common terminology criteria for adverse events (PRO-
CTCAE). J Clin Oncol 30:9047, 2012 


Protocol #:13-077 
Version Date: 2/23/2016 
 
60 
 
 
16. 
Rock EP, Kennedy DL, Furness MH, et al: Patient-reported outcomes supporting 
anticancer product approvals. J Clin Oncol 25:5094-9, 2007 
 
17. 
Fromme EK, Eilers KM, Mori M, et al: How accurate is clinician reporting of 
chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-
of-Life Questionnaire C30. J Clin Oncol 22:3485-90, 2004 
 
18. 
Basch E, Jia X, Heller G, et al: Adverse symptom event reporting by patients vs 
clinicians: relationships with clinical outcomes. J Natl Cancer Inst 101:1624-32, 2009 
 
19. 
Petersen MA, Larsen H, Pedersen L, et al: Assessing health-related quality of life 
in palliative care: comparing patient and physician assessments. Eur J Cancer 42:1159-66, 2006 
 
20. 
Quinten C, Maringwa J, Gotay CC, et al: Patient self-reports of symptoms and 
clinician ratings as predictors of overall cancer survival. J Natl Cancer Inst 103:1851-8, 2011 
 
21. 
Brady MJ, Cella DF, Mo F, et al: Reliability and validity of the Functional 
Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol 15:974-86, 1997 
 
22. 
Cella D, Wang M, Wagner L, et al: Survival-adjusted health-related quality of life 
(HRQL) among patients with metastatic breast cancer receiving paclitaxel plus bevacizumab 
versus paclitaxel alone: results from Eastern Cooperative Oncology Group Study 2100 (E2100). 
Breast Cancer Res Treat, 2011 
 
23. 
Calhoun EA, Welshman EE, Chang CH, et al: Psychometric evaluation of the 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 
(Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol 
Cancer 13:741-8, 2003 
 
24. 
Wozniak KM, Nomoto K, Lapidus RG, et al: Comparison of neuropathy-inducing 
effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 71:3952-62, 2011 
 
25. 
Amir E, Miller N, Geddie W, et al: Prospective study evaluating the impact of 
tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol 30:587-92, 
2012 
 
26. 
Rugo HS, Barry WT, Moreno-Aspitia A, et al: CALGB 40502/NCCTG N063H: 
Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin 
bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line 
therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 30:CRA1002, 2012 
 
27. 
Romond EH, Jeong JH, Rastogi P, et al: Seven-year follow-up assessment of 
cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and 
cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy 
for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. 
J Clin Oncol 30:3792-9, 2012 
 
28. 
Schneider B, Li L, Miller K, et al: Genetic associations with taxane-induced 
neuropathy by a genome-wide association study (GWAS) in E5103. J Clin Oncol 29:A1000, 
2011 
 
29. 
Schneider BP, Wang M, Radovich M, et al: Association of vascular endothelial 
growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with 
outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast 
cancer: ECOG 2100. J Clin Oncol 26:4672-8, 2008 
 
 
 


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17. 
APPENDICES 
17.1. Appendix 1 - Overview of RECIST v 1.1 for Evaluation of Tumor Response 
Tumor response assessments in this clinical study will use RECIST v 1.1 based on the 2009 article by 
Eisenhauer et al. entitled, New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1).Error! Bookmark not defined. This Appendix contains an overview of the RECIST v 1.1 
guidelines. For complete details, the Eisenhauer article, published in the European Journal of Cancer, 
is available online at: http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 
Baseline Tumor Assessment 
Subjects are required to have measurable disease, defined as the presence of at least one measurable 
lesion, to be eligible for entry into the study. Measurable and nonmeasurable lesions are defined as: 
 
Measurable lesions: Lesions that can be accurately measured in at least one dimension (longest 
diameter [LD] to be recorded) with a minimum size of >10 mm based on CT (CT slice thickness 
of ≤5 mm; for slice thicknesses >5 mm, measurable lesions must have a longest diameter ≥2 
times the slice thickness) or caliper measurement by clinical exam. 
A lymph node will be considered pathologically enlarged and measurable if its short axis is ≥15 
mm; the short axis should be measured and followed throughout. Nodes with a short axis ≥10 mm 
and <15 mm will be considered pathologically enlarged but nonmeasurable. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft-tissue components will be 
considered measurable if the soft-tissue component can be evaluated by cross-sectional imaging 
(i.e., CT scan) and meets the general definition of measurability. Blastic bone lesions are 
nonmeasurable. 
A lesion located in a previously irradiated area, or in an area previously subjected to any 
locoregional therapy, will be considered measurable only if there has been a documented increase 
in lesion size subsequent to prior treatment but before study entry. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules) 
and should be assessed using a metric ruler to estimate the size of the lesion. The minimum lesion 
size is ≥10 mm. 
 
Nonmeasurable lesions: All other lesions, including small lesions (LD <10 mm or pathological 
lymph nodes with a short axis of ≥10 mm to <15 mm), lesions that cannot be accurately measured 
with calipers, and truly nonmeasurable lesions: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. Lymph nodes with a short axis <10 mm are considered 
nonpathological and should not be recorded or followed. 
Simple cysts (cystic lesions) will not be considered malignant, and will be neither measurable nor 
nonmeasurable. Cystic lesions believed to be metastases may be considered measurable if they 
meet the general definition of measurability, but noncystic lesions are preferred as target lesions. 
Baseline evaluations should be performed as closely as possible to the start of treatment and within 21 
days before the first dose of study treatment (bone scans should be performed within 6 weeks of start of 
treatment).  
Methods of Tumor Measurement 
The same imaging modality and the same technique (including use or nonuse of oral and i.v. contrast) 
should be used to characterize each identified and reported lesion at Baseline/Screening and at 


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reassessment time points during the study. All measurements should be taken and recorded in metric 
notation, using calipers if clinically assessed. 
Computed tomography and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. Computed tomography should be performed with slices of 
5 mm or less in thickness (as a general rule, lesion diameter should be no less than double the slice 
thickness). This applies to tumors of the chest, abdomen, and pelvis. Magnetic resonance imaging is also 
acceptable in certain conditions (e.g., for body scans). A CT of the chest without contrast is preferred over 
MRI. 
Bone scans, positron emission tomography (PET) scan, or plain films are not sufficient to measure bone 
lesions and document objective response, but may be used to confirm the presence or disappearance of 
such lesions. Bone scans should be performed using 99m-technetium-labeled polyphosphonate 
scintigraphy. 
Chest x-rays should not be used for baseline assessment of the chest or for follow-up of known lesions. 
Chest CT should be used. 
Ultrasound should not be used to measure tumor lesions. 
Endoscopy and laparoscopy should not be used to measure tumor lesions. However, such techniques can 
be useful in confirming complete pathological response or determine relapse. 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal 
limit, they must normalize for a subject to be considered in complete clinical response when all lesions 
have disappeared.  
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after treatment 
to differentiate between residual benign lesions and residual malignant lesions in tumor types such as 
germ cell tumors). 
Documentation of “Target” and “Nontarget” Lesions 
Lesions are evaluated and classified at Baseline as either target or nontarget and all are then followed 
throughout the study. 
Target Lesions: 
Target lesions are all measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs. Target lesions should be selected on the basis of their size 
(those with the longest diameters) and their suitability for accurate repeated measurements. 
The short axis (≥15 mm) of any lymph nodes selected as target lesions at Baseline will be measured and 
recorded at each evaluation time point, even if the nodes become nonpathological (short axis <10 mm). 
The sum of the diameters of all target lesions (longest for non-nodal lesions, short axis for nodal lesions) 
will be calculated at Baseline and reported as the baseline sum diameter. This baseline sum diameter will 
be used as the reference by which to characterize objective tumor response. For lesions measurable in two 
or three dimensions, the LD must be reported at the time of each assessment. 
Target Lesions Too Small To Measure: 
Lesions that become too small to measure during treatment should be assigned a default measurement of 
either 0 mm (if the investigator believes the lesion has disappeared) or 5 mm (if the lesion is believed to 
be present and is faintly visible). 
Target Lesions That Split or Coalesce: 
If a non-nodal target lesion fragments during treatment, the longest diameters of each fragment should be 
added together to calculate the total sum for that lesion. When lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximal diameter measurements for each individual 
lesion. If the lesions are no longer separable, the vector of the longest diameter in this instance should be 


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the maximal longest diameter for the coalesced lesion. 
Nontarget Lesions: 
All other lesions (or sites of disease) should be identified as nontarget lesions and should also be 
recorded at Baseline. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout Follow-up. 
New Lesions: 
The finding of a new lesion should be unequivocal (i.e., not attributable to a change in scanning technique 
or imaging modality, and not thought to represent something other than a tumor). If a possible new lesion 
is equivocal, treatment and radiographic evaluation should continue per this protocol until confirmation of 
PD or until additional scans confirm the presence of a new lesion. In such a case, the date of progression 
will be the date of the initial scan. 
A lesion identified on a Follow-up study of an anatomical location not studied as Baseline will be 
considered a new lesion. 
Scanning with FDG-PET may be employed as a complement to CT scanning in the assessment of PD. A 
negative FDG-PET scan at Baseline with a positive scan during the study will be evidence of PD. If there 
is no FDG-PET scan at Baseline and a positive FDG-PET scan during the study, it will be considered 
evidence of PD if the positive FDG-PET corresponds to a new site of disease confirmed by CT scan. A 
positive postbaseline FDG-PET result corresponding to a pre-existing site of disease with no radiographic 
evidence of progression will not be considered evidence of PD. 
Evaluation of Response for an Individual Assessment Time Point 
To determine tumor response, the sum of all target lesions is calculated at Baseline and at each 
subsequent assessment time point (i.e., every 9 weeks). Each response parameter (target, nontarget, and 
new lesions) will be reported independently at each radiographic reading as shown in Table 1 for target 
lesions and Table 2 for nontarget lesions. The investigator will then make a determination of OR for each 
assessment time point based on a composite evaluation of target, nontarget, and new lesions, as shown in 
Table 3.  
 
Table 1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. All pathological lymph nodes 
(whether target or nontarget) must have a reduction in their short 
axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the Baseline sum diameters 
Progressive Disease (PD)  
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded at Baseline or 
during treatment. The sum must also have an absolute increase of 
≥5 mm. The appearance of one or more new lesions is also 
considered PD. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
Not 
Evaluable 
(NE) 
or 
Unevaluable 
No imaging/measurement done at all or only on a subset of lesions 
at a particular time point; a target lesion at Baseline which is 
subsequently 
not 
measured 
or 
which 
is 
unable 
to 
be 
evaluatedIncludes scans that are not performed at a specified time 


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point to evaluate the target lesion(s).  
 
Table 2 
Evaluation of Nontarget Lesions 
Complete Response (CR) 
Disappearance of all nontarget lesions; normalization of tumor 
marker level. All lymph nodes <10 mm (short axis) 
Non-CR/Non-PD 
Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
Progressive Disease (PD) 
Unequivocal progression (substantial worsening in nontarget 
disease such that overall tumor burden has increased sufficiently to 
warrant discontinuation of therapy); appearance of one or more new 
lesions and/or unequivocal progression of existing nontarget 
lesionsa 
Not Evaluable (NE) 
A nontarget lesion at Baseline which is subsequently not measured 
or which is unable to be evaluated 
a. Although a clear progression of “non target” lesions only is exceptional, in such circumstances, 
the opinion of the site radiologist should prevail. 
 
Table 3 
Overall Response at Each Assessment Time Point for Subjects with Target (+/- 
Nontarget) Disease 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated
No 
PR 
SD 
Non-PD or not all evaluated
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = disease progression; PR = partial response; SD = 
stable disease 
 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time point assessment should be classified as having 
“symptomatic deterioration.” Every effort should be made to document objective progression 
after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. 


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Evaluation of Best Overall Response and Confirmation of Response 
The best OR is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the subject's best response assignment will depend on the achievement of 
both measurement and confirmation criteria as shown in Table 4. 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for response are 
first met. In this study, bone scan and brain CT/MRI are performed at treating physician discretion. Scans 
can also occur as clinically indicated for new symptoms or to confirm disease response. Radiological 
scans that were negative at baseline do not have to be repeated unless clinically indicated.  
 
 
The main goal of confirmation of the PR or CR objective response is to avoid overestimating the 
response rate. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome that the response(s) are not confirmed. 
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 5 weeks for this protocol. 
 
Table 4 
Best Overall Response with Confirmation 
Unconfirmed 
Response 
(First Time Point) 
Confirmatory 
Response
(Subsequent Time Point) 
 
Best Overall Response of: 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa
CR 
SD 
SD or PDb
CR 
PD 
SD or PDb
CR 
NE 
SD or NEc
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SDb 
PR 
NE 
SDc 
NE 
NE 
NE 
BL = baseline; CR = complete response; NE = not evaluable; PD = disease progression; PR = partial 
response; SD = stable disease 
a: If a CR is truly met at first time point, then any reappearance of disease seen at a subsequent time 
point (including disease meeting PR criteria relative to BL) makes the disease PD at that time point 
b: Classify response as SD, provided that confirmatory scan a minimum of 5 weeks later is still “SD.” 
Otherwise, response classified as PD. 
c: Classify response as SD, provided that confirmatory scan a minimum of 5 weeks later is still “SD.” 
Otherwise, response classified as NE. 
 
Duration of Overall Response 
The duration of OR is measured from the date that measurement criteria are met for CR or PR (whichever 
status is recorded first) until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest sum LD recorded since the treatment started. 
Duration of Stable Disease 


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Stable disease is measured from the start of the treatment until the criteria for PD are met, taking as 
reference the smallest sum LD recorded since the treatment started. 
The clinical relevance of the duration of SD varies for different tumor types and grades. For this protocol, 
duration of stable disease is not being measured. 
Response Review 
For this Phase 2 study, response review will be performed at the site by appropriately qualified personnel 
(radiologist in conjunction with clinical investigator). 
Reporting of Results 
All subjects included in the study should be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. 


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67 
 
 
 
17.2. Appendix 2 - ECOG Performance Status Scale 
 
Score 
Status 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
ECOG =Eastern Cooperative Oncology Group. 
Adapted from Oken MM et al. Am J Clin Oncol. 1982;5:649-5.  
 


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17.3. Appendix 3 - Cockcroft and Gault Formula 
 
Male 
(140-age) x weight (kg)  
= XX mL/min 
Serum creatinine (mg/dL) x 72  
 
 
 
Female 
(140-age) x weight (kg)  
= XX mL/min x 0.85 
Serum creatinine (mg/dL) x 72  
. 
 
Adapted from Cockcroft DW et al. Nephron. 1976;16(1):31-41.Error! Bookmark not defined. 


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17.4. Appendix 4 - New York Heart Association Cardiac Disease Classification 
The New York Heart Association (NYHA) Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for cardiac subjects. Based on NYHA 
definitions, subjects are to be classified as follows: 
 
Class 
Definition 
Class I 
Subjects with no limitation of activities; they suffer no symptoms from ordinary activities. 
Class II 
Subjects with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion. 
Class III 
Subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Subjects who should be at complete rest, confined to bed or chair; any physical activity 
brings on discomfort and symptoms occur at rest. 
 


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17.5. Appendix 5 - Common Terminology Criteria for Adverse Events (version 4.0) 
The National Cancer Institute’s CTCAE v 4.0 published 28 May 2009 provides descriptive terminology 
to be used for AE reporting in clinical trials. A brief definition is provided to clarify the meaning of each 
AE term. To increase the accuracy of AE reporting, all AE terms in CTCAE version 4.0 have be 
correlated with single-concept, MedDRA® terms. 
Grades in CTCAEs v 4.0 refer to the severity of the AE. Grades of 1 through 5, with unique clinical 
descriptions of severity for each AE, are based on this general guideline: 
 
Grade 
Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling, limiting self-care ADL.b 
4 
Life-threatening consequences: urgent intervention indicated. 
5 
Death related to adverse event. 
ADL = Activities of Daily Living 
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Cancer 
Therapy 
Evaluation 
Program, 
NCI 
CTCAE 
v 
4.0. 
Available 
from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev 4.pdf.  
 
For further details regarding MedDRA, refer to the MedDRA website at: http://www.meddramsso.com. 
CTCAE v 4.0 is available online at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev 4.pdf. 


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17.6. Appendix 6 – Quality of Life Surveys 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study ID: _______________ 
 
 
 
 
Quality of Life Assessment: 
 
 
DF/HCC 13-077 
 
A Phase 2 Study of Eribulin in Patients with HER2-negative, Metastatic 
Breast Cancer: Evaluation of Efficacy, Toxicity, and Patient-Reported 
Outcomes 
 
 


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Thank you for completing this survey.  The first questions ask about some of your symptoms in 
the last 7 days.   
 
 
1. In the last 7 days, what was the 
SEVERITY of your constipation at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
2. In the last 7 days, how OFTEN did you 
have loose or watery stools 
(diarrhea)? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
3. In the last 7 days, what was the 
SEVERITY of your dry mouth at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
4. In the last 7 days, what was the 
SEVERITY of your mouth or throat 
sores at their WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
5. In the last 7 days, how much did mouth 
or throat sores INTERFERE with your 
usual or daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
6. In the last 7 days, how OFTEN did you 
have nausea? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
7. In the last 7 days, what was the 
SEVERITY of your nausea at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
8. In the last 7 days, how OFTEN did you 
have vomiting? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
9. In the last 7 days, what was the 
SEVERITY of your vomiting at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
10. In the last 7 days, did you have any hair 
loss? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
 
 


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11. In the last 7 days, how OFTEN did you 
have arm or leg swelling? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
12. In the last 7 days, what was the 
SEVERITY of your arm or leg swelling 
at its WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
13. In the last 7 days, how much did arm or 
leg swelling INTERFERES with your 
usual or daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
14. In the last 7 days, did you have any 
rash: 
 
    Yes 
    No 
 
 
15. In the last 7 days, what was the 
SEVERITY of your fatigue, tiredness, 
or lack of energy at its WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
16. In the last 7 days, how much did 
fatigue, tiredness, or lack of energy 
INTERFERE with your usual or daily 
activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
17. In the last 7 days, how OFTEN did you 
have pain? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
18. In the last 7 days, what was the 
SEVERITY of your pain at its WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
19. In the last 7 days, how much did pain 
INTERFERE with your usual or daily 
activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
20. In the last 7 days, what was the 
SEVERITY of your decreased appetite 
at its WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
21. In the last 7 days, how much did 
decreased appetite INTERFERE with 
your usual or daily activities? 
    Not at all 
    A little bit 
    Somewhat 
    Quite a bit 
    Very much 
 
 
 
 
 


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74 
 
 
 
22. In the last 7 days, what was the 
SEVERITY of your problems with 
concentration at their WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
23. In the last 7 days, how much did 
problems with concentration 
INTERFERE with your usual or daily 
activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
24. In the last 7 days, what was the 
SEVERITY of your problems with 
memory at their WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
25. In the last 7 days, how much did 
problems with memory INTERFERE 
with your usual or daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
26. In the last 7 days, what was the 
SEVERITY of your problems with 
tasting food or drink at their WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
 
27. In the last 7 days, how OFTEN did you 
have a headache? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
28. In the last 7 days, what was the 
SEVERITY of your headache at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
29. In the last 7 days, how much did your 
headache INTERFERE with your usual 
or daily activities? 
    Not at all 
    A little bit 
    Somewhat 
    Quite a bit 
    Very much 
 
 
30. In the last 7 days, what was the 
SEVERITY of your numbness or 
tingling in your hands or feet at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
31. In the last 7 days, how much did 
numbness or tingling in your hands 
or feet INTERFERE with your usual or 
daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
 


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75 
 
32. In the last 7 days, how OFTEN did you 
feel anxiety? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
33. In the last 7 days, what was the 
SEVERITY of your anxiety at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
34. In the last 7 days, how much did 
anxiety INTERFERE with your usual or 
daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
35. In the last 7 days, how OFTEN did you 
have sad or unhappy feelings? 
 
    Never 
    Rarely 
 
    Occasionally 
    Frequently 
    Almost constantly 
 
 
36. In the last 7 days, what was the 
SEVERITY of your sad or unhappy 
feelings at their WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
 
 
 
37. In the last 7 days, how much did sad or 
unhappy feelings INTERFERE with 
your usual or daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
38. In the last 7 days, what was the 
SEVERITY of your insomnia including 
difficulty falling asleep, staying 
asleep, or waking up early at its 
WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
39. In the last 7 days, how much did 
insomnia including difficulty falling 
asleep, staying asleep, or waking up 
early INTERFERE with your usual or 
daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 
 
 
40. In the last 7 days, what was the 
SEVERITY of your shortness of breath 
at its WORST? 
 
    None 
    Mild 
 
    Moderate 
    Severe 
    Very severe 
 
 
 
41. In the last 7 days, how much did 
shortness of breath INTERFERE with 
your usual or daily activities? 
 
    Not at all 
    A little bit 
 
    Somewhat 
    Quite a bit 
    Very much 


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Below is a list of statements that other people with your illness have said are important.  Please 
check one box per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much
I have a lack of energy ..........................................................
 
 
 
 
 
I have nausea .......................................................................
 
 
 
 
 
Because of my physical condition, I have trouble meeting 
the needs of my family ..........................................................
 
 
 
 
 
I have pain.............................................................................
 
 
 
 
 
I am bothered by side effects of treatment ...........................
 
 
 
 
 
I feel ill ...................................................................................
 
 
 
 
 
I am forced to spend time in bed ..........................................
 
 
 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much
I feel close to my friends .......................................................
 
 
 
 
 
I get emotional support from my family .................................
 
 
 
 
 
I get support from my friends ................................................
 
 
 
 
 
My family has accepted my illness .......................................
 
 
 
 
 
I am satisfied with family communication about my illness ...
 
 
 
 
 
I feel close to my partner (or the person who is my main 
support) .................................................................................
 
 
 
 
 
I am satisfied with my sex life ...............................................
 
 
 
 
 


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Please check one box per line to indicate your response as it applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much
I feel sad ................................................................................
 
 
 
 
 
I am satisfied with how I am coping with my illness ..............
 
 
 
 
 
I am losing hope in the fight against my illness ....................
 
 
 
 
 
I feel nervous .........................................................................
 
 
 
 
 
I worry about dying ................................................................
 
 
 
 
 
I worry that my condition will get worse ................................
 
 
 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much
I am able to work (include work at home) .............................
 
 
 
 
 
My work (include work at home) is fulfilling ..........................
 
 
 
 
 
I am able to enjoy life ............................................................
 
 
 
 
 
I have accepted my illness ....................................................
 
 
 
 
 
I am sleeping well..................................................................
 
 
 
 
 
I am enjoying the things I usually do for fun .........................
 
 
 
 
 
I am content with the quality of my life right now ..................
 
 
 
 
 
 


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Please check one box per line to indicate your response as it applies to the past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much
I have been short of breath ...................................................
 
 
 
 
 
I am self-conscious about the way I dress ............................
 
 
 
 
 
One or both of my arms are swollen or tender .....................
 
 
 
 
 
I feel sexually attractive .........................................................
 
 
 
 
 
I am bothered by hair loss .....................................................
 
 
 
 
 
I worry that other members of my family might someday 
get the same illness I have ...................................................
 
 
 
 
 
I worry about the effect of stress on my illness .....................
 
 
 
 
 
I am bothered by a change in weight ....................................
 
 
 
 
 
I am able to feel like a woman   ............................................
 
 
 
 
 
I have certain parts of my body where I experience pain .....
 
 
 
 
 
 
 


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Please check one box per line to indicate your response as it applies to the past 7 days. 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much
I have numbness or tingling in my hands .............................
 
 
 
 
 
I have numbness or tingling in my feet .................................
 
 
 
 
 
I feel discomfort in my hands ................................................
 
 
 
 
 
I feel discomfort in my feet ....................................................
 
 
 
 
 
I have joint pain or muscle cramps .......................................
 
 
 
 
 
I feel weak all over ................................................................
 
 
 
 
 
I have trouble hearing ...........................................................
 
 
 
 
 
I get a ringing or buzzing in my ears .....................................
 
 
 
 
 
I have trouble buttoning buttons ...........................................
 
 
 
 
 
I have trouble feeling the shape of small objects when 
they are in my hand ..............................................................
 
 
 
 
 
I have trouble walking ...........................................................
 
 
 
 
 
 
 
 
 
 
Thank you for completing the survey! 
 
 
 
 
 
 
 
 


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17.7. Appendix 7 - Blood Sampling for Pharmacogenomics Analysis 
 
Subjects enrolled in this clinical study will have blood samples collected for pharmacogenomic analysis.  
SAMPLE COLLECTION AND HANDLING 
Blood samples will be collected according to the Study Calendar. The DNA blood plasma/serum samples 
will be collected at the same time blood samples are collected for the main study; therefore, there is no 
additional risk to the study participant. The site staff will add the study center ID-subject number and 
collection time (hh:mm) to the tube. In addition, a sample sheet will be completed indicating the study ID, 
site number, subject number, visit number, and date and time of collection. Collection of the blood sample 
and informed consent will also be recorded in the subject’s eCRF. Frozen samples will be transferred 
from the central lab to a specialty laboratory for processing, analysis, and storage. 
 
Collection and Processing 
1 10ml EDTA tube will be collected at baseline for all participating patients. 
・ Freeze the whole tube at -80°C shortly after collection. 
・ Ship on dry ice. 
 
Samples will be shipped from sites in batches to the Laboratory of Bryan P. Schneider, MD for 
analysis. 
 
Laboratory of Bryan P. Schneider, M.D. 
Indiana Cancer Pavilion 
Walter Hall 
980 W. Walnut Street 
Indianapolis, IN 46202 
Phone: 317-274-6473 
Fax: 317-274-3646 
bpschnei@iupui.edu 
 
. 
SECURITY OF THE SAMPLES, USE OF THE SAMPLES, RETENTION OF THE SAMPLES 
Sample processing, including DNA/RNA extraction and genotyping, sequencing or other analysis will be 
performed by a local laboratory. Processing, analysis, and storage will be performed at a secure laboratory 
facility to protect the validity of the data and maintain subject privacy. 
Samples will be stored for up to 15 years after the completion of the study (defined as submission of the 
CSR to the appropriate regulatory agencies). At the end of the storage period, samples will be destroyed. 
Samples may be stored longer if a Health Authority (or medicinal product approval agency) has active 
questions about the study. In this special circumstance, the samples will be stored until the questions have 
been adequately addressed. 


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It is possible that future research and technological advances may identify genomic variants of interest, or 
allow alternative types of genomic analysis not foreseen at this time. Because it is not possible to 
prospectively define every avenue of future testing, all samples collected will be single- or double-coded 
(according to the ICH15 guidelines) to maintain subject privacy. 
RIGHT TO WITHDRAW 
If, during the time the samples are stored, a participant would like to withdraw his/her consent for 
participation in this research, the sponsor (DFCI) will destroy the samples, if they can still be identified 
(not anonymized). Once samples are anonymously labeled, it will not be possible to identify which 
samples have come from a particular individual. Therefore, it will not be possible to destroy those 
subject’s samples at that time. Information from any assays that have already been completed at the time 
of withdrawal of consent will continue to be used as necessary to protect the integrity of the research 
project. 
SUBJECT PRIVACY AND RETURN OF DATA 
No information that identifies the subject (e.g., initials, date of birth, government identifying number) will 
be associated with the sample. Samples that are processed for analysis (DNA/RNA extracted) may be 
double-coded. Double-coding involves removing the initial code and replacing with another code such 
that the subject can be re-identified by use of two code keys. The code keys are usually held by different 
parties. The key linking the sample ID to the subject number will be maintained separately from the 
sample. At this point, the samples will be double-coded (the first code being the subject number) as long 
as the initial tube does not contain any personal identifiers or the random code assigned by the central 
laboratory or biorepository. Laboratory personnel performing the genetic analysis will not have access to 
the “key.” Clinical data collected as part of the clinical trial will be cleaned of subject identifying 
information and linked by use of the sample ID “key.” 
Sample anonymization may occur by destruction of the “key.” Once the “key” is destroyed, it will not be 
possible to trace the pharmacogenomics assay results back to an individual. The Principal Investigator 
will take steps to ensure that data are protected accordingly and confidentiality is maintained to the extent 
possible. Data from subjects enrolled in this study may be analyzed worldwide, regardless of location of 
collection. 
The sponsor (DFCI) and its representatives and agents may share anonymous data with persons and 
organizations involved in the conduct or oversight of this research. These include: 
 
Clinical research organizations retained by the sponsor; 
 
Independent ethics committees or institutional review boards that have responsibility for this 
research study; 
 
National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or all of the 
anonymous data, in listing or summary format. Other publications (e.g., in peer-reviewed scientific 
journals) or public presentations of the study results will only include summaries of the study population, 
and no identified individual results will be disclosed. 
 
Given the exploratory nature of the planned analysis, it will not be possible to return individual data to 
subjects participating in the pharmacogenomics  research 


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17.8. Appendix 8: Provider-Reported CTCAE Form 
INSTRUCTIONS: Provide the worst grade the patient has experienced in the last 7 days for each 
adverse event listed below.  If the patient has not experienced the adverse event in the last 7 
days, mark “None”.  
 
Pt ID#_________            Pt Init:________            Visit#________            MRN#__________ 
 
System Organ Class (SOC) 
Adverse event 
None 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Gastrointestinal Disorders 
Constipation 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
Dry mouth 
 
 
 
 
 
Mucositis 
 
 
 
 
 
Nausea 
 
 
 
 
 
Vomiting 
 
 
 
 
 
General disorders and 
administration site 
conditions 
Hair Loss 
 
 
 
NA 
NA 
Edema limbs 
 
 
 
 
 
Fatigue 
 
 
 
 
 
Pain 
 
 
 
 
 
Metabolism and nutrition 
disorders 
Anorexia 
 
 
 
 
 
Nervous system disorders 
Concentration 
impairment 
 
 
 
 
 
Dysgeusia 
 
 
 
 
 
Headache 
 
 
 
 
 
Peripheral sensory 
neuropathy 
 
 
 
 
 
Psychiatric disorders 
Anxiety 
 
 
 
 
 
Depression  
 
 
 
 
 
Insomnia 
 
 
 
 
 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea 
 
 
 
 
 
 
Abbreviations: Not applicable  
 
Provider Signature:________________________________Date:________________ 
 
DF/HCC Sites: Please send this completed form to Danielle Gore: dgore@partners,org 
 
External sites: Please send this completed form to the DFCI Coordinating Center: CTOPM@dfci.harvard.edu 


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APPENDIX 9: DF/HCC Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
DFCI IRB Protocol #: 13-077 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
1. 
INTRODUCTION ............................................................................................................................................ 85 
1.1. 
Purpose ..................................................................................................................................................... 85 
1.2. 
Multi-Center Data and Safety Monitoring Plan Definitions .................................................................... 85 
2. 
GENERAL ROLES AND RESPONSIBILITIES.......................................................................................... 86 
2.1. 
DF/HCC Sponsor ..................................................................................................................................... 86 
2.2. 
Coordinating Center ................................................................................................................................. 87 
2.3. 
DF/HCC Quality Assurance Office for Clinical Trials (QACT) ............................................................... 87 
2.4. 
Participating Institution ........................................................................................................................... 87 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ....................................................... 88 
3.1. 
Protocol Distribution ................................................................................................................................ 88 
3.2. 
Protocol Revisions and Closures .............................................................................................................. 88 
3.3. 
Informed Consent Requirements ............................................................................................................... 89 
3.4. 
IRB Documentation .................................................................................................................................. 89 
3.5. 
IRB Re-Approval ...................................................................................................................................... 90 
3.6. 
Participant Confidentiality and Authorization Statement ......................................................................... 90 
3.7. 
DF/HCC Multi-Center Protocol Registration Policy ............................................................................... 90 
3.8. 
DF/HCC Protocol Case Number .............................................................................................................. 92 
3.9. 
Protocol Deviations, Exceptions and Violations ...................................................................................... 92 
3.10. 
Safety Assessments and Toxicity Monitoring ............................................................................................ 93 
3.11. 
Data Management .................................................................................................................................... 94 
4. 
REQUISITIONING DRUG ............................................................................................................................ 95 
5. 
MONITORING: QUALITY CONTROL ...................................................................................................... 95 
5.1. 
Ongoing Monitoring of Protocol Compliance .......................................................................................... 95 
5.2. 
Evaluation of Participating Institution Performance ............................................................................... 95 
6. 
AUDITING: QUALITY ASSURANCE ......................................................................................................... 96 
6.1. 
DF/HCC Sponsored Trials ....................................................................................................................... 96 
6.2. 
Participating Institution ........................................................................................................................... 96 
6.3. 
DF/HCC Sponsor and Coordinating Center ............................................................................................ 96 
6.4. 
Sub-Standard Performance ...................................................................................................................... 97 
 
 
 
 


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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1. Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures, and Cancer Therapy Evaluation  Program (CTEP) Multi-Center Guidelines.        
 
1.2.  Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines.  The Lead Institution is typically the 
home of the DF/HCC Sponsor. The Lead Institution also typically serves as the 
Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible 
for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the 
DF/HCC Sponsor is the same person as the DF/HCC Principal Investigator; however, both 
roles can be filled by two different people. 
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    


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Coordinating Center: The entity (i.e. Lead Institution) that provides administrative 
support to the DF/HCC Sponsor in order that he/she may fulfill the responsibilities 
outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines. In general, the Lead Institution is the Coordinating Center for the DF/HCC 
Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, the CRO will be 
deemed the Coordinating Center.   
 
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC 
developed to computerize and manage data, and to provide a Quality Control and Quality 
Assurance function for DF/HCC trials.   
 
2. GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1. DF/HCC Sponsor 
 
The DF/HCC Sponsor, Dr. Erica Mayer, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
 Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
 Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
 Assure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site.  


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2.2. Coordinating Center  
 
The Coordinating Center will assume the following general responsibilities: 
 Assist in protocol development  
 Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.   
 Distribute adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all participating investigators. 
 Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
 
 Monitor Participating Institutions either by on-site or virtual monitoring.  
 Maintain Regulatory documents of all Participating Institutions.  
 Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc).  
 Maintain documentation of all communications. 
 Ensure that each Participating Institution has the appropriate assurance on file with 
the Office of Human Research Protection (OHRP).     
 
2.3. DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
 
In addition to the Coordinating Center, the DF/HCC QACT provides the following 
support services to assist the DF/HCC Sponsor: 
 Develop protocol specific case report forms (eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide a central participant registration, which includes review of consent and 
eligibility. 
 Provide auditing services (funding and QACT approval required). 
 
2.4. Participating Institution 
 
Each Participating Institution is expected to comply with all applicable Federal 
Regulations and DF/HCC requirements, the protocol and HIPAA requirements. All 
Participating Institutions will provide a list of personnel assigned to the role for oversight 
of data management at their site to the Coordinating Center.  
 


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The general responsibilities for each Participating Institution are as follows: 
 Commit to the accrual of participants to the protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain a regulatory binder in accordance with DF/HCC requirements. 
 Provide the Coordinating Center with regulatory documents as requested. 
 Participate in protocol training prior to enrolling participants and throughout the 
trial as needed (i.e. teleconferences). 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center.  
 Submit source documents, research records, and CRFs per protocol specific 
submission guidelines to the Coordinating Center. 
 Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. For 
CTEP trials, submit SAE reports directly to CTEP and provide copies to the 
Coordinating Center  
 Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
 Secure and store investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA 
standards. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
  
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1. Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2. Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 


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 Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
 Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3. Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials).   
 
3.4. IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 Approval letter of the Participating Institution's IRB  
 Copy of the Informed Consent Form approved by the Participating Institution’s 
IRB  
 Participating IRB’s approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating 
Center their IRB approval for amendments to a protocol.    
 


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3.5. IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6. Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an Authorization.  This Authorization 
may or may not be separate from the informed consent document.  The Coordinating 
Center, with the approval from the DFCI IRB, will provide a consent template, which 
covered entities (Participating Institutions) must use.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per NCI requirements. These are the primary reasons why 
DF/HCC has chosen to use Authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements. 
 
3.6.1. DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center must 
have the participant’s full name & social security number “blacked out” and the assigned 
DF/HCC QACT case number (as described below) and DF/HCC protocol number written 
in (with the exception of the signed informed consent document). Participant initials may 
only be included or retained for cross verification of identification 
 
3.7. DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1. Participant Registration and Randomization  


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To register a participant, the following documents should be completed by the 
Participating Institution and faxed or e-mailed to the Coordinating Center Project 
Manager at CTOPM@dfci.harvard.edu or by fax at 617-632-5152: 
 Copy of required laboratory tests including: Hematology (CBC w/differential), 
Serum Chemistries, and a pregnancy test (for women of child-bearing potential 
only) 
 Signed informed consent document 
 HIPAA authorization form (if separate from the informed consent document) 
 Completed QACT Eligibility Checklist 
 Radiology Report of tumor assessments 
 Pathology report with documentation of ER, PR, and HER2 
 Clinic note documenting history and physical examination 
 ECG report 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will: 
 Register the participant on the study with the DF/HCC QACT 
 Upon receiving confirmation of registration by the QACT, the Coordinating Center 
will inform the Participating Institution and provide the study specific participant 
case number, and if applicable the dose treatment level.  
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
Randomization can only occur during QACT’s normal business hours, Monday through 
Friday from 8:00 AM to 5:00 PM Eastern Time. 
 
3.7.2. Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving study treatment.  
Treatment may not be initiated until the Participating Institution receives a faxed or e-mail 
copy of the participant’s registration confirmation memo from the Coordinating Center. 
Therapy must be initiated per protocol guidelines.  The DF/HCC Sponsor and DFCI IRB 
must be notified of any exceptions to this policy. 
 
3.7.3. Eligibility Exceptions 
 
The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC QACT requires each institution to fully 
comply with this requirement. 
 
3.7.4. Verification of Registration, Dose Levels, and Arm Designation 
 


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A registration confirmation memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution within one business day of 
the registration. 
 
Treatment may not be initiated until the site receives a faxed or e-mailed copy of the 
registration confirmation memo. 
 
3.8. DF/HCC Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the 
participant is assigned a five digit protocol case number.  This number is unique to the 
participant on this trial and must be used for QACT eCRF completion and 
correspondence, and correspondence with the Coordinating Center.   
 
3.9. Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.9.1. Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
3.9.2. Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 


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and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.10. 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety.   The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1. Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 11. 
 
 
 
 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB SAE Reporting Requirements.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  


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Participating Investigators will review any distributed AE reports, send a copy to their 
IRB according to their local IRB’s policies and procedures, and file a copy with their 
regulatory documents. 
 
3.10.2. Guidelines for Processing IND Safety Reports  
 
FDA regulations require sponsors of clinical studies to notify the FDA and all 
participating investigators of any adverse experience associated with the use of the 
investigational agent that is both serious and unexpected. The DF/HCC Sponsor will 
review all IND Safety Reports and ensure that all IND Safety Reports are distributed to 
the Participating Institutions.  The Participating Institutions will review and submit to their 
IRB according to their institutional policies and procedures. 
 
3.11. 
Data Management 
The DF/HCC QACT develops a set of electronic case report forms eCRFs, for use with 
the protocol.  These forms are designed to collect data for each study. The DF/HCC 
QACT provides a web based training for eCRF users. 
   
3.11.1. Data Forms Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for completeness, 
protocol treatment compliance, adverse events (toxicities) and response. Data submissions 
are monitored for timeliness and completeness of submission. Participating Institutions are 
notified of their data submission delinquencies in accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC QACT Data Analyst or study 
monitor.  Responses to all queries should be completed and submitted within 14 calendar 
days.  Responses may be returned on the written query or on an amended paper case report 
form, or in the case of electronic queries, within the electronic data capture (eDC) system. 
In the case of a written query for data submitted on a paper case report form, the query 
must be attached to the specific data being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC QACT and distributed a minimum of four times a 
year.  
 
 
 
 


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4. REQUISITIONING DRUG 
Eribulin will be supplied by Eisai Inc.  Participating Institutions are responsible for 
ordering their own supply of Eribulin.  Please refer to the protocol section 7.1 for more 
information. 
 
 
5. MONITORING: QUALITY CONTROL 
  
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the QACT provides quality 
control oversight for the protocol. 
 
5.1. Ongoing Monitoring of Protocol Compliance 
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety.  Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants, informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol deviations, pharmacy records, response 
assessments, and data management. Additionally, a plan will be formulated to provide 
regular and ongoing communication to Participating Institutions about study related 
information which will include participation in regular coordinating center initiated 
teleconferences. Teleconferences will occur approximately every other week beginning 
once sites are active and will continue regularly until the completion of accrual. Upon 
completion of accrual, teleconferences will occur quarterly thereafter (unless otherwise 
specified by the Protocol Chair) until study completion.  Additional communication may 
be distributed via “Newsletters” or email as deemed appropriate by the protocol chair.  
 
On-site and virtual monitoring will occur as specified in the study monitoring plan.  
Monitoring will be performed by the Coordinating Center’s Clinical Research Specialist 
(CRS).  The Participating Institutions will be required to submit de-identified participant 
source documents to the Coordinating Center for virtual monitoring visits.  The data will 
be reviewed for completeness, quality, and adherence to the protocol requirements. Sites 
will be asked to provide source documentation via fax, email, or mail as specified by the 
Clinical Research Specialist for all virtual monitoring visits. A virtual site initiation (SIV) 
will be conducted with each participating site prior to study activation. Participating sites 
may not begin enrolling until an SIV has occurred. 
 
5.2. Evaluation of Participating Institution Performance 
 


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5.2.1. Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual monitoring 
of Participating Institutions to ensure protocol compliance and ability to fulfill 
responsibilities of participating in the study. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the 
protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating 
Institutions may also be subject to an audit as determined by the DF/HCC Sponsor. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1. DF/HCC Sponsored Trials 
 
Annual on-site audits will be scheduled by the DFCI QACT assuming at least three new 
subjects have been treated on protocol each year. Approximately 3-4 subjects would be 
audited over a 2 day period.  . If violations which impact subject safety or the integrity of 
the study are found, more subject records may be audited.Also, an audit may be triggered if 
deficiencies are noted related to consent practices, eligibility, missing, incomplete, or 
questionable data submission, non-compliance or any other issue the protocol chair deems 
appropriate for audit.  
 
6.2. Participating Institution 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or external) and re-audit dates (if applicable), which 
involve this protocol. All institutions will forward a copy of final audit and/or re-audit 
reports and corrective action plans (if applicable) to the Coordinating Center, within 12 
weeks after the audit date.  
 
6.3. DF/HCC Sponsor and Coordinating Center  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT 
per DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 


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DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4. Sub-Standard Performance 
 
The DF/HCC Sponsor and DFCI IRB, is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.4.1. Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely accurate data, adherence to protocol requirements, and compliance with state and 
federal regulations, will be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
 


Protocol #13-077  D:2/22/2013 KAJ; F: 5/13/2013 LK 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
13-077 
Protocol Name: 
A Phase 2 Study of Eribulin in Patients with Her2-Negative, Metastatic Breast Cancer:  
Evaluation of Efficacy, Toxicity and Patient-Reported Outcomes 
DFCI Site PI: 
Erica Mayer, MD, MPH 
DFCI Research Nurse: 
Peg Haldoupis, RN; Liz Kasparian, RN; Mary O’Driscoll, RN; Kathy Roche, RN; Myra St. Amand, 
RN, Beth Tiani, RN 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
Eribulin is a synthetic derivative of the natural product halichondrin B, which is isolated from a marine sponge.  
Halichondrin B exhibits anti-cancer activity through a microtubule-destabilizing anti-mitotic mechanism of action.  
Eribulin exerts its effects by binding to microtubules which causes interference in the normal cell cycle.  This 
interference leads to cell death via apoptosis.  Study Design: Participants will be enrolled in 2 parallel cohorts.  
Cohort 1 = HR+/HER2-- and Cohort 2 = HR-- and HER2-- (TNBC) – Section 1.1; Study Rationale – Section 2.5  A 
cycle is 3 weeks (21 days) – Section 5.3 
Dose 
Calc. 
 
Eribulin dosing is calculated in mg/m2 – Section 5.4 
 
BSA is calculated on each treatment day according to institutional standard – Please review Section 5.4  
Study Drug  
Administration 
Eribulin Administration Guidelines are found in Sections 5.4 and 7 
 
IV, administered over approximately 2 to 5 minutes on Days 1 and 8 of each 3 week cycle 
 
May be injected directly as an IV infusion over approximately 2 to 5 minutes or diluted in up to 100mL 0.9% 
saline for IV infusion over approximately 2 to 5 minutes.  NOT compatible with solutions containing dextrose. 
 
No special tubing is required for administration 
 
Do not administer in the same IV line concurrent with other medicinal products 
 
Criteria to treat: See Section 5.4 
 
Dose 
Modifications 
& Toxicity 
Dose Modifications/Dosing Delay for Toxicity are outlined in Section 6 
 
This protocol uses NCI CTCAE criteria, version 4.0 – Section 13.1 
 
Expected toxicities are outlined in Section 6.1 
 
Dose modifications and delays are outlined in Section 6.2 and Table 1 
 
If Day 8 dosing is delayed, Day 1 dosing for the next cycle must be NO SOONER than 14 days later 
 
Concomitant 
Meds 
Concomitant Therapy Guidelines are in Section 5.6 
 
Permitted meds/therapies are in Section 5.6.2 
 
Prohibited meds/therapies are in Section 5.6.3 
 
Information on potential drug-drug interactions is in Section 5.6.4 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Sections 5.5, 9 and 10.5 – 10.7 
 
Please refer to Table 3 in Section 9 for the Schedule of Visits and Procedures 
Charting Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
 If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is 
permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical 
record. 
Please be sure to also DOCUMEN any additional vital signs, routes of administration, or injection sites