A Pilot Phase 2 Study of Eribulin in Angiosarcoma and Epithelioid Hemangioendothelioma (EHE)
Phase: PHASE2
Conditions: Angiosarcoma, Epithelioid Hemangioendothelioma
Sponsor: Massachusetts General Hospital

Page 1
DF/HCC Protocol #: 17-355
TITLE: A Pilot Phase 2 Study of Eribulin in Angiosarcoma and Epithelioid 
hemangioendothelioma (EHE)
Coordinating Center:
DF/HCC 
Principal Investigator (PI):
Gregory M Cote MD PhD
Massachusetts General Hospital
gcote@partners.org
Other Investigators:
Suzanne George, MD
Dana-Farber Cancer Institute
Suzanne_George@DFCI.HARVARD.EDU
Corrie Painter PhD
Broad Institute
painter@broadinstitute.org
Statistician:
Constance Barysauskas, MS
Dana-Farber Cancer Institute
Constance_Barysauskas@dfci.harvard.edu
Responsible Research Nurse:
Responsible Data Manager: 
Barbara Anderson
Lia Tamburello
Massachusetts General Hospital
Massachusetts General Hospital
Cancer Center Protocol Office
55 Fruit Street Yawkey 8, Room 8712
125 Nashua St.
Boston, MA 02114
Boston, MA 02114
Phone: 617-643-2427
Phone: 617-643-0207
Fax: 617-643-8744
Fax: 617-726-1655
BANDERSON15@PARTNERS.ORG
lmtamburello@partners.org
Study agent: Eribulin
Study Exempt from IND Requirements per 21 CFR 312.2(b).
 Protocol Version Date: 10-2-19
NCT03331250

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SCHEMA
16 patients with 
angiosarcoma or EHE
Screening and 
Registration
Eribulin
(21-day cycles)
Off-Study at PD 
or unacceptable 
toxicity

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objectives...................................................................................................5
1.3
Secondary Objectives...............................................................................................5
1.4
Exploratory Objectives ............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Study Disease(s).......................................................................................................5
2.2
Study Agent .............................................................................................................6
2.3
Rationale ................................................................................................................10
2.4
Correlative Studies Background ............................................................................10
3.
PARTICIPANT SELECTION...........................................................................................11
3.1
Eligibility Criteria..................................................................................................11
3.2
Exclusion Criteria ..................................................................................................12
3.3
Inclusion of Women and Minorities ......................................................................13
4.
REGISTRATION PROCEDURES ...................................................................................14
4.1
General Guidelines for DF/HCC Institutions ........................................................14
4.2
Registration Process for DF/HCC Institutions.......................................................14
4.3
General Guidelines for Other Investigative Sites ..................................................14
4.4
Registration Process for Other Investigative Sites.................................................14
5.
TREATMENT PLAN........................................................................................................14
5.1
Treatment Regimen................................................................................................14
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Cycle 1, Day 1........................................................................................................15
5.4
Cycle 1 day 8, Subsequent cycles day 1 and day 8................................................16
5.5
Eribulin Administration .........................................................................................17
5.6
General Concomitant Medication and Supportive Care Guidelines......................17
5.7
Criteria for Taking a Participant Off Protocol Therapy.........................................18
5.8
Duration of Follow Up...........................................................................................19
5.9
Criteria for Taking a Participant Off Study ...........................................................19
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................19
6.1
Eribulin Dosing Delays..........................................................................................20
6.2
Instructions for Dose Reduction ............................................................................20
6.3
Instructions for QTc Interval Prolongation............................................................21
6.4
Instructions for Peripheral Neuropathy..................................................................21
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................21
7.1
Definitions..............................................................................................................21

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8.
PHARMACEUTICAL INFORMATION..........................................................................28
8.1
Eribulin ..................................................................................................................28
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................31
9.1
Biomarker Studies..................................................................................................31
9.2
Laboratory Correlative Studies..............................................................................32
10.
STUDY CALENDAR .......................................................................................................34
11.
MEASUREMENT OF EFFECT .......................................................................................37
11.1
Antitumor Effect – Solid Tumors ..........................................................................37
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................43
12.1
Data Reporting.......................................................................................................43
12.2
Data Safety Monitoring..........................................................................................44
13.
STATISTICAL CONSIDERATIONS...............................................................................44
13.1
Study Design/Endpoints ........................................................................................44
13.2
Sample Size, Accrual Rate and Study Duration ....................................................44
13.3
Interim Monitoring Plan ........................................................................................45
13.4
Analysis of Primary Endpoints..............................................................................45
13.5
Analysis of Secondary Endpoints..........................................................................45
13.6
Reporting and Exclusions ......................................................................................45
14.
PUBLICATION PLAN .....................................................................................................46
15.
APPENDIX A PERFORMANCE STATUS CRITERIA..................................................47
16.
APPENDIX B DRUG REORDER FORM........................................................................48
17.
References..........................................................................................................................50

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1. OBJECTIVES
This is a pilot study to explore the clinical activity of Eribulin Mesylate (HALAVEN, hereafter 
referred to as Eribulin) as a single agent for the treatment of patients with metastatic or 
unresectable angiosarcoma or Epithelioid hemangioendothelioma (EHE). We hypothesize that 
Eribulin will lead to objective responses and/or durable disease control in patients with 
angiosarcoma or EHE.
 
1.1
Study Design
We propose a single arm, single stage pilot study to explore the clinical activity of Eribulin in 
angiosarcoma and EHE with the primary objective of Overall Response Rate (ORR, PR+CR) by 
RECIST 1.1.
Patients will receive Eribulin on day 1 and day 8 of a 21-day cycle. 
Imaging will be obtained every 6 weeks for the first 7 cycles (before C3, C5 and C7) and then 
every 9 weeks for C7 onwards (C10, C13, etc.). 
1.2
Primary Objectives

To determine the Objective response rate (ORR, partial response [PR]+complete 
response [CR]) by RECIST 1.1 of angiosarcoma/EHE patients treated with Eribulin
1.3
Secondary Objectives

To further characterize the clinical activity of Eribulin in this population by:
o
Progression-Free Survival (PFS)
o
Disease Control Rate (DCR = ORR + Stable Disease [SD] at 24 weeks) 

To further characterize the safety profile of Eribulin in this patient population
1.4
Exploratory Objectives

To determine any correlation between angiosarcoma or sarcoma subtype and response

To determine any correlation between response and genomic characterization of the 
sarcoma

To determine genomic and expression profile changes, via biopsy samples and/or 
circulating free DNA exome sequencing, over time after treatment with Eribulin
2. BACKGROUND
2.1
Study Disease(s)

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The sarcomas are a heterogeneous family of mesenchymal malignancies arising in bone or soft 
tissue. For patients with metastatic soft tissue sarcoma (STS), single agent or combination 
chemotherapy has led to a median survival of only 12 months across all histologies.(1, 2) 
Angiosarcoma (AS) is an uncommon STS that can arise in nearly any organ including the head 
and neck, breast, extremities, trunk, liver and bone. There is a peak incidence in the 7th decade 
of life.(3) The cause for most AS is unknown with subsets linked to exposure to radiation, 
foreign materials, toxins (e.g. vinyl chloride), chronic inflammation or lymphedema (Stewart-
Treves syndrome) and genetic syndromes (e.g. BRCA1, NF1, Maffucci’s).(4) 
Multimodality therapy, including surgery, radiation and standard chemotherapy agents including 
taxanes and anthracyclines, is the treatment backbone of this disease. There is ongoing research 
into the role of VEGF-directed therapies and tyrosine kinase inhibitors. However, despite this, 
angiosarcomas are extremely aggressive tumors with stage for stage worse survival than other 
STS. For example in one series half of patients had died by 11 months.(5) 
Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma with a variable clinical 
course.(3) EHE can develop in virtually any organ and it frequently metastasizes to the lung and 
liver. Most EHE is typically genomically characterized by the gene fusion WWTR1-CAMTA1. 
There are no treatments for EHE and where metastatic mortality remains high.
2.2
Study Agent
2.2.1
Eribulin
Eribulin mesylate (HALAVEN®) is a synthetic analog of halichondrin B (HalB), a natural 
product isolated from the marine sponge Halichondria okadai.   HalB is a large polyether 
macrolide that exerts potent anti-cancer effects in cell-based and animal models of cancer.(6-8) 
The structurally simplified synthetic analog Eribulin mesylate has shown potent anti-cancer 
properties in preclinical models.(8) 
2.2.2
Therapeutic Pathway
Results of in vitro studies demonstrate that eribulin inhibits cell growth with sub- to low-nmol/L 
half-maximal inhibitory concentration (IC50) values in a wide range of established human cancer 
cell lines, including breast, colon, prostate, ovarian, small cell and non-small cell lung cancer, as 
well as histiocytic lymphoma, promyelocytic leukemia, pharyngeal squamous cell carcinoma 
(head and neck cancer), melanoma, and uterine sarcoma.  Eribulin exerts its anti-cancer effects 
via a tubulin-based antimitotic mechanism, leading to G2/M (GAP 2/mitosis stages of cell cycle) 

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cell cycle blocks, disruption of mitotic spindles, and ultimately apoptotic cell death after 
prolonged mitotic blockage.
Eribulin is mechanistically distinct as an inhibitor of microtubule dynamics, leading to inhibition 
of microtubule growth in the absence of effects on microtubule shortening, and formation of 
non-productive tubulin aggregates.  This pattern of inhibitory effects on microtubule dynamics is 
not shared by known tubulin-targeted agents.(9) 
Eribulin may have additional effects on tumor vascular remodeling and reversal of EMT. It has 
been reported that the abnormal vasculature present in tumors impairs blood perfusion and 
oxygenation, leading to hypoxic conditions, which promotes invasion, metastasis, and overall 
aggressiveness of tumor cells through epithelial mesenchymal transition (EMT)-related 
processes. Normalization of vascular perfusion is therefore gaining interest as a therapeutic 
approach to inhibit motility, invasiveness, and aggressiveness of tumor cells.
Preclinical data suggest that eribulin mesylate improves tumor blood perfusion through vascular 
remodeling, which may indirectly contribute to reduced metastasis, invasion, and reversal of 
EMT in the tumor microenvironment, leading to a normoxic tumor microenvironment.(10-13) 
2.2.3
Clinical Experience with Eribulin
Nine Phase 1 clinical studies have been completed with eribulin.  The National Cancer Institute 
(NCI)-sponsored two Phase 1 studies of eribulin:  NCI Study 5730 and NCI Study 7444.  Eisai 
has sponsored seven studies:  E7389-A001-101, E7389-A001-102, E7389-E044-103, 
E7389-J081-105, E7389-E044-108, E7389-E044-109, and E7389-E044-110.
In general, the pharmacokinetics (PK) of eribulin is characterized by a rapid distribution phase, 
with a prolonged elimination phase after intravenous (IV) infusion.  The disposition of eribulin 
follows linear kinetics over the dose range studied, as shown by consistent dose independent PK 
parameters (t½, clearance [CL], volume of distribution at steady state [Vss]) and similar 
dose-normalized parameters (Cmax/Dose, AUC0-t/Dose and AUC0-∞/Dose) between eribulin doses 
ranging from 0.25 to 1.4 mg/m2 (E7389-A001-101) and from 0.25 to 4.0 mg/m2 
(E7389-A001-102).
Eribulin demonstrated activity across all identified subgroups of subjects, including subjects with 
advanced/metastatic breast cancer (MBC) (E7389-A001-201, E7389-J081-221 and 
E7389-G000-211), advanced/metastatic hormone-refractory prostate cancer (E7389-G000-204), 
or non-small cell lung cancer (NSCLC) (E7389-A001-202).  The response rate, clinical benefit 
rate (CBR) and PFS were reported across breast cancer phenotypes.  Eribulin demonstrated 
activity in subjects with heavily pretreated MBC who were refractory to anti-cancer therapy, 
including anthracyclines, taxanes, and/or capecitabine.(14) 
Results of an Eisai-sponsored, Phase 2 study conducted by the European Organisation for 
Research and Treatment of Cancer (EORTC) in advanced STS was reported at the annual 
conference of the American Society of Clinical Oncology (ASCO) in 2010.(15)  These results 
have since been published.(16)  Patients with histological proven advanced STS of high or 

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intermediate grade with disease progression within 6 months prior to study entry and no more 
than one prior combination regimen, or two prior single agents for advanced STS, was treated 
with eribulin 1.4 mg/m² on Days 1 and 8, every 21 days in four STS strata: adipocytic sarcoma 
(ADI), leiomyosarcoma (LMS), synovial sarcoma, and other types of sarcoma.  The primary 
endpoint was progression-free rate at Week 12 (PFR12wks). 
The PFR12wks was 46.9% (95% CI, 29.9 - 62.8) for ADI sarcoma, 44.7% (95% CI, 28.7 - 59.6) 
for LMS, 31.6% (95% CI, 12.9 - 52.3) for synovial sarcoma and 24% (95% CI, 9.8 - 41.7) in 
other types of sarcoma.Error! Reference source not found.
Figure 1
Protocol E7389-E044-207: Proportion Progression-Free 
The median PFS for LMS was 2.9 months (95 % CI, 2.4 - 4.6), the OS at 6 months (Figure ) 
from the start of treatment (OS6mths) 86.8% (95% CI, 71.2 - 94.3).  The median PFS for ADI 
sarcoma was 2.6 months (95% CI, 1.7 - 6.2), the OS6mths 74.6% (95% CI, 55.5 - 86.4). The 
median PFS for synovial sarcoma was 2.6 months (95% CI, 2.3 - 4.3), the OS6mths 71.1% 
(95% CI, 43.7 - 86.8).  The median PFS for other types of sarcoma was 2.1 months 
(95% CI, 1.4 - 2.9), the OS6mths 52.9% (95% CI, 31.2 - 70.7).  Responses included complete 
response ([CR], one subject in the ADI stratum) and partial responses ([PR], one subject each in 
ADI, synovial and other type of sarcoma strata).

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Figure 2
Protocol E7389-E044-207: Overall Survival
The most frequent adverse events (AEs) in the EORTC study were hematologic, with Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 leukopenia reported in 34.6%, 
neutropenia reported in 51.9% and anemia reported in 7.1% of subjects, respectively. CTCAE 
Grade 3 or 4 non-hematologic AEs occurred relatively rarely, with fatigue being the most 
common (7.1%).  CTCAE Grade 3 (and no Grade 4) sensory neuropathy was reported in 3.1% of 
the subjects.  Eribulin was associated with manageable tolerability in subjects with STS. 
In addition to these completed clinical studies, a program of two Phase 3 studies in advanced, 
refractory breast cancer has been undertaken.  As of 30 June 2010 enrollment is complete in 
Study E7389-G000-301 and Study E7389-G000-305.
Study E7389-G000-301 results have since been published. The Phase 3 Eisai Study 301(17) 
compared eribulin mesylate versus capecitabine monotherapy in patients with locally advanced 
or metastatic breast cancer. The subject population was predominantly HER2/neu negative 
(68.5%) and second-line MBC (52%; first- and third-line subjects were also included). 
Exploratory efficacy subgroupanalysis showed that HER2/neu negative subjects had an increased 
overall survival (OS) of 2.4 months (median OS of 15.9 months for eribulin mesylate and 13.5 
months for capecitabine; nominal P = 0.0299). However, PFS (4 months) and ORR (9.9%) by 
independent review for eribulin mesylate were similar to the control treatment group (E7389-
G000-301 Clinical Study Report).

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Study E7389-G000-305 is a Phase 3, open-label, randomized, multicenter study comparing the 
OS in heavily pretreated subjects with locally recurrent or MBC who have received two to five 
prior chemotherapeutic regimens (≥2 regimens for advanced disease), including an anthracycline 
and a taxane (unless contraindicated), when treated with Eribulin or treatment of physician’s 
choice.  The primary analysis has been completed and reported at the ASCO conference in 2010 
and the results have since been published.(14)  The study met its primary endpoint with a 
statistically significant improvement in OS by a median of 2.5 months in the Eribulin arm.  
Eribulin demonstrated a manageable tolerability profile in this late-line setting.  
Please refer to the Investigator’s Brochure for further details.
2.3
Rationale
Clinical data has demonstrated that AS is sensitive to taxanes.(18-22)  Indeed at our institution 
first line therapy is paclitaxel or gemcitabine with taxotere.  However, all patients with advanced 
disease will eventually progress.  
Eribulin, a novel microtubule-depolymerizing drug has shown clear activity in metastatic breast 
and sarcoma patients, despite failure of prior taxanes in many of these patients.  
There is now emerging evidence in breast cancer models that Eribulin induces tumor vasculature 
remodeling as well as altering angiogenesis signaling pathways involved in endothelial cell-
pericyte interactions as well as VEGF expression.(12) Moreover, there is further evidence of the 
Eribulin-mediated vascular remodeling hypothesis in PDX and human breast cancer patients 
where Eribulin can decreases tumor hypoxia.(23)  
In addition to the above there are now anecdotal reports as well as a published report of 
angiosarcoma patients responding to Eribulin.(24)
Together these data suggest Eribulin’s anti-tumor activity is through multiple mechanisms 
including microtubule targeting, alterations in angiogenesis signaling/vasculature remodeling 
and tumor hypoxia changes. Thus, we hypothesize that Eribulin will show anti-cancer activity in 
vascular malignancies including angiosarcoma and progressing epithelioid 
hemangioendothelioma.
2.4
Correlative Studies Background
In this pilot study, we seek to determine if there are expression and/or genomic variations that 
correlate with mechanisms of response and/or resistance to Eribulin as a single agent in patients 
with metastatic or unresectable angiosarcoma. Tumor samples from core needle biopsies pre- 
and post-treatment will be analyzed by RNA seq and whole exome sequencing. Whole exome 
sequencing from cell free DNA (cfDNA) will be analyzed from peripheral blood from 
angiosarcoma patients.

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The Broad Institute has sequenced exomes or genomes of over 5000 tumors and has also pursued 
RNA-seq in hundreds of tumors to discover gene fusions, splice isoforms, and mutations. The 
Institute has extensive experience in the application of genomics to studies of cancer drug 
response and resistance in multiple cancer types (Wagle, Emery et al, Journal of Clinical 
Oncology 2011(25); Van Allen, Wagle, et al, Cancer Discovery, 2014a(26); Wagle, Van Allen, 
et al, Cancer Discovery, 2014b; Wagle et al, Cancer Discovery, 2014c; Wagle et al, New 
England Journal of Medicine, 2014(27)).  In addition, Broad teams have experience performing 
sequencing from small amounts of starting material. The Broad Institute now routinely generates 
WES and RNA-seq data using DNA/RNA obtained from a single core biopsy.
The proposed blood biopsy pilot will be performed in collaboration with Dr. Viktor 
Adalsteinsson, who leads the Blood Biopsy Team at the Broad Institute. Dr. Adalsteinsson’s 
group consists of a multi-institutional collaboration that is focused on identifying mechanisms of 
response and resistance to therapies. His group has piloted an approach to performing WES of 
cfDNA obtained from blood biopsies in patients with metastatic breast cancer (Adalsteinsson et 
al, In Revision). These pilot efforts have been highly successful in demonstrating their ability to 
capture and sequence cfDNA. Using an efficient, low-cost method they have developed to assess 
purity of tumor-derived cfDNA, they found that 85.2% of 251 patients with ER+ MBC had 
greater than 3% purity of tumor-derived cfDNA and 40.6% had greater than 10%. They 
performed WES on cfDNA and matched metastatic biopsies from 15 of these patients. WES 
from cfDNA in these 15 patients identified 90% of the clonal mutations found WES from 
matched metastatic biopsies (on average; range 60-100%). WES from cfDNA detected 46% of 
the subclonal mutations identified in the metastatic biopsies (on average; range 10-87%).  Copy 
number alterations were also highly concordant with matched metastatic biopsies, suggesting 
that cfDNA can also be used for copy number analysis. Dr. Adalsteinsson has also shown that 
numerous tumor types can be studied by this method (verbal communication), which provides 
rationale for determining whether this method can be applied to studying cfDNA in 
angiosarcoma patients.
3. PARTICIPANT SELECTION
3.1
Eligibility Criteria 
3.1.1
Metastatic or locally advanced angiosarcoma, treated with at least one prior 
systemic therapy where no standard of care curable therapy is available OR 
metastatic or locally advanced malignant and progressive epithelioid 
hemangioendothelioma (EHE). 
3.1.1.1 A maximum of 5 EHE patients will be accrued on this study
3.1.2
Archival tissue confirming the diagnosis must be reviewed by BWH/DFCI/MGH 
pathology. 
3.1.3
Progression on at least one prior systemic therapy or progression during an 
observation phase of no anti-cancer therapy within the prior 3 months; prior 
taxanes are allowed

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3.1.4
Participants must have measurable disease by RECIST 1.1, defined as at least one 
lesion that can be accurately measured in at least one dimension (longest diameter 
to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease.
3.1.5
Age > 18 years.  
3.1.6
ECOG performance status ≤2 (see Appendix A)
3.1.7
Life expectancy of greater than 3 months 
3.1.8
Participants must have normal organ and marrow function as defined below:

leukocytes
≥3,000/mcL

absolute neutrophil count
≥1,000/mcL

platelets
≥100,000/mcL

total bilirubin
within normal institutional limits

AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal

creatinine clearance
≥50 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal.
3.1.9
Baseline QTcF < grade 2
3.1.10 The effects of Eribulin on the developing human fetus are unknown (Please also 
see exclusion criteria 3.2.6).  For this reason and because of the risk of 
teratogenicity, women of child-bearing potential must agree to use adequate 
contraception prior to study entry and for the duration of study participation, and 
4 months after completion of Eribulin administration.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 4 months after completion of 
Eribulin administration. Please see section 5.6 for complete details on 
contraception.
3.1.11 Willingness to undergo serial tumor biopsies before and on treatment. 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document.
3.2
Exclusion Criteria

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3.2.1
Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks 
for nitrosoureas or mitomycin C), immunotherapy within 3 weeks, targeted 
therapies (e.g. small molecule inhibitors such as pazopanib) within 2 weeks prior 
to entering the study or those who have not recovered from adverse events due to 
agents administered more than 4 weeks earlier. Not clinically significant or 
clinically stable adverse events from prior therapy (e.g. immunotherapy related 
hypothyroidism or insulin-dependent diabetes stable on medication or TKI-related 
hypertension or rash etc.) is allowed.
3.2.2
Participants who are receiving any other investigational agents.
3.2.3
Participants with with brain or subdural metastases are not eligible, unless they 
have completed local therapy and have discontinued the use of corticosteroids for 
this indication for at least 4 weeks before starting treatment in this study.  Any 
signs (e.g. radiologic) or symptoms of brain metastases must be stable for at least 
4 weeks before starting study treatment. Participants with  leptomeningeal disease 
should be excluded from this clinical trial because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other adverse events.
3.2.4
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to eribulin.
3.2.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (NYHA Class II), unstable angina 
pectoris or myocardial infarction within 6 months of enrollment, serious or life-
threatening cardiac arrhythmia, subjects with a high probability of Long QT 
syndrome or QTcF prolongation of > 501 mcsec (grade 2) on at least two separate 
ECG following correction of any electrolyte imbalance or psychiatric 
illness/social situations that would limit compliance with study requirements.
3.2.6
Females who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human 
chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or 
equivalent units of ß-hCG [or hCG]).  A separate baseline assessment is required 
if a negative screening pregnancy test was obtained more than 72 hours before the 
first dose of study drug. 
3.2.7
HIV-positive participants on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with Eribulin.  In 
addition, these participants 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. 
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. 

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4. REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. 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 must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5. TREATMENT PLAN
5.1
Treatment Regimen
Eribulin will be administered on day 1 and day 8 of a 21-day cycle. Treatment will be 
administered on an outpatient basis.  Reported adverse events and potential risks are described in 
Section 7.  Appropriate dose modifications are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the participant's malignancy.
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length

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Eribulin
No 
premedication 
requirements
1.4 mg/m2 
administer
ed directly 
or diluted 
in NS
IV over 2-5 
minutes 
Days 1 and 
8
21 days 
Prophylactic GCSF will be administered according to national guidelines or institution standard.
Body surface area (BSA) will be calculated using the Dubois formula on day 1 of each cycle or 
per institution standard of care.  
5.2
Pre-Treatment Criteria
Prior to any study related testing, patients will sign the informed consent form and undergo 
medical evaluation to establish their baseline condition and determine eligibility. The following 
studies will be obtained within 30 days of enrollment for the purpose of baseline assessment:
Complete medical history and physical examination including:

Complete medical history

Documentation status of disease

Documentation of prior therapies 

Documentation of current medications 

Complete physical examination, including vital signs and assessment of ECOG 
performance status 

Pre-existing conditions will be assessed and evaluated according to the NCI CTCAE 
v4.03 to establish the patient’s baseline condition
Disease-Specific Laboratory Tests- Pathology and Tumor Imaging

Confirm institutional review of diagnostic pathologic material

Baseline tumor imaging studies will be either CT or MRI. The modality chosen for any 
individual patient will be the same throughout the duration of the study.
The following screening tests will be performed within 15 days prior to Day 1 of treatment:

CBC with differential

Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, AST, ALT, total 
protein, albumin

PT and PTT

Urinalysis

Urine or serum pregnancy test (for premenopausal women)

ECG  
5.3
Cycle 1, Day 1

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Patients who have signed the informed consent form, completed the screening process, and met 
the criteria for enrollment will be entered into the trial and assigned an identification number. In 
addition the following will be performed:

Certification that patient meets all inclusion and exclusion criteria and is able to comply 
with all requirements of the clinical trial

Review concomitant medications since screening

Perform physical examination with vital signs and ECOG performance status

Laboratory testing – to be done if screening labs were done more than 7 days prior to Day 
1.  Patient will wait for the lab results on this day to re-confirm lab parameters for 
eligibility.
o
CBC with differential
o
Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, AST, 
ALT, total protein, albumin
o
Urine or serum pregnancy test (for premenopausal women) if not performed 
within 7 days of cycle 1 day 1

Required core or excisional biopsy 1 will occur after registration and prior to cycle 1 day 
1.  

It is recommended to correct hypokalemia and hypomagnesemia prior to treatment

Administer Eribulin cycle 1 day 1 if treatment criteria are met

HOLD Eribulin administration if:
o
ANC <1000/mm3
o
Platelets < 75,000/mm3

ECG does not need to be repeated if obtained before cycle 1 day 1, unless clinically 
indicated
5.4
Cycle 1 day 8, Subsequent cycles day 1 and day 8 

See section 6 for Criteria for Treatment Continuation and dosing delays/modifications

Review concomitant medications 

Perform physical examination with vital signs (temperature, heart rate, blood pressure, 
oxygen saturation, respiratory rate, and weight) and ECOG performance status

Laboratory testing
o
CBC with differential
o
Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, AST, 
ALT, total protein, albumin

ECG for QTc on day 1 of each cycle for cycles 2 and 3. See section 6.3. ECG monitoring 
on day 1 should be continued for patients with bradyarrhythmias, patients on drugs 
known to prolong the QT, and patients with electrolyte abnormalities. If there is no QT 
prolongation for cycles 2 and 3, ECG monitoring on day 1 may be discontinued. 

Administer Eribulin if treatment criteria are met

It is recommended to correct hypokalemia and hypomagnesemia to grade 1 or better prior 
to treatment

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
HOLD Eribulin administration if:
o
ANC <1000/mm3
o
Platelets < 75,000/mm3
o
CTCAE Grade 3 or 4 AE attributable to Eribulin with the specific exclusion of 
Grade 3 or 4 lymphopenia or Grade 3 hypophosphatemia, hypokalemia, 
hypocalcemia or hypomagnesemia responsive to oral supplementation 
5.5
Eribulin Administration
Eribulin will be administered of 1.4 mg/m2 as an IV infusion over 2-5 minutes on Days 1 and 8 
of every 21-day cycle.
Before dose administration, the amount of Eribulin mesylate needed for each subject must be 
calculated in the following manner:
1. Scheduled dose (mg/m2) × body surface area (m2) = Dose (mg)
2. Dose (mg) × 2 = the number of mL of Eribulin mesylate to withdraw from vials for 
administration.
Body surface area (BSA) will be calculated using the Dubois formula on day 1 of each cycle or 
per institution standard of care.  
Height and body weight will be recorded during the Screening Period. Thereafter, body weight 
will be recorded on Day 1 of each treatment cycle to recalculate BSA (in the event that weight 
has changed by 5% or more).
5.6
General Concomitant Medication and Supportive Care Guidelines
Any medications, with the exceptions noted below, which are considered necessary for the 
patient's welfare, and which are not known to interact with the study medication, may be given at 
the discretion of the Investigator, providing the medications, the doses, dates and reasons for 
administration are recorded in the eCRF.
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the eCRF.
All medications (prescriptions or over-the-counter medications) continued at the start of the trial 
or started during the study or until 30 days from the end of the last protocol treatment and 
different from the study medication must be documented.
Contraception:
Patients of child bearing potential and their partners, who are sexually active, must agree to the 
use of two highly effective forms of contraception throughout their participation in the study and 
for 4 months after last dose of study drug(s). 

Condom with spermicide and one of the following:

Oral contraceptive or hormonal therapy (e.g. hormone implants)

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
Placement of an intra-uterine device 
Acceptable non-hormonal birth control methods include: 

Total sexual abstinence.  Abstinence must be for the total duration of the study and the 
drug washout period.

Vasectomised sexual partner plus male condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia

Tubal occlusion plus male condom with spermicide

Intrauterine Device (IUD) plus male condom+spermicide.  Provided coils are copper-
banded
Acceptable hormonal methods:

Etonogestrel implants (eg, Implanon, Norplan)+male condom with spermicide

Normal and low dose combined oral pills+male condom with spermicide

Norelgestromin/ethinyl estradiol (EE) transdermal system+male condom with spermicide

Intravaginal device+male condom with spermicide (eg, EE and etonogestrel) 

Cerazette (desogestrel)+male condom with spermicide.  Cerazette is currently the only 
highly efficacious progesterone based pill.
Growth factor is permitted according to institution and national guidelines. 
No drug-drug interactions are expected with cytochrome P-450 (CYP) 3A4 inhibitors and P-
glycoprotein (P-gp) inhibitors. The effect of ketoconazole, a strong inhibitor of CYP3A4 and a 
P-gp inhibitor, on the PK of eribulin was studied in an open-label, two-treatment, two-sequence, 
two-way crossover trial in 12 subjects with advanced solid tumors. The mean dose-normalized 
AUC values were similar when eribulin was administered with or without ketoconazole (ratio of 
the mean AUC: 0.97; 90% CI, 0.83 - 1.12). Population PK analysis showed no effect of CYP3A4 
inducers on eribulin exposure. Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 
enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma 
concentrations of drugs that are substrates of these enzymes.
Palliative Radiation:
Patients are permitted to receive palliative radiation at any point provided the radiated lesion is 
not a RECIST 1.1 target.  Eribulin should be held during radiation.  
5.7
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

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
Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Gregory M. Cote MD PhD at 617-724-4000 or pager 12865. 
5.8
Duration of Follow Up
End of treatment assessment for all subjects will be collected within 28 days of last dose. All 
AEs must be followed for 28 days after the subjects last dose, or until resolution, whichever 
comes first. All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
5.9
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 

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6.1
Eribulin Dosing Delays

On day 1 or day 8 HOLD Eribulin administration if:
o
ANC <1000/mm3
o
Platelets < 75,000/mm3
o
CTCAE Grade 3 or 4 AE attributable to Eribulin with the specific exclusion of 
Grade 3 or 4 lymphopenia or Grade 3 hypophosphatemia, hypokalemia, 
hypocalcemia, or hypomagnesemia responsive to oral supplementation 

Day 1: If Eribulin cannot be administered on Day 1, the dose should be delayed until 
recovery to above these values. The Day 1 dose will be rescheduled for when the criteria 
for Eribulin administration are met. The dose of Eribulin must be reduced following a 
dose delay in accordance to the instructions for dose reduction.

Day 8: If Eribulin cannot be administered on Day 8, the dose should be delayed until 
recovery to above these values. The Day 8 dose will be delayed for a maximum of 7 days
o
If the criteria above for Eribulin administration are met on, or before Day 15 of a 
cycle, administer Eribulin at a reduced dose according to section 6.2
o
Eribulin administration on Day 1 of the next cycle must be NO SOONER than 14 
days later.
o
If the criteria above for Eribulin administration are NOT being met by Day 15 of 
a cycle, OMIT the Day 8 dose of Eribulin for that cycle and administer Eribulin at 
a reduced dose on Day 1 of the next scheduled cycle according to section 6.2.

Clinical judgment will be used to determine appropriate management of the patient 
during any adverse event. Temporary interruption or permanent discontinuation of the 
study drug should be considered if clinically indicated.

As long as the patient is deriving clinical benefit, there is no limit to the length of time 
Eribulin may be held.   
6.2
Instructions for Dose Reduction
•
Do not re-escalate Eribulin dose after it has been reduced.
•
Reduce the dose of Eribulin if any of the following values are present after the preceding 
dose:
o
Absolute Neutrophil Count <1,000/mm3 with fever and/or infection, or <500/mm3 for 
more than 7 days, despite use of growth factors
o
Platelet Count <50,000/mm3 requiring platelet transfusion, or <25,000/mm3 
o
Possibly, probably or definitely related non-hematologic, clinically significant 
toxicity CTCAE Grade 3 or 4 
o
Day 8 dose delay or omission due to treatment-related toxicity other than outlined 
above under neutropenia
o
Recurrence of any Grade 3 or 4 event despite reduction to 0.7 mg/m2, consider 
discontinuation
Dose Level
Eribulin Dose
Dose 1
1.4 mg/m2
Dose -1
1.1 mg/m2

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Dose -2
0.7 mg/m2
6.3
Instructions for QTc Interval Prolongation

QTc prolongation has been observed in patients receiving Eribulin. ECG monitoring is 
required for screening, and day 1 for cycle 2 and 3. It is recommended to continue day 1 
monitoring beyond cycle 3 for subjects during the treatment who have:
o
Grade 2 QTc interval prolongation
o
Clinically relevant electrolyte abnormalities
o
Bradyarrhythmias and/or congestive heart failure
o
Coadministration of medicinal products known to prolong the QT interval, 
including Class Ia and III anti-arrhythmics

For subjects who develop Grade 3 or Grade 4 QTc interval prolongation, discontinue 
Eribulin and monitor ECGs and electrolytes frequently until the QTc interval returns to 
baseline. If a reversible etiology not related to Eribulin is determined to be the cause of 
the QTc interval prolongation rechallenge may be considered after discussion with the 
overall PI and resolution to grade 2 or better QTc interval prolongation. 
6.4
Instructions for Peripheral Neuropathy
Grade 3 and 4 peripheral neuropathy has been observed in patients receiving Eribulin. 
Patients should be monitored for signs of neuropathy.  For patients with grade 3 or 4 peripheral 
neuropathy Eribulin should be held until improvement to Grade 2 or better. Dose reductions 
apply as per section 6.2.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1
Definitions
7.1.1 Adverse Event (AE)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  
All such AEs will be collected regardless of expectedness or assumed relationship to study drug.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an investigational product, whether or not 
considered related to the investigational product (Note:  Every sign or symptom should not 
be listed as a separate AE if the applicable disease [diagnosis] is being reported as an AE)

Any new disease or exacerbation of an existing disease.  However, worsening of the primary 
disease should be captured under efficacy assessments as disease progression rather than as 
an AE.

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
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding of 
study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit.  SAEs will be collected for 28 
days after the last dose.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, whichever 
comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
Subjects with onset of an AE or deterioration of a preexisting AE will be followed until 
resolution to baseline, start of a new anticancer treatment, or death.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to Common Terminology Criteria for 
Adverse Event (CTCAE v4.03)   Investigators will report CTCAE grades for all AEs (for both 
increasing and decreasing severity).  
7.1.2
Serious Adverse Event (SAE)
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

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
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event as it 
occurred; this does not include an event that, had it occurred in a more severe form or was 
allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the study 
drug)
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 
should also be considered SAEs.  Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or exposure 
to study drug through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error.  These events associated with special situations are to be captured using the 
SAE procedures but are to be considered as SAEs only if they meet one of the above criteria.  All 
AEs associated with special situations are to be reported on the CRF whether or not they meet 
the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
7.1.3
Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself. The cause 
of death should be recorded as the SAE term instead. When available, the autopsy report will be 
provided to the Sponsor.
Grade 5 should be used for events which lead immediately and directly to death, and grade 4 
should be used with outcome death for events which lead to death after a longer time period, and 
that may also be linked to additional morbidities.
7.1.4
Life-threatening Event
Any event in which the patient was at risk of death at the time of the event is considered life-
threatening; it does not refer to an event which hypothetically might have caused death if it were 
more severe.
7.1.5
Hospitalization or Prolongation of Hospitalization
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or worsens 
during the course of a patient’s participation in a clinical trial must be reported as a SAE unless 
exempted from SAE reporting. Prolongation of hospitalization is defined as any extension of an 
inpatient hospitalization beyond the stay anticipated/required for the initial admission, as 
determined by the Investigator or treating physician.

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The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration of 
study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
Other situations that MUST NOT be considered as hospitalizations are the following:
a.
An emergency visit due to an accident where the patient is treated and discharged.
b. When the patient is held 24 hours for observation and finally is not admitted.
c.
Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc.).
7.1.6
Unlisted/Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference safety 
information.
The Sponsor and the Sponsor designee will use as the reference safety information for the 
evaluation of listedness/expectedness in the IB and the Summary of Product Characteristics 
(SmPC) for Eribulin as described in the FDA package insert.
7.1.7
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related to any 
dose administered. This definition covers also medication errors and uses outside what is 
foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse of the product.
Overdose
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose (If applicable, define the study-specific criteria 
for overdose that should be applied when determining whether an 
overdose occurred.)
Misuse
Intentional and inappropriate use of study drug not in accordance with the 
protocol (Use the following definition, if appropriate, for postmarketing 
studies) Intentional and inappropriate use of study drug not in accordance 
with the prescribed or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a prescription 
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects

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Medication error
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel 
or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on the 
Adverse Event CRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 7.2.2) even if the AEs do not meet serious criteria.  Abuse is always to 
be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or medication error 
does not meet serious criteria, it must still be reported using the SAE form and in an expedited 
manner but should be noted as nonserious on the SAE form and the Adverse Event CRF.
7.1.8
Adverse Events Related to the Study Drug
An AE is considered related to a study drug/IMP if the Investigator’s assessment of causal 
relationship to the IMP(s) is “Y (yes)” (see Section 7.1.10). 
The Investigator will assess the causal relationship of the IMP(s) to the SAE.
The Sponsor may also consider related to the study drug(s)/IMP(s) those events for which the 
Investigator assesses the causal relationship with the IMP(s) as “Uk (unknown)” when it cannot 
rule out a role of the IMP(s) in the event.
7.1.9
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting according to the applicable 
legislation.
7.1.10 Assessment of Causal Relationship to the Study Drug
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other similar 
treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with the 
occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:

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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility.
7.2 Adverse Events Reporting Procedures
7.2.1
Reporting Adverse Events
The Sponsor will collect AEs until 28 days after administration of the last dose of study 
drug(s)/IMP(s), or until resolution, whichever comes first. All AEs suspected to be related to the 
study drug/IMP must be followed-up after the time of therapy discontinuation until the event or 
its sequelae resolve or stabilize at an acceptable level to the Investigator and the Sponsor. 
All AEs, including misuse, overdose and abuse, must be recorded in English using medical 
terminology in the source document and the CRF. Whenever possible, the Investigator will 
record the main diagnosis instead of the signs and symptoms normally included in the diagnoses. 
Investigators must assess severity (grade) of the event following the NCI-CTCAE v. 4 and assign 
a relationship to each study drug(s)/IMP(s); and pursue and obtain information adequate both to 
determine the outcome and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the Sponsor and the Sponsor designee. The Investigator must 
provide any relevant information as requested by the Sponsor or the Sponsor designee in addition 
to that on the CRF.
Abnormal laboratory tests occurring during the study should only be recorded in the AE section 
of the CRF if the disorder:
Is associated with clinically significant symptoms, and/or
Leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or
Leads to any of the outcomes included in the definition of a SAE.
Otherwise laboratory results should be reported in the corresponding section of the CRF (e.g. 
biochemistry, hematology).
All episodes of febrile neutropenia must always be reported within 24 hours following the same 
procedure for reporting SAEs (see Section 7.2.2), including episodes that occurred in patients 
without seriousness criteria. For these cases, the seriousness criterion should be reported as a 
medically significant event.
7.2.2
Reporting Serious Adverse Events
The Sponsor will collect SAEs from the time of signing of the informed consent form (ICF) until 
28 days after administration of the last dose of study drug(s)/IMP(s) or until the start of a new 

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antitumor therapy or until the date of death, whichever occurs first. Beyond this period of time, 
only those SAEs suspected to be related to the IMP will be collected. Nonetheless, the Sponsor 
will evaluate any safety information that is spontaneously reported by an Investigator beyond the 
time frame specified in the protocol.
All SAEs (as defined above) occurred after patient registration regardless of relationship to the 
study drug(s)/IMP(s) must be reported immediately and always within 24 hours to the Sponsor 
and the Sponsor designee: electronically by completing the applicable e-CRF section. 
SAEs will be reported within one business day of notification to the Sponsor Dr. Gregory Cote 
by email (gcote @mgh.harvard.edu) or telephone (617-726-8748) and Eisai Safety Center Safety 
Hotline (ESI_Safety@eisai.com or Right Fax: 1-732-791-1111) using Eisai SAE/AEASS report 
form.
 SAEs occurring during the screening phase (e.g., from ICF signature to randomization), SAEs 
that may occur off-study, or in case the electronic system fails or is not available. SAEs initially 
reported by alternative methods (not electronically), must be followed by a completed electronic 
SAE reporting on e-CRF from the investigational staff within one business day.
All SAEs suspected to be related to the IMP(s) must be followed until the event or its sequelae 
resolves or stabilizes at an acceptable level by the Investigator.
7.2.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on pregnancies 
occurring during clinical trials, in which exposure to the IMP(s) at any time during pregnancy, 
via either maternal or paternal exposure, is suspected. 
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test regardless of 
age or disease state) of patient occurring while the patient is on study drug, or within 28 days 
after the administration of the last dose of the study drug(s)/IMP(s), are considered immediately 
reportable events. Beyond this timeframe, the investigator will report any pregnancy if there is 
any suspicion that the study drug(s)/IMP(s) might have an impact on the occurrence of the 
pregnancy.
The Investigator will report the following events immediately and always within 24 hours from 
first knowledge:

Any occurrence of a pregnancy where any kind of exposure to the IMP(s) is suspected.

Possible exposure of a pregnant woman.

All reports of elevated/questionable or indeterminate beta human chorionic 
gonadotropins (β-hCGs).
Immediately after detecting a case of suspected pregnancy in a patient, the decision on her 
continued participation in the clinical trial will be jointly taken by the patient, the Investigator 
and the Sponsor, with the patient’s best interest in mind. A decision to continue the pregnancy 
will require immediate withdrawal from the trial. 

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Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the Sponsor 
and the Sponsor designee immediately using the Pregnancy Report form.
The Investigator will follow the pregnancy until its outcome, and must notify the Sponsor and 
the Sponsor designee the outcome of the pregnancy within 24 hours of first knowledge as a 
follow-up to the initial report.
For any event during the pregnancy which meets a seriousness criterion (including fetal or 
neonatal death or congenital anomaly) the Investigator will also follow the procedures for 
reporting SAEs (complete and send the SAE form to the Sponsor and the Sponsor designee 
within 24 hours of the Investigator’s knowledge of the event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death at any time thereafter that the Investigator 
suspects is related to the exposure to the study drug(s)/IMP(s) should also be reported to the 
Sponsor and the Sponsor designee by facsimile within 24 hours of the Investigators’ knowledge 
of the event.
7.3 Adverse Events Monitoring
Safety review will be performed by the Sponsor designee once SAE forms have been received 
and the CRFs electronically completed by the Investigator. 
At every monitoring visit performed by the designed clinical research monitor in charge of the 
study, the consistency between the CRF/SAE data reported to the Sponsor / Sponsor designee  
and the patient's source data will be reviewed. When a discrepancy is found during the review, 
data will be amended/updated in the CRF and the SAE form/information reported to the Sponsor 
and the Sponsor designee (when applicable), according to source data. 
SAEs will be continuously collected, assessed and reported throughout all the study as per the 
applicable legislation by the Sponsor designee. Periodic safety reviews of SAE reports including 
events of special interest (e.g., neutropenia and thrombocytopenia) are to be conducted and 
documented by the Sponsor designee.
Non-serious AEs will be verified during monitoring visits by the clinical trial monitor, who will 
discuss them with the Investigators, if applicable. The personnel in charge of this process are 
defined in the section “Study Contacts” of this protocol. Periodic safety review of safety data 
from the clinical database, i.e. AEs and laboratory data, will be performed along the study by the 
Sponsor Pharmacovigilance, Clinical Oncology and Data Management departments.
8. PHARMACEUTICAL INFORMATION
8.1
Eribulin

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8.1.1
Description

Generic name (INN): eribulin mesylate

Chemical name (USAN/INN): 
(2R,3R,3aS,7R,8AS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-
[(2S)-3-Amino-2-hydroxypropyl]3-methoxy-26-methyl-20,27-dimethyli 
denehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-
9H,15,Hfuro[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin 5(4H)-
one methanesul fonate (salt).

Molecular formula: C41H63NO14S (C40H59NO11・CH4O3S)

Molecular weight: 826.00

Labeling will include the manufacturer, chemical name/identifier, lot/batch 
number, storage conditions, expiration date

A list of the adverse events and potential risks associated with the 
investigational in this study can be found in Section 7.1.

The PK of Eribulin is linear with mean elimination half-life of 40 hours, a 
mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 
1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 
mg/m2 The human plasma protein binding of eribulin at concentrations of 100 
ng/mL to 1,000 ng/mL ranges from 49% to 65% Eribulin exposure after 
multiple dosing is comparable to that following a single dose. No 
accumulation of eribulin is observed with weekly administration.

Unchanged eribulin was the major circulating species in plasma following 
administration of 14C-eribulin to patients. Metabolite concentrations 
represented <0.6% of parent compound, confirming that there are no major 
human metabolites of eribulin.

Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro. 
Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is 
unlikely that eribulin will substantially increase the plasma levels of CYP3A4 
substrates. Eribulin shows no induction potential for CYP1A, CYP2C9, 
CYP2C19, and CYP3A in primary human hepatocytes. No significant 
inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was 
detected with eribulin concentrations up to 5 μM in pooled human liver 
microsomes. In vitro drug interaction studies indicate that eribulin does not 
inhibit drugs that are substrates of these enzymes and it is unlikely that 
eribulin will affect plasma levels of drugs that are substrates of CYP enzymes. 
Eribulin is a substrate and a weak inhibitor of the drug efflux transporter P-gp 
in vitro

Eribulin is eliminated primarily in feces unchanged. After administration of 
14C-eribulin to patients, approximately 82% of the dose was eliminated in 
feces and 9% in urine. Unchanged eribulin accounted for approximately 88% 
and 91% of the dose in feces and urine, respectively.
8.1.2
Form

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Eribulin will be supplied to the sites in glass vials containing 1.0 mg Eribulin mesylate in 2.0 mL 
of clear, colorless, and sterile solution.
8.1.3
Storage and Stability
Study drug will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range. The PI or designee is responsible for ensuring that the 
temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature will be monitored continuously by using either an in-house validated 
data acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
8.1.4
Compatibility
Do not mix with other drugs or administer with dextrose- containing solutions 
8.1.5
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. 
8.1.6
Availability
Eisai will package eribulin as open-label supplies. Eribulin will be supplied to the sites in glass 
vials containing 1.0 mg Eribulin mesylate in 2.0 mL of clear, colorless, and sterile solution.
Excipients of the Eribulin formulation are ethanol, hydrochloric acid, sodium hydroxide, and 
water for injection.
8.1.7
Preparation
The amount of Eribulin required will be withdrawn from the appropriate number of vials (each 
vial contains 1.0 mg of Eribulin mesylate in 2.0 mL solution [concentration: 0.5 mg/mL]) into a 
syringe. 
Store undiluted HALAVEN 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 HALAVEN for up to 4 hours 
at room temperature or up to 24 hours under refrigeration.
8.1.8
Administration

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Before dose administration, the amount of study treatment needed for each subject will be 
calculated by the Dubois formula or institutional standard of care at day 1 of each cycle. 
The dose of study treatment, time of administration, volume infused, and start/stop dates of the 
administration of study treatment will be recorded on the eCRFs. In addition, any changes to 
administration such as dose reduction, delay, or interruption will be adequately documented in 
the subject’s drug administration chart and recorded on the eCRFs. 
Treatment criteria according to section 5.2 must be met prior to the infusion.
Subjects will receive Eribulin mesylate at a dose of 1.4 mg/m2 as an IV infusion over
2-5 minutes on Days 1 and 8 of every 21-day cycle.
8.1.9
Ordering
Eribulin mesylate will be supplied in glass vials containing 1.0 mg Eribulin in 2.0 mL of clear, 
colorless, and sterile solution by Eisai.
Drug supply will be requested by the Drug Supply Re-ordering Form (appendix B). 
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
8.1.11 Destruction and Return
All unused drug supplied by Eisai will be properly destroyed at the study site. Documentation of 
this procedure will be provided to Eisai by the study team on request.  
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
As angiosarcomas, and other vascular sarcomas, are ultra-orphan diseases with incidences of less 
than 200 patients per year, very little is known about the genomic drivers behind these 
malignancies. Moreover, mechanisms of the vascular effects of Eribulin remain elusive.  Thus, to 
this end we believe it will be critical to capture genomic data to help us understand this disease 
and any indicators of resistance or sensitivity to chemotherapies, such as Eribulin. In this 
protocol we will collect circulating cell free DNA (cfDNA) for whole exome sequencing (WES) 
as well as pre and on treatment biopsies for WES and RNA seq.  

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We hypothesize that these exploratory analyses will provide insight into angiosarcoma and EHE 
oncogenesis, as well Eribulin anti-cancer activity. 
9.2
Laboratory Correlative Studies
9.2.1
Peripheral blood cfDNA
9.2.1.1
Collection of Specimen(s): Two tubes of peripheral blood will be collected in Streck 
tubes (10 mL per tube) on each cycle day 1 prior to Eribulin infusion. 
9.2.1.2
Shipping of Specimen(s): The samples will be immediately sent to the Broad Institute 
by courier at room temperature.
9.2.1.3
Site(s) Performing Correlative Study: Analysis of cfDNA by WES will be performed 
at the Broad Institute. Within three hours of collection, we will perform high-speed 
centrifugation to separate plasma and cells. We will extract cfDNA using magnetic 
bead-based protocols. To qualify the cfDNA obtained from each blood biopsy for 
WES, we will first assess the purity of tumor-derived cfDNA using ultra-low-pass 
whole genome sequencing (ULP-WGS).  
 
The ULP-WGS is a low-cost approach to nominate samples containing sufficient 
fraction of tumor-derived DNA for WES. Briefly, cfDNA samples will be subjected 
to whole genome sequencing to an average of 0.1X genome-wide sequencing 
coverage.  Samples with fewer than 150,000 reads (0.005X) will be excluded due to 
insufficient coverage for analysis. We will utilize the statistical approach from the 
HMMcopy software(28) to correct for GC-content and mappability (sequence 
uniqueness) biases in read counts within genomic bins of 1Mb, which substantially 
improves signal to noise ratio.  Next, we will use a modified approach from the 
TITAN(29) framework to perform segmentation, copy number prediction, and purity 
and ploidy estimation.  This approach is optimized for increased sensitivity to detect 
events from low purity tumor-derived DNA in the absence of a control sample.  
Benchmarking of the purity estimates has been carried out using simulation of tumor-
normal mixing and comparison to corresponding WES data, revealing a robust lower 
estimation level of 5% purity. As described in our Preliminary Data, we expect at 
least 50% of blood biopsies to have sufficient tumor-derived cfDNA to proceed with 
WES. 
In those samples deemed by ULP-WGS to be adequate for WES, the exome will be 
selected using solution-phase hybrid capture and sequencing will be performed using 
the Illumina HiSeq2500, as described above. WES data will be analyzed for base 
substitutions, small insertions/deletions, and copy number alterations(30-34).  

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9.2.2
Sarcoma whole exome (WES) and transcriptome sequencing (RNA Seq)
9.2.2.1
Core or excisional biopsies will be performed 1. After registration but before C1D1 
and 2. Prior to the first imaging and C3D1
9.2.2.2
Handling of Specimens(s): Specimens will be divided either at the bedside or in the 
frozen laboratory by pathology for correlative studies and submission to the MGH or 
BWH pathology. Research samples will be placed in 2 mL cryovials and packaged 
for shipping on dry ice. 
9.2.2.3
Shipping of Specimen(s): Research specimens will be couriered to the Broad Institute 
immediately after processing.  
9.2.2.4
Site(s) Performing Correlative Study: Analysis of DNA by WES will be performed at 
the Broad Institute
9.2.2.5
Methods: Our approach will characterize specimen “sets” consisting of pre-treatment 
and, when applicable, post-treatment tumor samples from each patient. Genomic 
DNA and polyadenylated RNA will be extracted from tumor using standard 
techniques, and WES and RNA-seq will be performed by the Broad Institute 
Genomics Platform. The exome will be selected using solution-phase hybrid 
capture(35-38) and sequencing will be performed using the Illumina HiSeq2500, 
yielding an average depth of coverage of >150-fold. WES data will be analyzed for 
base substitutions, small insertions/deletions, and copy number alterations(30-34). 
For RNA-seq, strand-specific cDNA libraries will be generated, and Illumina 
sequencing libraries will be prepared following established protocols. Each sample 
will be sequenced with an Illumina HiSeq2500. RNA-seq data will be analyzed for 
fusions, chimeric read-through transcripts, point mutations, and instances of 
alternative splicing. RNA-seq data will also be used to determine gene expression 
levels. Data from RNA-seq will be combined with the WES results to nominate 
candidate genomic alterations. Differences in genomic alterations between pre- and 
post-treatment tissues will be analyzed by algorithms described below. 
The purpose of RNA-seq here is three-fold. First, RNA-seq can identify structural 
genomic changes that cannot be detected by WES, such as rearrangements and 
alternatively spliced isoforms(39). Second, expression data from RNA-seq can be 
cross-referenced with WES data to determine if genomic alterations detected by WES 
are expressed. Finally, the transcriptional profiles can be used to classify tumors 
based on signatures as described below. In particular, comparison of signatures 
between pre-treatment samples and post-treatment samples should identify 
genes/signatures whose expression changes can then be correlated with treatment.
9.2.3
Analysis of WES and RNA Seq Data
Analysis of the sequencing data will be performed in conjunction with the Cancer Genome 
Analysis group (CGA) of the Broad Institute. The CGA group has developed a wide range of 
computational tools designed to identify distinct classes of genomic alterations in individual 
tumors, and incorporated them into a single pipeline called FireHose. In total, FireHose 
accomplishes the following: (i) direct comparison of matched tumor and normal samples, (ii) 
detection of events that may be present at widely different ratios (rather than 0, 50 or 100% for 
germline alleles), (iii) detection of amplifications, deletions and rearrangements, and (iv) 

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overcoming contamination from admixture of normal tissue. Specifically, SNVs and indels are 
identified using MuTect(30) and indelocator(31), respectively. Copy number alterations (CNAs) 
are identified using ReCapSeg (unpublished). RNA-seq data will be analyzed using dRanger 
which identifies pairs of reads with abnormal distance and orientation compared to the 
distribution in the library, and uses a ‘split-read aligner’ to characterize the breakpoints to the 
base-level level. A variation on this approach can be used to identify alternatively spliced 
products or gene fusions present in RNA-seq data. 
To annotate the results of the various calling methods for biological significance, one first 
models the background mutational processes (and their rates) and then calculates a p-value, i.e. 
the probability to generate from the background model a set of alterations that are at least as 
extreme as the observed ones. Finally, one needs to correct for multiple hypotheses testing (all 
genes, all SNPs or all pathways, depending on the events that are analyzed), which we perform 
by calculating False Discovery Rate q-values using the Benjamini-Hochberg procedure(32). Two 
methods have been developed that follow this approach. Recurrent CNAs are identified using the 
GISTIC2.0 algorithm(33), a tool that detects significant copy-number alterations, distinguishing 
between chromosome arm-level events and focal events. Recurrent SNV and indels in are 
identified using MutSigCV(34), an algorithm that analyzes mutation data in genes and pathways, 
incorporates the background mutation rates of different categories of mutations (e.g. mutations in 
CpGs, other Cs or Gs, A/T, indels, etc.) and identifies genes whose mutations are unlikely to 
have emerged by chance.
10. STUDY CALENDAR
Scans and x-rays must be done <4 weeks prior to the start of therapy.  Screening laboratory tests 
and ECG will be performed within 15 days prior to the start of therapy. In the event that the 
participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. Laboratory testing must be repeated if done more 
than 7 days prior to day 1.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. Dosing delays beyond noted windows for non-clinical reasons (e.g. weather, 
holidays) are permitted with approval of the overall PI. 

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Pre-
study
Cycle 1
Cycle 2 and beyond
Off 
StudyH
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Wk 6
EribulinA
X
X
X
X
Informed 
consent
X
Pathology 
ReviewB
X
Demographics
X
Medical Hx
X
Concurrent 
Meds
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Vital Signs 
including 
weight
X
X
X
X
X
X
Height
X
ECOG PS
X
X
X
X
Laboratory 
testingC
X
X
X
X
X
X
ECG
XI
XI
Adverse Event 
Evaluation
X
X
X
X
X
X
X
Tumor 
MeasurementsD
X
Every 6 weeks for the first 7 cycles (before C3, C5, 
C7) and then every 9 weeks onward (before C10, 
C13, etc) 
Urine or serum 
B-HCGE
X
Required 
BiopsyF
X
X
Blood sample 
for cfDNAG
X
X
A- Eribulin will be administered of 1.4 mg/m2 as an IV infusion over 2-5 minutes on 
Days 1 and 8 of every 21-day cycle
B- Pathology review any time prior to the study
C- CBC/diff, chemistries (sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, 
AST, ALT, total protein, albumin); urinalysis only required on prescreening 
testing and PT/PTT only required on prescreening testing and before Biopsy 2.  
Screening laboratory tests will be performed within 15 days prior to Day 1 of 
treatment
D- The modality (e.g. CT, MRI) should be consistent through the protocol. The 
window is +/- 1 week for the first 3 sets of scans/imaging then +/- 2 weeks 
thereafter; baseline tumor measurements should be performed within 28 days prior 
to Day 1 of treatment

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E- Urine or serum beta-HCG Must be repeated if not performed within 72 hours of 
cycle 1 day 1
F- Biopsy 1 will occur after registration and prior to C1D1. Biopsy 2 will occur prior 
to the first imaging and C3D1. Platelet count and PT/PTT required pre biopsy 2 or 
per institutional standards.  When possible the biopsy should be multiple cores or 
excisional. If the biopsy is considered unsafe the requirement may be waived after 
discussion with the overall PI. 
G- cfDNA will be collected after registration (prior to C1D1) and every D1 thereafter
H- See section 5.8 for AE and SAE follow-up. 
I-
ECG monitoring only required for screening, C2D1 and C3D1 unless the criteria 
for continued monitoring are met as per section 6.3. ECG does not need to be 
repeated on C1D1 if obtained within 15 days of C1D1, unless clinically indicated.

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11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 6 weeks for 
the first 7 cycles (before C3, C5, C7) and then every 9 weeks onward (before C10, C13, etc.).  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.

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Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 

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evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 

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prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
.
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.3.1
Evaluation of Target Lesions

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Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.3.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.1.3.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 

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indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.3.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated

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Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.4 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.5 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting

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12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. 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 Overall PI and study 
team.
The DSMC will review each protocol up to four times a year 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 with 30 
days of intervention for Phase I or II protocols; for gene therapy 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. 
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This is a pilot phase II clinical trial with a primary endpoint of objective response per RECIST 
1.1 among patients with metastatic or unresectable angiosarcoma and EHE treated with Eribulin. 
For the primary endpoint of best overall objective response with a null hypothesis of 10% and an 
alternative hypothesis of 35%, we would need 16 patients in a single-stage design.  We will need 
to observe at least 4 responses out of 16 patients to accept the treatment.  The power for this 
design is 87% using the exact binomial distribution. The operating characteristics of this design 
are calculated using one-sided 10% type I error. 
 
13.2
Sample Size, Accrual Rate and Study Duration
For the primary endpoint of best overall objective response with parameters as described in 13.1, 
a total sample size of 16 patients is needed in a single-stage design.  A minimum accrual rate is 

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expected to be 1 subjects per two months.  With a minimal accrual rate of 0.5 subjects per 
month, we expect the study enrollment to last approximately 32 months.
13.3
Interim Monitoring Plan
Please see section 12.1 for safety monitoring by the DF/HCC DSMB.  There is no other interim 
monitoring plan for this pilot study.
13.4
Analysis of Primary Endpoints
The best overall objective response rate is defined as, the proportion of patients with complete 
[CR] or partial response [PR] per RECIST 1.1 among all eligible angiosarcoma and EHE 
patients treated with Eribulin.  Disease assessment will be performed every 6 weeks for the first 
8 cycles and then every 9 weeks or as clinically indicated thereafter.  The two-sided 95% exact 
binomial confidence interval will be computed for objective response.
13.5
Analysis of Secondary Endpoints
There is at least 74% probability of observing one or more rare (8% true probability) events, and 
93% probability of observing toxicities that have a true occurrence of at least 15%.  With 16 
treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for 
any estimated adverse event proportion will be no wider than ±22%.
Progression-free survival will also be calculated.  Progression-free survival, will be defined as 
the duration of time from start of treatment to time of progression or death, whichever occurs 
first and will be estimated using the Kaplan-Meier method. The disease control rate (Complete 
Response, Partial Response, and Stable Disease) at 24 weeks will also be calculated using the 
exact binomial distribution and 95% confidence interval.
We will explore the relationship between integrated biomarkers detected by cfDNA exome 
sequencing, WES, RNAseq expression profiling and response to Eribulin.  We will use Fisher’s 
Exact Test to assess the relationship between each biomarker and response to eribulin assuming a 
best overall objective response of 35%.  Biomarkers may be continuous or binary.  For example, 
with this design, assuming tissue is available on 100% of the sample, the probability of 
concluding eribulin response is related to the exploratory biomarker is 82%; given the unknown 
true response is 70% and 4% in positive marker versus negative marker patients, respectively, 
assuming 50% of the population is over-expressed for the biomarker or the biomarker is 
continuous and split at the median.  The operating characteristics of this design are calculated 
using a two-sided exact test with 10% type I error.
We will explore the relationship between changes in the integrated biomarkers from baseline to 
cycle 3 due to eribulin treatment using a paired t-test. With 16 patients, we will have 81% power 
to detect an effect size of 0.67 using a paired t-test with a 0.1 two-sided significance level.
13.6
Reporting and Exclusions

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13.6.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment. All patients 
who receive at least one dose of Eribulin will be included in the toxicity analysis.  This includes 
participants who receive study drug and are ultimately deemed ineligible.
13.6.2 Evaluation of the Primary Efficacy Endpoint
All participants who received at least one dose of Eribulin will be included in the overall 
response rate analysis.  All eligible participants included in the study must be assessed for 
response to treatment, even if the patient is ineligible or there are major protocol therapy 
deviations, following intent-to-treat. 
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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

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16. APPENDIX B
DRUG REORDER FORM 

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