Clinical trial NCT02513472
Conditions: Breast Neoplasm
Keywords: Eribulin Mesylate Pembrolizumab Metastatic Triple-Negative Breast Cancer mTNBC
Sponsor: Eisai Inc.
Start date: 2015-08-28; Completion date: 2021-04-06
Enrollment: 258 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-arm, multicenter, Phase 1b/2 study of eribulin mesylate in combination with pembrolizumab in participants with mTNBC previously treated with 0 (stratum 1) or 1 to 2 (stratum 2) lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.

Detailed description:
The Phase 1b part will evaluate the safety and tolerability of eribulin mesylate in combination with pembrolizumab. Approximately 6 participants may be enrolled in the Phase 1b part of the study. The Phase 2 part will evaluate the tumor objective response rate (ORR) when treated with eribulin mesylate in combination with pembrolizumab in all participants and will also evaluate ORR in stratum 2 participants and compare with the historical response rate of pembrolizumab monotherapy 10 percent (%) in participants with mTNBC previously treated with \>=1 line of prior chemotherapy in the metastatic setting. Approximately 170 mTNBC participants (including participants in Phase 1b who are on RP2D level) will be enrolled in Phase 2.

Arms: arm 1: Participants with mTNBC previously treated with 0 (stratum 1) or 1 to 2 (stratum 2) lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.
Interventions: intervention 1: Eribulin Mesylate intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Eribulin Mesylate will be administered as a 1.4 milligram per square meter (mg/m\^2) IV (intravenous) infusion on Day 1 and Day 8 of each 21-day cycle in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression occurs, or until the participant withdraws consent. intervention 2: Pembrolizumab will be administered as a 200 milligram (mg) IV infusion on Day 1 of each 21-day cycle in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression occurs, or until the participant withdraws consent.

Protocol documents:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E7389-M001-218
Study Title:
ENHANCE 1: An Open-Label, Single-Arm, Multicenter 
Phase 1b/2 Study to Evaluate the Efficacy and Safety of 
Eribulin Mesylate in Combination With Pembrolizumab in 
Subjects With Metastatic Triple-Negative Breast Cancer 
(mTNBC)
Sponsor.
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Investigational Product 
Names:
Eribulin mesylate (E7389) and pembrolizumab (MK-3475)
Indication:
Metastatic Triple-Negative Breast Cancer (mTNBC)
Phase:
1b/2
Approval Dates:
27 Apr 2015 (Original Protocol)
03 Aug 2016 (Amendment 01)
26 Sep 2016 (Amendment 02)
11Sep 2017 (Amendment 03)
29 May 2018 (Amendment 04)
26 Jun 2020 (Amendment 05)
IND Number:
113851
GCP Statement:
This study is to be performed in full compliance with 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  
All required study documentation will be archived as required 
by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or disclosure 


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of such information that is not authorized in writing by the 
sponsor is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study.


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REVISION HISTORY
Protocol Amendment 05
Date: 26 June 2020
Change
Rationale
Affected Protocol 
Sections
The overall study duration was changed from 
approximately 48 to 60 months and November 
2020 was added as the expected time for 
completion of study (ie, last subject expected to 
complete the study). 
Revised to provide updated 
information based on 
current study milestones.
Synopsis – Study 
Period and Phase of 
Development
The End of Study is clarified to refer to the last 
subject’s last visit/assessment (or the end of the 
90-day follow up for serious adverse events 
[SAEs]/events of clinical interest [ECIs]), after 
which all subjects will have completed their 
Off-Treatment visit.  It is also clarified that as of
this amendment (Protocol Amendment 05), 
Follow-Up assessments in the Posttreatment Phase 
will not be performed after the subject completes 
the Off-Treatment visit assessments.
The recommended Phase 2 dose (RP2D; eribulin 
1.4 mg/m2 IV on Day 1 and Day 8 with 
pembrolizumab 200 mg IV on Day 1 of each 
21-day cycle) determined during Phase 1b part of 
the study was added.
To revise and clarify the 
End of Study definition to 
be the the last subject’s last 
visit/assessment (or the end 
of the 90-day follow up for 
SAEs]/ECIs).  Also, to 
clarify that as of this 
amendment, no 
posttreatment follow-up 
assessments will be 
performed.
To specify that the dose 
assessed during the 
Phase 1b part of the study 
based on Cycle 1 
dose-limiting toxicities was 
the determined RP2D.
Clinical Protocol 
Synopsis Study Design
Section 9.1
Section 9.1.3
Clinical Protocol 
Synopsis Study Design
Section 9.1
Added text to clarify that for subjects experiencing 
prolonged clinical benefit, temporary interruption
of study treatment for up to 3 months may be 
permitted after discussion with the treating 
physician and sponsor.  Also, added that after such 
interruption, the investigators are strongly 
encouraged to rescan the subject to rule out interim 
disease progression.
New information to 
provide additional 
treatment and scanning 
guidance for subjects 
experiencing prolonged 
clinical benefit.
Clinical Protocol 
Synopsis – Duration of 
Treatment

Section 9.4.1
Added text to specify that after the last subject 
enrolled in the study has completed 35 cycles of 
pembrolizumab treatment, all ongoing subjects 
will be transitioned off study. Additionally, it was
clarified that subjects still receiving eribulin 
monotherapy at that time may continue to receive 
eribulin off study through their pharmacy (if 
commercially available for that individual subject) 
or through a patient assistance program 
administered by the sponsor.
Further, it was clarified that prior to transitioning 
ongoing subjects to commercial eribulin or an 
access program, eribulin investigational product 
will be provided to the ongoing subjects and they 
To allow for all ongoing 
subjects to be transitioned 
off study, but provide a 
mechanism for subjects 
still receiving eribulin at 
the end of study to be 
transferred to commercial 
eribulin supply outside the
study or through an access 
program.
To clarify that all ongoing 
subjects receiving eribulin 
will continue to receive 
eribulin study treatment 
Clinical Protocol 
Synopsis – Duration of 
Treatment

Section 9.1.3

Section 9.4.1

Section 9.5.5


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will continue to be assessed according to the study 
Schedule of Procedures/Assessments until they 
have had their Off-Treatment visit.
until their Off-Treatment 
visit and will continue to 
be assessed according to 
the study Schedule of 
Assessments, prior to their 
transition to commercial 
eribulin or an access 
program.
The duration of monitoring after the first year of 
follow-up for subjects who discontinued therapy 
without disease progression was changed from 
‘every 12 (±1) weeks’ to ‘every 9 to 12 (±1) weeks 
per standard of care’ until start of new anticancer 
treatment, disease progression, death, or end of 
study.
To revise the follow-up 
imaging schedule for 
monitoring disease status 
for subjects who 
discontinued therapy 
without disease 
progression to follow the 
local standard of care after 
the first year of follow-up.
Clinical Protocol 
Synopsis –
Assessments (Efficacy)
Section 9.3.3
Section 9.5.1.4.1
Section 9.5.1.4.2
Section 9.5.2.1
(Table 8 footnote n)
Section 12
(Appendix 4)
Added note to clarify that as of this amendment
(Protocol Amendment 05), tumor assessment scans 
will no longer be sent to the independent core 
imaging laboratory for efficacy assessment.
No requirement to send 
tumor assessment scans to 
independent imaging 
laboratory following 
completion of the final
efficacy analysis.
Clinical Protocol 
Synopsis –
Assessments (Efficacy)
Section 9.5.1.4.1
Section 9.5.1.4.2
Section 12
(Appendix 4)
Added text to clarify that as of this amendment 
(Protocol Amendment 05), thyroid function 
assessment will be done at the discretion of the 
investigator.
To allow for thyroid 
function assessment to be 
done at the investigator’s 
discretion.
Section 9.5.1.6.3
(Table 7 footnote a)
Section 9.5.2.1
(Table 8 footnote i)
Revised text in statistical and analytical plans 
section on extent of study treatment exposure 
analysis in relation to analysis and presentation of 
extent of exposure data for pembrolizumab.
Updated information to 
clarify study treatment 
exposure analysis and data 
presentation.

Section 9.7.1.8.1
Revisions to Amendment 04 of the Protocol
Date: 29 May 2018
Change
Rationale
Affected Protocol 
Section
Enrollment is extended for Stratum 2 to recruit a 
total of at least 100 evaluable subjects (total of 170 
subjects enrolled)
To assess the precision of 
the ORR point estimate 
and confidence intervals
Protocol Synopsis

Section 9.1

Section 9.3

Section 9.7.1.6.1

Section 9.7.2


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Change
Rationale
Affected Protocol 
Section
Updated pembrolizumab background information
The background was 
updated to reflect the 
PK/ADA data available

Section 7.1
Added dose modification guidelines for 
Myocarditis and redefined All other immune-
related AEs
The dose modification 
information was updated to 
reflect current data and 
label information

Section 9.4.1.2, Table 
4
Additional information about study removal of 
subjects
To clarify the criteria to be 
considered prior to 
removing a subject from 
the study

Section 9.4.6.3
Updated definition of clinically stable criteria
Administrative change to 
incorporate 
pembrolizomab standard 
language that was not 
previously listed in the 
protocol.

Section 9.5.1.4.2
Clarified discontinuation criteria 
Clarification of the criteria 
for pembrolizumab 
discontinuation

Section 9.5.5
Protocol Amendment 3 changes are being made to the Protocol Amendment 1 
document. Although Protocol Amendment 2 adding a urothelial cancer cohort was 
drafted and submitted to the FDA for review it was not issued to the sites or 
implemented. 
Revisions to Amendment 03 of the Protocol
Date:  11 Sep 2017
Change
Rationale
Affected Protocol 
Section
The overall duration of the study is extended from 
24 to 38 months. 
To allow time for 
recruitment of additional 
subjects in Stratum 2

Clinical Protocol 
Synopsis
Enrollment is extended for Stratum 2 to recruit a 
total of 80 evaluable subjects (total of 150 subjects 
enrolled)
To provide more consistent  
and robust clinical data 
(related with the current 
promissory results 
obtained)  to justify the 
possibility to obtained a 
conditional approval 
during the next  FDA Type 
B meeting

Clinical Protocol 
Synopsis Study 
Design, sample Size 
rationale

Section 9.1

Section 9.3

Section 9.7.2
The study interval is extended from Dec. 2017 to 
May 2018.
To allow time for 
recruitment of additional 

Clinical Protocol 
Synopsis


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Change
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Section
subjects in Stratum 2
A secondary objective to evaluate efficacy in 
subjects previously treated with 1 to 2 lines of 
systemic anticancer therapy in a metastatic setting 
was added. (Clinical Benefit Rate)
To better estimate efficacy 
in Stratum 2

Clinical Protocol 
Synopsis

Section 8.2
ORR was added as a primary objective in Phase 2 
of the study.
To evaluate objective 
response rate in subjects 
with metastatic triple-
negative breast cancer 
previously treated with 1 to 
2 lines of systemic 
anticancer therapy in the 
metastatic setting.

Clinical protocol 
Synopsis

Section 8.1
The primary objectives for the 2 phases of the 
study were updated to include subjects with 
mTNBC previously treated with 0 Stratum 1 or 1 
to 2 (Stratum 2) lines of systemic anticancer 
therapy in the metastatic setting and currently 
treated with eribulin mesylate in combination with 
pembrolizumab.

Clinical protocol 
Synopsis

Section 8.1
ORR was to be evaluated per RECIST 1.1 by IIR 
in Stratum 2 subjects in Phase 2 of the study and 
compared with the historical response rate of 
pembrolizumab monotherapy of 10%.
Updated due to clinical 
interest in ORR in Stratum 
2 subjects in comparison 
with historical 
pembrolizumab 
monotherapy response rate

Clinical protocol 
Synopsis

Section 8.1
Exclusion criterion #14 was modified to include 
severe hypersensitivity (≥ Grade 3) to 
pembrolizumab or its excipients.
To clarify the exclusion 
criteria based on new 
safety language provided 
by Merck

Clinical protocol 
Synopsis

Section 9.3.2
Exclusion Criterion #16 was modified to exclude 
subjects with a diagnosis of immunodeficiency or 
who is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone 
equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to 
the first dose of trial treatment.  The use of 
physiologic doses of corticosteroids may be 
approved after consultation with the sponsor.
To clarify the exclusion 
criteria based on new 
safety language provided 
by Merck

Clinical Protocol 
Synopsis

Section 9.3.2
Duration of treatment was clarified to note 
subjects can receive up to 35 treatments (~2 years) 
with pembrolizumab until discontinued due to 
confirmed CR treatment for at least 8 cycles with 
pembrolizumab and have had at least 2 treatments 
with pembrolizumab beyond date initial CR was 
declared
To better define the 
duration and 
discontinuation of 
pembrolizumab treatment

Clinical Protocol 
Synopsis

Section 9.5.5
Exploratory endpoint of time to response (TTR) 
This endpoint is considered 

Clinical Protocol 


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Change
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Affected Protocol 
Section
was added.
of clinical interest.
Synopsis

Section 8.3

Section 9.7.1.1.3
The Full Analysis Set (FAS) noted to be used for 
analysis of PFS and OS.
PFS was added to get a 
more conservative 
estimation 

Clinical Protocol 
Synopsis

Section 9.7.1.2
Bayesian PP no longer used for continuous 
monitoring of efficacy and futility. 
Study will not be stopped 
for either

Clinical Protocol 
Synopsis

Section 9.7.1.6.1
Exploratory efficacy outcomes were further 
evaluated in the PD-L1 positive set after a cutoff 
point was determined using external data.
This language was moved 
to the next section for 
clarity.

Clinical Protocol 
Synopsis

Section 9.7.1.6.3
Clinical Experience with Pembrolizumab was 
updated.
Section updated per latest 
language provided by 
Merck

Section 7.1.3.2
Procedure for dose modification and management 
of toxicities (infusion reactions) of pembrolizumab 
during treatment was updated.
Section updated per latest 
language provided by 
Merck

Section 9.4.1.2

Section 9.4.6.1

Table 5
IRRECIST was used after the initial radiologic 
progression and the use of RECIST 1.1 was 
adapted to account for the unique tumor response 
seen with immunotherapeutic drugs.
Updated per current 
irRECIST guidelines 

Clinical Protocol 
Synopsis Efficacy 
Analysis

Section 9.5.1.4.2

Table 6
The acceptable liver function tests for ALT and 
AST were clarified in inclusion criterion #8
Updated to reflect industry 
standard criteria for 
subjects with liver 
metastases 

Clinical Protocol 
Synopsis

Section 9.3.1
Independent imaging review was used for 
assessment of ORR (primary objective) and other 
objectives PFS, DOR, CBR and TTR. 
ORR, PFS, DOR CBR and TTR, based on 
investigator/local radiology assessment, could also 
be secondary endpoints.
Updated per FDA guidance 
regarding tumor 
assessment for 
registrational studies

Clinical Protocol 
Synopsis

Section 9.5.1.4

Section 8
CBR, defined as the proportion of subjects who 
had BOR of CR, PR, or stable disease of ≥24 
weeks, was deleted as an exploratory endpoint and 
added as a secondary endpoint.
Upgraded CBR to 
secondary objectives due 
to clinical interest.

Clinical Protocol 
Synopsis

Section 9.7.1.1.2
The indication for pembrolizumab was clarified to 
include other tumor types, package insert.
Updated per latest 
pembrolizumab package 
insert

Section 7.1


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Change
Rationale
Affected Protocol 
Section
A reference to a Phase 2 study of pembrolizumab 
as monotherapy for previously treated TNBC was 
added
Updated per latest 
pembrolizumab clinical 
study results 

Section 7.2 
Results of pembrolizumab KN086 study were 
added to Table 1
Updated per latest 
pembrolizumab clinical 
study results

Section 7.2
The duration of monitoring for subjects who 
discontinued therapy without disease progression 
was changed from every 12 weeks to every 
9 weeks for the first year of follow-up and every 
12 weeks until start of new anticancer treatment, 
disease progression, death, or end of study.
To maintain the imaging 
schedule that is already in 
place as part of the 
protocol, For patients 
within the 1st year of 
treatment on study, 
imaging will be performed 
every 9 weeks +/- 1 week, 
and for subjects beyond the 
1st year of treatment, 
imaging will be performed 
every 12 weeks +/- 1 week

Clinical Protocol 
Synopsis

Section 9.5.1.4.1

Table 6

Section 9.5.2.1, Table 
8, Footnote ‘n’
A 2-sided Clopper-Pearson test was added to 
assess CBR, a secondary efficacy analysis.
Updated due to CBR being 
changed to a secondary 
objective.

Section 9.7.1.6.2
Moved Phase 1b safety run-in cohort used for 
assessing subjects for dose-limiting toxicity (DLT) 
in the first cycle and to study safety of the 2-drug 
combination from Primary Efficacy Analysis to 
Safety Analyses. 
This analysis is more 
appropriate in the safety 
analyses section rather than 
the primary efficacy 

Clinical Protocol 
Synopsis

Section 9.7.1.8
Updated sub-section headings to Primary Efficacy 
Endpoints, Secondary Efficacy Endpoints and 
Exploratory Efficacy Endpoints 
Updated sub-section 
headings for clarity

Clinical Protocol 
Synopsis

Section 9.7.1.1
Protocol Amendment 2 adding a urothelial cancer cohort was drafted and submitted to 
the FDA for review.  However, Amendment 02 was not issued to the sites or 
implemented. 
Revisions to Amendment 02 of the Protocol
Date: 26 Sep 2016
Change
Rationale
Affected Protocol Section
The strata include first-line subjects who are 
cisplatin ineligible based on renal impairment 
(creatinine clearance calculated by 
Cockcroft-Gault method <60ml/min), grade 2 
hearing loss (stratum 1) and subjects who have 
progressed within 12 months of treatment with a 
platinum containing regimen [cisplatin or 
carboplatin or novel platinum] in either the 

Synopsis, Study 
Design 

Section 9.1 

Section 9.4.3


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Change
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metastatic or perioperative setting (stratum 2).
Approximately 40% and 60% of subjects will be 
enrolled from strata 1 and 2, respectively.
mUC cohort: up to 50 evaluable mUC subjects 
will be enrolled in the study. ORR in the historical 
control is assumed to be 30%. The ORR in this 
study is estimated as 50%, which is deemed a 
clinical meaningful improvement. The null and 
alternative hypotheses are set as follows:

Synopsis, Primary 
Efficacy Parameter

Section 9.7.1.6.1
The strata include subjects first-line subjects who 
are cisplatin ineligible based on renal impairment 
(creatinine clearance calculated by Cockcroft-
Gault method <60ml/min), grade 2 hearing loss 
(stratum 1) and subjects who have progressed 
within 12 months of treatment with a platinum 
containing regimen [cisplatin or carboplatin or 
novel platinum] in either in the metastatic or 
perioperative setting (stratum 2). The 2 strata will 
have approximately 40% (stratum 1) and 60% 
(stratum 2) of the total subjects.  

Synopsis, Sample Size 
Rationale 

Section 9.7.2
Number of study sites increased from 25 to 30
Will help to ensure that 
protocol-specified sample 
size is achieved within 
study timelines

Clinical Protocol 
synopsis

Section 6

Section 9.3
Revised the study sample size (including evaluable 
number of subjects) and strata allocation.
There is clinical interest to 
have a more precise 
estimation of the response 

Clinical Protocol 
Synopsis

Section 9.1

Section 9.3

Section 9.4.3

Section 9.7.1.6.1

Section 9.7.2
Inclusion Criteria #2
Added text
Provides additional 
clarification for sites with 
respect to:

Clinical Protocol 
synopsis

Section 9.3.1
Text revised that describes reasons for 
discontinuation from the study.
The eCRF does not collect 
“primary” and “secondary” 
reasons for 
discontinuation.
Unnecessary to name 
eCRF form being used to 
collect study disposition, 
so such text is deleted.

Section 9.3.3

Section 9.5.5

Section 9.6.2
Included new text for supportive care guidelines 
with respect to the use of corticosteroids and 
revised specific text regarding rescue medications 
Updated to remain 
consistent with the latest 
pembrolizumab protocol 

Section 9.4.6.1


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Change
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Affected Protocol Section
for treatment of pembrolizumab-related toxicities.
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 
06-Jun-2016
Added text “Treatment with bisphosphonates 
and/or denosumab will be allowed for subjects 
with bone metastases.”
Text added to provide 
guidance to sites regarding 
allowed concomitant 
medications for subjects 
with bone metastases

Section 9.4.6
Prohibited Concomitant Therapies and Drugs:
Changed to “Systemic glucocorticosteroids for any 
purpose other than to modulate symptoms of 
suspected immunologic etiology” 
Changed to “For subjects who, in the assessment 
by the investigator, require the use of any of the 
aforementioned treatments for clinical 
management, continuation of the study medication 
and further participation in the study must be 
discussed and agreed upon with the sponsor.”
Text revised to provide 
clarification for use of 
corticosteroids in any 
instance of suspected 
immunologic etiology.
Text revised to provide 
more specific guidance 
with regard to continuation 
of study medication under 
circumstances that require 
use of prohibited 
concomitant medications.

Section 9.4.6.3
Text revised and/or added regarding the return of 
or destruction of unused study medication 
Original text was not 
consistent with the Eisai 
protocol template language 
and is now revised.

Section 9.4.8
Revised text for serum and urine pregnancy testing
(protocol version 1.0, Table 8 changed to protocol 
version 2.0, Table 7).
Clarification that 
pregnancy testing is 
allowed using either serum 
or urine β-hCG.

Section 9.5.1.2

Table 7

Schedule of 
Procedures/ 
Assessments
Added new text “SAEs and ECIs will be collected 
for 90 days after the last dose or 30 days following 
the last dose if the subject initiates new anticancer 
therapy, whichever is earlier.  An AE will not be 
reported on the Adverse Event CRF if other 
anticancer treatment is started.  All SAEs will be 
reported on the Adverse Event CRF.”
Updated to clarify 
collection timeframe for 
SAEs and ECIs (see 
revised ECI definition 
Section 9.5.4.3.2) 

Section 9.5.1.6.1

Section 9.5.4.1
Deleted text regarding definition of Events of 
Clinical Interest; 
Deleted the protocol version 1.0, Table 7 (and 
renumber subsequent remaining tables); 
Deleted protocol version 1.0, Appendix 8 
(“Pembrolizumab Events of Clinical Interest 
Guidance”) 
Merck notified Eisai that 
the ECI guidance 
document has been retired.

Section 9.5.1.6.2
Laboratory Measurements:  
Text added to better define sample collection 
windows for all visits
Clarification of blood draw 
(hematology, chemistries) 
and urinalysis windows for 
C1D1 and all subsequent 
visits

Section 9.5.1.6.3

Schedule of 
Procedures/ 
Assessments

Table 7


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Change
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Various text additions and revisions to Schedule of 
Procedures/Assessments (added ECG assessments 
at C1D1 and C1D8; revised footnote ‘d’; revised 
footnote ‘f’)
Revisions made to keep 
consistency with text 
changes in protocol body.
Footnote ‘d’ revised to 
clarify that subjects may 
need repeat pregnancy test 
at Baseline (to be 
consistent with Exclusion 
Criteria #11

Schedule of 
Procedures/
Assessments 
(Footnotes ‘d’ and
‘f”)
Changed text to “Any pregnancy in which the 
estimated date of conception is either before the 
last visit or within 120 days of last study treatment 
or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever 
is earlier, must be reported.  Also, any exposure to 
study drug through breastfeeding during study 
treatment or within 120 days of last study 
treatment or 30 days following last study treatment 
if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported.”
Clarification of reporting 
timeframes for pregnancy 
to remain consistent with 
the latest pembrolizumab 
protocol template provided 
by Merck 
(“Pembrolizumab Text for 
Eisai PN150 
06-Jun-2016”).

Section 9.5.4.2
Revised text for section describing reporting of
AEs associated with study drug overdose, misuse, 
abuse, or medication error.
Eisai protocol template 
standard language included 
to emphasize that overdose 
will not be captured as an 
AE.  Instead, AEs 
associated with drug 
overdose, misuse, abuse, 
and medication error will 
be captured as an AE and 
also reported using SAE 
reporting procedures.
Also, the definition of 
pembrolizumab overdose 
was updated in  latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 
06-Jun-2016”).

Section 9.5.4.3.1
Text revised to indicate that certain liver function 
test values (ALT, AST, total bilirubin, and alkaline 
phosphatase) will remain as the only Events of 
Clinical Interest for the trial. 
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 
06-Jun-2016”).

Section 9.5.4.3.2
Text deleted that describes the Data Management 
Plan.
This text considered to be 
unnecessary for the 
protocol and is deleted.

Section 9.6.2
Updated table for Bayesian Stopping Boundaries
In association with 
increased sample size, the 
table in this Appendix is 

Appendix 1 


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Change
Rationale
Affected Protocol Section
expanded to include 
Bayesian stopping 
boundaries for up to 100 
evaluable subjects.
Deleted text “20 mm by chest x ray”
Although this is standard 
RECIST per the paper it is 
not acceptable to follow 
chest lesions by x-ray 
alone and any chest 
imaging must be computed 
tomography.  The only 
acceptable use of x-ray is 
for the detection of a new 
lesion.  Therefore, text was 
removed.

Appendix 3
Changed to “For this study, similar to that allowed 
for RECIST 1.1, irRECIST allows the site to select 
up to 5 target lesions at baseline, 2 per organ …”  
Changed to “Identify up to 5 lesions, not more 
than 2 from 1 organ system…”
To clarify that RECIST 1.1 
criteria for allowed number 
of target lesions will be 
followed throughout the 
study.  

Appendix 4
Title and contents of protocol version 1.0, 
Appendix 8 (“Pembrolizumab Events of Clinical 
Interest Guidance”) changed to “Breast Cancer 
TNM Staging System” 
Disease stage is being 
collected (Demographics 
and Other Baseline 
Characteristics) during this 
study, therefore Screening 
Assessments is revised to 
reflect this requirement and 
new Appendix 8 (Breast 
Cancer TNM Staging 
System) is provided in the 
protocol for reference.

Appendix 8 

Section 9.5.1.2

Schedule of 
Procedures/ 
Assessments

Section 9.7.1.4
Revisions to Amendment 01 of the Protocol
Date: 03 Aug 2016
Change
Rationale
Affected Protocol 
Section
Number of study sites increased from 10 to 25.  
Will help to ensure that 
protocol-specified sample 
size is achieved within 
study timelines

Clinical Protocol 
synopsis

Section 6

Section 9.3
Revised the term “chemotherapy” to “systemic 
anticancer therapy” in several sections and defined 
further in Study Design and Inclusion Criteria #2.
To provide principle 
investigators clarity for 
determining eligibility 
based on the number of 
lines of therapy used by the 
subject prior to Screening.

Clinical Protocol 
Synopsis

Section 7.1

Section 8.1 

Section 9.1

Section 9.3 


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Change
Rationale
Affected Protocol 
Section

Section 9.3.1

Section 9.4.3
Revised the study sample size (including evaluable 
number of subjects) and strata allocation.
There is clinical interest to 
have a more precise 
estimation of the response 
rate for Stratum 2.  
Therefore, the sample size 
was increased, allowing for 
additional Stratum 2
enrollment, and thus 
increase the statistical 
power for this cohort of 
subjects. Other numbers 
related to change of sample 
size (eg, number of 
evaluable subjects) are also 
updated.

Clinical Protocol 
Synopsis

Section 9.1

Section 9.3

Section 9.4.3

Section 9.7.1.6.1

Section 9.7.2
Inclusion Criteria #2
Changed to:
“Metastatic triple-negative breast cancer 
(confirmed from most recent tissue sample) 
meeting the following criteria:
a.  Estrogen receptor (ER) and progesterone 
receptor (a tumor is ER and/or progesterone 
receptor positive if at least 1% of the cells 
examined have estrogen and/or progesterone 
receptors) and human epidermal growth factor 
receptor 2 (HER2)-negative (defined as 
immunohistochemistry [IHC] <2+ or fluorescence 
in situ hybridization [FISH] negative).
b.  Previously treated with 0 to 2 lines of systemic 
anticancer therapy (cytotoxic or targeted 
anticancer agents) in the metastatic setting.  
Hormonal therapy and bone metastases treatment 
(eg, bisphosphonates, denosumab, etc) are not 
considered forms of systemic anticancer therapy.”
Provides additional 
clarification for sites with 
respect to:
a. The cut-off for ER/PR 
receptor positive.
b.  Determination of 
eligibility based on the 
number of lines and types 
of therapy used by subject 
prior to Screening.  

Clinical Protocol 
synopsis

Section 9.3.1
Exclusion Criteria #2
Changed to “Active autoimmune disease that has 
required systemic treatment in the past 2 years (ie, 
with use of disease modifying agents, 
corticosteroids, or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc) is not 
considered a form of systemic treatment.”
Revised to remain 
consistent with the latest 
pembrolizumab template 
provided by Merck 
(“Pembrolizumab Text 
for”) Eisai PN150 06-Jun-
2016

Clinical Protocol 
synopsis

Section 9.3.2
Exclusion Criteria #4
Changed to “Current enrollment in another 
interventional clinical study…”
Clarification that the 
intention is to exclude 
those on interventional 

Clinical Protocol 
synopsis

Section 9.3.2


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Change
Rationale
Affected Protocol 
Section
studies (not observational, 
long term follow-up 
studies).
Exclusion Criteria #15
Changed to “Scheduled for major surgery during 
the study.”
Updated to simplify and 
clarify.

Clinical Protocol 
synopsis

Section 9.3.2
Exclusion Criteria #17
Changed to “Has a history of (non-infectious) 
pneumonitis that required steroids or current 
pneumonitis.”
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 06-
Jun-2016

Clinical Protocol 
synopsis

Section 9.3.2
Exclusion Criteria #20
Changed to “Has received a live-virus vaccination 
within 30 days of planned start of study therapy. 
Seasonal flu vaccines that do not contain live virus 
are permitted.”
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 06-
Jun-2016

Clinical Protocol 
synopsis

Section 9.3.2
Added text that tumor assessments are to be 
performed every 9 weeks ±1 week after the start of 
study treatment (or sooner if there is evidence of 
progressive disease).
Clarification of text 
describing timing of tumor 
assessments if there is 
evidence of progressive 
disease.

Clinical Protocol 
synopsis

Section 9.5.1.4.1

Schedule of 
Procedures/ 
Assessments
ECG assessments (both before and after eribulin 
infusion) at Baseline/C1D1 and C1D8 have been 
included in the safety assessments.
One Screen Visit 
determination for ECG 
may be insufficient in 
order to confirm the safety 
profile or detect any safety 
alert (eg, QTc 
prolongation) of the 
eribulin plus 
pembrolizumab 
combination.

Clinical Protocol 
synopsis

Section 9.5.1.6.6

Schedule of 
Procedures/ 
Assessments
Revised definition for the Evaluable Analysis Set
Using the modified 
evaluable analysis set will 
more accurately estimate 
the primary efficacy 
endpoint (ORR).

Clinical Protocol 
synopsis

Section 9.7.1.2
Updated description of clinical experience with 
Pembrolizumab
Revised to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for” Eisai PN150 06-

Section 7.1.3.2


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Change
Rationale
Affected Protocol 
Section
Jun-2016).
Text revised that describes reasons for 
discontinuation from the study.
The eCRF does not collect 
“primary” and “secondary” 
reasons for 
discontinuation.
Unnecessary to name 
eCRF form being used to 
collect study disposition, 
so such text is deleted.

Section 9.3.3

Section 9.5.5
Added text to clarify exactly when study drugs 
should be initially administered, and added text to 
provide guidance for correction of hypokalemia 
and/or hypomagnesemia prior to first dose of 
eribulin.
To provide clarification for 
when to administer first 
dose of study drugs; 
To provide guidance that is 
consistent with the eribulin 
mesylate Package Insert 
regarding correction of 
hypokalemia and 
hypomagnesemia prior to 
initiation of eribulin.

Section 9.4.1
Added text “Note: If institutional guidelines 
require BSA recalculation starting at 5% or more 
weight change, this will be acceptable.”
Text added to allow sites 
more flexibility and 
consistency with their 
institutional guidelines.

Section 9.4.1
Changed text associated with guidance for study 
drug administration (eg, timing and  treatment 
windows clarified)
Clarification provided to 
ensure that study drug 
treatment guidelines are 
strictly followed.

Section 9.4.1

Section 9.4.5

Schedule of 
Procedures/ 
Assessments
Text and table amended for eribulin dose delays 
and modifications.
Eribulin dose delays and 
modifications revised to be 
more consistent with
Package Insert guidance.

Section 9.4.1.1

Table 3
Updated Dose Modification Guideline for 
Pembrolizumab-Related Adverse Events
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 06-
Jun-2016

Section 9.4.1.2

Table 4
Included new text for supportive care guidelines 
with respect to the use of corticosteroids and 
revised specific text regarding rescue medications 
for treatment of pembrolizumab-related toxicities.
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 06-
Jun-2016

Section 9.4.6.1


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Change
Rationale
Affected Protocol 
Section
Added text “Treatment with bisphosphonates 
and/or denosumab will be allowed for subjects 
with bone metastases.”
Text added to provide 
guidance to sites regarding 
allowed  concomitant 
medications for subjects 
with bone metastases

Section 9.4.6
Prohibited Concomitant Therapies and Drugs:
Changed to “Systemic glucocorticosteroids for any 
purpose other than to modulate symptoms of 
suspected immunologic etiology” 
Changed to “For subjects who, in the assessment 
by the investigator, require the use of any of the 
aforementioned treatments for clinical 
management, continuation of the study medication 
and further participation in the study must be 
discussed and agreed upon with the sponsor.”
Text revised to provide 
clarification for use of 
corticosteroids in any 
instance of suspected 
immunologic etiology.
Text revised to provide 
more specific guidance 
with regard to continuation 
of study medication under 
circumstances that require 
use of prohibited 
concomitant medications.

Section 9.4.6.3
Text revised and/or added regarding the return of 
or destruction of unused study medication 
Original text was not 
consistent with the Eisai 
protocol template language 
and is now revised.

Section 9.4.8
Revised text for serum and urine pregnancy testing 
(protocol version 1.0, Table 8 changed to  protocol 
version 2.0, Table 7)
Clarification that 
pregnancy testing is 
allowed using either serum 
or urine β-hCG.

Section 9.5.1.2

Table 7

Schedule of 
Procedures/ 
Assessments
Added new text “SAEs and ECIs will be collected 
for 90 days after the last dose or 30 days following 
the last dose if the subject initiates new anticancer 
therapy, whichever is earlier.  An AE will not be 
reported on the Adverse Event CRF if other 
anticancer treatment is started.  All SAEs will be 
reported on the Adverse Event CRF.”
Updated to clarify 
collection timeframe for 
SAEs and ECIs (see 
revised ECI definition 
Section 9.5.4.3.2) 

Section 9.5.1.6.1

Section 9.5.4.1
Deleted text regarding definition of Events of 
Clinical Interest; 
Deleted the protocol version 1.0, Table 7 (and 
renumber subsequent remaining tables); 
Deleted protocol version 1.0, Appendix 8 
(“Pembrolizumab Events of Clinical Interest 
Guidance”) 
Merck notified Eisai that 
the ECI guidance 
document has been retired.

Section 9.5.1.6.2
Laboratory Measurements:  
Text added to better define sample collection 
windows for all visits.
Clarification of blood draw 
(hematology, chemistries) 
and urinalysis windows for 
C1D1 and all subsequent 
visits

Section 9.5.1.6.3

Schedule of 
Procedures/ 
Assessments

Table 7
Various text additions and revisions to Schedule of 
Revisions made to keep 

Schedule of 


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Change
Rationale
Affected Protocol 
Section
Procedures/Assessments (added ECG assessments 
at C1D1 and C1D8; revised footnote ‘d’; revised 
footnote ‘f’)
consistency with text 
changes in protocol body.
Footnote ‘d’ revised to 
clarify that subjects may 
need repeat pregnancy test 
at Baseline (to be 
consistent with Exclusion 
Criteria #11
Procedures/
Assessments 
(Footnotes ‘d’ and
‘f”)
Changed text to “Any pregnancy in which the 
estimated date of conception is either before the 
last visit or within 120 days of last study treatment 
or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever 
is earlier, must be reported.  Also, any exposure to 
study drug through breastfeeding during study 
treatment or within 120 days of last study 
treatment or 30 days following last study treatment 
if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported.”
Clarification of reporting 
timeframes for pregnancy 
to remain consistent with 
the latest pembrolizumab 
protocol template provided 
by Merck 
(“Pembrolizumab Text for 
Eisai PN150 06-Jun-
2016”).

Section 9.5.4.2
Revised text for section describing reporting of 
AEs associated with study drug overdose, misuse, 
abuse, or medication error.
Eisai protocol template 
standard language included 
to emphasize that overdose 
will not be captured as an 
AE.  Instead, AEs 
associated with drug 
overdose, misuse, abuse, 
and medication error will 
be captured as an AE and 
also reported using SAE 
reporting procedures.
Also, the definition of 
pembrolizumab overdose 
was updated in  latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 
06-Jun-2016”).

Section 9.5.4.3.1
Text revised to indicate that certain liver function 
test values (ALT, AST, total bilirubin, and alkaline 
phosphatase) will remain as the only Events of 
Clinical Interest for the trial. 
Updated to remain 
consistent with the latest 
pembrolizumab protocol 
template provided by 
Merck (“Pembrolizumab 
Text for Eisai PN150 
06-Jun-2016”).

Section 9.5.4.3.2
Text deleted that describes the Data Management 
Plan.
This text considered to be 
unnecessary for the 
protocol and is deleted.

Section 9.6.2


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Change
Rationale
Affected Protocol 
Section
Updated table for Bayesian Stopping Boundaries
In association with 
increased sample size, the 
table in this Appendix is 
expanded to include 
Bayesian stopping 
boundaries for up to 100 
evaluable subjects.

Appendix 1 
Changed confirmatory scans for SD to occur at 
least 8 weeks after initial response. 
The confirmation of 
response for stable disease 
was required at a minimum 
of 5 weeks after initial 
response incorrectly. This 
minimum time period was 
corrected to be 8 weeks 
and is now consistent 
throughout the protocol.

Appendix 3
Deleted text “20 mm by chest x ray”
Although this is standard 
RECIST per the paper it is 
not acceptable to follow 
chest lesions by x-ray 
alone and any chest 
imaging must be computed 
tomography. The only 
acceptable use of x-ray is 
for the detection of a new 
lesion.  Therefore, text was 
removed.

Appendix 3
Changed to “For this study, similar to that allowed 
for RECIST 1.1, irRECIST allows the site to select 
up to 5 target lesions at baseline, 2 per organ …”  
Changed to “Identify up to 5 lesions, not more 
than 2 from 1 organ system…”
To clarify that RECIST 1.1 
criteria for allowed number 
of target lesions will be 
followed throughout the 
study.  

Appendix 4
Title and contents of protocol version 1.0, 
Appendix 8 (“Pembrolizumab Events of Clinical 
Interest Guidance”) changed to “Breast Cancer 
TNM Staging System” 
Disease stage is being 
collected (Demographics 
and Other Baseline 
Characteristics) during this 
study, therefore Screening 
Assessments is revised to 
reflect this requirement and 
new Appendix 8 (Breast 
Cancer TNM Staging 
System) is provided in the 
protocol for reference.

Appendix 8 

Section 9.5.1.2

Schedule of 
Procedures/ 
Assessments

Section 9.7.1.4


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.  E7389, MK-3475
Name of Active Ingredients:  Eribulin mesylate and pembrolizumab
Study Protocol Title
ENHANCE 1: An Open-Label, Single-Arm, Multicenter Phase 1b/2 Study to Evaluate the Efficacy 
and Safety of Eribulin Mesylate in Combination With Pembrolizumab in Subjects With Metastatic 
Triple-Negative Breast Cancer (mTNBC)
Investigators
To be determined
Sites
Approximately 25 study sites in the United States (US)
Study Period and Phase of Development
Phase:  Phase 1b/2
Duration Overall:  Approximately 60 months
Duration by Subject:  Estimated median treatment duration is 6 months, although subjects may 
remain on study treatment as long as the subject demonstrates clinical benefit.  
Study Interval:  The original study enrollment was estimated to begin in August 2015 and end in or 
before February 2017. The study enrollment is being extended with Protocol Amendment 4 to 
recruit a total of at least 100 evaluable subjects in Stratum 2 (approximately 170 total subjects) by 
October 2018.  Based on the current status of subjects ongoing on study as of 
Protocol Amendment 05, the last subject is expected to complete the study by November 2020.
Objectives
Primary Objectives
In subjects with metastatic triple-negative breast cancer (mTNBC) previously treated with 0 
(Stratum1) or 1 to 2 (Stratum 2) lines of systemic anticancer therapy in the metastatic setting and 
currently treated with eribulin mesylate in combination with pembrolizumab:

For the Phase 1b part – to determine safety and tolerability of eribulin mesylate in 
combination with pembrolizumab in all subjects (ie, Stratum 1 and 2).

For the Phase 2 part – to evaluate objective response rate (ORR) per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1) by independent imaging review (IIR) in 
all subjects.

For the Phase 2 part – to evaluate ORR per RECIST 1.1 by IIR in Stratum 2 subjects and 
compare with the historical response rate of pembrolizumab monotherapy of 10%.
Secondary Objectives

For the Phase 2 part, in all subjects and separately in Stratum 2 subjects, to evaluate 
progression-free survival (PFS) per RECIST 1.1 by IIR.

To evaluate overall survival (OS).

To evaluate duration of response (DOR) per RECIST 1.1 by IIR.

To evaluate clinical benefit rate (CBR) per RECIST 1.1 by IIR.


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
To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by
investigator review.

To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by IIR and 
OS outcome by PD-L1 (programmed death receptor-ligand 1) expression.

To evaluate the safety and tolerability of the combination.
Exploratory Objectives

To evaluate time to response (TTR) per RECIST 1.1 by IIR in all subjects and separately in 
Stratum 2 subjects.

To evaluate exposure-response relationship in all subjects.

To explore potential effects of pembrolizumab co-administration on the pharmacokinetics 
(PK) of eribulin mesylate in all subjects.

To explore efficacy outcomes (ORR, PFS, DOR, and CBR) per immune-related RECIST 
1.1 (irRECIST) by IIR and investigator review for all subjects and separately in Stratum 2 
subjects.
Study Design
This is an open-label, single-arm, multicenter, Phase 1b/2 study of eribulin mesylate in 
combination with pembrolizumab in subjects with metastatic triple-negative breast cancer 
previously treated with 0 to 2 lines of systemic anticancer therapy (cytotoxic or targeted anticancer 
agents) in the metastatic setting.  Subjects may have received prior neo/adjuvant chemotherapy.  
The Phase 1b part includes 1 initial safety run-in cohort in which at least 6 subjects will receive 
eribulin mesylate 1.4 mg/m2 intravenously (IV) on Days 1 and 8 of a 21-day cycle and 
pembrolizumab 200 mg IV on Day 1 of a 21-day cycle (Dose Level 1).  Dose-limiting toxicity 
(DLT) will be assessed in the first cycle.  Dose level 1 can be selected as the recommended Phase 2 
dose (RP2D) if no more than 1 subject has a DLT.  Otherwise, eribulin mesylate dose will be 
lowered from 1.4 mg/m2 to 1.1 mg/m2 on Days 1 and 8 of a 21-day cycle (Dose Level 0).  If no 
more than 1 out of 6 subjects at Dose Level 0 has a DLT, the Phase 2 part will proceed with Dose 
Level 0.  Approximately 12 subjects may be enrolled in the Phase 1b part of the study.  
As of Protocol Amendment 05, the RP2D was determined to be eribulin 1.4 mg/m2 IV 
administered on Day 1 and Day 8 of each 21-day cycle with pembrolizumab 200 mg IV 
administered on Day 1 of each 21-day cycle.
Under Protocol Amendment 1, 107 subjects (including subjects in Phase 1b who are on RP2D 
level) were enrolled in 2 strata and received the same combination treatment at the RP2D level.  
The strata include no prior systemic anticancer therapy in the metastatic setting (Stratum 1) and 
previously treated with 1 to 2 lines of systemic anticancer therapy in the metastatic setting 
(Stratum 2). Bayesian predictive probability (PP) of response rate was used to monitor the 
response rate after postbaseline tumor assessments for at least 38 subjects were available.  The 
study could be stopped early for efficacy or futility if PP crosses the prespecified boundary.  
Hence, efficacy conclusion of the primary efficacy endpoint of ORR could be made on the basis of 
the predictive probability prior to the full enrollment of 100 evaluable subjects in the study (see 
Statistical Methods for details). 
There is clinical interest to have a more precise estimation of the efficacy data for Stratum 2.  
Therefore, per Protocol Amendment 3, additional subjects will be added to Stratum 2 in order to 
include a total of 80 evaluable subjects in Stratum 2 for final analysis.  As a result, approximately 
150 subjects in total (145 evaluable with 80 in Stratum 2) will be enrolled. Per Protocol 
Amendment 4, 20 additional subjects will be added to Stratum 2 in order to include a total of at 


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least 100 evaluable subjects in Stratum 2 for final analysis.
Pharmacokinetic (PK) assessments of eribulin mesylate will be performed in all subjects in the 
Phase 1b part of the study.  Subjects in the Phase 2 part will undergo sparse PK sampling for 
population pharmacokinetic/pharmacodynamic (PK/PD) analysis where feasible.
The last subject last assessment is the End of Study, which will be the date of the 
End-of-Treatment visit (or the end of the 90-day follow up for serious adverse events 
[SAEs]/events of clinical interest [ECIs]) for the last subject. As of Protocol Amendment 05, the 
Follow-Up asessments in the Posttreatment Phase will no longer need to be performed.
Number of Subjects
A total of approximately 170 adult female or male subjects previously treated with 0 to 2 lines of 
systemic anticancer therapy in the metastatic setting will be enrolled (including at least 6 subjects 
from the Phase 1b part).  It is estimated that 165 of the 170 subjects will be evaluable for the 
primary analysis.
Inclusion Criteria
1.
Females or males, aged ≥18 years at the time of signing the informed consent form (ICF)
2.
Metastatic triple-negative breast cancer (confirmed from most recent tissue sample)
meeting the following criteria:
a.
Estrogen receptor (ER) and progesterone receptor negative (a tumor is ER and/or 
progesterone receptor positive if at least 1% of the cells examined have estrogen 
and/or progesterone receptors) and human epidermal growth factor receptor 2 
(HER2) -negative (defined as immunohistochemistry [IHC] <2+ or fluorescence in 
situ hybridization [FISH] negative).
b.
Previously treated with 0 to 2 lines of systemic anticancer therapy (cytotoxic or 
targeted anticancer agents) in the metastatic setting.  Hormonal therapy and bone 
metastases treatment (eg, bisphosphonates, denosumab, etc) are not considered 
forms of systemic anticancer therapy.
3.
Presence of measureable disease meeting the following criteria:
a.
At least 1 lesion of ≥10 mm in long axis diameter for nonlymph nodes or ≥15 mm 
in short axis diameter for lymph nodes that is serially measurable according to 
RECIST 1.1 using computerized tomography or magnetic resonance imaging or 
panoramic and close-up color photography. 
b. Lesions that have had radiotherapy must show subsequent radiographic evidence of 
increased size to be deemed a target lesion.
4.
Life expectancy of ≥3 months
5.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
6.
Adequate renal function as evidenced by serum creatinine ≤1.5 mg/dL or calculated
creatinine clearance ≥50 mL/minute according to the Cockcroft and Gault formula
7.
Adequate bone marrow function, defined as:
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L 
b. Hemoglobin (Hb) ≥10.0 g/dL (can be corrected by growth factor or transfusion)
c. Platelet count ≥100 × 109/L 
8.
Adequate liver function, defined as:
a. Total bilirubin ≤1.5 × upper limit of normal (ULN)
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN unless there are bone metastases, in which case 
liver specific alkaline phosphatase must be separated from the total and used to 


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assess the liver function instead of the total alkaline phosphatase. ALT and AST ≤ 
5 × ULN if subject has liver metastases
9.
Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1 severity or 
lower, except for stable sensory neuropathy (≤Grade 2) and alopecia
10. Archived tissue sample or new biopsy sample
11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a 
negative 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.
12. All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
13. Females of childbearing potential must not have had unprotected sexual intercourse within 
30 days before study entry and must agree to use a highly effective method of 
contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as 
condom plus diaphragm with spermicide], a contraceptive implant, a combination oral 
contraceptive (estrogen/progesterone), or have a vasectomized partner with confirmed 
azoospermia) throughout the entire study period and for 120 days after study drug 
discontinuation.  If currently abstinent, the subject must agree to use a double barrier 
method as described above if she becomes sexually active during the study period or for 
120 days after study drug discontinuation.  Females who are using hormonal contraceptives 
must have been on a stable dose of the same hormonal contraceptive product for at least 28 
days before dosing and must continue to use the same contraceptive during the study and 
for 120 days after study drug discontinuation.
14. Males who have had a successful vasectomy (confirmed azoospermia) or they and their 
female partners meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period or for 120 days after study drug 
discontinuation).  No sperm donation is allowed during the study period or for 120 days 
after study drug discontinuation.
15. Willing and able to comply with all aspects of the treatment protocol
16. Provide written informed consent.
Exclusion Criteria
1.
Previous treatment with eribulin mesylate or any anti-PD-1, PD-L1, or PD-L2 agent
2.
Active autoimmune disease that has required systemic treatment in the past 2 years (ie, 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic 
treatment.
3.
Less than 6 months since prior adjuvant chemotherapy
4.
Current enrollment in another interventional clinical study or used any investigational drug 
or device within the past 28 days preceding informed consent  
5.
Treatment with chemotherapy or biological therapy within the previous 3 weeks, radiation 
or small molecule targeted therapy within the previous 2 weeks
6.
Known central nervous system (CNS) disease, except for those subjects with treated brain 


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metastasis who are stable for at least 1 month, having no evidence of progression or 
hemorrhage after treatment and no ongoing requirement for corticosteroids, as ascertained 
by clinical examination and brain imaging (magnetic resonance imaging [MRI] or 
computed tomography [CT]) during the screening period. 
7.
Known history of human immunodeficiency virus (HIV) positive
8.
Known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, HCV RNA detected).
9.
Existing anticancer treatment-related toxicities of Grades ≥2 (except for alopecia and 
Grade 2 sensory neuropathy) according to Common Terminology Criteria for Adverse 
Events (CTCAE v4.03)
10. Any other malignancy that required treatment or has shown evidence of recurrence (except 
for nonmelanoma skin cancer, or histologically confirmed complete excision of carcinoma 
in situ) during the 5 years prior to enrollment in this study 
11. History of significant cardiovascular disease, defined as:
a.
congestive heart failure greater than New York Heart Association (NYHA) 
Class II according to the NYHA Functional Classification
b.
unstable angina or myocardial infarction within 6 months of enrollment
c.
serious cardiac arrhythmia
12. Clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline 
prolonged QT/QTc ([QT interval/corrected QT interval], eg, a repeated demonstration of a 
QTc interval >500 ms)
13. History of concomitant medical conditions or infectious diseases that, in the opinion of the
investigator, would compromise the subject’s ability to safely complete the study
14. Hypersensitivity to the active substance or any other excipients of the eribulin mesylate
drug product, or severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients
15. Scheduled for major surgery during the study
16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment.  The 
use of physiologic doses of corticosteroids may be approved after consultation with the 
sponsor.
17. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
18. Has a history of interstitial lung disease
19. Has an active infection requiring systemic therapy
20. Has received a live-virus vaccination within 30 days of planned start of study therapy.  
Seasonal flu vaccines that do not contain live virus are permitted.
21. The investigator’s belief that the subject is medically unfit to receive eribulin mesylate and 
pembrolizumab or unsuitable for any other reason
Study Treatments
Investigational drugs:  Combination doses will be investigated in 1 cohort.  Eribulin mesylate 
1.4 mg/m2 via IV injection over 2 to 5 minutes administered on Day 1 and Day 8 and 
pembrolizumab 200 mg via IV infusion over 30 minutes administered on Day 1 (21-day cycle).  
Alternative doses may be explored to identify the RP2D prior to the start of the Phase 2 part if 
necessary.  The eribulin mesylate dose may be reduced/ delayed; the pembrolizumab dose may be 


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delayed per protocol in the event of toxicity.  
Comparator Drug:  Not applicable.
Dose Delays and Modifications: Dose delays and modifications for toxicities associated with 
eribulin mesylate and pembrolizumab are described in detail in Section 9.4.1.1 and Section 9.4.1.2, 
respectively.  
Duration of Treatment
Subjects will be treated with eribulin mesylate and pembrolizumab and can remain on one or both 
study drugs in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, or 
disease progression occurs, or until the subject withdraws consent.
For subjects experiencing prolonged clinical benefit, temporary interruption (up to 3 months) of 
study treatment may be permitted after discussion with the treating physician and the sponsor.  
After such interruption, investigators are strongly encouraged to rescan the subject to rule out 
interim progression of disease.
Subjects can receive up to 35 treatments (approximately 2 years) with pembrolizumab. During that 
time, subjects may continue until disease progression, unacceptable toxicity, withdrawal of 
consent, physician's decision to stop therapy for the subject, or sponsor’s decision to terminate the 
study. 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 8 cycles (24 weeks) with pembrolizumab and had at least 
2 treatments with pembrolizumab beyond the date when the initial CR was declared.
After the last subject has completed 35 cycles of pembrolizumab or has discontinued 
pembrolizumab for other reasons, all ongoing subjects will be transitioned off study.  Subjects still 
receiving eribulin monotherapy at this time may continue to receive eribulin treatment off study 
through their pharmacy (if commercially available for that individual subject) or through a patient 
assistance program administered by the sponsor.  Subjects will continue to receive eribulin 
investigational product and will continue to be assessed according to the Schedule of 
Procedures/Assessments until they complete the End-of-Treatment visit, prior to their transition to 
commercial eribulin or an access program. 
Concomitant Drug/Therapy
Permitted therapy:  includes but is not limited to granulocyte colony-stimulating factor (G-CSF).
Excluded therapy:  includes other investigational drugs/devices.  
Rescue Medications for pembrolizumab and management of infusion reactions associated with the 
use of pembrolizumab are described in detail in Section 9.4.6 (Prior and Concomitant Therapy).  
Assessments
Definition of Dose-Limiting Toxicity:
A DLT is defined as one of the following toxicities occurring during the DLT assessment window 
and considered by the investigator to be related to either of the study drugs.
Hematologic Toxicities:

Any Grade 4 thrombocytopenia or neutropenia lasting >7 days
Nonhematologic Toxicities:

Episcleritis, uveitis, or iritis of Grade 2 or higher 

Any Grade 4 toxicity

Any Grade 3 toxicity EXCLUDING:


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o
Nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours
o
Grade 3 rash in the absence of desquamation, no mucosal involvement, does not 
require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab.
o
Transient Grade 3 AST or ALT elevation, defined as no more than 3 days with or 
without steroid use

Discontinuation or delay of more than 2 weeks of either study drug due to treatment-
related AE will be considered as a DLT
All subjects enrolled in Phase 1b will be assessed for DLTs during a DLT assessment window of 
the first cycle of 21 days.  Subjects who discontinue study treatment prior to completing the DLT 
assessment window for any reason other than a DLT will be replaced.
Efficacy
Tumor assessment will be performed by the investigator based on both RECIST 1.1 and irRECIST.  
Copies of all tumor assessment scans will be sent to an imaging core laboratory designated by the 
sponsor for independent review of efficacy assessment.  Note:  As of Protocol Amendment 05,
tumor assessment scans will no longer be sent to an independent imaging core laboratory.  Detailed 
methodology for assessment by independent review will be provided in an Independent Imaging 
Review Charter.  Tumor assessments are to be performed every 9 weeks ± 1 week after the start of 
study treatment (or sooner if there is evidence of progressive disease) using consistent imaging 
methodology (ie, computed tomography [CT] scan/magnetic resonance imaging [MRI] or bone 
scan and consistent use or nonuse of contrast media).  In subjects who discontinue study therapy 
without documented disease progression, every effort should be made to continue monitoring their 
disease status by radiologic imaging every 9 weeks ± 1 week during Year 1, and every 9 to 12 
weeks ± 1 week thereafter according to standard of care, until (1) the start of new anticancer 
treatment, (2) disease progression (3) death, or (4) the end of the study, whichever occurs first. In 
addition, overall survival (OS) status (disposition) will be assessed throughout the study.  
Treatment After Initial Radiologic Progression
Pembrolizumab, like other immunotherapeutic agents, may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with such
an approach may extend beyond the typical time course of image responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
For any subject who showed first radiologic evidence of progressive disease (PD) and is deemed 
clinically stable, it is at the discretion of the investigator to continue treating the subject until 
progression is confirmed at least 4 weeks from the date of the first radiologic evidence of PD.  If 
progression is confirmed, the subject will be discontinued from study treatment.  Otherwise, the 
subject will continue treatment and radiographic scans.  Any subject who had initial radiologic 
progression and is deemed clinically unstable should be discontinued from both study drugs and no 
subsequent scan for confirmation is required.  
Safety:
Safety and tolerability will be evaluated by the following assessments:  
•
Adverse events (AEs), serious adverse events (SAEs), drug-related AEs, AEs leading to 
discontinuation, drug-related AEs leading to discontinuation reported by the investigator 
(coded according to the current version of the Medical Dictionary for Regulatory Activities 
[MedDRA], graded according to the National Cancer Institute [NCI] CTCAE Grades 0 to 
5), and collected throughout the study.  All AEs must be followed for 30 days after the 


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subject’s last dose, or until resolution, or the start of new anticancer therapy, whichever 
comes first.  SAEs and must be followed for 90 days and events of clinical interest (ECIs) 
must be followed for 30 days (see Section 9.5.1.6.2) after the subject’s last dose of study 
drug or, if the subject initiates new anticancer therapy, for 30 days following the last dose, 
whichever is earlier. All SAEs and ECIs should be followed to resolution or, if resolution 
is unlikely, to stabilization. 
•
Laboratory safety tests, which should be reviewed prior to pembrolizumab and eribulin 
mesylate administration.  Hematology will be assessed on Days 1 and 8 of every cycle,
serum chemistry will be assessed on Day 1 of every cycle, and urinalysis will be assessed 
on Day 1 at Cycles 2 and 4.
•
An electrocardiogram (ECG) performed at screening, and on Day 1 and Day 8 of Cycle 1.
•
Physical examinations (symptom-directed) performed throughout study.
•
Vital signs performed throughout study.
•
ECOG PS (assessed every cycle)
The schedule of efficacy and safety assessments performed in the study is presented in Table 8,
Schedule of Procedures/Assessments.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Bioanalytical Methods
Plasma concentrations of eribulin mesylate will be determined using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) method.
Statistical Methods
RECIST 1.1 criteria will be used in the evaluation of tumor status for the primary, secondary and 
exploratory endpoints, irRECIST criteria will be used in the evaluation of tumor status for the 
exploratory endpoints. Tumor response data obtained per RECIST 1.1 by IIR will be utilized in the 
main analysis of ORR, PFS and DOR. In addition, tumor assessment data assessed per RECIST1.1 
by investigator review and per irRECIST by IIR and investigator review will be considered as 
secondary or exploratory. 
Study Endpoints
Primary Efficacy Endpoint

Objective Response Rate (ORR) – defined as the proportion of subjects who had BOR of 
CR or partial response (PR).
Secondary Efficacy Endpoints

Progression-Free Survival (PFS) – defined as the time from date of first dose of study drug 
to date of first documentation of disease progression or death, whichever occurs first

Overall Survival (OS) – defined as the time from the date of first dose of study drug until 
date of death from any cause

Duration of Response (DOR) – defined as the time from the date that a confirmed objective 
response is first documented to the date of PD or death due to any cause for those subjects 
with a confirmed PR or CR.   

Clinical Benefit Rate (CBR)– defined as the proportion of subjects who had BOR of CR, 
PR, or durable stable disease (SD) (≥24 weeks) 

Estimates of ORR, PFS, OS, DOR and CBR in the PD-L1 Positive Set.
Exploratory Efficacy Endpoints

Time to response (TTR) - defined as the time from the date of first dose of study drug to 


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the first documented CR or PR for those subjects with a confirmed PR or CR.  

ORR, PFS, DOR, and CBR using irRECIST
All above endpoints based on tumor measurement will be assessed according to RECIST 1.1, 
unless otherwise specified.
Analysis Sets

The DLT Evaluable Set includes subjects who complete the first treatment cycle (ie, take at 
least 2 doses of eribulin mesylate with no more than 1 dose reduction and at least 1 dose of 
pembrolizumab) and have sufficient safety evaluation.  Subjects who had a DLT event will 
be considered evaluable for the dose-limiting toxicity as well.  It is the analysis set for DLT 
evaluation in the Phase 1b part of the study.

The Full Analysis Set (Safety Analysis Set) includes all subjects who received any amount 
of either study drug.  This is the analysis set for safety analyses and analysis of PFS and
OS.  

The Evaluable Analysis Set (subset of Full Analysis Set) includes all subjects who have 
both an evaluable baseline tumor assessment and an evaluable postbaseline tumor 
assessment, unless discontinued early or death.  It is the analysis set for efficacy analyses. 

The PD-L1 Positive Set (subset of Evaluable Analysis Set) includes evaluable subjects 
whose PD-L1 expression level is above the threshold that is to be specified prior to the 
final analysis.  Key primary and secondary efficacy endpoints (ie, ORR, PFS, OS, DOR
and CBR) will be summarized in this analysis set.
Efficacy Analyses
Primary Efficacy
Approximately 165 evaluable subjects on RP2D will be enrolled in the study, including phase 1b 
and 2.
Bayesian Predictive Probability (PP) design was used in original study design. Under original 
design, in the combined Stratum 1 and 2 subjects, the ORR value per RECIST 1.1 by IIR was 
assumed to be 0.20 for the historical control based on the recent studies (Table 1). The ORR in this 
study is estimated to be 0.35. Under protocol amendment 1, approximately 100 evaluable subjects 
were expected to be enrolled, Bayesian PP was used to monitor the response rate after postbaseline 
tumor assessments of at least 38 subjects were available.  Tumor response data per RECIST 1.1 by 
investigator review were used for continuous monitoring. The calculation of PP is based on the 
goal of claiming superiority of the combination at the end of the study if
                                  P(p>0.2|data)≥0.95    (1)
where p was the response rate of the combination, 0.2 was the response rate of historical control, 
based on single-agent pembrolizumab and eribulin mesylate in recent studies; 0.95 was the 
prespecified target probability (θT) and P(p>0.2|data) was the posterior probability.  On the basis of 
the accumulated data thus far in the study, the probabilities of all possible future outcomes that lead 
to equation (1) at the end of the study would be added in order to obtain the predictive probability. 
Therefore, early decision of study termination prior to reaching approximately 100 evaluable 
subjects was possible for claiming the combination is promising when PP is above a prespecified 
upper threshold (θU) or for claiming futility when PP is below a prespecified lower threshold (θL).  
The upper and lower cutoff probabilities for decision making, θU and θL, were set as 0.99 and 
0.025. Under the predictive monitoring, the study proceeded as follows:
If PP> θU(=0.99), stop the study and claim the combination promising
If PP< θL(=0.025), stop the study and claim the combination not promising


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Otherwise, continue the study until the number of evaluable subjects reaches to 100
See Section 9.7.1.6.1 for more details of the Bayesian stopping boundaries. After completion of 
enrollment under protocol amendment 1, Bayesian PP is no longer used for continuous monitoring
of efficacy and futility as the study will not be stopped early for either efficacy or futility. 
Under protocol amendment 3, in Stratum 2 subjects, the hypotheses for ORR per RECIST by IIR
are updated to be H0: ORR=0.10 vs. Ha: ORR=0.25, based on the most recent pembrolizumab 
monotherapy KN086 study (Table 1). Therefore, additional subjects will be enrolled to ensure 80 
evaluable subjects in Stratum 2 to provide >90% power for the comparison of H0: ORR=0.10 vs. 
Ha: ORR=0.25 at 1-sided alpha value of 0.025 using a binomial exact test. Under protocol 
amendment 4, additional subjects will be enrolled to ensure at least 100 evaluable subjects are 
enrolled in Stratum 2 to obtain a more precise estimate of ORR. 
Final Analysis
In all evaluable subjects (i.e., Stratum 1 and 2), Bayesian Posterior probability in equation (1) will 
be evaluated to determine the efficacy after the tumor response status has been collected from the 
last evaluable subjects. That is, to claim efficacy if P (p>0.2|data) ≥0.95. A 2-sided 95% credible 
interval of objective response rate in the evaluable subjects will be constructed to aid the 
interpretation of the results Details of predictive and posterior probabilities calculation will be 
provided in the Statistical Analysis Plan (SAP). 
In the evaluable Stratum 2 subjects, a binomial exact test will be used to test the estimated ORR 
versus a historical response rate of 10% at 1-sided alpha value of 0.025. 
Subjects in the Phase 1b part who were treated at the RP2D and were deemed evaluable will be 
combined with Phase 2 subjects in the efficacy analysis. 
Secondary Efficacy
PFS, OS, and DOR
Progression-free survival (PFS), OS, and DOR will be analyzed using Kaplan-Meier product-limit 
estimates.  Median PFS and OS and the cumulative probability of PFS, OS, and DOR at 6 and 
12 months will be presented with 2-sided 95% confidence intervals (CIs) if estimable.  Censoring 
rules for PFS and DOR will be provided in the SAP.
The cumulative PFS, OS, and DOR will be plotted over time.  The median and first and third 
quartiles from Kaplan–Meier estimation for PFS, OS, and DOR will be provided with 95% CIs if 
estimable. 
Clinical Benefit Rate
A 2-sided Clopper–Pearson 95% CI will be constructed for calculating exact binomial intervals. 
Exploratory Efficacy
In addition to RECIST1.1, tumor assessment data (ie, ORR, PFS, DOR, and CBR) will be assessed 
using irRECIST in the sensitivity analysis.  
The analysis of time to response (TTR) will follow the analysis of PFS.  The analysis will be 
performed in the subjects with confirmed PR/CR per RECIST1.1 by IIR.  
All efficacy analyses will be performed in all subjects and separately for each stratum.
Efficacy outcomes will be further evaluated in the PD-L1 Positive Set after a cutoff point is 
determined with external data.  The clinical utility of PD-L1 as a predictive marker in mTNBC 
subjects who receive eribulin mesylate and pembrolizumab combination treatment will be assessed. 
In addition to RECIST1.1, tumor assessment data (ie, ORR, PFS, DOR, and CBR) will be assessed 


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using irRECIST in the sensitivity analysis.  
Safety Analyses
RP2D and DLT
The Phase 1b study will include at least 1 safety run-in cohort in which 6 metastatic triple-negative 
breast cancer (mTNBC) subjects who receive eribulin mesylate 1.4 mg/m2 on Days 1 and 8 and 
pembrolizumab 200 mg on Day 1 of a 21-day cycle (Dose Level 1).  Subjects will be observed for 
dose-limiting toxicity (DLT) in the first cycle.  The purpose of the safety run-in cohort(s) is to 
study safety of the 2-drug combination.  The Phase 2 part will proceed with Dose Level 1 when no 
more than 1 subject has a DLT.  Otherwise, a lower eribulin mesylate dose of 1.1 mg/m2 and 
pembrolizumab 200 mg will be evaluated in another cohort of 6 subjects.  If no more than 1 subject 
has a DLT in the first cycle, the Phase 2 part will proceed with Dose Level 0 as the RP2D.  
Otherwise, alternative doses (eribulin mesylate 0.7 mg/m2) will be explored prior to the start of the 
Phase 2 part.
The DLT rate will be summarized descriptively at each combination dose level. Subsequent DLTs
will be reported and summarized as well.
Adverse Events
The incidence of treatment-emergent adverse events throughout the study (graded according to 
NCI CTCAE 4.03) will be coded according to MedDRA and descriptively summarized overall, by 
grade, seriousness, action taken on study drug (including discontinuation and dose modification), 
and outcome for the Full Analysis Set (Safety Analysis Set).  
General Safety

Hematology, serum chemistry and qualitative urinalysis laboratory analyses will be 
summarized descriptively for observed values, by grade, and by change from Baseline by 
cycle.  

Vital sign variables (body temperature, heart rate, blood pressure, and body weight) will be 
summarized descriptively for observed values, by grade, and change from Baseline.  

Physical examination results determined by the investigator to be clinically significant will 
be reported as an adverse event

ECOG performance status will be summarized descriptively for observed values, by grade, 
and by change from Baseline.  
Interim Analyses
Under Protocol Amendment 1, interim decisions could be made based on the expected response 
rate at the end of the study, which compromises the current information with the future sample size 
via predictive probability approach.  The Bayesian design can continuously update the predictive 
probability of the study outcome, such that early termination of a study was possible for either 
superiority or futility.  One interim analysis was performed after the first 39 enrolled subjects 
completed at least 2 post-baseline tumor assessments or discontinued due to PD or death.
Under Protocol Amendment 3, Bayesian PP continuous monitoring will not be applied.
Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetics
Plasma concentrations of eribulin mesylate will be analyzed to determine PK parameters including 
maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), clearance 
(CL), area under the concentration-time curve (AUC), and terminal elimination phase half-life (t½).
These PK parameters will be calculated at a minimum and additional parameters will be calculated 


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if the data allow. 
Pharmacokinetic–Pharmacodynamic:  Eribulin mesylate PK/PD analysis will be conducted to 
evaluate the relationship between exposure and efficacy and exposure and safety when eribulin 
mesylate is coadministered with pembrolizumab.  Exploratory graphical analysis will be conducted 
for PK/PD evaluations and may be followed by model-based analysis.  Further details will be 
provided in a separate document.
Sample Size Rationale
A total of approximately 170 subjects (at least 165 evaluable with 100 in Stratum 2) will be 
enrolled.
Under Protocol Amendment 1, 107 subjects including at least 6 from the Phase 1b part were 
enrolled in the study.  Enrollment was split into 2 strata, which include first-line (Stratum 1) versus
second- and third-line (Stratum 2) subjects.  Bayesian predictive probability was used to monitor 
the study after response data from the first 38 subjects were available.  Sample size calculation was 
carried out assuming the historical response rate of 0.2.  Using simulation, the model parameters 
(θL=0.025, θU =0.99, and θT=0.95) were calibrated such that the frequentist 1-sided Type I error 
was 0.0326 when the tumor response rate in the combination regimen was 0.2 (under frequentist’s 
null hypothesis H0), and the power was 0.9278 when the response rate was 0.35 (under 
frequentist’s alternative hypothesis Ha).  The expected numbers of subjects needed to reach the 
decisions were 56 and 61 when p=0.2 (under H0) and 0.35 (under Ha), respectively.  A vague beta 
prior distribution for response rate, p, was specified in PP calculation; that is, p~beta (0.2, 0.8).  PP 
was updated for every 3 new subjects in the simulations, which mimics the group sequential 
decision-making in a real study setting.  Without Bayesian interim monitoring, the Type I error was 
estimated as 0.0358, and power was estimated as 0.9418 in demonstrating posterior probability 
P(p>0.2|data) ≥0.95.  Five thousand simulations were run to estimate these design characteristics.
Per Amendment 3, additional subjects will be enrolled to ensure 80 evaluable subjects in Stratum 2.
Using binomial exact test, the power is 0.92 with 80 evaluable subjects to demonstrate statistical 
significance at 1-sided alpha of 0.025 for the assumptions of H0: ORR=0.10 vs. Ha: ORR=0.25.
With 80 subjects, the 95% confidence interval for ORR from binomial distribution will be 
0.160-0.359 if the observed ORR is 0.25. Per Amendment 4, additional subjects will be enrolled to 
ensure 100 evaluable subjects in Stratum 2. With 100 subjects, power will be increased to 98% and 
the 95% confidence interval for ORR from binomial distribution will be 0.169-0.347 if the 
observed ORR is 0.25. 


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................19
3
TABLE OF CONTENTS.............................................................................................31
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................36
5
ETHICS.......................................................................................................................40
5.1
Institutional Review Boards/Independent Ethics Committees.............................40
5.2
Ethical Conduct of the Study..............................................................................40
5.3
Subject Information and Informed Consent ........................................................41
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................42
7
INTRODUCTION.......................................................................................................42
7.1
Indication...........................................................................................................42
7.1.1
Current Therapeutic Options.....................................................................43
7.1.2
Eribulin Mesylate .....................................................................................43
7.1.2.1
Mechanism of Action of Eribulin Mesylate.......................................43
7.1.2.2
Clinical Experience with Eribulin Mesylate ......................................43
7.1.3
Pembrolizumab ........................................................................................44
7.1.3.1
Mechanism of Action of Pembrolizumab..........................................44
7.1.3.2
Pre-clinical and Clinical Experience with Pembrolizumab ................44
7.2
Study Rationale..................................................................................................45
8
STUDY OBJECTIVES................................................................................................47
8.1
Primary Objectives.............................................................................................47
8.2
Secondary Objectives.........................................................................................47
8.3
Exploratory Objectives.......................................................................................48
9
INVESTIGATIONAL PLAN ......................................................................................48
9.1
Overall Study Design and Plan...........................................................................48
9.1.1
Pretreatment Phase ...................................................................................49
9.1.2
Treatment Phase.......................................................................................49
9.1.3
Posttreatment Phase..................................................................................49
9.2
Discussion of Study Design, Including Choice of Control Groups......................50
9.3
Selection of Study Population ............................................................................50
9.3.1
Inclusion Criteria......................................................................................51
9.3.2
Exclusion Criteria.....................................................................................53
9.3.3
Removal of Subjects From Therapy or Assessment ..................................54
9.4
Treatments.........................................................................................................55
9.4.1
Treatments Administered..........................................................................55
9.4.1.1
Eribulin Mesylate Dose Modification During Treatment...................56


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9.4.1.2
Pembrolizumab Dose Modification During Treatment ......................58
9.4.2
Identity of Investigational Products ..........................................................62
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesylate ................62
9.4.2.2
Chemical Name, Structural Formula of Pembrolizumab....................63
9.4.2.3
Comparator Drug..............................................................................63
9.4.2.4
Labeling for Study Drugs..................................................................63
9.4.2.5
Storage Conditions ...........................................................................63
9.4.3
Method of Assigning Subjects to Treatment Groups.................................64
9.4.4
Selection of Doses in the Study ................................................................64
9.4.5
Selection and Timing of Dose for Each Subject........................................64
9.4.6
Prior and Concomitant Therapy................................................................65
9.4.6.1
Treatments for Pembrolizumab-Related Toxicities............................65
9.4.6.2
Drug-Drug Interactions.....................................................................68
9.4.6.3
Prohibited Concomitant Therapies and Drugs ...................................68
9.4.7
Treatment Compliance .............................................................................69
9.4.8
Drug Supplies and Accountability ............................................................69
9.5
Study Assessments.............................................................................................71
9.5.1
Assessments .............................................................................................71
9.5.1.1
Demography.....................................................................................71
9.5.1.2
Pretreatment/Screening Assessments ................................................71
9.5.1.3
Treatment/End of Treatment Assessments ........................................72
9.5.1.4
Efficacy Assessments .......................................................................73
9.5.1.4.1
Tumor Response Assessment......................................................73
9.5.1.4.2
irRECIST After Initial Radiologic Progression............................74
9.5.1.5
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Assessments .....................................................................................76
9.5.1.5.1
Pharmacokinetic Assessments.....................................................76
9.5.1.5.2
Pharmacodynamic Assessments..................................................77
9.5.1.5.3
Other Biomarker Assessments.....................................................77
9.5.1.6
Safety Assessments...........................................................................77
9.5.1.6.1
Adverse Events and Events Associated with Special Situations...77
9.5.1.6.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................79
9.5.1.6.3
Laboratory Measurements...........................................................80
9.5.1.6.4
Vital Signs and Weight Measurements........................................81
9.5.1.6.5
Physical Examinations ................................................................81
9.5.1.6.6
Electrocardiograms .....................................................................82
9.5.1.6.7
Other Safety Assessments ...........................................................82


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9.5.2
Schedule of Procedures/Assessments........................................................82
9.5.2.1
Schedule of Procedures/Assessments................................................83
9.5.2.2
Description of Procedures/Assessments Schedule .............................88
9.5.3
Appropriateness of Measurements............................................................88
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................88
9.5.4.1
Reporting of Serious Adverse Events................................................88
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................89
9.5.4.3
Reporting of Events Associated with Special Situations....................89
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................89
9.5.4.3.2
Reporting of Study-Specific Events/Events of Clinical Interest ...90
9.5.4.4
Expedited Reporting .........................................................................91
9.5.4.5
Breaking the Blind............................................................................91
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................91
9.5.5
Completion/Discontinuation of Subjects...................................................91
9.5.6
Abuse or Diversion of Study Drug............................................................92
9.5.7
Confirmation of Medical Care by Another Physician................................92
9.6
Data Quality Assurance......................................................................................92
9.6.1
Data Collection.........................................................................................92
9.6.2
Clinical Data Management .......................................................................93
9.7
Statistical Methods.............................................................................................93
9.7.1
Statistical and Analytical Plans.................................................................93
9.7.1.1
Study Endpoints................................................................................93
9.7.1.1.1
Primary efficacy Endpoint...........................................................93
9.7.1.1.2
Secondary efficacy Endpoints .....................................................94
9.7.1.1.3
Exploratory efficacy Endpoints...................................................94
9.7.1.2
Definitions of Analysis Sets..............................................................94
9.7.1.3
Subject Disposition...........................................................................95
9.7.1.4
Demographic and Other Baseline Characteristics..............................95
9.7.1.5
Prior and Concomitant Therapy ........................................................95
9.7.1.6
Efficacy Analyses.............................................................................95
9.7.1.6.1
Primary Efficacy Analysis...........................................................95
9.7.1.6.2
Secondary Efficacy Analysis.......................................................97
9.7.1.6.3
Exploratory Efficacy Analysis.....................................................97
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................97


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9.7.1.7.1
Pharmacokinetic Analyses ..........................................................97
9.7.1.7.2
Pharmacodynamic Analyses........................................................98
9.7.1.7.3
Pharmacogenomic and Other Biomarker Analyses......................98
9.7.1.8
Safety Analyses ................................................................................98
9.7.1.8.1
Extent of Exposure......................................................................98
9.7.1.8.2
Adverse Events...........................................................................99
9.7.1.8.3
Laboratory Values.......................................................................99
9.7.1.8.4
Vital Signs ................................................................................100
9.7.1.8.5
ECOG Performance Status........................................................100
9.7.1.8.6
Electrocardiograms ...................................................................100
9.7.2
Determination of Sample Size ................................................................100
9.7.3
Interim Analysis.....................................................................................101
9.7.4
Other Statistical/Analytical Issues ..........................................................101
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................101
10
REFERENCE LIST...................................................................................................102
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....105
11.1
Changes to the Protocol....................................................................................105
11.2
Adherence to the Protocol................................................................................105
11.3
Monitoring Procedures.....................................................................................105
11.4
Recording of Data............................................................................................106
11.5
Identification of Source Data............................................................................106
11.6
Retention of Records........................................................................................107
11.7
Auditing Procedures and Inspection .................................................................107
11.8
Handling of Study Drug ...................................................................................107
11.9
Publication of Results ......................................................................................108
11.10 Disclosure and Confidentiality .........................................................................108
11.11 Discontinuation of Study..................................................................................108
11.12 Subject Insurance and Indemnity......................................................................109
12
APPENDICES...........................................................................................................110
LIST OF IN-TEXT TABLES
Table 1
Efficacies of Eisai Study 305 and Study 301 in mTNBC and 
Pembrolizumab Studies in Advanced TNBC ..........................................46
Table 2
Treatments Administered........................................................................55
Table 3
Eribulin Mesylate Dose Adjustments for Toxicity ..................................57
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated with Pembrolizumab.........................................59


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Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ..............................................................................................66
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease...................................................................................................75
Table 7
Clinical Laboratory Tests........................................................................81
Table 8
Schedule of Procedures/Assessments......................................................84
LIST OF APPENDICES
Appendix 1
Bayesian Stopping Boundaries .............................................................110
Appendix 2
Sponsor’s Grading for Laboratory Values.............................................111
Appendix 3
Overview of RECIST v1.1 for Evaluation of Tumors Response............114
Appendix 4
Immune-related Response Evaluation Criteria in Solid Tumors 
(irRECIST)...........................................................................................115
Appendix 5
New York Heart Association Cardiac Disease Classification ................120
Appendix 6
Common Terminology for Adverse Events (version 4.03) ....................121
Appendix 7
ECOG Performance Status Scale ..........................................................122
Appendix 8
Breast Cancer TNM Staging System.....................................................123


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ß -hCG
beta-human chorionic gonadotropin
BOR
best overall response
BSA
body surface area
CA
Competent Authority
CBR
clinical benefit rate
CFR
Code of Federal Regulations
CL
Clearance
Cmax
maximum plasma concentration
CNS
central nervous system
CPMP
Committee for Proprietary Medicinal Products
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CR
complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
curriculum vitae
CYP
cytochrome-P450
DCR
disease control rate
DDI
drug-drug interaction
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity


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Abbreviation
Term
DOR
duration of response
ECG
Electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
EMT
epithelial mesenchymal transition
ER
estrogen receptor
FDA
US food and drug administration 
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
Hb
Hemoglobin
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HR
hazard ratio
G-CSF
granulocyte colony-stimulating factor
IB
investigator’s brochure
ICF
informed consent form 
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee 
IHC
Immunohistochemistry
irAE
immune-related adverse events
irCR
immune-related complete response
irPD
immune-related progressive disease
IIR
independent imaging review
IRB
Institutional Review Board 
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IV
Intravenous
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LLT
Lower level term
mAb
monoclonal antibody


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Abbreviation
Term
MBC
metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTNBC
metastatic triple-negative breast cancer
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed death receptor-1
PD-L1
programmed death receptor-ligand 1
PET-CT
positron emission tomography-CT
PK
pharmacokinetic 
PK/PD
pharmacokinetic/pharmacodynamic
PFS
progression-free survival
PP
predictive probability
PR
partial response 
PS
performance status
PT
preferred term
Q3W
every 3 weeks
QT/QTc
QT interval/corrected QT interval
RBC
red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumors (version 1.1)
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SOC
system organ class
T4
Thyroxine
t½
terminal elimination phase half-life


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Abbreviation
Term
TEAE
treatment-emergent adverse event
T1DM
Type 1 diabetes mellitus
tmax
time to maximum plasma concentration
TNBC
triple negative breast cancer
TNM
Tumor-Node-Metastases
TPC
Treatment of Physician’s Choice 
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WHO
World Health Organization


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
(Good Clinical Practice [GCP]), Section 3, and Federal Regulations, Title 21 Code of Federal 
Regulations (CFR) Part 56.  Any protocol amendment or revision to the ICF will be 
resubmitted to the IRB/IEC for review and approval, except for changes involving only 
logistical or administrative aspects of the study (eg, change in clinical research associates 
[CRAs], change of telephone number[s]).  Documentation of IRB/IEC compliance with the 
ICH E6 and any local regulations regarding constitution and review conduct will be provided 
to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
the sponsor, depending on local regulatory obligations.  If the investigator is required to 
report to the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic 
report.  The investigator(s) or the sponsor will submit, depending on local regulations, 
periodic reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days. The end of the study will be the date of the data cutoff for the final 
statistical analysis.  The sponsor should also provide the IRB/IEC with a summary of the 
study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:


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
Principles of the World Medical Association Declaration of Helsinki 2013.

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he or she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his or her subsequent medical treatment 
or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and has signed and personally dated the ICF, the witness should sign and personally date the 
consent form.  The subject will be asked to sign an ICF at the Screening Visit before any 
study-specific procedures are performed.  No subject can enter the study before his or her 
informed consent has been obtained.   
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, Federal Regulations, Title 21 CFR Part 50, and any applicable local 
regulations.  Each subject must sign an approved ICF before study participation.  The form 
must be signed and dated by the appropriate parties.  The original, signed ICF for each 
subject will be verified by the sponsor and kept on file according to local procedures at the 
site. Subjects will be asked to sign either a separate ICF for pharmacokinetic (PK)
assessments or provide consent for PK assessments within the main ICF. Subjects may also 
be asked to sign either a separate ICF or provide consent within the main ICF to allow the 
sponsor to request scans of their tumor assessments for central review.  
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 25 investigational sites in the United States (US).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization (CRO) are listed in the Regulatory 
Binder provided to each site.
7
INTRODUCTION
7.1
Indication
This is an open-label, single-arm multicenter Phase 1b/2 study to evaluate the efficacy and 
safety of eribulin mesylate in combination with pembrolizumab in subjects with metastatic 
triple-negative breast cancer (mTNBC) previously treated with 0 to 2 lines of systemic 
anticancer therapy in the metastatic setting.
Eribulin mesylate (HALAVEN®) is a microtubule inhibitor indicated for the treatment of 
patients with metastatic breast cancer who have previously received at least 
2 chemotherapeutic regimens for the treatment of metastatic disease.  Prior therapy should 
have included an anthracycline and a taxane in either the adjuvant or metastatic setting
(HALAVEN package insert). 
Pembrolizumab (KEYTRUDA®) is a potent, humanized immunoglobulin G4 (IgG4) 
monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 
(PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) 
and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (IV) immunotherapy for advanced malignancies. Keytruda®
(pembrolizumab) is indicated for the treatment of patients across a number of indications. 
For more details on specific indications refer to the Investigator’s Brochure.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pembrolizumab is also being investigated for treatment of mTNBC.  Results of “A Phase 1b 
Study of Pembrolizumab in Patients with Advanced Triple-Negative Breast Cancer” 
indicated that it is effective and safe in this population (Nanda, et al., 2014).
This study will evaluate whether this combination results in better efficacy than eribulin 
mesylate or pembrolizumab monotherapy and provides an acceptable safety profile in 
treating the mTNBC patient population.


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7.1.1
Current Therapeutic Options
Triple negative breast cancer (TNBC) is a challenging disease with the poorest prognosis of 
all breast cancer subtypes. Importantly, there are currently no known molecular targets for 
this subgroup. Cytotoxic chemotherapy is the only systemic treatment option for patients 
with mTNBC. To identify a targeted anticancer agent effective against mTNBC in 
combination with chemotherapy is a major unmet need in breast cancer treatment.
7.1.2
Eribulin Mesylate
7.1.2.1
Mechanism of Action of Eribulin Mesylate
Direct Cytotoxicity
Halichondrin B is a large polyether macrolide isolated from the rare marine sponge 
Halichondrin okadai.  It exhibits potent anticancer effects both in vitro and in vivo (Lin, et 
al., 2000; Wang, et al., 1999; Chang, et al., 1999) with a tubulin-based mechanism that 
appears to be distinct from all other antitubulin agents (Lin, et al., 2000; Morse, et al., 2005; 
Rein, et al., 2000). Eribulin mesylate (E7389) is a structurally simplified, synthetic analog of 
this marine natural product that exhibits similar anticancer properties in preclinical models 
(Roninson, et al., 2001) through a tubulin-based antimitotic mechanism similar to that of 
halichondrin B.  It is a nontaxane microtubule dynamics inhibitor that suppresses 
microtubule growth and sequesters tubulin into nonfunctional aggregates, preventing mitotic 
spindle formation with subsequent G2-M arrest and apoptosis.  It exhibited potent anticancer 
effects in preclinical models of various malignancies, including breast cancer (Lin, et al., 
2000; Morse, et al., 2005; Roninson, et al., 2001; Ellis, et al., 1997; Stearns, et al., 2003; 
Arends, et al., 1990). This mechanism of action is distinct from that of other antitubulins, 
such that it may be effective in patients with disease that is resistant to these agents.  In fact, 
eribulin mesylate demonstrated antitumor activity in preclinical studies with cell lines that 
are paclitaxel resistant as a result of beta tubulin mutations (Gauthier, et al., 1996).  The in 
vivo animal model data also predicted that this agent would achieve greater efficacy than the 
taxanes and with fewer adverse effects. 
Effects on Tumor Vascular Remodeling and reversal of EMT in Pre-Clinical Models
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 (Yoshida, et al., 2014; Funahashi, et al., 2014).
7.1.2.2
Clinical Experience with Eribulin Mesylate 
Eribulin mesylate was first approved on 15 Nov 2010 in the US for the treatment of patients 
with metastatic breast cancer (MBC) who have previously received at least 


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2 chemotherapeutic regimens for the treatment of metastatic disease.  Approval has been 
obtained in 54 countries.
Overall, approximately 5457 subjects have been enrolled in clinical studies since the 
Development International Birth Date; approximately 3984 subjects have received eribulin 
mesylate up to the data lock point of 14 May 2014 (HALAVEN® Investigator Brochure).
Of the total of 1349 serious adverse events (SAEs) reported in subjects who received eribulin 
mesylate, 510 were assessed by the investigator as related to eribulin mesylate and 839 were 
reported as unrelated to eribulin mesylate.  The most frequent treatment-related SAEs were 
febrile neutropenia, neutropenia and pyrexia (HALAVEN® Investigator’s Brochure).
In summary, eribulin mesylate provides clinical benefit for the treatment of patients with 
locally recurring breast cancer and MBC previously treated with chemotherapeutic regimens.  
Eribulin mesylate has an acceptable safety profile.  The risk of toxicity with eribulin 
mesylate is comparable or less than that for other agents currently used in this population.  
Proposed precautions and dose adjustments will allow the toxicity of eribulin mesylate to be 
managed appropriately.  Eribulin mesylate is provided as a ready-to-use formulation that is 
easily administered without the need for premedications to prevent hypersensitivity.  It is 
therefore concluded that the benefit-risk ratio of eribulin mesylate continues to be favorable.
7.1.3
Pembrolizumab
7.1.3.1
Mechanism of Action of Pembrolizumab
Immune Restoration
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda® (Pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
Investigator’s Brochure (IB).
Refer to the Investigator’s Brochure/approved labeling for detailed background information 
on MK-3475.
7.1.3.2
Clinical Experience with Pembrolizumab
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy studies
in subjects with non-small cell lung cancer, head and neck squamous cell carcinoma, 
urothelial cancer, gastric cancer, triple negative breast cancer and Hodgkin’s Lymphoma as 
determined by response rate.  Ongoing clinical studies are being conducted in these tumor 
types as well as a number of other advanced solid tumor indications and hematologic 
malignancies.  For study details please refer to the Investigator’s Brochure.


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The most frequent potential immune-mediated adverse reactions reported in patients treated 
with pembrolizumab were hypo/hyperthyroidism, pneumonitis, colitis, hepatitis, nephritis, 
and hypophysitis (KEYTRUDA® Package Insert, Pembrolizumab Investigator’s Brochure).
7.2
Study Rationale
There are currently no known molecular targets for mTNBC and cytotoxic chemotherapy is 
the only systemic treatment option for these patients.
Recent advances in genomics and gene expression profiling have shed new light on the 
significant heterogeneity within TNBC. In particular, the Cancer Genome Atlas RNA 
sequencing data was used (Mittendorf, et al., 2014) to show significantly greater expression 
of the T-cell inhibitory molecule programmed cell death receptor-1 (PD-1) ligand 1 (PD-L1)
gene in TNBC (n = 120) compared with non-TNBC (n = 716; P <0.001). Breast tumor tissue 
microarrays were also evaluated for PD-L1 expression, which was present in 19% (20 of 
105) of TNBC specimens.  
Pembrolizumab, an anti-PD-1 monoclonal antibody that releases antitumor immune response 
blocked by the PD-L1 pathway, is being investigated for mTNBC and a preliminary study 
indicated that it is safe and effective in this population (Nanda, et al., 2014). Preliminary 
result of a Phase 2 study of pembrolizumab monotherapy for previously treated mTNBC also 
showed potential efficacy (Adams, et al., 2017).
Eisai clinical studies (Study 305 and Study 301) showed that eribulin mesylate has better 
efficacy than the Treatment of Physician’s Choice (TPC) and capecitabine, respectively, in 
mTNBC. 
Efficacies of Study 305 and Study 301 in mTNBC, as well as a pembrolizumab studies in 
patients with advanced TNBC, are listed in Table 1.


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Table 1
Efficacies of Eisai Study 305 and Study 301 in 
mTNBC and Pembrolizumab Studies in Advanced 
TNBC
Eisai Study 305
Eisai Study 301
Pembrolizumab
Studya
Pembrolizumab 
KN086 Studyb
Patient 
Population
mTNBC with 2-5 lines of 
prior chemotherapy
mTNBC with 0-2 lines of 
prior chemotherapy
Advanced 
TNBC with ≥0 
line of prior 
chemotherapy
mTNBC with ≥1 
line  of prior 
chemotherapy 
Cohort A
Treatment
Eribulin 
TPC 
Eribulin 
Capecitabine
Pembrolizumab
Pembrolizumab
No. of 
Patients
84
40
150
134
27
170
Median OS 
(days)
288
193
439
285
NA
8.9 months
Median PFS 
(days)
67
57
87
71
57 (1.9 months)
2.0 months
Complete 
Response
0 (0%)
0 (0%)
1 (0.7%)
0 (0%)
1 (3.7%)
0.6%
Partial 
Response
3 (3.6%)
2 (5.0%)
14 (9.3%)
8 (6.0%)
4 (14.8%)
4%
Stable 
Disease
32 (38.1%)
12 (30.0%)
76 (50.7%)
61 (45.5%)
7 (25.9%)
21%
Progressive 
Disease
44 (52.4%)
26 (65.0%)
40 (23.7%)
51 (38.1%)
12 (44.4%)
63%
Not 
Evaluable/  
Unknown
5 (6.0%)
0 (0%)
19 (12.6%)
14 (10.4%)
3 (11.1%)
mTNBC = metastatic triple-negative breast cancer, OS = overall survival, PFS = progression free survival, TNBC = triple 
negative breast cancer, TPC = Treatment of Physician’s Choice.
a: Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R,  et al.  A phase Ib study of pembrolizumab (MK-3475) in 
patients with advanced triple-negative breast cancer.  Presented at 2014 San Antonio Breast Cancer Symposium; 
December 9-13, 2014; San Antonio, Texas.  Abstract S1-09. 
b: Adams S., et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative 
breast cancer mTNBC): KEYNOTE-086 cohort A. (Abstract 1008). Presented at 2017 ASCO Annual Meeting. June 2-6, 
2017. Chicago, Illinois.
Eribulin mesylate and pembrolizumab each have a unique mechanism of action (direct 
cytotoxicity and immune restoration, respectively) and a different safety profile, hence
combination therapy with these 2 agents may provide better antitumor outcomes over that 
seen with either agent alone (Table 1).
In addition to its direct cytotoxicity actions, preclinical data suggest that eribulin mesylate
has significant beneficial effects on tumor vascular remodeling that could potentially result in 
improved tumor blood perfusion.  Therefore, eribulin mesylate may lead to increased 


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pembrolizumab concentrations in tumor tissue and thus indirectly enhance permbrolizumab’s 
antitumor activity in the clinical setting when the 2 drugs are administered simultaneously.  
From a safety perspective, the most frequent SAEs associated with eribulin mesylate
(eg, neutropenia) and most frequent adverse reactions associated with pembrolizumab
(eg, immune-mediated adverse reactions) are not overlapping. Thus, it is not expected that 
these individual toxicities will be exacerbated with combined use of the 2 drugs.
Therefore, this study combining eribulin mesylate and pembrolizumab may provide a new 
systematic treatment option for mTNBC.
8
STUDY OBJECTIVES
8.1
Primary Objectives
The primary objectives for the 2 phases of the study are as follows:
In subjects with metastatic triple-negative breast cancer (mTNBC) previously treated with 0 
(Stratum 1) or 1 to 2 (Stratum 2) lines of systemic anticancer therapy in the metastatic setting 
and currently treated with eribulin mesylate in combination with pembrolizumab:

For the Phase 1b part – to determine the safety and tolerability of eribulin mesylate in 
combination with pembrolizumab in all subjects (ie, Stratum 1 and 2).  

For the Phase 2 part – to evaluate the objective response rate (ORR) per Response
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by independent imaging 
review (IIR) in all subjects.  

For the Phase 2 part – to evaluate ORR per RECIST 1.1 by IIR in Stratum 2 subjects and 
compare with the historical response rate of pembrolizumab monotherapy of 10%.
8.2
Secondary Objectives
The secondary objectives for the study are as follows:

For the Phase 2 part, in all subjects and separately in Stratum 2 subjects, to evaluate 
Progression-Free Survival (PFS) per RECIST 1.1 by IIR

To evaluate overall survival (OS)

To evaluate duration of response (DOR) per RECIST 1.1 by IIR

To evaluate clinical benefit rate (CBR) per RECIST 1.1 by IIR

To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by 
investigator review 

To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by IIR and 
OS outcome by PD-L1 expression.  

To evaluate the safety and tolerability of the combination 


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8.3
Exploratory Objectives
The exploratory objectives for the study are as follows:

To evaluate time to response (TTR) per RECIST 1.1 by IIR in all subjects and separately 
in Stratum 2 subjects

To evaluate exposure-response relationship in all subjects

To explore potential effects of pembrolizumab co-administration on the pharmacokinetics 
(PK) of eribulin mesylate in all subjects

To explore efficacy outcomes (ORR, PFS, DOR, and CBR) per immune-related 
RECIST 1.1 (irRECIST) by IIR and investigator review for all subjects and separately in
Stratum 2 subjects
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open-label, single-arm, multicenter, Phase 1b/2 study of eribulin mesylate in 
combination with pembrolizumab in subjects with metastatic triple-negative breast cancer 
previously treated with 0 to 2 lines of systemic anticancer therapy (cytotoxic or targeted 
anticancer agents) in the metastatic setting.  Subjects may have received prior neo/adjuvant 
chemotherapy.  
The Phase 1b part includes 1 initial safety run-in cohort in which at least 6 subjects (up to a 
maximum of 12) will receive eribulin mesylate 1.4 mg/m2 intravenously (IV) on Days 1 and 
8 of a 21-day cycle and pembrolizumab 200 mg IV on Day 1 of a 21-day cycle (Dose Level 
1).  Dose-limiting toxicity (DLT) will be assessed in the first cycle.  Dose Level 1 can be 
selected as the recommended Phase 2 dose (RP2D) if no more than 1 subject has a DLT.  
Otherwise, the eribulin mesylate dose will be lowered from 1.4 mg/ m2 to 1.1 mg/m2 on Days 
1 and 8 of a 21-day cycle (Dose Level 0).  If no more than 1 out of 6 subjects at Dose Level 0 
has a DLT, the Phase 2 part will proceed with Dose Level 0.  Approximately 12 subjects may 
be enrolled in the Phase 1b part of the study.  
As of Protocol Amendment 05, the RP2D was determined to be eribulin 1.4 mg/m2 IV 
administered on Day 1 and Day 8 of each 21-day cycle with pembrolizumab 200 mg IV 
administered on Day 1 of each 21-day cycle.
Approximately 170 subjects in total (including subjects in Phase 1b who are on RP2D level) 
will be enrolled in 2 strata and receive the same combination treatment at the RP2D level.  
The strata include no prior systemic anticancer therapy in the metastatic setting (Stratum 1) 
and previously treated with 1 to 2 lines of systemic anticancer therapy in the metastatic 
setting (Stratum 2). 
Under Protocol Amendment 1, for the first 100 evaluable subjects enrolled, Bayesian 
predictive probability (PP) of response rate will be used to monitor the response rate after 


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postbaseline tumor assessments for at least 38 subjects are available.  The study could be 
stopped early for efficacy or futility if PP crosses the prespecified boundary.  Hence, efficacy 
conclusion of the primary endpoint ORR could be made on the basis of the predictive 
probability prior to the full enrollment of 100 evaluable subjects in the study (see the
Statistical Methods Section 9.7 for details).
Per Protocol Amendment 3, additional subjects will be added to Stratum 2 in order to include 
a total of 80 evaluable subjects in Stratum 2 for final analysis. Therefore, a total of 
approximately 150 subjects (145 evaluable with 80 in Stratum 2) will be enrolled. 
Per Protocol Amendment 4, 20 additional subjects will be added to Stratum 2 in order to 
include a total of at least 100 evaluable subjects in Stratum 2 for final analysis. Therefore, a 
total of approximately 170 subjects (at least 165 evaluable with 100 in Stratum 2) will be 
enrolled.
Pharmacokinetic assessments of eribulin mesylate will be performed in all subjects in the 
Phase 1b part of the study.  Subjects in the Phase 2 part will undergo sparse PK sampling for 
population PK/pharmacodynamic (PK/PD) analysis where feasible.
The last subject last assessment is the End of Study, which will be the date of the 
End-of-Treatment visit (or the end of the 90-day follow up for serious adverse events 
[SAEs]/events of clinical interest [ECIs]) for the last subject.  As of Protocol Amendment 05, 
Follow-Up asessments in the Posttreatment Phase will no longer need to be performed.
9.1.1
Pretreatment Phase
The Pretreatment Phase consists of the Screening Period, which will occur between Day –21 
and Day –1.  The purpose of the Screening Period is to obtain informed consent and to 
establish protocol eligibility.  Informed consent will be obtained after the study has been 
fully explained to each subject and before the conduct of any screening procedures or 
assessments.  Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.
9.1.2
Treatment Phase
The Treatment Phase of the study will begin with the first dose of study drug administration 
in Cycle 1 and continue in 21-day cycles until completion of the End of Treatment 
assessments (within 30 days after the last study drug administration) or subject 
discontinuation, whichever occurs first.  In the presence of clinical benefit, subjects will 
remain on study treatment until intercurrent illness, unacceptable toxicity or disease 
progression occurs or the subject withdraws consent.  
9.1.3
Posttreatment Phase  
The Posttreatment Phase consists of the End of Treatment Period and the Follow-Up Period.  
The End of Treatment Period will occur within 30 days of the final treatment and consists of 
end of treatment assessments (see Schedule of Procedures/Assessments, Table 8).  Subjects 


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with SAEs and/or ECIs at the time of End of Treatment will be followed for 90 days after the 
last dose of study drug or, if the subject initiates new anticancer therapy, for 30 days 
following the last dose of study drug, whichever is earlier.
The Follow-Up Period will begin immediately after the End of Treatment assessments have 
been completed and will continue as long as the study subject is alive or the study subject 
withdraws consent.  Subjects who discontinue study treatment before disease progression 
will continue to undergo disease assessment every 12 weeks ±1 week until documentation of 
disease progression or start of another anticancer therapy.  Subjects who are being followed 
for survival at the time of data cutoff for the primary analysis (ie, at the end of the Treatment 
Phase) will continue to be followed for survival during the posttreatment Follow-Up Period.
Note: As of Protocol Amendment 05, Follow-Up asessments no longer need to be 
performed.
After the last subject has completed 35 cycles of pembrolizumab, all ongoing subjects will be 
transitioned off study.  Subjects still receiving eribulin monotherapy at this time may
continue to receive eribulin treatment off study through their pharmacy (if commercially 
available for that individual subject) or through a patient assistance program administered by 
the sponsor.  Subjects will continue to receive eribulin investigational product and will be 
assessed according to the Schedule of Procedures/Assessments (Table 8) until they complete 
the End-of-Treatment visit, prior to their transition to commercial eribulin or an access 
program. 
The last subject last assessment is the End of Study, which will be the date of the 
End-of-Treatment visit (or the end of the 90-day follow-up for SAEs/ECIs) for the last 
subject.  
9.2
Discussion of Study Design, Including Choice of Control Groups
This is an open-label study in metastatic breast cancer that will evaluate the combination of 2
drugs with proven anticancer activity to determine whether the agents have improved activity 
with an acceptable toxicity profile.  The study design was adapted from previous studies of 
these agents and may offer a new systematic treatment option for the indication.
The inclusion and exclusion criteria are standard for anticancer studies in the desired 
population and are designed to enroll subjects who can possibly benefit from treatment and at 
the same time limit possible harmful effects both to study subjects and to unborn children 
from unplanned pregnancies. 
The key endpoints are standard for cancer studies. 
9.3
Selection of Study Population
A total of approximately 170 adult female or male subjects previously treated with 0 to 
2 lines of systemic anticancer therapy in the metastatic setting will be enrolled (including at 
least 6 subjects from the Phase 1b part).  It is estimated that 165 (at least 100 in Stratum 2) of 
the 170 subjects will be evaluable for the primary analysis.  Approximately 25 study sites in 


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the United States will enroll subjects for this study.  Subjects who do not meet all of the 
inclusion criteria or who meet any of the exclusion criteria will not be eligible to receive 
study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in the study.
1. Females or males, aged ≥18 years at the time of signing the informed consent form 
(ICF)
2. Metastatic triple-negative breast cancer (confirmed from most recent tissue sample) 
meeting the following criteria:
a.
Estrogen receptor (ER) and progesterone receptor negative (a tumor is ER 
and/or progesterone receptor positive if at least 1% of the cells examined have 
estrogen and/or progesterone receptors) and human epidermal growth factor 
receptor 2 (HER2) -negative (defined as immunohistochemistry (IHC) <2+ or 
fluorescence in situ hybridization (FISH) negative).
b. Previously treated with 0 to 2 lines of systemic anticancer therapy (cytotoxic 
or targeted anticancer agents) in the metastatic setting.  Hormonal therapy and 
bone metastases treatment (eg, bisphosphonates, denosumab, etc) are not 
considered forms of systemic anticancer therapy.
3. Presence of measureable disease meeting the following criteria:
a.
At least 1 lesion of >10 mm in long axis diameter for nonlymph nodes or
>15 mm in short axis diameter for lymph nodes that is serially measurable 
according to RECIST 1.1 using either computerized tomography or magnetic 
resonance imaging or panoramic and close-up color photography.  
b. Lesions that have had radiotherapy must show subsequent radiographic 
evidence of increased size to be deemed a target lesion. 
4. Life expectancy of ≥3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
6. Adequate renal function as evidenced by serum creatinine ≤1.5 mg/dL or calculated 
creatinine clearance ≥50 mL/minute according to the Cockcroft and Gault formula
7. Adequate bone marrow function, defined as:
a.
Absolute neutrophil count (ANC) ≥1.5 × 109/L 
b. Hemoglobin (Hb) ≥10.0 g/dL (can be corrected by growth factor or 
transfusion)
c.
Platelet count ≥100 × 109/L 
8. Adequate liver function, defined as:
a.
Total bilirubin ≤1.5 × upper limit of normal (ULN)


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b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and 
aspartate aminotransferase (AST) ≤3 × ULN unless there are bone 
metastases, in which case liver specific alkaline phosphatase must be 
separated from the total and used to assess the liver function instead of the 
total alkaline phosphatase. ALT and AST ≤ 5 × ULN if subject has liver 
metastases
9. Resolution of all chemotherapy- or radiation-related toxicities to Grade 1 severity or 
lower except for stable sensory neuropathy (≤Grade 2) and alopecia
10. Archived tissue sample or new biopsy sample
11. Females must not be lactating or pregnant at Screening or Baseline (as documented 
by a negative 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.
12. All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause) or have been sterilized 
surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing).
13. Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days before study entry and must agree to use a highly effective method of 
contraception (eg, total abstinence, an intrauterine device, a double-barrier method 
[such as condom plus diaphragm with spermicide], a contraceptive implant, a 
combination oral contraceptive (estrogen/progesterone), or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
120 days after study drug discontinuation.  If currently abstinent, the subject must 
agree to use a double barrier method as described above if she becomes sexually 
active during the study period or for 120 days after study drug discontinuation.  
Females who are using hormonal contraceptives must have been on a stable dose of 
the same hormonal contraceptive product for at least 28 days before dosing and must 
continue to use the same contraceptive during the study and for 120 days after study 
drug discontinuation.
14. Males who have had a successful vasectomy (confirmed azoospermia) or they and 
their female partners meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period or for 120 days 
after study drug discontinuation).  No sperm donation is allowed during the study 
period or for 120 days after study drug discontinuation.
15. Willing and able to comply with all aspects of the treatment protocol
16. Provide written informed consent.


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9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Previous treatment with eribulin mesylate or any anti-PD-1, PD-L1, PD-L2 agent
2. Active autoimmune disease that has required systemic treatment in the past 2 years
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a 
form of systemic treatment.
3. Less than 6 months since prior adjuvant chemotherapy
4. Current enrollment in another interventional clinical study or used any investigational 
drug or device within the past 28 days preceding informed consent  
5. Treatment with chemotherapy or biological therapy within the previous 3 weeks, 
radiation or small molecule targeted therapy within the previous 2 weeks
6. Known central nervous system (CNS) disease, except for those subjects with treated 
brain metastasis, who are stable for at least 1 month, having no evidence of 
progression or hemorrhage after treatment and no ongoing requirement for 
corticosteroids, as ascertained by clinical examination and brain imaging magnetic 
resonance imaging [MRI] or computed tomography [CT]) during the screening period
7. Known history of HIV positive
8. Known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, HCV RNA 
detected)
9. Existing anticancer treatment-related toxicities of Grades ≥2 (except for alopecia and 
Grade 2 sensory neuropathy) according to Common Terminology Criteria for 
Adverse Events (CTCAE 4.03)
10. Any other malignancy that required treatment or has shown evidence of recurrence 
(except for nonmelanoma skin cancer or histologically confirmed complete excision 
of carcinoma in situ) during the 5 years prior to enrollment in this study.
11. History of significant cardiovascular disease, defined as:
a.
congestive heart failure greater than New York Heart Association 
(NYHA) Class II according to the NYHA Functional Classification
(Appendix 5)
b.
unstable angina or myocardial infarction within 6 months of enrollment
c.
serious cardiac arrhythmia
12. Clinically significant electrocardiogram (ECG) abnormality, including a marked 
Baseline prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval 
>500 ms)
13. History of concomitant medical conditions or infectious disease that, in the opinion of 
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14. Hypersensitivity to the active substance or any other excipients of the eribulin 
mesylate drug product, or severe hypersensitivity (≥Grade 3) to pembrolizumab
and/or any of its excipients
15. Scheduled for major surgery during the study
16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
The use of physiologic doses of corticosteroids may be approved after consultation 
with the sponsor.
17. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
18. Has a history of interstitial lung disease.
19. Has an active infection requiring systemic therapy.
20. Has received a live-virus vaccination within 30 days of planned start of study therapy.  
Seasonal flu vaccines that do not contain live virus are permitted.
21. The investigator’s belief that the subject is medically unfit to receive eribulin 
mesylate and pembrolizumab or unsuitable for any other reason.
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Posttreatment Phase and complete protocol-specified 
off-treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Subject Disposition case report form 
(CRF) page will be completed indicating the reason for discontinuation from treatment.  In 
addition, the date of last dose of study drugs will be recorded on the Study Drug Dosing CRF 
page.
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
every 9 weeks ± 1 week during Year 1, and every 9 to 12 weeks ±1 week thereafter
according to standard of care, until (1) the start of new anticancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first.
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis.


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9.4
Treatments
9.4.1
Treatments Administered
Study drugs eribulin mesylate and pembrolizumab will be administered throughout the study 
as described in Table 2.  The study drugs will be administered after all the Inclusion and none 
of the Exclusion Criteria are met (Section 9.3.1 and Section 9.3.2) and all procedures and 
assessments have been completed as detailed on the Schedule of Procedures/Assessments
(Table 8).  Prior to initiating eribulin mesylate on C1D1, correct for hypokalemia and 
hypomagnesemia and monitor these electrolytes periodically during therapy (Table 7).
Table 2
Treatments Administered
Drug Name
Dose
Dose Form
Infusion Rate
Day/Cycle
Eribulin Mesylate
1.4 mg/m2
IV infusion
Infused over 2-5 minutes
Day 1 and Day 8 of each 
21-day cycle
Pembrolizumab
200 mg
IV infusion
Infused over 30 minutes 
(-5 min/+10 min range 
allowed)
Day 1 of each 21-day cycle
IV = intravenous, mg/m2 = milligram per square meter.
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 any method that is accepted and 
customarily used by the investigational site, such as the Mosteller formula:
BSA (m2) = ([Height ([cm] × Weight (kg))] / 3600)½
Height and body weight will be recorded at the screening visit.  Thereafter, body weight will 
be recorded on Day 1 of each treatment cycle to recalculate BSA (in the event that weight 
has changed by 10% or more*). 
*Note: If institutional guidelines require BSA recalculation starting at 5% or more weight 
change, this will be acceptable. 
The amount of eribulin mesylate required (as calculated above) will be withdrawn from the 
appropriate number of vials into a syringe.  This may be administered directly as an 
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infusion over 2 to 5 minutes.  No special tubing is required for IV administration of eribulin 
mesylate.
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion and administration of infusion solution.
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Pembrolizumab and eribulin mesylate must be administered on Day 1 of each 21-day cycle;
pembrolizumab will be given first and followed immediately by eribulin mesylate.
Eribulin mesylate alone will be administered on Day 8 of each 21-day cycle.
Pembrolizumab and eribulin mesylate may be administered up to 3 days before or after the 
scheduled Day 1 of each 21-day cycle due to administrative reasons.  Correspondingly, 
eribulin mesylate alone may be administered up to 2 days before or after the scheduled Day 8 
of each 21-day cycle due to administrative reasons.
Subjects initially treated with eribulin mesylate and pembrolizumab can remain on 1 or both 
study drugs in the presence of clinical benefit until intercurrent illness, unacceptable toxicity, 
or disease progression occurs, or until the subject withdraws consent.
For subjects experiencing prolonged clinical benefit, temporary interruption (up to 3 months) 
of study treatment may be permitted after discussion with the treating physician and the 
sponsor.  After such interruption, investigators are strongly encouraged to rescan the subject
to rule out interim progression of disease.  In the event of an AE leading to treatment 
interruption or delay of either study drug, the subject may continue treatment with the other 
study drug, as long as there is a clinical benefit.
After the last subject has completed 35 cycles of pembrolizumab, all ongoing subjects will be 
transitioned off study.  Subjects still receiving eribulin monotherapy at this time may
continue to receive eribulin treatment off study through their pharmacy (if commercially 
available for that individual subject) or through a patient assistance program administered by 
the sponsor. Subjects should continue to receive eribulin investigational product and be 
assessed according to the Schedule of Procedures/Assessments (Table 8) until they complete 
the End-of-Treatment visit, prior to their transition to commercial eribulin or an access 
program. 
9.4.1.1
Eribulin Mesylate Dose Modification During Treatment
Eribulin mesylate dose may need to be delayed and reduced during the study.  Dose 
interruption and dose reduction instructions for subjects who experience eribulin mesylate 
toxicity are presented in Table 3.
Recommended dose delays:

Do not administer eribulin mesylate on Day 1 or Day 8 for any of the following:


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o
Absolute neutrophil count (ANC) <1,000/mm3
o
Platelets <75,000/mm3
o
Grade 3 or 4 nonhematological toxicities

Eribulin mesylate Day 8 dose may be delayed for a maximum of 1 week.
o
If toxicities do not resolve or improve to ≤Grade 2 severity by Day 15, omit the 
dose.
o
If toxicities resolve or improve to ≤Grade 2 severity by Day 15, administer 
eribulin mesylate at a reduced dose and initiate the next cycle no sooner than 
2 weeks later.
Recommended dose reductions:
If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or 
less, resume eribulin mesylate at a reduced dose as set out in Table 3.
Do not re-escalate the mesylate eribulin dose after it has been reduced.
Table 3
Eribulin Mesylate Dose Adjustments for Toxicity
Adverse Reaction / Toxicitya
Eribulin Mesylate Dose    
Modification
Permanently reduce the 1.4 mg/m2 eribulin mesylate dose for any of the 
following:
ANC <500/mm3 for >7 days
ANC <1,000/mm3 with fever or infection
Platelets <25,000/mm3
Platelets <50,000/mm3 requiring transfusion
Non-hematologic Grade 3 or 4 toxicities
Omission or delay of Day 8 eribulin mesylate dose in previous cycle 
for toxicity
1.1 mg/m2
Occurrence of any event requiring permanent dose reduction while 
receiving 1.1 mg/m2
0.7 mg/m2
Occurrence of any event requiring permanent dose reduction while 
receiving 0.7 mg/m2
If unable to administer a scheduled dose of eribulin mesylate for more than 
21 days of study, discuss with sponsor prior to continuing treatment
Discontinue
eribulin mesylate
ANC = absolute neutrophil count.
a: Toxicities graded in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.03 (NCI-CTCAE, v 4.03).


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9.4.1.2
Pembrolizumab Dose Modification During Treatment
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 4.
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines.
Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance. Refer to 
Table 4 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.


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Table 4
Dose Modification and Toxicity Management Guidelines for 
Immune-Related AEs Associated With Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor subjects for 
signs and symptoms of 
pneumonitis

Evaluate subjects with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor subjects for 
signs and symptoms of 
enterocolitis (ie,
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (ie,
peritoneal signs and 
ileus).

Subjects with ≥ Grade 2 
diarrhea suspecting 
colitis should consider 
GI consultation and 
performing endoscopy 
to rule out colitis. 

Subjects with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of clear 
fluids.  If sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes should be 
Grade 4
Permanently 
discontinue


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Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
substituted via IV 
infusion.
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure
Withhold

Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM 

Administer anti-
hyperglycemic 
in subjects with 
hyperglycemia 

Monitor subjects for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and initiate 
hormonal 
replacements 
as clinically 
indicated.  

Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with 
non-selective 
beta-blockers 
(eg,
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1


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Immune-related 
AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (eg,
levothyroxine 
or 
liothyroinine) 
per standard of 
care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 1-
2 mg/kg or 
equivalent) 
followed by 
taper.

Monitor changes of 
renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on 
severity of AE 
administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent 
Grade 2
Withhold

Based on type 
and severity of 
AE administer 
corticosteroids 

Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Grade 3
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to: 
Guillain-Barre
Syndrome, 
encephalitis            
Grade 4 or 
recurrent 
Grade 3
Permanently 
discontinue
NOTES: 
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician.  
2.
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab 
is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with 
hormonal replacement therapy or achieved metabolic control (in case of T1DM).  


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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the sponsor. The reason for interruption should be documented in 
the patient's study record
9.4.2
Identity of Investigational Products
The study drugs will be supplied by the sponsor in labeled containers.  The final drug will be 
prepared by the institution’s pharmacist.  The sponsor will provide the investigational 
products (eribulin mesylate and pembrolizumab) as open-label supplies.  Eribulin mesylate 
and pembrolizumab will be labeled as investigational product per local regulations and 
supplied to the clinical site by a third-party vendor.  The investigational products will be 
addressed only to the pharmacist (or designee).
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesylate
Eribulin mesylate will be supplied to the study sites in glass vials containing 1.0 mg eribulin 
mesylate in 2.0 mL of clear, colorless, and sterile solution.
!
Test drug code:  E7389
!
Generic name:  eribulin mesylate
!
Chemical name:  
(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-
dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-
9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one 
methanesulfonate (salt)
!
Molecular formula:  C40H59NO11CH4O3S
!
Molecular weight:  826.0
!
Structural formula:  


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9.4.2.2
Chemical Name, Structural Formula of Pembrolizumab
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials. Each vial will be reconstituted and diluted for 
intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab 
and is formulated in L-histidine (3.1 mg), polysorbate-80 (0.4 mg), sucrose (140 mg). The 
solution may contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.

Test drug code: MK-3475

Generic name:  Pembrolizumab

Chemical name:  Humanized X PD-1_mAB (H409A11)IgG4

Molecular formula: not applicable

Molecular weight: 149 kDa (approximate)

Structural formula:  not applicable
9.4.2.3
Comparator Drug
Not applicable.
9.4.2.4
Labeling for Study Drugs
Eribulin mesylate and pembrolizumab will be labeled in accordance with text that is in full 
regulatory compliance with FDA regulations.  
The clinical study labels will contain, but are not limited to:

Name, address, and telephone number of the sponsor

Pharmaceutical dosage form, route of administration, quantity of dosage units, 
identifier, and potency

Lot number

Protocol number

Directions of use (if applicable)

Storage conditions

Storage restrictions (if applicable)

Expiration date (if applicable, and not required for US)

Caution: New Drug-Limited by Federal (US) Law to Investigational Use
9.4.2.5
Storage Conditions
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drugs are maintained 
within an established temperature range.  The investigator or designee is responsible for 


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ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should 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.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all the eligibility requirements (Section 9.3) will be 
assigned to receive eribulin mesylate in combination with pembrolizumab.  There is no 
randomization in this study. Subjects will be enrolled from 2 strata: no prior systemic 
anticancer therapy in the metastatic setting and previously treated with 1 to 2 lines of 
systemic anticancer therapy in the metastatic setting.
9.4.4
Selection of Doses in the Study
The level 1 dose of eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) was
selected based on the FDA approved label.
The pembrolizumab dose used in the study of metastatic melanoma was 2 mg/kg every 
3 weeks (Q3W) and in advanced TNBC was 10 mg/kg every 2 weeks (Q2W).  This study 
will use a 200 mg Q3W fixed dose.  The rationale to use a 200 mg Q3W fixed dose is based 
on a population PK analysis from 476 subjects with the following findings:

the relationship between clearance and body weight, with an allometric exponent of 
0.59, supports both body weight normalized dosing and a fixed dose across all body 
weights

pembrolizumab has a wide therapeutic range (exposure margins of 0.5 – 5.0) based 
on the melanoma indication

exposure is similar between melanoma and other solid tumor indications.
Therefore, the 200 mg Q3W fixed dose regimen is likely similar, with regard to efficacy and 
tolerability, to the 10 mg/kg Q2W dose regimen, and there are no anticipated changes in 
exposure between different indication settings.  
9.4.5
Selection and Timing of Dose for Each Subject
All subjects will receive pembrolizumab first, followed immediately by eribulin mesylate on 
Day 1 of each cycle.  On Day 8 of each cycle, the subjects will receive eribulin mesylate 
only. 
The Phase 1b part includes 1 initial safety run-in cohort in which 6 subjects will receive 
eribulin mesylate 1.4 mg/m2 intravenously (IV) on Days 1 and 8 of a 21-day cycle and 
pembrolizumab 200 mg IV on Day 1 of a 21-day cycle (Dose Level 1).  Dose-limiting 
toxicity will be assessed in the first cycle as described in Section 9.1.  


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In the Phase 2 part subjects will receive the RP2D of eribulin mesylate IV on Days 1 and 8 of 
a 21-day cycle and pembrolizumab 200 mg IV on Day 1 of a 21-day cycle.   
9.4.6
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 days (90 days if 
given for SAEs and/or events of clinical interest [ECIs]) after the final dose of study drug 
will be recorded.  Additionally, all diagnostic, therapeutic, or surgical procedures relating to 
malignancy should be recorded.  Any medication that is considered necessary for the 
subject’s health and that is not expected to interfere with the evaluation of, or interact with,
eribulin mesylate or pembrolizumab may be continued during the study.
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) eribulin mesylate or pembrolizumab.
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
Treatment with bisphosphonates and/or denosumab will be allowed for subjects with bone 
metastases.
9.4.6.1
Treatments for Pembrolizumab-Related Toxicities
Infusion Reactions:
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5. 


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Table 5
Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment.
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of _____ with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
No subsequent dosing


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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov


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9.4.6.2
Drug-Drug Interactions
Please refer to the investigator brochure (IB) for eribulin mesylate and the IB for 
pembrolizumab for the most current information.
No drug-drug interactions affecting eribulin mesylate are expected with CYP3A4 inhibitors, 
CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors.  Clinically meaningful differences in 
exposure (AUC) were not observed in patients with advanced solid tumors when eribulin 
mesylate was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and 
a P-gp inhibitor) and when eribulin mesylate was administered with or without rifampin (a 
CYP3A4 inducer).  Eribulin mesylate does not inhibit CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or 
CYP3A4 enzymes at relevant clinical concentrations.  Eribulin mesylate is not expected to 
alter the plasma concentrations of drugs that are substrates of these enzymes. 
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab. 
9.4.6.3
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If subjects receive 
additional antitumor therapies, such as chemotherapy, hormone therapy, or immunotherapy, 
this will be judged to represent evidence of disease recurrence or progression, and study drug 
will be discontinued. These subjects should complete all off-treatment assessments and 
continue to be followed for survival in the Posttreatment Phase.
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than eribulin mesylate and pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be considered on an exceptional case-by-case basis after consultation with 
sponsor.  The subject must have clear measurable disease outside the radiated 
field.  Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS.

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 


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virus vaccines and are allowed. However, intranasal influenza vaccines (eg,
FluMist®) are live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE that is suspected to have an immunologic etiology.  The use of physiologic doses 
of corticosteroids may be approved after consultation with the sponsor.
o
Note:  Inhaled steroids are allowed for management of asthma.
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the sponsor.  
Subjects may receive other medications that the investigator deems to be medically necessary
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
9.4.7
Treatment Compliance
Both study drugs will be administered IV, and the site will keep a record for each subject 
during the study.  Clinical research associates (CRAs) will review treatment compliance 
during site visits and at the completion of the study.
9.4.8
Drug Supplies and Accountability
Compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
A signed and dated confidentiality agreement
A copy of the final protocol signature page, signed and dated by both the sponsor and 
the investigator
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this protocol
An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 
1572, where applicable
Financial Disclosure form(s) for the principal investigator (PI) and all 
subinvestigators listed on Form FDA 1572, where applicable
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s 
current medical license or medical registration number on the CV


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A signed and dated clinical studies agreement
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are shipped to site but not dispensed to subjects, and return of reconciled study 
drugs to the sponsor. This includes, but may not be limited to:  (a) documentation of receipt 
of study drugs, (b) study drugs dispensing/return reconciliation log, (c) study drugs 
accountability log, (d) all shipping service receipts, (e) documentation of returns to the 
sponsor, and (f) certificates of destruction for any destruction of study drugs/study supplies 
that occurs at the site. All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority 
(eg, FDA).  Unused study drugs that was shipped to the site but not dispensed to subjects, are 
to be returned to the sponsor’s designated central or local depot(s) during the study or at the 
conclusion of the study, unless provision is made by the sponsor for destruction of study drug 
and containers at the site.  Destruction at the site will only occur under circumstances where 
regulation or supply type prohibits the return of study drug to the central or local depot(s).  
Approval for destruction to occur at the site must be provided by the sponsor in advance.  
Upon completion of drug accountability and reconciliation procedures by the site’s personnel 
and documentation procedures by the sponsor’s personnel, study drug that is to be returned to 
the sponsor’s designated central or local depot(s) must be boxed, sealed, and shipped back to 
the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drug may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  Where study drug is approved for destruction at the site, destruction 
will occur following the site’s standard procedures and certificates of destruction will be 
provided to the sponsor.  
Drug accountability will be reviewed during site visits and at the completion of the study.


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9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity.
9.5.1.2
Pretreatment/Screening Assessments
Baseline characteristics and assessments will be collected during the Pretreatment
Phase/Screening Period, which will last from -21 days to -1 day before the Treatment Phase 
begins.  All Pretreatment and Screening assessments are listed in the Schedule of 
Procedures/Assessments (Table 8).
Medical/Surgical History and Physical Examination
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  Significant findings prior to the start of study drug will be recorded on the Medical 
History and Current Medical Conditions CRF.
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 8).  A physical examination will include 
evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, skin, and a complete neurological examination.  A urogenital examination 
will be required only in the presence of clinical symptoms related to this region.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Significant findings at the Screening Visit will be recorded on the Medical History 
and Current Medical Conditions CRF.  Changes during treatment from the screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
Pregnancy Test
A serum (a 6-mL sample of blood will be collected) or urine beta-human chorionic 
gonadotropin (β-hCG) test will be performed for premenopausal women and postmenopausal 
women who have been amenorrheic for less than 12 months.  Please refer to the Schedule of 
Procedures/Assessments (Table 8).
Electrocardiogram (ECG)
Electrocardiograms will be obtained at Screening as designated in the Schedule of 
Procedures/Assessments (Table 8).  Complete, standardized, 12-lead ECG recordings that 
permit all 12 leads to be displayed on a single page with an accompanying lead II rhythm 
strip below the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a 


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minimum of 3 full complexes should be recorded from each lead simultaneously.  Subjects 
must be in the recumbent position for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.6.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
Other assessments
Additional Screening assessments will include safety laboratory assessments, vital signs,
ECOG, mTNBC diagnosis, TNM staging at diagnosis (Appendix 8), prior anticancer therapy,
and tumor tissue for PD-L1 expression.
9.5.1.3
Treatment/End of Treatment Assessments
Treatment and End of Treatment assessments are listed in the Schedule of 
Procedures/Assessments (Table 8).
Dose-limiting toxicity (DLT) assessments will be conducted for Phase 1b subjects.  A DLT is 
defined as one of the following toxicities occurring during the DLT assessment window and 
considered by the investigator to be related to either of the study drugs. 
Hematologic Toxicities:

Any Grade 4 thrombocytopenia or neutropenia lasting >7 days
Nonhematologic Toxicities:

Episcleritis, uveitis, or iritis of Grade 2 or higher 

Any Grade 4 toxicity

Any Grade 3 toxicity EXCLUDING:
o
Nausea/vomiting/diarrhea controlled by medical intervention within 72 hours
o
Grade 3 rash in the absence of desquamation, no mucosal involvement, does 
not require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab
o
Transient Grade 3 AST or ALT elevation, defined as no more than 3 days 
with or without steroid use

Discontinuation or delay of more than 2 weeks of either study medication due to 
treatment-related AE will be considered as a DLT
All subjects enrolled in Phase 1b will be assessed for DLTs during a DLT assessment 
window of the first cycle of 21 days.  Subjects who discontinue study treatment prior to 
completing the DLT assessment window for any reason other than a DLT will be replaced.
End of Treatment assessments for all subjects will be collected within 30 days of the last 
dose of study drug.  Subjects with SAEs and/or ECIs at the time of End of Treatment will be 
followed for 90 days after the last dose of study drug or, if the subject initiates new 
anticancer therapy, for 30 days following the last dose of study drug, whichever is earlier.


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9.5.1.4
Efficacy Assessments
Tumor response data utilized in the main analysis of ORR, PFS and DOR will be obtained 
from an independent review of the imaging scans. In addition, these analyses will be 
performed using the investigators’ determination of tumor response, which will be 
considered secondary. Detailed methodology for assessment by independent review will be 
provided in an Independent Imaging Review Charter. Secondary endpoint OS will be 
assessed throughout the study.  
9.5.1.4.1
TUMOR RESPONSE ASSESSMENT
Tumor assessments will be performed using RECIST 1.1 (Appendix 3).  Investigator 
assessment will be performed at each assessment time point and entered onto the CRFs. 
Copies of all tumor assessment scans will be sent to an independent core laboratory 
designated by the sponsor for efficacy assessment. Note:  As of Protocol Amendment 05,
tumor assessment scans will no longer be sent to an independent imaging core laboratory. 
Tumor assessments will be carried out during the Pretreatment Phase and then every 9 weeks
± 1 week (or sooner if there is evidence of progressive disease) after the start of study 
treatment.  Computed tomography/MRI scans of chest, abdomen, and pelvis and of other 
known sites of disease will be obtained at Screening (within 28 days prior to Cycle 1/Day 1), 
at all tumor assessment time points, and as indicated clinically.  Color photographs 
containing a mm scale must be taken of all skin lesions being used as target lesions.  
Historical standard of care scans that are performed with scanning parameters consistent with 
the requirements for this protocol within 28 days prior to dosing are acceptable.  
The CT scan should be a diagnostic quality spiral or multidetector CT with oral and iodinated 
IV contrast, and the MRI scan should be performed with IV gadolinium chelate.  Scans of the 
abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest must be done with CT.  If iodinated IV contrast is contraindicated, the 
chest evaluation should be done with non-contrast CT, and the abdomen and pelvis 
evaluation should be performed using either CT with oral contrast (without IV contrast) or 
MRI with gadolinium chelate IV contrast (the latter is preferred).  Spiral/multidetector CT 
should be performed with a 5-mm contiguous slice reconstruction algorithm. If body MRI 
scans are performed, contiguous slices of 5 mm are also recommended. 
Low-dose non-contrast CT transmission scans from a positron emission tomography-CT 
(PET-CT) combination scanner are not acceptable.  Ultrasound should not be used for 
radiographic tumor assessment.  Chest disease may not be followed using chest x-ray.  
A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at 
Screening (within 28 days prior to Cycle 1/Day 1), to assess potential CNS disease and/or 
metastases.  For subjects with previously treated eligible brain metastases, a brain scan will 
be performed at tumor assessment time points, if clinically indicated.    
The tumor assessment schedule should not be affected by interruptions in study treatment.


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The same method of assessment used at Screening must be used at all time points.
Throughout the study it is critical that the same imaging methodology be applied and contrast 
be consistently provided unless IV contrast becomes medically contraindicated during the 
course of treatment or the dose of contrast needs to be adjusted based on the subject’s health 
status.  
Bone scans will be performed at Screening, every 27 weeks, or sooner if clinically indicated, 
and at confirmation of CR.  A bone scan (99m-technetium polyphosphonate scintigraphy, 
whole body bone MRI, or 18F-NaF-PET) to assess bone metastases will be performed within 
6 weeks prior to C1D1 (historical scans are acceptable) and then every 27 weeks (within that 
27th week) from C1D1, or sooner if clinically indicated.  In subjects whose body CT/MRI 
scans indicate CR has been achieved, a bone scan will be required at confirmation of CR to 
exclude new bone metastases.  The same methodology and acquisition techniques used at 
screening should be used throughout the study to ensure comparability.  Lesions detected on 
bone scans must be followed with cross-sectional imaging.
Tumor response will be confirmed by a second examination performed no less than 4 weeks 
after the first observation of response.  Best overall response (BOR) of stable disease requires 
at least 1 posttreatment assessment that meets the SD criteria at least 8 weeks after the start 
of treatment.
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
9 weeks ± 1 week during Year 1, and every 9 to 12 weeks ± 1 week thereafter according to 
standard of care, until (1) the start of new anticancer treatment, (2) disease progression (3) 
death, or (4) the end of the study, whichever occurs first.
9.5.1.4.2
IRRECIST AFTER INITIAL RADIOLOGIC PROGRESSION
Since pembrolizumab, like other immunotherapeutic agents, may produce antitumor effects 
after an initial increase in tumor burden, standard RECIST criteria may not provide a 
complete response assessment of its efficacy.  irRECIST is RECIST 1.1 adapted as described 
below to account for the unique tumor response seen with immunotherapeutic drugs. 
irRECIST will be used by site investigator/local radiology review to assess tumor response 
and progression, and make treatment decisions. This data will be collected in the clinical 
database. Treatment efficacy based on irRECIST as assessed by central imaging vendor 
review will be evaluated retrospectively.
The key changes for irRECIST from RECIST v1.1 is the ability to continue treatment, if 
clinically stable, until a repeat imaging scan ≥4 weeks after the first radiologic evidence of 
PD confirms progressive disease.  Therefore, in addition to radiographic assessment of tumor 
response or progression, irRECIST (see Appendix 4) takes into account the clinical 
condition/stability of subjects (Table 6). 
Clinically stable is defined by the following criteria:


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
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor(s) at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Table 6
Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging 
Treatment
1st radiologic 
evidence of PD 
by RECIST 1.1
Repeat imaging at 
>4 weeks at site to 
confirm PD
May continue study 
treatment at the local 
site investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST
Repeat imaging at 
>4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging 
confirms PD
by irRECIST at 
the local site
No additional 
imaging required
Discontinue 
treatment (exception 
is possible upon 
consultation with 
sponsor)
No additional 
imaging required
N/A
Repeat tumor 
imaging shows 
SD, PR or CR
by irRECIST by 
the local site
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the local 
site investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor image should 
occur according to 
the every 9 weeks
(±1 week) imaging 
schedule 
CR = complete response. N/A = not applicable, PD = progressive disease, PR = partial response, SD = stable disease.

In determining whether or not the tumor burden has increased or decreased, local 
study site investigators should consider all target lesions as well as non-target 
lesions. Subjects that are deemed clinically unstable are not required to have repeat 
tumor imaging for confirmation.

For a clinically stable subject with first radiologic evidence of progressive disease by 
RECIST 1.1 (ie, unconfirmed progression of disease), it is at the discretion of the


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site investigator to continue treating the subject with the assigned treatment per 
protocol until progression of disease is confirmed at least 28 days from the date of the 
scan first suggesting PD. If radiologic progression is confirmed by subsequent scan 
then the subject will be discontinued from study treatment. If radiologic progression 
is not confirmed by irRECIST per the site, then the subjects may continue on 
treatment and follow the regular imaging schedule intervals until progression is 
confirmed at a later time point by the site. 
o
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at 
least 4 weeks apart demonstrating progressive disease) per irRECIST, but the 
subject is achieving a clinically meaningful benefit, and there is no further 
increase in the tumor burden at the confirmatory tumor imaging, an exception 
to continue treatment may be considered following consultation with the 
sponsor. In this case, if treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in sections 6.0 
Study Flowchart and be submitted to the central imaging vendor.  Note:  As of 
Protocol Amendment 05, tumor assessment scans will no longer be sent to the 
central imaging laboratory.

Any subject deemed clinically unstable should be discontinued from study treatment 
at 1st radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.

In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor 
imaging using the same imaging schedule used while on treatment (every 9 weeks 
± 1 week in Year 1, and every 9 to 12 weeks ± 1 week thereafter according to 
standard of care), until (1) the start of new anti-cancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first.
irRECIST data will be collected in the clinical database.
9.5.1.5
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Assessments
9.5.1.5.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected for PK analysis on eribulin mesylate only.  Time points for 
PK sample collections are as follows:

For all Phase 1b subjects, PK samples will be collected on C1D1 at predose (0 hour), 
15, 30 minutes and 1, 2, 4, 8, 24, 48, 72, 96, 120, and 144 hours after the infusion of 
study drug. These PK sample collection times may be adjusted for certain time points 
only for administrative reasons, and only with sponsor approval. 

For Phase 2 subjects, PK samples will be collected, if feasible, on C1D1 (at the end of 
the infusion, 0.5 to 6 hours and 24 to 120 hours after infusion) and on C1D8 (predose 
and at the end of the infusion). 


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Plasma concentrations of eribulin mesylate will be determined using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) method.
9.5.1.5.2
PHARMACODYNAMIC ASSESSMENTS
Eribulin mesylate PK/PD analysis will be conducted to evaluate the relationship between 
exposure and efficacy and exposure and safety when eribulin mesylate is coadministered 
with pembrolizumab.  
9.5.1.5.3
OTHER BIOMARKER ASSESSMENTS
Archived and/or fresh (if possible) tissue samples will be collected at screening for 
assessment of PD-1/PD-L1 expression.  Fresh biopsy tissues should be limited to readily 
accessible tumor lesions (eg, breast, peripheral lymph node, or skin).
Collected tumor tissues may be used for potential assessment of mutations and other genetic 
alterations or genes that may be important in the development and progression of cancer as 
well as for potential use in diagnostic development.  The decision to perform other biomarker 
assessments may be based on the clinical outcome of this study and/or the signals observed 
in other clinical studies or other information available at that time.
9.5.1.6
Safety Assessments
Safety assessments will consist of the monitoring and recording of all AEs, including all 
CTCAE v4.03 grades for both increasing and decreasing severity (Appendix 6), and SAEs;
regular monitoring of hematology, clinical chemistry, and urine; periodic measurement of
vital signs; and the performance of physical examinations, as detailed in Table 8.
9.5.1.6.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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.  For this study, the study drugs are eribulin mesylate 
and pembrolizumab.
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 observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF and for 30 days after the last dose of study treatment.
SAEs will be collected for 90 days and ECIs will be collected for 30 days after the last dose
or 30 days following the last dose if the subject initiates new anticancer therapy, whichever is 
earlier. An AE will not be reported on the Adverse Event CRF if other anticancer treatment 
is started.  All SAEs will be reported on the Adverse Event CRF.
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 whether 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. 
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, or the 
start of new anticancer therapy, whichever comes first.  SAEs must be followed for 90 days 
and ECIs for 30 days (see Section 9.5.1.6.2) after the last dose of study drug or, if the subject 
initiates new anticancer therapy, for 30 days following the last dose of study drug, whichever 
is earlier. However, treatment-emergent peripheral neuropathy of any grade will be followed 
until return to baseline or until another anticancer therapy is started, whichever occurs first.  
All SAEs should be followed to resolution or, if resolution is unlikely, to stabilization.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline), or:
Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or
Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Disease progression is a study endpoint and should be captured in the CRF as per the 
guidelines for reporting disease progression.
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment.


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Assessing Severity of Adverse Events
AEs will be graded on a 5-point scale according to Common Terminology Criteria for 
Adverse Events ([CTCAE v4.03]; see Appendix 6; also available from: 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  
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:
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.
9.5.1.6.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

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


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
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 1 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.
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
9.5.1.6.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 7.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 8) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Efforts should be made to conduct study visits on the day scheduled. However, the Cycle 1 
Day 1 hematology and chemistry assessments may be performed within 3 days prior to the 
scheduled visit, while subsequent hematology or chemistry assessments may be performed 
within 24 hours prior to the scheduled visit.  On all occasions when study drug administration 
is scheduled, all hematology, blood chemistry, and urinalysis samples are to be obtained prior 
to study drug administration and results reviewed prior to administration/dispensing of study 
drug.  Refer to Appendix 2 for the management of clinically significant laboratory 
abnormalities.


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Table 7
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), ANC
Clinical Chemistry
     Electrolytes
Sodium, potassium, chloride, calcium, magnesium
     Liver Function Tests
ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin
     Renal Function
BUN, serum creatinine
     Thyroid Function
TSH, T4a
     Pregnancy
Serum β-hCG (if urine not done)
     Other
LDH, total protein, glucose (fastingb)
Urinalysis
Glucose, ketones, pH, protein, RBCs, WBCs, specific gravity
Urine β-hCG (if serum not done)
ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, β-hCG = 
beta-human chorionic gonadotropin, BUN = blood urea nitrogen, LDH = lactate dehydrogenase, RBC = red blood cells, 
T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cells.
a:  Thyroid function will be assessed at the Screening Visit and then every 2 cycles (starting at C2) throughout the study.  
As of Protocol Amendment 05, TSH and T4 will be done at the discretion of the investigator.
b: Fasting glucose at Screen only.
Clinical laboratory tests during the study will be performed by trained staff at the study sites.  
Local laboratories will perform tests throughout the study.  Laboratory certification as 
available will be included in the final clinical study report for this study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.6.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.6.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg)
will be obtained as designated in the Schedule of Procedures/Assessments (Table 8) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person, if feasible. 
9.5.1.6.5
PHYSICAL EXAMINATIONS
Comprehensive and abbreviated physical examinations will be performed at the Screening 
Visit as previously described in Section 9.5.1.2 and throughout the study as designated in the 
Schedule of Procedures/Assessments (Table 8).  Documentation of the physical examination 
will be included in the source documentation at the site.  Significant findings at the Screening 


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Visit will be recorded on the Medical History and Current Medical Conditions CRF.  
Changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the Adverse Events CRF.
Comprehensive Physical Examination
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, 
throat, neck, chest (including heart and lungs), abdomen, limbs, and skin and a complete 
neurological examination.  The subject will be queried regarding physical status and 
subjective symptoms as well.  A urogenital examination will be required only in the presence 
of clinical symptoms related to this region.
Abbreviated Physical Examination
Health status will be assessed by brief evaluation of the chest (including heart and lungs), 
abdomen, and limbs, and other physical conditions of note.  The subject must be queried 
regarding changes in physical status since the last examination.
9.5.1.6.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Procedures/
Assessments (Table 8).  Complete, standardized, 12-lead ECG recordings that permit all 
12 leads to be displayed on a single page with an accompanying lead II rhythm strip below 
the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a minimum of
3 full complexes should be recorded from each lead simultaneously.  Subjects must be in the 
recumbent position for a period of 5 minutes prior to the ECG.  Electrocardiograms obtained 
at C1D1 and C1D8 should be performed just prior to and immediately after receiving the 
eribulin mesylate infusion.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.6) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.6.7
OTHER SAFETY ASSESSMENTS
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group performance status will be assessed at the Screening
Visit, Day 1 of each treatment cycle, and at End of Treatment Visits. The table in Appendix 
7 will be used to assess performance status.
9.5.2
Schedule of Procedures/Assessments 
Refer to Table 8 for the description and timing of each procedure and assessment in the 
Pretreatment, Treatment, and Posttreatment Phases.


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9.5.2.1
Schedule of Procedures/Assessments
Table 8 presents the schedule of procedures and assessments for the study.


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Table 8
Schedule of Procedures/Assessments
Phase
Pretreatment
Treatment 
Posttreatment
Period
Screening
Treatment Cycle 1 Through Last 
Cycle
(21-day cycle)
End of Treatment
Follow-upo
Day
Days -21 to -1
Day 1 (includes 
Baseline C1/D1)
Day 8
Within 30a days of 
final treatment
Every 12 
weeks 
Assessments
Informed consent
X
Inclusion and Exclusion Criteria
X
Demographicb
X
Medical/surgical history
X
TNM Stagingc
X
mTNBC diagnosis
X
Prior anticancer therapy
X
Pregnancy testd
X
PKe
X
X
Tumor tissue for PD-L1 expression
X
ECGf
X
Xf
Xf
Hematologyg
X
X
X
X
Chemistryh
X
X
X
TSH and free T4 levelsi
X
X
X
Urinalysis (dipstick)j
X
X
X
ECOG
X
X
X
Vital signs
X
X
X
X
Physical examinationk
X
X
X
X
Eribulin mesylatel
X
X
Pembrolizumabm
X
Disposition
X


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Table 8
Schedule of Procedures/Assessments
Phase
Pretreatment
Treatment 
Posttreatment
Period
Screening
Treatment Cycle 1 Through Last 
Cycle
(21-day cycle)
End of Treatment
Follow-upo
Day
Days -21 to -1
Day 1 (includes 
Baseline C1/D1)
Day 8
Within 30a days of 
final treatment
Every 12 
weeks 
Tumor assessmentsn
Throughout Study
X
Adverse events/SAEs
Throughout Study
X
Concomitant medications
Throughout Study
Survival informationo
X
AE = adverse event, β-hCG = beta-human chorionic gonadotropin, C1D1 = Cycle 1 Day 1, CT = computerized tomography, eCRF = electronic case report form, 
ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, CR = complete response, irCR = immune-related Complete Response, IV = 
intravenous, PK = pharmacokinetic, SAE = serious adverse event, MRI = magnetic resonance imaging, RBC = red blood cells, TNM = tumor-node-metastases, 
TSH = thyroid stimulating hormone, T4 = thyroxine, WBC = white blood cell.
a:
End of Treatment assessments for all subjects will be collected within 30 days of the last dose of study drug.  Subjects with SAEs and/or ECIs at the 
time of End of Treatment will be followed for 90 days after the last dose of study drug or, if the subject initiates new anticancer therapy, for 30 days 
following the last dose of study drug, whichever is earlier. However, treatment-emergent peripheral neuropathy of any grade will be followed until 
resolution or until another anticancer therapy is started, whichever occurs first.  All SAEs should be followed to resolution or, if resolution is unlikely, to 
stabilization.
b:
Demography information includes date of birth (or age), sex, and race/ethnicity.
c:
TNM staging at the time of diagnosis should be recorded in the eCRF.
d:
A serum (6-mL blood sample will be collected) or urine β-hCG test will be performed at the Screening Visit for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months.  If a negative screening pregnancy test is obtained more than 72 hours 
before the planned first dose of pembrolizumab and eribulin mesylate, a separate serum or urine sample must be obtained and tested at the Baseline Visit 
assessment on C1D1. 
e:
Pharmacokinetic blood samples will be collected only for eribulin mesylate PK analysis.  Time points for PK sample collections are as follows: For all 
Phase 1b subjects, PK samples will be collected on C1D1 at predose (0 hour), 15, 30 minutes and 1, 2, 4, 8, 24, 48, 72, 96, 120, and 144 hours after the 
study drug infusion.  For Phase 2 subjects, PK samples will be collected, if feasible, on C1D1 (at the end of the infusion, 0.5 to 6 hours and 24 to 120 
hours after study drug infusion) and on C1D8 (predose and at the end of the infusion).
f:
Electrocardiogram (ECG) will be performed at Screening, C1D1, C1D8, and at any unscheduled visits as clinically indicated.  ECGs obtained at C1D1 
and C1D8 should be performed just prior to and immediately after receiving the eribulin mesylate infusion.


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g:
Hematology laboratory assessment must be reviewed prior to every eribulin mesylate administration.  Cycle 1 Day 1 hematology assessments may be 
performed within 3 days prior to the scheduled visit.  Subsequent hematology assessments may be performed within 24 hours before the scheduled visit.
h:
Chemistry laboratory assessment must be reviewed prior to every pembrolizumab administration.  Cycle 1 Day 1 chemistry assessments may be 
performed within 3 days prior to the scheduled visit.  Subsequent chemistry assessments may be performed within 24 hours before the scheduled visit.  
i:
Assessment of TSH and free T4 levels are to be performed at the Screening Visit and then every 2 cycles (starting at Cycle 2) throughout the study.  As 
of Protocol Amendment 05, TSH and T4 will be done at the discretion of the investigator.
j:
Urinalysis will be assessed at the Screening Visit and on Day 1 at Cycles 2 and 4.  Urinalysis will include glucose, ketones, pH, protein, WBCs, 
hemoglobin (or RBCs), and specific gravity.  If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory.
k:
Symptom-directed physical examination and abnormal clinically significant findings should be recorded on AE page of the CRF.
l:
Eribulin mesylate will be given immediately following pembrolizumab on Day 1 (±3 day window is allowed) and alone on Day 8 (±2 day window is 
allowed) of a 3 week cycle.  
m:
Pembrolizumab will be given prior to eribulin mesylate, only on Day 1 of a 3-week cycle (±3 day window is allowed).  
n:
Screening tumor assessments using CT of the chest, abdomen, and pelvis and other areas of known disease or newly suspected disease should be 
performed within 28 days prior to C1D1.  Scans of the abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest should be done with CT.  CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium 
chelate unless there is a medical contraindication to contrast.  If iodinated IV contrast is contraindicated, chest CT should be done without IV contrast.
Treatment Phase:  Tumor assessments of the chest, abdomen, and pelvis and other areas where scans were performed at screening or newly suspected 
disease should be performed every 9 weeks ±1 week after the start of study treatment (or sooner if there is evidence of progressive disease) and should 
use the same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) as were used for the screening 
assessments.  Objective responses must be confirmed at least 4 weeks later (eg, generally at the next tumor assessment time point).  
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 28 days prior to C1D1.  During the Treatment 
Phase, CT/MRI of the brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves an irCR.  For subjects with 
history of treated brain metastases, brain scans will be performed at tumor assessment time points if clinically indicated.  The same methodology and 
scan acquisition techniques used at screening should be used throughout the study to ensure comparability.
A bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF) to assess bone metastases will be performed within 
6 weeks prior to C1D1 (historical scans are acceptable) and then every 27 weeks (within that 27th week) from C1D1, or sooner if clinically indicated.  
In subjects whose body CT/MRI scans indicate CR has been achieved, a bone scan will be required at confirmation of CR to exclude new bone 
metastases.  The same methodology and acquisition techniques used at screening should be used throughout the study to ensure comparability.  Lesions 
detected on bone scans must be followed with cross-sectional imaging.


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In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease 
status by radiologic imaging every 9 weeks ± 1 week during Year 1, and every 9 to 12 weeks ± 1 week thereafter per standard of care, until (1) the start 
of new anticancer treatment, (2) disease progression (3) death, or (4) the end of the study, whichever occurs first.
o:
As of Protocol Amendment 05, Follow-Up assessments in the Posttreatment Phase will not be performed after the subject completes the Off-Treatment 
visit assessments (or after the 90 day monitoring for subjects with SAEs and/or events of clinical interest).


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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 8 for the Schedule of Procedures/ Assessments. 
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in oncology studies.  
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, pregnancy tests, radiologic studies, and assessment of AEs, are standard ICH 
GCP evaluations to ensure subject safety.  The use of RECIST v1.1 for tumor assessment is 
widely accepted.  See Appendix 3.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the event.
Serious adverse events and ECIs, regardless of causality assessment, must be collected 
through the last visit and for 90 days after the subject’s last dose, or 30 days following the 
last doses if the subject initiates new anticancer therapy, whichever is earlier. All SAEs 
and/or ECIs must be followed to resolution or, if resolution is unlikely, until the event or 
sequelae stabilize. Any SAE judged by the investigator to be related to the study treatment 
or any protocol-required procedure should be reported to the sponsor regardless of the length 
of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study
File. 
For urgent safety issues, please ensure that all appropriate medical care is administered to 
the subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.


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The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by his/her institution.  A copy of this communication must be forwarded to the
sponsor to be filed in the sponsor’s Study Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 120 days of last study treatment or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported.  Also, any 
exposure to study drug through breastfeeding during study treatment or within 120 days of 
last study treatment or 30 days following last study treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in
the same format as all other SAEs (see Reporting of Serious Adverse Events,
Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study (all off-treatment study 
assessments should apply). 
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Study drugs will be given IV by the study staff at the investigator site.  No abuse or errors are 
anticipated.  
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drugs outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:


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Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose.  For this study, an overdose of 
pembrolizumab will be defined as ≥1000 mg (5 times the 200 mg 
dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol. 
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or systems, including prescribing, order 
communication, product labeling/packaging/nomenclature, 
compounding, dispensing, distribution, administration, education, 
monitoring, or use.
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 9.5.4.1), 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 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.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS/EVENTS OF CLINICAL INTEREST
Study-specific events (Events of Clinical Interest [ECIs]) should always be considered as 
serious important medical events and be entered on the Adverse Event CRF and reported 
using the procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even 
if the study-specific event does not meet other serious criteria. 
Events of clinical interest for this study include: an elevated AST or ALT lab value that is 
greater than or equal to 3 × ULN and an elevated total bilirubin lab value that is greater than 
or equal to 2× ULN and, at the same time, an alkaline phosphatase lab value that is less than 
2 × ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents.  The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 


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additional evaluation for an underlying etiology.  The study site guidance for assessment and 
follow up of these criteria can be found in the Investigator Study File Binder (or equivalent). 
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
Not applicable. 
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
Discontinuation of study treatment does not represent withdrawal from the study.  
A subject must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:

Recurrent Grade 2 pneumonitis

Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 8 cycles (24 weeks) with 
pembrolizumab and had at least 2 doses of pembrolizumab beyond the date when the 
initial CR was declared.

Completion of 35 treatments (approximately 2 years) with pembrolizumab.
Note: The number of treatments is calculated starting with the first dose of pembrolizumab.
The investigator may withdraw the subject from the study at any time for safety or
administrative reasons. A subject may elect to discontinue the study at any time for any
reason. All subjects who discontinue the study are to complete the End of Treatment 
procedures indicated in the Schedule of Procedures/Assessments (Table 8).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and will provide appropriate medical treatment and other 


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necessary measures for the subject.  A subject who has stopped returning for visits will be 
followed up by mail, phone, or other means to gather information such as the reason for 
failure to return, the presence or absence of AEs, and clinical courses of signs and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these reasons: 
AE(s), lost to follow-up, subject choice, (ie, subject chooses to discontinue from the 
treatment but is willing to participate in the Follow-Up portion of the study), progression of 
disease, withdrawal of consent (ie, subject no longer wishes to participate in the study and be 
contacted), pregnancy, sponsor discontinuation of the study, or other. Subjects will be 
judged as lost to follow-up only if they cannot be reached after 3 documented attempts (at 
least 1 week apart) by the site to contact them.
After the last subject has completed 35 cycles of pembrolizumab, all ongoing subjects will be 
transitioned off study.  Subjects still receiving eribulin monotherapy at this time may
continue to receive eribulin treatment off study through their pharmacy (if commercially 
available for that individual subject) or through a patient assistance program administered by 
the sponsor. Subjects will continue to receive eribulin investigational product and will be 
assessed according to the Schedule of Procedures/Assessments (Table 8) until they complete 
the End-of-Treatment visit, prior to their transition to commercial eribulin or an access 
program. 
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 


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guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed by 
use of SAS software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
RECIST 1.1 criteria will be used in the evaluation of tumor status for the primary, secondary 
and exploratory endpoints, irRECIST criteria will be used in the evaluation of tumor status 
for one of the exploratory endpoints. Tumor response data obtained per RECIST 1.1 by IIR 
will be utilized in the main analysis of ORR, PFS and DOR. In addition, tumor assessment 
data assessed per RECIST1.1 by investigator review and per irRECIST by IIR and 
investigator review will be considered as secondary or exploratory. 
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Objective Response Rate (ORR) - defined as the proportion of subjects who had a
BOR of CR or PR.


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9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS

Progression-Free Survival (PFS) – defined as the time from date of first dose of study 
drug to date of first documentation of disease progression or death, whichever occurs 
first
Overall Survival (OS) – defined as the time from the date of first dose of study drug 
until date of death from any cause
Duration of Response (DOR) – defined as the time from the date that a confirmed 
objective response is first documented to the date of PD or death due to any cause for 
those subjects with a confirmed PR or CR.  
Clinical Benefit Rate (CBR) is defined as the proportion of subjects who had BOR of 
CR, PR, or durable stable disease (SD) (≥24 weeks) 
Estimates of ORR, PFS, OS,   DOR and CBR in the PD-L1 Positive Set.
9.7.1.1.3
EXPLORATORY EFFICACY ENDPOINTS 
Time to Response (TTR) is defined as the time from the date of first dose of study 
drug to the first documented CR or PR for those subjects with a confirmed PR or 
CR.  
ORR, PFS, DOR, and CBR using irRECIST
All above endpoints based on tumor measurement will be assessed according to RECIST 1.1, 
unless otherwise specified.
9.7.1.2
Definitions of Analysis Sets
The DLT Evaluable Set includes subjects who complete the first treatment cycle (ie, 
take at least 2 doses of eribulin mesylate with no more than 1 dose reduction and at 
least 1 dose of pembrolizumab) and have sufficient safety evaluation.  Subjects who 
had a DLT event will be considered evaluable for the dose-limiting toxicity as well. 
It is the analysis set for DLT evaluation in the Phase 1b part.
The Full Analysis Set (Safety Analysis Set) includes all subjects who received any 
amount of either study drug.  This is the analysis set for safety analyses and analysis 
of PFS and OS.  
The Evaluable Analysis Set (subset of Full Analysis Set) includes all subjects who 
have both an evaluable baseline tumor assessment and an evaluable postbaseline 
tumor assessment, unless discontinued early or death.  It is the analysis set for 
efficacy analyses. 


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The PD-L1 Positive Set (subset of Evaluable Analysis Set) includes evaluable 
subjects whose PD-L1 expression level is above the threshold that is to be specified 
prior to the final analysis.  Key primary and secondary efficacy endpoints (ie, ORR, 
PFS, OS, and DOR) will be summarized in this analysis set.
9.7.1.3
Subject Disposition
The number and percentage of subjects who completed the study/discontinued from the study 
and reasons for discontinuation will be summarized.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized in the Full Analysis Set, 
using descriptive statistics.  Continuous variables include age, weight, vital signs, time since 
MBC diagnosis; categorical variables include sex, age group, race, disease stage (Appendix
8), ECOG-PS, bone, skin, liver, and lung metastases.
9.7.1.5
Prior and Concomitant Therapy
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization (WHO) Drug Dictionary drug codes.  Concomitant medications will be further 
coded to the appropriate Anatomical Therapeutic Chemical (ATC) code indicating 
therapeutic classification.  Prior and concomitant medications will be summarized and listed 
by drug and drug class in the clinical study report for this protocol.  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug up to 30 days (90 days if given for SAEs and/or ECIs)
after the subject’s last dose.  A listing of prior and concomitant medications will be included 
in the clinical study report of this protocol.
9.7.1.6
Efficacy Analyses
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
At least 165 evaluable subjects on RP2D will be enrolled in the study, including Phases 1b 
and 2.
Bayesian predictive probability (PP) design was used in original study design. Under 
original design, in the combined Stratum 1 and 2 subjects, the ORR value per RECIST 1.1 by 
IRR was assumed to be 0.20 for the historical control based on the recent studies (Table 1). 
The ORR in this study is estimated to be 0.35. Under protocol amendment 1, approximately 
100 evaluable subjects were expected to be enrolled. Bayesian PP was used to monitor the 
response rate after postbaseline tumor assessments of at least 38 subjects were available.  The 
calculation of PP was based on the goal of claiming superiority of the combination at the end 
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P(p>0.2|data)≥0.95        (1)
where p was the response rate of the combination, 0.2 was the response rate of historical 
control based on single agents pembrolizumab and eribulin in recent studies (Table 1), 0.95 
was the prespecified target probability (θT), and P(p>0.2|data) is the posterior probability.  
On the basis of the accumulated data thus far in the study, the probabilities of all possible 
future outcomes that lead to equation (1) at the end of the study would be added in order to 
obtain the predictive probability.  Therefore, early decision of study termination prior to 
reaching approximately 100 evaluable subjects was possible for claiming the combination is 
promising when PP is above a prespecified upper threshold (θU) or for claiming futility when 
PP is below a prespecified lower threshold (θL).  The upper and lower cutoff probabilities for 
decision-making, θU and θL, were set as 0.99 and 0.025.  Under the predictive monitoring, the 
study proceeded as follows:
If PP> θU(=0.99), stop the study and claim the combination promising
If PP< θL(=0.025), stop the study and claim the combination not promising
Otherwise, continue the study until the number of evaluable subjects reaches to 100
The Bayesian stopping boundaries are included in Appendix 1.
After completion of enrollment under protocol amendment 1, Bayesian PP is no longer used 
for continuous monitoring of efficacy and futility as the study will not be stopped early for 
either efficacy or futility. 
Under protocol amendment 3, in Stratum 2 subjects, the hypotheses for ORR per RECIST by 
IIR are updated to be H0: ORR=0.10 vs. Ha: ORR=0.25, based on the most recent 
pembrolizumab monotherapy study (Table 1). Therefore, additional subjects will be enrolled 
to ensure 80 evaluable subjects in Stratum 2 to provide >90% power for the comparison of 
H0: ORR=0.10 vs. Ha: ORR=0.25 at 1-sided alpha value of 0.025. Under Protocol 
Amendment 4, additional subjects will be enrolled to ensure 100 evaluable subjects in 
Stratum 2 to obtain more precise estimate of ORR. 
Final Analysis
In the evaluable subjects in Stratum 1 and 2 combined, Bayesian posterior probability in 
equation (1) will be evaluated to determine the efficacy of the combination regimen after the 
tumor response status has been collected from the last evaluable subjects.  That is, to claim 
efficacy if P(p>0.2|data)≥0.95.  A 2-sided 95% credible interval of objective response rate in 
the evaluable subjects will be constructed to aid the interpretation of the results.  Details of 
predictive and posterior probabilities calculation will be provided in the SAP. 
In the evaluable Stratum 2 subjects, a binomial exact test will be used to test the estimated 
ORR per RECIST 1.1 by IIR versus a historical response rate of 10% at 1-sided alpha value 
of 0.025. 


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Subjects in the Phase 1b part who were treated at the RP2D and were deemed evaluable will 
be combined with Phase 2 subjects in the efficacy analysis.
9.7.1.6.2
SECONDARY EFFICACY ANALYSIS
PFS, OS, and DOR
Progression-free survival (PFS), OS, and DOR will be analyzed using Kaplan–Meier 
product-limit estimates.  Median PFS and OS and the cumulative probability of PFS, OS, and
DOR at 6 and 12 months will be presented with 2-sided 95% CIs if estimable.  Censoring 
rules for PFS and DOR will be provided in the SAP.
The cumulative PFS, OS, and DOR will be plotted over time.  The median, first, and third 
quartiles from Kaplan–Meier estimation for PFS, OS, and DOR will be provided with 95% 
CIs if estimable. 
Clinical Benefit Rate
A 2-sided Clopper–Pearson 95% CI will be constructed for calculating exact binomial 
intervals. 
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSIS
The analysis of time to response (TTR) will follow the analysis of PFS.  The analysis will be 
performed in the subjects with confirmed PR/CR by RECIST1.1.  
In addition to RECIST1.1 by IIR, tumor assessment data (ie, ORR, PFS, DOR, and CBR) 
will be assessed per RECIST1.1 by investigator review and per irRECISTby IIR and 
investigator review in the sensitivity analysis.  
All efficacy analyses will be performed in overall subjects and also for each stratum.
Efficacy outcomes will be further evaluated in the PD-L1 Positive Set.  The clinical utility of 
PD-L1 as a predictive marker in mTNBC subjects who receive eribulin mesylate and 
pembrolizumab combination treatment will be assessed. 
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
Pharmacokinetic assessments of eribulin mesylate will be performed in all subjects in the 
Phase 1b part of the study.  Subjects in the Phase 2 part will undergo sparse PK sampling for 
population PK/PD analysis where feasible.
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Plasma concentrations of eribulin mesylate will be analyzed to determine PK parameters 
including maximum plasma concentration (Cmax), time to maximum plasma/serum 


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concentration (tmax), clearance (CL), area under the concentration-time curve (AUC), and 
terminal elimination phase half-life (t½).  These PK parameters will be calculated at a 
minimum and additional parameters will be calculated if the data allow.  Further details on 
PK parameters will be included in the SAP.
Details of the PK analyses will be provided in a separate analysis plan.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Exploratory graphical analysis will be conducted for PK/PD evaluations and may be 
followed by model-based analysis.  
Further details will be provided in a separate document.
9.7.1.7.3
PHARMACOGENOMIC AND OTHER BIOMARKER ANALYSES
Pharmacogenomic and other biomarker analyses may be performed and reported separately.  
Details of these analyses may be described in a separate analysis plan.
9.7.1.8
Safety Analyses
Safety analyses will be performed for the Safety Analysis Set.  Safety data that will be 
evaluated include AEs, clinical laboratory results, vital signs, and ECGs.  Safety will be 
summarized separately for subjects enrolled in Phase 1b and Phase 2 and combined, unless 
otherwise specified in the SAP.
RP2D and DLT
The Phase 1b study will include at least 1 safety run-in cohort in which 6 metastatic 
triple-negative breast cancer (mTNBC) subjects who receive eribulin mesylate 1.4 mg/m2 on 
Days 1 and 8 and pembrolizumab 200 mg on Day 1 of a 21-day cycle (Dose Level 1).  
Subjects will be observed for dose-limiting toxicity (DLT) in the first cycle.  The purpose of 
the safety run-in cohort(s) is to study safety of the 2-drug combination.  The Phase 2 part will 
proceed with Dose Level 1 when no more than 1 subject has a DLT. Otherwise, a lower 
eribulin mesylate dose of 1.1 mg/m2 and pembrolizumab 200 mg will be evaluated in another 
cohort of 6 subjects.  If no more than 1 subject has a DLT in the first cycle, the Phase 2 part 
will proceed with Dose Level 0 as the RP2D.  Otherwise, alternative doses (eribulin mesylate 
0.7 mg/m2) will be explored prior to the start of the Phase 2 part.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/duration on treatment, quantity of study treatment administered, dose 
intensity (ie, mg/m2/week for eribulin mesylate) and the number of subjects requiring dose 
reductions, dose omission, and dose delay will be summarized for eribulin mesylate. The 
number of administrations of pembrolizumab will be summarized.  


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Relative dose intensity (RDI) for each study drug will be calculated as Dea/Dep, where Dea is 
the actual total dose received and Dep is the total planned dose.  Dep of eribulin mesylate is 
calculated based on a subject’s body surface area (BSA). 
The duration of exposure for each study drug in days is defined as the date of the last dose –
the date of the first dose +1.  Average cycle length is defined as the duration of exposure 
divided by the number of cycles in the study.
9.7.1.8.2
ADVERSE EVENTS
Dose-limiting toxicity in the first cycle will be used to determine the RP2D. The DLT rate 
will be summarized descriptively at each combination dose level in the DLT evaluable set.  
Subsequent dose-limiting toxicity will be reported and summarized as well.
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 17 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that had an onset date, or a worsening in severity from baseline 
(pretreatment), on or after the first dose of study drug administration up to 30 days (90 days 
for SAEs and/or ECIs) following study drug discontinuation.
Only those AEs that were treatment emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by CTCAE v4.03.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
each study drug.  Treatment-related TEAEs include those events considered by the 
investigator to be possibly or probably related to study treatment or with missing assessment 
of the causal relationship.  Serious adverse events (SAEs), deaths, TEAE with Grade 3 or 
above, and TEAEs that led to treatment discontinuation, dose reduction or dose interruption 
will be summarized.
Adverse events of clinical interest, described in Section 9.5.4.3.2, will be summarized 
descriptively.  Details will be provided in the SAP. 
9.7.1.8.3
LABORATORY VALUES
Clinical laboratory (ie, hematology, serum chemistry and qualitative urinalysis) values will 
be evaluated for each laboratory parameter by subject.  Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range.  Reference 


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(normal) ranges for laboratory parameters will be included in the clinical study report for this 
protocol.  Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n[%] for categorical variables) for laboratory parameters 
and their changes from baseline will be calculated. 
Laboratory parameters that are graded in CTCAE (v4.03) will be summarized by CTCAE 
grade.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
9.7.1.8.5
ECOG PERFORMANCE STATUS
ECOG performance status will be summarized descriptively and by change from Baseline.
9.7.1.8.6
ELECTROCARDIOGRAMS
Electrocardiogram results will be evaluated on an individual basis by subject. Abnormal 
readings will be identified as those outside (above or below) the reference range.  
Electrocardiogram findings will be summarized.
9.7.2
Determination of Sample Size
A total of approximately 170 subjects (approximately 165 evaluable with at least 100 in 
Stratum 2) will be enrolled. 
Under Protocol Amendment 1, 107 subjects including at least 6 from the Phase 1b part were
enrolled in the study.  Enrollment was into 2 strata, which included first-line (Stratum 1) 
versus second- and third-line (Stratum 2) subjects.  Bayesian predictive probability was used 
to monitor the study after response data from the first 38 subjects were available.  Sample 
size calculation was carried out assuming the historical response rate of 0.2.  Using 
simulation, the model parameters (θL=0.025, θU =0.99, and θT=0.95) were calibrated such that 
the frequentist 1-sided Type I error was 0.0326 when the tumor response rate in the 
combination regimen was 0.2 (under frequentist’s null hypothesis H0), and the power was 
0.9278 when the response rate was 0.35 (under frequentist’s alternative hypothesis Ha).  The 
expected numbers of subjects needed to reach the decisions were 56 and 61 when p=0.2 
(under H0) and 0.35 (under Ha), respectively.  A vague beta prior distribution for response 
rate, p, was specified in PP calculation; that is, p~beta (0.2, 0.8).  PP was updated for every 3 
new subjects in the simulations, which mimics the group sequential decision making in a real 
study setting.  Without Bayesian interim monitoring, the Type I error was estimated as 
0.0358, and power was estimated as 0.9418 in demonstrating posterior probability 
P(p>0.2|data) ≥0.95.  Five thousand simulations were run to estimate these design 
characteristics.


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Per Amendment 3, additional subjects will be enrolled to ensure 80 evaluable subjects in 
Stratum 2. Using binomial exact test, the power is 0.92 with 80 evaluable subjects to 
demonstrate statistical significance at 1-sided alpha of 0.025 for the assumptions of H0: 
ORR=0.10 vs. Ha: ORR=0.25. With 80 subjects, the 95% confidence interval for ORR from 
binomial distribution will be 0.160-0.359 if the observed ORR is 0.25. 
Per Amendment 4, additional subjects will be enrolled to ensure 100 evaluable subjects in 
Stratum 2. With 100 subjects, power will be increased to 98% and the 95% confidence 
interval for ORR from binomial distribution will be 0.169-0.347 if the observed ORR is 0.25.
9.7.3
Interim Analysis
Under Protocol Amendment 1, interim decisions could be made on the basis of the expected 
response rate at the end of the study, which compromises the current information with the 
future sample size via a predictive probability approach.  The Bayesian design can 
continuously update the predictive probability of the study outcome, such that early 
termination of a study is possible for either superiority or futility.  The prespecified Bayesian 
stopping boundaries are included in Appendix 1. One interim analysis was performed after 
the first 39 enrolled subjects completed at least 2 tumor assessments or discontinued due to 
PD or death.
9.7.4
Other Statistical/Analytical Issues
Primary, secondary, and exploratory endpoints ORR, PFS, DOR, and CBR will be 
summarized in the evaluable analysis set in which an evaluable baseline tumor assessment 
and at least 1 evaluable postbaseline tumor assessment are required.  In the analyses 
described above and any other sensitivity analysis, subjects with missing data will be 
considered as nonresponders in ORR and CBR calculation and nonresponders will be
excluded in the analysis of DOR.
Any other statistical/analytical issues will be discussed in the SAP.
9.7.5
Procedure for Revising the Statistical Analysis Plan
The SAP will be finalized prior to the database lock in this exploratory study.  Any deviation 
from analysis plan described in the protocol will be documented in the SAP. 


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10 REFERENCE LIST
Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, et al. Phase 2 study of 
pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative 
breast cancer mTNBC): KEYNOTE-086 cohort A. (Abstr 1008). Presented at 2017 ASCO 
Annual Meeting. June 2-6, 2017. Chicago, Illinois.
Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease.  Am J Pathol. 
1990; 136:593-608.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-1 4_QuickReference_8.5x11.pdf. 
Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, et al. A senescence-like 
phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure 
to anticancer agents.  Cancer Res. 1999;59:3761-7.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
Ellis PA, Smith IE, McCarthy K, Detre S, Salter J, Dowsett M. Preoperative chemotherapy 
induces apoptosis in early breast cancer. Lancet. 1997;349:849.
Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate 
reduces tumor microenvironment abnormality by vascular remodeling in preclinical human 
breast cancer models. Cancer Sci. 2014 Oct;105(10):1334-42.
Gauthier VJ, Tyler LN, Mannik M. Blood clearance kinetics and liver uptake of 
mononucleosomes in mice. J Immunol. 1996;156:1151-6.
HALAVEN® Investigator’s Brochure. Edition 12;25 Jul 2014.
HALAVEN® package insert. Dec 2014. 
KEYTRUDA® package insert. 01 Jan 2015
Lin HL, Liu TY, Chau GY, Lui WY, Chi CW. Comparison of 2-methoxyestradiol-induced, 
docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation 
with reactive oxygen species. Cancer. 2000;89:983-94.


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Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, et al. PD-L1 
expression in triple-negative breast cancer. Cancer Immunol Res. 2014;(4);361–70. Available 
from: http://cancerimmunolres.aacrjournals.org/content/2/4/361.short.
Morse DL, Gray H, Payne CM, Gillie RJ. Docetaxel induces cell death through mitotic 
catastrophe in human breast cancer cells. Mol Cancer Ther. 2005;4:1495-504.
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. A phase Ib study of 
pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer [abstract]. 
Paper  presentation at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; 
San Antonio, Texas. Abstract S1-09.
Oken MM, Creech RH, Torney DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55.
Pembrolizumab® Investigator’s Brochure. Edition 18; 10 March 2020.
Rein DT, Schöndorf T, Breidenbach M, Janát MM, Weikelt A, Göhring UJ, et al. Lack of 
correlation between P53 expression, BCL-2 expression, apoptosis and ex vivo 
chemosensitivity in advanced human breast cancer. Anticancer Res. 2000;20:5069-72.
Roninson IB, Broude EV, Chang BD. If not apoptosis, then what? Treatment-induced 
senescence and mitotic catastrophe in tumor cells. Drug Resist Updat. 2001;4:303-13.
Stearns V, Singh B, Tsangaris T, Crawford JG, Novielli A, Ellis MJ, et al. A prospective 
randomized pilot study to evaluate predictors of response in serial core biopsies to single 
agent neoadjuvant doxorubicin or paclitaxel for patients with locally advanced breast cancer.  
Clin Cancer Res. 2003;9:124-33.
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, Brown & 
Co; 1994:253-6.
Wang LG, Liu XM, Kreis W, Budman DR. The effect of antimicrotubule agents on signal 
transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol. 1999;44:355-61.
Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate 
suppresses experimental metastasis of breast cancer cells by reversing phenotype from 
epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. 
Br J Cancer. 2014 Mar 18;110(6):1497-505.
Eisai Clinical Study Reports
Study E7389-G000-301.  A phase III open label, randomized two-parallel-arm multicenter 
study of E7389 versus capecitabine in patients with locally advanced or metastatic breast 


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cancer previously treated with anthracyclines and taxanes.  Clinical Study Report 301. 21 
Feb 2013.
Study E7389-G000-305.  Phase III open label, randomized parallel two-arm multicenter 
study of E7389 versus ‘Treatment of physician’s Choice’ in patients with locally recurrent or 
metastatic breast cancer, previously treated with at least two and a maximum of five prior 
chemotherapy regimens, including an anthracycline and a taxane. 19 Mar 2010. 


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
There are to be no changes to the protocol without written approval from the sponsor.  
Protocols will be followed as written.
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and the IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator or 
designee will allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to 
assure compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and IRB/IEC review.


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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for 
accuracy after production

Recorded data from automated instruments such as x-rays and other imaging 
reports, (eg, PET/CT scans, magnetic resonance images, ECGs) regardless of how 
these images are stored, including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs 

Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and 
serve as their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data:

Study treatment compliance (eg, the reason for dose increase/reduction)

Discontinuation information

Sampling date and time for the drug concentration

Sampling date and time for the clinical laboratory test


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
Comments and other information on AEs (eg, severity, relationship to study 
treatment, outcome)
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that the investigator contact the sponsor at the completion of the required 
retention period, or should the investigator retire or relocate, allowing the sponsor the option 
of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department must conduct audits of clinical research activities in accordance with the 
sponsor’s SOPs to evaluate compliance with the principles of ICH GCP and all applicable 
local regulations.  If a government regulatory authority requests an inspection during the 
study or after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.


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11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission,
pursuant to the terms and conditions set forth in the executed Clinical Study Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Study Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical 
Study Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.


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11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES
Appendix 1
Bayesian Stopping Boundaries
N
LB
UB
N
LB
UB
N
LB
UB
38
6
16
60
12
22
82
19
27
39
6
16
61
12
22
83
19
27
40
6
17
62
12
23
84
19
27
41
7
17
63
13
23
85
20
27
42
7
17
64
13
23
86
20
27
43
7
18
65
13
23
87
20
28
44
7
18
66
14
23
88
21
28
45
8
18
67
14
24
89
21
28
46
8
18
68
14
24
90
22
28
47
8
19
69
14
24
91
22
28
48
9
19
70
15
24
92
22
28
49
9
19
71
15
25
93
23
28
50
9
20
72
15
25
94
23
28
51
9
20
73
16
25
95
24
28
52
10
20
74
16
25
96
24
28
53
10
20
75
16
25
97
25
28
54
10
21
76
17
26
98
25
28
55
10
21
77
17
26
99
26
28
56
11
21
78
17
26
100
27
28
57
11
21
79
18
26
58
11
22
80
18
26
59
12
22
81
18
27


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Appendix 2
Sponsor’s Grading for Laboratory Values
The table below is an example of the Sponsor’s Grading Laboratory Values based on 
Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 
May 28, 2009 (v4.03: June 14, 2010).  The study team should assess whether the sponsor’s 
Grading for Laboratory Values is appropriate for individual studies.  If this appendix is used, 
it is the study team’s responsibility to ensure that the current version of the sponsor’s 
Grading Laboratory Values is placed in the appendix.
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 
mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion 
indicated
life-threatening 
consequences; 
urgent 
intervention 
indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN –
75.0109/L
<LLN –
75,000/mm3
<75.0 –
50.0109/L
<75,000 –
50,000/mm3
<50.0 – 25.0109/L
<50,000 –
25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/
LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; 
urgent 
intervention 
indicated
Alkaline phosphatase 
>ULN – 3.0ULN >3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN >3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN >3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN >1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low 
<LLN – 8.0 mg/dL <8.0 – 7.0 mg/dL
<7.0 – 6.0 mg/dL
<6.0 mg/dL


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypocalcemia) 
<LLN – 2.0 
mmol/L
<2.0 – 1.75 
mmol/L
<1.75 – 1.5 
mmol/L
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>ULN – 11.5 
mg/dL
>ULN – 2.9 
mmol/L
>11.5 – 12.5 
mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 
mg/dL
>ULN – 7.75 
mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 
mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 
mmol/L 
>500 mg/dL
>12.92 
mmol/L 
Creatinine
>ULN – 1.5ULN >1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl 
transpeptidase) 
>ULN – 3.0ULN >3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high 
(hyperglycemia)
Fasting glucose 
value:
>ULN – 160 
mg/dL
>ULN – 8.9 
mmol/L 
Fasting glucose 
value:
>160 – 250 mg/dL
>8.9 – 13.9 
mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 
mmol/L;
hospitalization 
indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low 
(hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 
mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 
mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
>ULN – 5.5 
mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization 
indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low 
(hypokalemia) 
<LLN – 3.0 
mmol/L
<LLN – 3.0 
mmol/L; 
symptomatic; 
intervention 
indicated
<3.0 – 2.5 mmol/L
hospitalization 
indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high 
(hypernatremia)
>ULN – 150 
mmol/L
>150 – 155 
mmol/L
>155 – 160 
mmol/L
hospitalization 
indicated
>160 mmol/L
life-threatening 
consequences


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Sodium, serum-low 
(hyponatremia)
<LLN – 130 
mmol/L
N/A
<130 – 120 
mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 
mmol/L
>300 – 500 mg/dL
>3.42 –
5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 
mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high 
(hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L 
without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum 
glutamic oxaloacetic transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, 
ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 
14, 2010).


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Appendix 3
Overview of RECIST v1.1 for Evaluation of Tumors 
Response 
Tumor response assessments in this clinical study will use RECIST v1.1 guidelines based on 
the article by Eisenhauer, et al., 2009, entitled “New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1).”  This appendix contains an overview of 
the RECIST v1.1 guidelines.  For complete details, the Eisenhauer article, published in the 
European Journal of Cancer, is available online at: http://www.ejcancer.com/article/S0959-
8049(08)00873-3/abstract


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Appendix 4
Immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST)
Investigators should follow the guidelines provided here, which are an adaptation of RECIST 
1.1 and immune-related response criteria (irRC).  The following guide represents a summary 
of irRECIST and is meant to help investigators in providing more objective and reproducible 
immune therapy-related tumor response assessments in solid tumors.
The key changes for irRECIST are:
For this study, similar to that allowed for RECIST 1.1, irRECIST allows the site to 
select up to 5 target lesions at baseline, 2 per organ, if clinically relevant via CT/MRI 
scans or by electronic calipers for skin lesions. The ability to continue treatment, if 
clinically stable, until repeat imaging scans ≥ 4 weeks later (in most cases at the next 
scanning time point) to confirm immune-related progressive disease (irPD)
irRECIST Lexicon
1.
Baseline Assessments
Measurable 
(Target) Lesions
Measurable lesions must be accurately measured in at least 1 dimension with a 
minimum size of:
10 mm in the longest diameter (LDi) by CT or MRI scan (or no less than double 
the slice thickness) for non-nodal lesions and ≥15 mm in short axis (SDi) for nodal 
lesions
10 mm in LDi for clinical lesions (must be measured using electronic calipers)
Identify up to 5 lesions, not more than 2 from 1 organ system. Lymph nodes are 
considered 1 organ system
Likely to be reproducible across all time points
Representative of tumor burden
May include lesions in previously irradiated areas ONLY if there is demonstrated 
progression in that lesion after irradiation
Sum of diameters (SOD) of all target lesions including nodal and non-nodal are 
reported as baseline SOD which is used for assessing tumor response at follow-up 
time points
Bone Lesions
Regardless of the imaging modality, blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component 
≥10 mm can be selected as target lesions.
Cystic and 
Necrotic Lesions 
as Target 
Lesions
Lesions that are partially cystic or necrotic can be selected as target lesions. The 
longest diameter of such a lesion will be added to the SOD of all target lesions at 
baseline. If other lesions with a nonliquid/nonnecrotic component are present, those 
should be preferred.
Lesions with 
Prior Local 
Treatment
During target lesion selection the radiologist will consider information on the 
anatomical sites of previous intervention (eg, previous irradiation, RF-ablation, TACE, 
surgery, etc).  Lesions undergoing prior intervention will not be selected as target 
lesions unless there has been a demonstration of progression in the lesion.
Nonmeasurable 
(Nontarget) 
Lesions
Non-target lesions will include:
Measurable lesions not selected as target lesions.  There is no limit to the number 
of nontarget lesions that can be recorded at baseline
Other types of lesions that are confidently felt to represent neoplastic tissue, but 
are difficult to measure in a reproducible manner.  These include bone metastases, 


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leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, 
ascites, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, 
ill-defined abdominal masses, etc.
Multiple non target lesions from the same organ may be captured as a single item 
on the CRF (eg, multiple liver metastases)
Non-target lesions should be reported as present at baseline
SOD baseline
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal target lesions
2.
Time point Assessments after Baseline
Target lesion 
measurements
Locate image that optimizes the LDi of the non-nodal target lesion or short axis of 
target node(s).  There is no need to go to an identical slice from baseline.
Measure the respective LDi and SDi for all target lesions and calculate time point SOD 
(SOD timepoint).
Special consideration for target lesions:
If a target lesion is too small to measure, a default value of 5 mm should be entered 
on CRF.
If a target lesion is between 5-10 mm, actual diameter should be entered on the 
CRF.
If a target lesion splits into 2 or more lesion then the LDi of split lesions will be 
added and entered in place of that lesion.
If 2 target lesions merged to form 1 lesion, then the LDi of 1 should be entered as 
“0 mm” while the other lesion should have the diameter of the merged lesion.
Nontarget Lesion 
Assessment
Nontarget lesions are evaluated qualitatively as present, absent, not evaluable (NE) or 
unequivocal progression.  The response of nontarget lesions primarily contributes to 
the overall response assessments of irCR.  Nontarget lesions do not affect irPR and 
irSD assessments.  Only a massive and unequivocal worsening of nontarget lesions 
alone, even in the presence of stable disease or a PR in the target lesion is indicative of 
irPD.  IrCR is not possible unless all nontarget lesions are absent.
Definition of 
New lesion
Any lesion which was not recorded at baseline.  There is no minimum size criteria to 
identify a new lesion and clinical judgment must be used by the PI

May include a lesion in an anatomical location that was not scanned at baseline 
(ie, brain)

Should be unequivocal and not due to differences in scanning technique

If equivocal, should be assessed at next time point; if present, irPD is the date the 
lesion was first seen (not the date confirmed)
3.
irRECIST Overall Tumor Assessment
irCR

Complete disappearance of all measurable and nonmeasurable lesions (from 
baseline) and there are no unequivocal new lesions (unconfirmed irCR).

Lymph nodes must decrease to <10 mm in short axis.

Confirmation of response is required ≥ 4 weeks later, preferably at next time point, 
to be considered a confirmed irCR.
irPR

If the SODtimepoint of TLs decreases by ≥30 % compared to SODbaseline and there 
are no unequivocal new lesions, and no progression of nontarget disease, it is an 
irPR (unconfirmed). 

Confirmation is required ≥ 4 weeks later, preferably at next time point, to be 
considered a confirmed irPR.
irSD
Failure to meet criteria for irCR or irPR in the absence of irPD.

If the sum of the TLs and the status of the nontarget lesions do not reach the 
criteria to meet irPR or irPD (an increase of ≥20% and at least 5 mm absolute 
increase in SOD compared to nadir†), the response is irSD.


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
irSD = neither 30% decrease compared to SODbaseline or 20% increase  and at 
least 5 mm absolute change compared to nadir.

†SODnadir: Lowest measure SOD of TLs at any time point from baseline onward.
irPD
A minimum 20% increase and a minimum 5 mm absolute increase in SOD compared 
to nadir, or irPD for nontarget lesion(s) or unequivocal new lesion(s).

Confirmation of progression is recommended at a minimum of 4 weeks after the 
first irPD assessment (preferably at the next tumor assessment time point).
The decision to continue study treatment after the first evidence of PD is at the 
investigator’s discretion based on the clinical status of the subject as described in table 
below:
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
by RECIST 1.1
Repeat 
imaging at >4 
weeks (next 
TA time
point) to 
confirm PD
May continue 
study treatment 
at the local site 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site by 
irRECIST
Repeat 
imaging at >4 
weeks to 
confirm PD 
per physician 
discretion only
Discontinue 
treatment
Subsequent 
tumor imaging 
confirms PD by 
irRECIST at 
the local site
No additional 
imaging 
required
Discontinue 
treatment
(exception is 
possible upon 
consultation with 
sponsor)
No additional 
imaging 
required
N/A
Subsequent 
tumor imaging 
shows SD, PR,
or CR
by irRECIST at 
the local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart 
study 
treatment if 
condition has 
improved 
and/or 
clinically 
stable per 
investigator’s
discretion. 
Next tumor 
image should 
occur 
according to 
the every 9
weeks ± 1
week) 
imaging 
schedule 
Subjects may continue receiving study treatment while waiting for confirmation of 


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irPD if they are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, site 
must contact the sponsor to discuss continuing treatment.
irNE
Used in exceptional cases where insufficient data exists due to poor quality of scans or 
missed scans or procedure.
In determining whether or not the tumor burden has increased or decreased, local study site 
investigators should consider all target lesions as well as non-target lesions.  Subjects that are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation.  
•
For a clinically stable subject with first radiologic evidence of progressive disease by 
RECIST 1.1 (ie, unconfirmed progression of disease), it is at the discretion of the site 
investigator to continue treating the subject with the assigned treatment per protocol until 
progression of disease is confirmed at least 28 days from the date of the scan first suggesting 
PD. If radiologic progression is confirmed by subsequent scan then the subject will be 
discontinued from study treatment.  If radiologic progression is not confirmed by irRECIST 
per the site, then the subjects may continue on treatment and follow the regular imaging 
schedule intervals until progression is confirmed at a later timepoint by the site. 
o
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in sections 6.0 
Study Flowchart and be submitted to the central imaging vendor.  Note:  As of 
Protocol Amendment 05, tumor assessment scans will no longer be sent to the central
imaging laboratory.
•
Any subject deemed clinically unstable should be discontinued from study treatment at 
1st radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
•
In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 9 weeks ± 1 week in Year 1, 
and every 9 to 12 weeks ± 1 week thereafter according to standard of care), until (1) the start 
of new anti-cancer treatment, (2) disease progression (3) death, or (4) the end of the study, 
whichever occurs first.


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Derivation of irRECIST overall responses
Measurable response 
Nonmeasureable response
Target Lesions
(% change in SOD)*
Nontarget Lesions 
Status
New Lesions Status
Overall Response 
(irRECIST)
100
Absent
Absent
irCR¥
100
Present/NE
Absent
irPR¥
≥30
Present/Absent/NE
Absent
irPR¥
<30 to <20
Present/Absent/NE
Absent
irSD
100
≥30
<30 to <20
NE
Present/Absent/NE
Present
irPD¥
100
≥30
<30 to <20
NE
Unequivocal 
progression
Any
irPD¥
≥20 from nadir
Any
Any
irPD¥
NE
Present/Absent/NE
Absent
irNE¥
CR = complete response, CRF = case report form, ECOG = Eastern Cooperative Oncology Group, irCR = immune-
related complete response, irNE = immune-related neuropathy, irPD = immune-related progressive disease, irSD = 
immune-related stable disease, N/A = not applicable, PD = progressive disease, SD = stable disease, SOD = sum of 
diameters, TA = tumor assessment, TL = target lesion.
* Decreases assessed relative to baseline, including measureable lesions only.
¥ Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 weeks
apart.


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Appendix 5
New York Heart Association Cardiac Disease Classification
The New York Heart Association (NYHA) Cardiac Disease Classification provides a 
functional and therapeutic classification for the prescription of physical activity for cardiac 
subjects.  On the basis of NYHA definitions, subjects are to be classified as follows:
Class
Definition
Class I
Subjects with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II
Subjects with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable only at rest.
Class IV
Subjects who should be at complete rest, confined to bed or chair; any physical activity 
brings on discomfort and symptoms occur at rest.
  Adapted from The Criteria Committee of the New York Heart Association, 1994.


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Appendix 6
Common Terminology for Adverse Events (version 4.03)
The National Cancer Institute's CTCAE v4.0 published 28 May 2009 (v4.03: June 14, 2010) 
provides descriptive terminology to be used for AE reporting in clinical studies.  A brief 
definition is provided to clarify the meaning of each AE term.  To increase the accuracy of 
AE reporting, all AE terms in CTCAE version 4.0 have be correlated with single-concept, 
MedDRA terms.
Grades in CTCAEs v4.03 refer to the severity of the AE.  Grades of 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline:
Grade
Status
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.
2
Moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.a
3
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling, limiting self-care ADL.b
4
Life-threatening consequences: urgent intervention indicated.
5
Death related to adverse event.
ADL = Activities of Daily Living.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
Cancer Therapy Evaluation Program, NCI CTCAE v4.0. Available from:
http://ctep.cancer.gov/protocolDevelopmentielectronic applications/docs/ctcaev 4.pdf
For further details regarding MedDRA, refer to the MedDRA website at:
http://www.meddramsso.com. CTCAE v4.0 is available online at:
http://ctep.cancer.gov/protocoIDevelopmentielectronic applications/docs/ctcaev 4.pdf.


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Appendix 7
ECOG Performance Status Scale
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light house work, office work).
2
Ambulatory and capable of all self-care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
ECOG = Eastern Cooperative Oncology Group.
Adapted from Oken, et al., 1982.


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Appendix 8
Breast Cancer TNM Staging System
Tumor (T), Node(N), Metastases (M)
Stage
Thickness/Characteristics
T Classification
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ; intraductal carcinoma, lobular carcinoma in situ or Paget's disease of the nipple 
with no associated tumor
T1
Tumor ≤2.0 cm in greatest dimension
T1mic
Microinvasion of ≤0.1 cm in greatest dimension
T1a
Tumor >0.1 cm, but ≤0.5 cm in greatest dimension
T1b
Tumor >0.5 cm, but ≤1.0 cm in greatest dimension
T1c
Tumor >1.0 cm, but ≤2.0 cm in greatest dimension
T2
Tumor >2.0 cm, but ≤5.0 cm in greatest dimension
T3
Tumor >5 cm in greatest dimension
T4
Tumor of any size with direct extension to (a) chest wall or (b) skin
T4a
Tumor of any size with direct extension to chest wall
T4b
Edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin nodules 
confined to the same breast
T4c
Both Ta and Tb
T4d
Inflammatory carcinomaa
Regional Lymph Nodes (N) Classification
NX
Regional lymph nodes cannot be assessed (eg, previously removed)
N0
No regional lymph node metastasis
N1
Metastases to movable ipsilateral level I, II axillary lymph node(s)
N2
Metastases to ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in 
clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary 
lymph node metastases
N3
Metastases in ipsilateral infraclavicular (level III axillary) lymph nodes with or without level I, II 
axillary lymph node involvement; or in clinically detected ipsilateral internal mammary lymph 
node(s) with clinically evident level I, II axillary lymph node involvement; or metastases in 
ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node 
involvement
N3a
Metastases in ipsilateral infraclavicular lymph node(s)


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Tumor (T), Node(N), Metastases (M)
Stage
Thickness/Characteristics
N3b
Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
Pathologic (pN) Classification
pNX
Regional lymph nodes cannot be assessed (not removed for pathologic study or previously removed)
pN0
No regional lymph node metastasis identified histologically
pN1
Micrometastases, or metastases in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes 
with metastases detected by sentinel lymph node biopsy but not clinically detected
pN1a
Metastases in 1 to 3 axillary lymph nodes (at least one >2.0 mm)
pN1b
Metastasis in internal mammary lymph nodes with micro- or macrometastases detected by sentinel 
lymph node biopsy but not clinically detected
pN1c
Metastases in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with micro- or
macrometastases detected by sentinel lymph node biopsy but not clinically detected
pN2
Metastases in 4 to 9 axillary lymph nodes or in clinically detected and in internal mammary lymph 
nodes in the absence of axillary lymph node metastases
pN2a
Metastases in 4 to 9 axillary lymph nodes (at least one tumor deposit >2.0 mm)
pN2b
Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph 
node metastases
pN3
Metastases in 10 or more axillary lymph nodes or in infraclavicular (level III axillary) lymph nodes 
or in clinically detected ipsilateral internal mammary lymph nodes in the presence of 1 or more 
positive level I, II axillary lymph nodes; or in >3 axillary lymph nodes and in internal mammary 
lymph nodes with micro- or macrometastases detected by sentinel lymph node biopsy but not 
clinically detected; or in ipsilateral supraclavicular lymph nodes
pN3a
Metastases in 10 or more axillary lymph nodes (at least one tumor deposit >2.0 mm) or metastases 
to the infraclavicular (level III axillary) lymph nodes
pN3b
Metastases in clinically detected ipsilateral internal mammary lymph nodes in the presence of 1 or 
more positive axillary lymph nodes with micro- or macrometastases detected by sentinel lymph node 
biopsy but not clinically detected
pN3c
Metastases in ipsilateral supraclavicular lymph nodes
Distant Metastases (M) Classification
MX
Presence of distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis present (includes metastasis to ipsilateral supraclavicular lymph nodes)
Clinical detection: as detected by imaging studies.
a:  Inflammatory carcinoma is a clinicopathologic entity characterized by diffuse brawny induration of the skin 
of the breast with an erysipeloid edge, usually without an underlying palpable mass. Radiographically there 
may be a detectable mass and characteristic thickening of the skin over the breast. This clinical presentation is 


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due to tumor embolization of derrnal lymphatics with engagement of superficial capillaries.
Available from https://cancerstaging.org/references-tools/quickreferences/Pages/default.aspx
American Joint Committee on Cancer: Stage Groupings for Breast Cancer
Clinical Stage
0
Tis
N0
M0
IA
T1, T1mic
N0
M0
IB
T0
N1mic
M0
T1, T1mic
N1mic
M0
IIA
T0
N1
M0
T1, T1mic
N1
M0
T2
N0
M0
IIB
T2
N1
M0
T3
N0
M0
IIIA
T0
N2
M0
T1, T1mic
N2
M0
T2
N2
M0
T3
N1, N2
M0
IIIB
T4
N0, N1, N2
M0
IIIC
Any T
N3
M0
IV
Any T
Any N
M1
Available from https://cancerstaging.org/references-tools/quickreferences/Pages/default.aspx


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7389-M001-218
Study Protocol Title:
An Open-Label Single-Arm Multicenter Phase 1b/2 Study to 
Evaluate the Efficacy and Safety of Eribulin Mesylate in 
Combination with Pembrolizumab in Subjects with Metastatic 
Triple-Negative Breast Cancer (mTNBC)
Investigational Product 
Name:
E7389/eribulin mesylate and pembroluzimab
IND Number:
113851
SIGNATURES
Authors:
Eisai Inc.
Date
Eisai Ltd.
Date
Eisai Ltd.
Date
Date
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7389-M001-218
Study Protocol Title:
ENHANCE 1: An Open-Label Single-Arm Multicenter 
Phase 1b/2 Study to Evaluate the Efficacy and Safety of 
Eribulin Mesylate in Combination with Pembrolizumab in 
Subjects with Metastatic Triple-Negative Breast Cancer 
(mTNBC)
Investigational Product 
Name:
E7389/eribulin mesylate/ pembrolizumab
IND Number:
113851
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date

SAP_001.pdf: 
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1
TITLE PAGE
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7389-M001-218
Study Protocol 
Title:
An Open-Label Single-Arm Multicenter Phase 1b/2 Study to Evaluate the 
Efficacy and Safety of Eribulin Mesylate in Combination with 
Pembrolizumab in Subjects with Metastatic Triple Negative Breast Cancer 
(mTNBC)
Date:
08 Oct 2019
Version:
Final Version 1.0


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2
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
TABLE OF CONTENTS...................................................................................................2
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
4
INTRODUCTION .............................................................................................................8
4.1
Study Objectives ......................................................................................................8
4.1.1
Primary Objective..........................................................................................8
4.1.2
Secondary Objectives.....................................................................................8
4.1.3
Exploratory Objectives ..................................................................................9
4.2
Overall Study Design and Plan................................................................................9
5
DETERMINATION OF SAMPLE SIZE........................................................................10
6
STATISTICAL METHODS............................................................................................10
6.1
Study Endpoints.....................................................................................................11
6.1.1
Primary Endpoint.........................................................................................11
6.1.2
Secondary Endpoints ...................................................................................11
6.1.3
Exploratory Endpoints .................................................................................11
6.2
Study Subjects........................................................................................................11
6.2.1
Definitions of Analysis Sets.........................................................................11
6.2.2
Subject Disposition......................................................................................12
6.2.3
Protocol Deviations......................................................................................12
6.2.4
Demographic and Other Baseline Characteristics .......................................12
6.2.5
Medical History ...........................................................................................13
6.2.6
Prior and Concomitant Therapy...................................................................13
6.2.7
Treatment Compliance.................................................................................13
6.3
Data Analysis General Considerations ..................................................................13
6.3.1
Pooling of Centers........................................................................................13
6.3.2
Adjustments for Covariates..........................................................................14
6.3.3
Multiple Comparisons/Multiplicity .............................................................14
6.3.4
Examination of Subgroups...........................................................................14
6.3.5
Handling of Missing Data, Drop-outs, and Outliers....................................14
6.3.6
Other Considerations ...................................................................................15
6.4
Efficacy Analyses ..................................................................................................15
6.4.1
Primary Efficacy Analyses ..........................................................................15
6.4.1.1
ORR in All Subjects...........................................................................15
6.4.1.2
ORR in Stratum 2...............................................................................17


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6.4.2
Secondary Efficacy Analyses ......................................................................18
6.4.3
Other Efficacy Analyses ..............................................................................18
6.5
Pharmacokinetic, Pharmacodynamic and Pharmacogenomic Analysis ................18
6.5.1
Pharmacokinetic Analyses...........................................................................18
6.5.2
Pharmacodynamic Analyses........................................................................19
6.5.3
Pharmacokinetic / Pharmacodynamic Analyses ..........................................19
6.5.4
Pharmacogenomic and Biomarker Analyses ...............................................19
6.6
Safety Analyses......................................................................................................19
6.6.1
RP2D and Dose-limiting Toxicity in Phase1b.............................................19
6.6.2
Extent of Exposure.......................................................................................20
6.6.3
Adverse Events ............................................................................................20
6.6.4
Treatment-Emergent Adverse Events of Special Interest............................22
6.6.5
Laboratory Values........................................................................................22
6.6.6
Vital Signs....................................................................................................23
6.6.7
Electrocardiograms ......................................................................................23
6.6.8
Other Safety Analyses..................................................................................24
6.7
Other Analyses.......................................................................................................24
6.8
Exploratory Analyses.............................................................................................24
7
INTERIM ANALYSES...................................................................................................24
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................24
9
PROGRAMMING SPECIFICATIONS ..........................................................................32
10
STATISTICAL SOFTWARE..........................................................................................32
11
MOCK TABLES, LISTINGS AND GRAPHS (TLGS)..................................................32
12
REFERENCES ................................................................................................................33
13
APPENDICES .................................................................................................................34
13.1
Bayesian Stopping Boundaries ..............................................................................34


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3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC Level 1
anatomical therapeutic chemical  class
ATC Level 3
Pharmacological class
AUC(0-t)
area under the concentration-time curve from zero time (pre-dose) to 
the time of last quantifiable concentration 
AUC(0-inf)
area under the concentration-time curve from zero time (pre-dose) 
extrapolated to infinite time
ß -hCG
beta-human chorionic gonadotropin
BLQ
Below the limit of quantification
BMI
body mass index
BOR
best overall response
BSA
body surface area
BUN
blood urea nitrogen
CBR
clinical benefit rate
CI
confidence interval
CL
total clearance
Cmax
maximum observed concentration
CR
complete response
CRF
Case Report Forms  
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
C1D1
Cycle 1 Day 1


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Abbreviation
Term
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
EAS
Evaluable Analysis Set 
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
ER
estrogen 
FDA
US food and drug administration 
FAS
Full Analysis Set 
HER-2
human epidermal growth factor receptor 2
irAE
immune-related adverse events
irRECIST
Immune-related Response Evaluation Criteria In Solid Tumors
IV
Intravenous
LDH
Lactate Dehydrogenase
LLT
lower level term
LLOQ
lower limit of quantification 
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MRT
mean residence time
mTNBC
metastatic triple-negative breast cancer
NCA
Non-compartmental analysis 
NCI
National Cancer Institute
NE
not evaluable 
ORR
objective response rate


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Abbreviation
Term
OS
overall survival
PK/PD
Pharmacokinetic/pharmacodynamics
PD
progressive disease
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PP
predictive probability
PR
Partial Response
PT
preferred term 
Q1
first quantile
Q3
third quantile
RBC
red blood cell
RDI
relative dose intensity
RECIST 1.1
Response Evaluation Criteria in Solid Tumors (version 1.1)
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease 
SD
standard deviation
SMQ
Standardized MedDRA Queries 
SOC
system organ class 
t1/2
terminal elimination phase half-life
T4
thyroxine  
TEAE
treatment-emergent adverse event
tmax
time at which the highest drug concentration occurs
tlast
the time of the last measurable (positive) concentration.


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Abbreviation
Term
TSH
thyroid stimulating hormone,
TTR
time to response 
ULN
upper limit normal
UNK
unknown response 
Vz
volume of distribution at terminal phase
WBC
white blood cells
WHO DD
WHO Drug Dictionary


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4
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze the efficacy and safety variables and report results for Eisai 
Protocol E7389-M001-218, An Open-Label Single-Arm Multicenter Phase 1b/2 Study to Evaluate the 
Efficacy and Safety of Eribulin Mesylate in Combination with Pembrolizumab in Subjects with 
Metastatic Triple Negative Breast Cancer (mTNBC). The focus of this SAP is for the planned 
primary, secondary and exploratory efficacy and safety analyses during the interim monitoring and at 
the final analysis in the study. The analysis details for Pharmacokinetic, Pharmacodynamics, 
Pharmacogenomics, and Biomarker analyses are not described herein this SAP. Separate analysis 
plans will be completed for these specific analysis variables and attached to the final SAP and clinical 
study report.
Reference materials for this statistical analysis plan (SAP) include the protocol amendment 04 of 
E7389-M001-218 (dated 2019-05-29) and Case Report Forms (CRF, Version, 2017-2-21). If the 
protocol or case report forms are amended or updated then appropriate adjustments to the SAP may 
be made if they are related to the planned analyses.  
The SAP described hereafter is an a priori plan. This is an open label study and the SAP will be 
finalized and approved before database lock. Statistical programming may occur as study data 
accumulate in order to have analysis programs ready at the time the study finishes.
4.1
Study Objectives
In subjects with mTNBC previously treated with 0 (Stratum1) or 1 to 2 (Stratum 2) lines of systemic 
anticancer therapy in the metastatic setting and currently treated with eribulin mesylate in 
combination with pembrolizumab: 
4.1.1
Primary Objective

For the Phase 1b part – to determine safety and tolerability of eribulin mesylate in 
combination with pembrolizumab in all subjects (ie, Stratum 1 and 2). 

For the Phase 2 part – to evaluate objective response rate (ORR) per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1) by independent imaging review (IIR) in 
all subjects.

For the Phase 2 part – to evaluate ORR per RECIST 1.1 by IIR in Stratum 2 subjects and 
compare with the historical response rate of pembrolizumab monotherapy of 10%.
4.1.2
Secondary Objectives

For the Phase 2 part, in all subjects and separately in Stratum 2 subjects, to evaluate 
Progression-Free Survival (PFS) per RECIST 1.1 by IIR.

To evaluate Overall Survival (OS).

To evaluate Duration of Response (DOR) per RECIST 1.1 by IIR.

To evaluate Clinical Benefit Rate (CBR) per RECIST 1.1 by IIR.


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
To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by investigator 
review.

To evaluate efficacy outcomes (ORR, PFS, DOR and CBR) per RECIST 1.1 by IIR and OS 
outcome by PD-L1 (programmed death receptor-ligand 1) expression.

To evaluate the safety and tolerability of the combination.
4.1.3
Exploratory Objectives

To evaluate time to response (TTR) per RECIST 1.1 by IIR in all subjects and separately in 
Stratum 2 subjects.

To evaluate exposure-response relationship in all subjects.

To explore potential effects of pembrolizumab co-administration on the pharmacokinetics 
(PK) of eribulin mesylate in all subjects.

To explore efficacy outcomes (ORR, PFS, DOR, and CBR) per immune-related RECIST 1.1 
(irRECIST) by IIR and investigator review for all subjects and separately in Stratum 2 
subjects.
4.2
Overall Study Design and Plan
This is an open-label, single-arm, multicenter, Phase 1b/2 study of eribulin mesylate in combination 
with pembrolizumab in subjects with metastatic triple-negative breast cancer previously treated with 
0 to 2 lines of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic 
setting.  Subjects may have received prior neo/adjuvant chemotherapy.  
The Phase 1b part includes 1 initial safety run-in cohort in which at least 6 subjects will receive 
eribulin mesylate 1.4 mg/m2 intravenously (IV) on Days 1 and 8 of a 21-day cycle and 
pembrolizumab 200 mg IV on Day 1 of a 21-day cycle (dose level 1).  Dose-limiting toxicity (DLT) 
will be assessed in the first cycle.  Dose level 1 can be selected as the recommended Phase 2 dose 
(RP2D) if no more than 1 subject has a DLT.  Otherwise, eribulin mesylate dose will be lowered from 
1.4 mg/m2 to 1.1 mg/m2 on Days 1 and 8 of a 21-day cycle (dose level 0).  If no more than 1 out of 6 
subjects at dose level 0 has a DLT, the Phase 2 part will proceed with dose level 0.  Approximately 12 
subjects may be enrolled in the Phase 1b part of the study.  
Under protocol amendment 1, 107 subjects (including subjects in Phase 1b who are on RP2D level) 
were enrolled in 2 strata and received the same combination treatment at the RP2D level.  The strata 
include no prior systemic anticancer therapy in the metastatic setting (Stratum 1) and previously 
treated with 1 to 2 lines of systemic anticancer therapy in the metastatic setting (Stratum 2).    
Bayesian predictive probability (PP) of response rate was used to monitor the response rate after 
postbaseline tumor assessments for at least 38 subjects were available.  The study could be stopped 
early for efficacy or futility if PP crosses the prespecified boundary.  Hence, efficacy conclusion of 
the primary efficacy endpoint of ORR could be made on the basis of the predictive probability prior 
to the full enrollment of 100 evaluable subjects in the study . 


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There is clinical interest to have a more precise estimation of the efficacy data for Stratum 2.  
Therefore, per protocol amendment 3, additional subjects will be added to Stratum 2 in order to 
include a total of 80 evaluable subjects in Stratum 2 for final analysis.  As a result, approximately 150 
subjects in total (145 evaluable with 80 in Stratum 2) will be enrolled. Per protocol amendment 4, 
additional subjects will be added to Stratum 2 in order to include a total of at least 100 evaluable 
subjects in Stratum 2 for final analysis.
5
DETERMINATION OF SAMPLE SIZE
A total of approximately 170 subjects (165 evaluable with 80 in Stratum 2) will be enrolled. 
Under protocol amendment 1, 107 subjects including at least 6 from the Phase 1b part were enrolled 
in the study.  Enrollment was into 2 strata, which included first-line (Stratum 1) versus second- and 
third-line (Stratum 2) subjects.  Bayesian predictive probability was used to monitor the study after 
response data from the first 38 subjects were available.  Sample size calculation was carried out 
assuming the historical response rate of 0.2.  Using simulation, the model parameters (θL=0.025, θU 
=0.99, and θT=0.95) were calibrated such that the frequentist 1-sided Type I error was 0.0326 when 
the tumor response rate in the combination regimen was 0.2  (under frequentist’s null hypothesis H0), 
and the power was 0.9278 when the response rate was 0.35 (under frequentist’s alternative hypothesis 
Ha).  The expected numbers of subjects needed to reach the decisions were 56 and 61 when p=0.2 
(under H0) and 0.35 (under Ha), respectively.  A vague beta prior distribution for response rate, p, was 
specified in PP calculation; that is, p~beta (0.2, 0.8).  PP was updated for every 3 new subjects in the 
simulations, which mimics the group sequential decision making in a real trial setting.  Without 
Bayesian interim monitoring, the Type I error was estimated as 0.0358, and power was estimated as 
0.9418 in demonstrating posterior probability P(p>0.2|data) ≥0.95.  Five thousand simulations were 
run to estimate these design characteristics.
Per protocol amendment 3, additional subjects will be enrolled to ensure 80 evaluable subjects in 
Stratum 2. Using binomial exact test, the power is 0.92 with 80 evaluable subjects to demonstrate 
statistical significance at 1-sided alpha of 0.025 for the assumptions of H0: ORR=0.10 vs. Ha: 
ORR=0.25.  With 80 subjects, the 95% confidence interval for ORR from binomial distribution will 
be 0.160-0.359 if the observed ORR is 0.25. 
Per protocol amendment 4, additional subjects will be added to Stratum 2 in order to include a total of 
at least 100 evaluable subjects in Stratum 2 for final analysis.
6
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, Q1, Q3, minimum and maximum. Categorical variables will be summarized as number 
(percentage) of subjects.


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6.1
Study Endpoints 
RECIST 1.1 criteria will be used in the evaluation of tumor status for the primary, secondary and 
exploratory endpoints, irRECIST criteria will be used in the evaluation of tumor status for one of the 
exploratory endpoints. Tumor response data obtained per RECIST 1.1 by IIR will be utilized in the 
main analysis of ORR, PFS and DOR. In addition, tumor assessment data assessed per RECIST1.1 by 
investigator review and per irRECIST by IIR and by investigator review will be considered as 
secondary or exploratory (CTCAE, 2009). 
6.1.1
Primary Endpoint
Objective Response Rate (ORR) - defined as the proportion of subjects who had best overall 
response (BOR) of Complete Response (CR) or Partial Response (PR).
6.1.2
Secondary Endpoints
The secondary efficacy endpoints are as follows:

Progression-Free Survival (PFS) - defined as the time from date of first dose of study drug to 
date of first documentation of disease progression or death, whichever occurs first.

Overall Survival (OS) – defined as the time from the date of first dose of study drug until date 
of death from any cause.

Duration of Response (DOR) – defined as the time from the date that a confirmed objective 
response is first documented to the date of PD or death due to any cause for those subjects with a 
confirmed PR or CR.

Clinical Benefit Rate (CBR) – defined as the proportion of subjects who had BOR of CR, PR, 
or durable SD (≥24 weeks).

Estimates of ORR, PFS, OS and DOR in the PD-L1 Positive Set.
6.1.3
Exploratory Endpoints 

Time to Response (TTR) – defined as the time from the first dose date to the date that the 
confirmed objective response is first documented for subjects who had BOR of CR or PR based 
on RECIST 1.1. 

ORR, BOR, PFS, DOR, CBR and DCR using irRECIST 
6.2
Study Subjects
6.2.1
Definitions of Analysis Sets
The DLT Evaluable Set includes subjects in Phase 1b who complete the first treatment cycle (i.e., 
take at least 2 doses of eribulin mesylate with no more than one dose reduction and at least 1 dose of 


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pembrolizumab).  Subjects in phase 2 who had a DLT event will be considered evaluable for the 
dose-limiting toxicity as well.  It is the analysis set for DLT evaluation in the Phase 1b part.
The Full Analysis Set (FAS) (Safety Analysis Set) includes all subjects who received any amount of 
either study drug.  This is the analysis set for safety analyses and analyses of PFS and OS.
The Evaluable Analysis Set (EAS) (subset of Full Analysis Set) includes all subjects treated at RP2D 
level who have both an evaluable baseline tumor assessment and an evaluable postbaseline tumor 
assessment, unless discontinued early or death.  It is the analysis set for efficacy analyses.
The PD-L1 Positive Set (subset of Evaluable Analysis Set) includes evaluable subjects whose PD-L1 
expression level is above the threshold that is to be specified prior to the final analysis.  Key primary 
and secondary efficacy endpoints (i.e., ORR, PFS, OS, and DOR) will be summarized in this analysis 
set.
6.2.2
Subject Disposition
The number (percentage) of enrolled and treated subjects will be summarized as well as subjects who 
discontinued single drug and subjects who discontinued the combination treatment and reasons for 
discontinuation. Survival status at the last follow-up visit before data cutoff date will be summarized 
as well. In addition, the number (percentage) of subjects who remain in each phase at data cutoff date 
(i.e. treatment phase) will be summarized. 
Subject disposition will be summarized by stratum and combined. 
6.2.3
Protocol Deviations
Major protocol deviation criteria will be established and subjects with major protocol deviations will 
be identified and documented before the database lock for the primary analysis of ORR.
Major protocol deviations will be summarized and listed by each category.  All protocol deviations 
identified according to study entry criteria and during treatment will be listed.
6.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS will be summarized by stratum and 
combined using descriptive statistics.  The derivation of baseline is given in Section 8. 
Continuous variables include age, weight, vital signs, height, BMI, and BSA; categorical variables 
include sex, age group, race, ethnicity, PD-L1 status, pregnancy test status at baseline, ECOG status  
and enrollment strata. In addition, disease characteristics including time from original breast cancer 
diagnosis to first study dose, age at original histological/cytological diagnosis, time from MBC
diagnosis to first study dose, histology/cytology of the primary tumor, HER-2 status, estrogen (ER) 
status, progesterone status, lesions baseline, tumor staging at study entry, baseline metastases,  and 
baseline lactate dehydrogenase (LDH) level will be summarized. 


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6.2.5
Medical History
The number (percentage) of subjects reporting a history of any medical condition, as recorded on the 
CRF, will be summarized by stratum and overall.  A subject data listing of medical and surgical 
history will be provided. Medical History will be coded using MedDRA (version 22.0) and 
summaries completed by System Organ Class and Preferred term.
6.2.6
Prior and Concomitant Therapy
All investigator terms (verbatim terms) for medications recorded in the CRF will be coded to an 11-
digit code using the World Health Organization Drug Dictionary (WHO DD, version
WHODDMAR18_HD_B2) drug codes. The number (percentage) of subjects who took prior or  
concomitant medications will be summarized on the FAS by Anatomical Therapeutic Chemical (ATC 
Level 1) class, Pharmacological (ATC Level 3) Class and WHO DD preferred term. Prior 
medications will be defined as medications that stopped before the first dose of study drug. 
Concomitant medications will be defined as medications that (1) started before the first dose of study 
drug and were continuing at the time of the first dose of study drug, or (2) started on or after the date 
of the first dose of study drug up to 30 days (90 days if given for adverse events) after the subject’s 
last dose.  A listing of prior and concomitant medications will be included in the clinical study report 
for this protocol.
6.2.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical research 
associates will review treatment compliance during investigational site visits and at the completion of 
the study. Treatment compliance will not be summarized since the data will not be entered in the 
clinical database. However, dose modifications (i.e., reduction/delay/omission) for eribulin will be 
summarized in Section 6.6.2.
6.3
Data Analysis General Considerations
All efficacy analyses will be summarized in the appropriate analysis set defined in Section 6.2.1 with 
available data in the clinical database at the data cutoff, by stratum and combined. 
6.3.1
Pooling of Centers 
Data from all centers will be pooled in the analysis. No adjustment of center effect is planned in the 
models for the primary, secondary and exploratory endpoints.    


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6.3.2
Adjustments for Covariates
No adjustments for covariates are planned for primary and secondary analyses in the study. Baseline 
factors may be used in the model as covariates as supportive analyses for endpoints.
6.3.3
Multiple Comparisons/Multiplicity
No multiplicity adjustments will be made in the exploratory trial. A two-sided alpha of 0.05 will be 
used in the frequentist tests unless otherwise specified.
6.3.4
Examination of Subgroups
The summaries for primary efficacy endpoint, ORR, and key secondary efficacy endpoints, PFS and 
OS, will be provided by the following subgroups. Test statistics (i.e. ORR and corresponding 95% CI, 
median and 95% CI for PFS and OS) for each category will be presented.

stratification factor (Stratum 1 vs. 2)

PD-L1 expression (positive vs. negative)

age group (<50 vs. ≥50 Years)

race (White, Non-White)

baseline Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1)

with vs. without bone involvement

with vs. without liver involvement

with vs. without lung involvement

with vs. without brain involvement

histology type of breast tumor (Ductal Adenocarcinoma vs. Lobular Adenocarcinoma)

Site of disease (visceral vs. non-visceral only)

time from original diagnosis to the first study dose (<2 yrs vs. ≥ 2 yrs)  

time from metastatic disease to the first study dose (<3 mos vs. ≥ 3 mos)

number of organs involved (≤2 vs. >2)

baseline LDH level (≤1.5xULN vs. >1.5 ULN; ≤2xULN vs.>2ULN)
Additional subgroup analyses may also be conducted after all study data have been examined to better 
provide an understanding the treatment responses, if deemed necessary.
6.3.5
Handling of Missing Data, Drop-outs, and Outliers
At the time of primary analysis, if death or disease progression is not observed from a subject, 
corresponding censoring rules for OS and PFS will be followed. They are defined in Section 8. 


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Potential outlier values will be investigated. They will be analyzed as is in the locked database.
6.3.6
Other Considerations
Not applicable.
6.4
Efficacy Analyses
Approximately 165 evaluable subjects on RP2D will be enrolled in the study, including phase 1b and 
2. Subjects enrolled in phase 1b and treated on RP2D level will be pooled with subjects in phase 2 for 
efficacy analysis. The analysis methods described in Section 6.4 will be applied to the Evaluable 
Analysis Set (EAS) unless otherwise stated. 
6.4.1
Primary Efficacy Analyses
6.4.1.1
ORR in All Subjects 
Bayesian predictive probability (PP) design was used in original study design (Yin, 2012). Under 
original design, in the combined Stratum 1 and 2 subjects, the ORR value per RECIST 1.1 by IIR was 
assumed to be 0.20 for the historical control (see Table 1 footnote a in protocol amendment 04) and
the ORR in this trial was expected to be 0.35. Under protocol amendment 1, approximately 100 
evaluable subjects were expected to be enrolled. Bayesian PP was used to monitor the response rate 
after postbaseline tumor assessments of at least 38 subjects were available.  The calculation of PP was 
based on the goal of claiming superiority of the combination therapy at the end of the study if
P(p>0.2|data)≥0.95        (1)
where p was the response rate of the combination therapy, 0.2 was the response rate of historical 
control based on single agents pembrolizumab and eribulin in recent trials (Table 1 in Protocol 
Amendment 4), 0.95 was the prespecified target probability (θT), and P(p>0.2|data) is the posterior 
probability.  On the basis of the accumulated data up to time of data monitor in the study, the 
probabilities of all possible future outcomes that lead to equation (1) at the end of the study would be 
added in order to obtain the predictive probability as given in (2) below.  Therefore, early decision of 
study termination prior to reaching approximately 100 evaluable subjects was possible for claiming 
the combination therapy is promising when PP is above a prespecified upper threshold (θU) or for 
claiming futility when PP is below a prespecified lower threshold (θL).  The upper and lower cutoff 
probabilities for decision-making, θU and θL, were set as 0.99 and 0.025.  Under the predictive 
monitoring, the study proceeded as follows:

If PP> θU(=0.99), stop the study and claim the combination therapy promising

If PP< θL(=0.025), stop the study and claim the combination therapy not promising

Otherwise, continue the study until the number of evaluable subjects reaches to 100
The Bayesian stopping boundaries are included in Appendix 13.1.


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After completion of enrollment under protocol amendment 1, Bayesian PP is no longer used for 
continuous monitoring of efficacy and futility as the study will not be stopped early for either efficacy 
or futility. 
Details of Bayesian Approach
Objective Response Rate (p) will be compared to a historical control rate (p0) of 0.2 via Bayesian 
posterior probability:
Pr(p>p0=0.2|data)≥θT
        
                               (1)
where a pre-specified target probability (θT) is set at 0.95. Without any interim analysis, the trial 
requires the posterior probability of p>0.2 to be at least 0.95 at the end of the trial in order to 
demonstrate the superiority of combination therapy over historical control.
Since interim monitoring is implemented in the trial, Bayesian predictive probability (PP) is 
calculated when there are 38 patients in the Interim Analysis Set (definition in interim analysis 
section) to evaluate how likely the trial would complete its full enrollment. Specifically, on the basis 
of the accumulated data up to the time of data monitor in the trial, PP is calculated by adding the 
probabilities of all possible future outcomes that lead to equation (1). 
Suppose a maximum number of accrued subjects is set as Nmax and assume the number of responders 
X among the current n subjects follows a binomial(n, p) distribution, the posterior distribution 
p|x~beta(a+x, b+n-x) where a (=0.2) and b (=0.8) are parameters in the prior beta distribution, 
p~beta(a,b). Let Y be the number of ORR in the potential m=Nmax - n future subjects, Y ~beta-
binomial (m, a+x, b+n-x). When Y=i, the posterior distribution of p|(X=x,Y=i)~beta(a+x+i, b+Nmax-
x-i). The PP can then be calculated as follows,
}
95
.0
i)
Y
x,
|
0.2
I{Pr(p
)
|
Pr(
      
x}
|
0.95
Y)]
x,
|
0.2
>
E{I[Pr(p
=
PP
0








m
i
x
i
Y
       (2)
Where I[A]=1 if A is true and I[A]=0 if A is false. PP characterizes the future trial conclusion given 
the strength of the currently observed data. 
Therefore, early decision of trial termination is possible for efficacy when PP is above a pre-specified 
upper threshold (θU) or for futility when PP is below a pre-specified lower threshold (θL). In the 
current trial, the upper (θU) and lower (θL) cutoff probabilities for decision making are set as 0.99 and 
0.025. Under the predictive monitoring, the trial proceeds as follows:

If PP> θU(=0.99), stop the trial and claim the combo promising

If PP< θL(=0.025), stop the trial and claim the combo not promising

Otherwise, continue the trial until the number of evaluable subjects reaches 100


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The Bayesian stopping boundaries are included in Appendix 13.1. During the trial, PP will be 
calculated with updated response information till the boundary is crossed. In case continuous PP 
monitoring is not conducted because of operational and logistic reasons (e.g. delayed TA assessments 
and fast enrollment) or it is decided to take the trial to full enrollment even θU is crossed in order to 
gather more efficacy data, posterior probability in equation (1) will be evaluated to determine the 
efficacy of the combination regimen after the tumor response status has been collected from the last 
evaluable subjects.  That is, to claim efficacy if Pr(p>0.2|data)≥0.95. A two-sided 95% credible 
interval of ORR based on posterior distribution of p will be constructed to aid the interpretation of the 
results.   
Final Analysis
In the evaluable subjects in Stratum 1 and 2 combined, Bayesian posterior probability in equation (1) 
will be evaluated to determine the efficacy of the combination regimen after the tumor response status 
has been collected from the last evaluable subjects.  That is, to claim efficacy if P(p>0.2|data)≥0.95.  
A 2-sided 95% credible interval of ORR in the evaluable subjects will be constructed to aid the 
interpretation of the results.   
Sensitivity Analysis 
Sensitivity analyses of ORR for the evaluable subjects in Stratum 1 and 2 combined will be 
performed using frequentist approach. The hypotheses for the test of ORR are as follows:
H0: p=0.2
H1: p>0.2
Assuming number of ORR follows a binomial (Nmax, p) distribution, the binomial exact test will be 
used in hypothesis testing. A 2-sided Clopper-Pearson 95% CI will also be constructed.
6.4.1.2
ORR in Stratum 2
Under protocol amendment 3, in Stratum 2 subjects, the hypotheses for ORR per RECIST by IIR are 
updated to be H0: ORR=0.10 vs. Ha: ORR=0.25, based on the most recent pembrolizumab 
monotherapy trial (Table 1 in protocol amendment 4). Therefore, additional subjects will be enrolled 
to ensure 80 evaluable subjects in Stratum 2 to provide >90% power for the comparison of H0: 
ORR=0.10 vs. Ha: ORR=0.25 at 1-sided alpha value of 0.025. 
Under Protocol Amendment 4, additional subjects will be enrolled to ensure 100 evaluable subjects in 
Stratum 2 to obtain more precise estimate of ORR.
Final Analysis 


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In the evaluable Stratum 2 subjects, a binomial exact test will be used to test the estimated ORR per 
RECIST 1.1 by IIR versus a historical response rate of 10% at 1-sided alpha value of 0.025. A 2-sided 
Clopper–Pearson 95% CI of ORR will be constructed for calculating exact binomial intervals.
6.4.2
Secondary Efficacy Analyses
PFS, OS and DOR
Progression-Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR) will be 
analyzed using Kaplan-Meier product-limit estimates.  Median PFS and OS and the survival rate of 
PFS (at 6, 9 and 12 months) and OS (at 6, 12 and 18 months), probability of DOR ≥ 6, 9 and 12 
months will be presented with two-sided 95% CIs, if they can be estimated from the model. 
Censoring rules and data handling are described for each variable in Section 8 of this SAP.
The probability of PFS, OS and DOR will be plotted over time.  The median, first and third quartiles 
from Kaplan-Meier estimation for PFS, OS and DOR will be provided with 95% CIs if estimable.
Clinical Benefit Rate
A 2-sided Clopper–Pearson 95% CI will be constructed for calculating exact binomial intervals. 
6.4.3
Other Efficacy Analyses
The analysis of time to response (TTR) will follow the analysis of PFS.  The analysis will be 
performed in the subjects with confirmed PR/CR by RECIST1.1.  
In addition to RECIST1.1 by IIR, tumor assessment data (i.e., ORR, PFS, DOR, and CBR) will be 
assessed per RECIST1.1 by investigator review and per irRECIST by IIR and investigator review in 
the sensitivity analysis.   
All efficacy analyses will be performed in overall subjects and also for each stratum.
Efficacy outcomes will be further evaluated in the PD-L1 Positive Set.  The clinical utility of PD-L1 
as a predictive marker in mTNBC subjects who receive eribulin mesylate and pembrolizumab 
combination treatment will be assessed.  
6.5
Pharmacokinetic, Pharmacodynamic and Pharmacogenomic 
Analysis
6.5.1
Pharmacokinetic Analyses
Plasma concentration versus time data will be analyzed using a population PK approach to estimate 
population PK parameters.  Scatter plots of dose normalized plasma concentration and associated 
tabulations will be generated by actual sample collection time and for each PK sample collection visit.  
A separate Population PK data analysis plan will be developed that will describe selection of 


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appropriate PK structural model, estimation of model parameters and related variability, covariate 
testing on model parameters as appropriate.
Individual eribulin PK parameters for phase 1b will be, but not limited to t1/2, tmax, Cmax, AUC(0-t), tlast, 
AUC(0-inf), , CL, Vz will be calculated based on Cycle 1 Day 1 (C1D1).
6.5.2
Pharmacodynamic Analyses
The effect of soluble biomarkers  will be summarized.  The analyses will be detailed in a separate 
analysis plan.
6.5.3
Pharmacokinetic / Pharmacodynamic Analyses
Exploratory/graphical analyses will be conducted for PK/PD evaluations with data from Phase 1b and 
Phase 2, and be followed by model based analyses. These analyses will be detailed in a separate data 
analysis plan to be handled by Modeling&Simulation group.
6.5.4
Pharmacogenomic and Biomarker Analyses
Pharmacogenomic and biomarker analyses will be performed and reported separately.  Details of 
these analyses will be described in a separate analysis plan.
6.6
Safety Analyses
All safety analyses will be performed in the Safety Analysis Set.  The incidence of treatment-
emergent adverse events (TEAEs, Section 6.6.3) and SAEs will be summarized. Laboratory test 
results, vital signs and their changes from baseline will be summarized using descriptive statistics
(e.g., n, mean, standard deviation, median, Q1, Q3, minimum, and maximum for continuous 
variables; and n [%] for categorical variables.  Abnormal values will be flagged.
Safety information will be summarized by stratum and combined. 
6.6.1
RP2D and Dose-limiting Toxicity in Phase1b
The Phase 1b study will include at least 1 safety run-in cohort in which 6 mTNBC subjects who 
receive eribulin mesylate 1.4 mg/m2 on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of a 21-
day cycle (dose level 1).  Subjects will be observed for dose-limiting toxicity (DLT) in the first cycle.  
The purpose of the safety run-in cohort(s) is to study safety of the 2-drug combination.  The Phase 2 
part will proceed with dose level 1 when no more than 1 subject has a DLT.  Otherwise, a lower 
eribulin mesylate dose of 1.1 mg/m2 and pembrolizumab 200 mg will be evaluated in another cohort 
of 6 subjects.  If no more than 1 subject has a DLT in the first cycle, the Phase 2 part will proceed 
with dose level 0 as the RP2D.  Otherwise, alternative doses (eribulin mesylate 0.7 mg/m2) will be 
explored prior to the start of the Phase 2 part. 


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6.6.2
Extent of Exposure
The number of cycles/dose taken on treatment, the number of subjects requiring dose reductions, dose 
delays, and dose omissions(dose omission were determined by number of study drug not administered 
as pre-specified from the study drug exposure CRF) for eribulin, and the number of administration of 
pembrolizumab will be summarized.  One cycle is defined as 21 days of treatment. Specifically:

The number of cycles received and the number of doses taken will be summarized for 
eribulin with descriptive statistics. Subject is considered received one cycle if the subject 
received at least one doses on either day 1 or day 8 of a cycle. Also the number of 
administration of pembrolizumab will be summarized with descriptive statistics.

The duration of treatment (weeks) by each study drug and overall will be summarized with 
descriptive statistics. It will be calculated as (date of last infusion with administrated positive
dose – date of first infusion + 1)/7 for each drug. It will be calculated as (date of last infusion 
with administrated positive dose of study drugs – date of first infusion of study drugs + 1)/7
for overall. 

For eribulin, the number of subjects with dose reductions, dose omissions and dose delays
will be summarized by counts and percentages according to study medication data. In 
addition, frequency of dose reductions, dose omissions and dose delays will be summarized 
by categories (0, 1, and ≥2).

Total dose of eribulin (two definitions: mg and mg/m2) per subject will be computed as the 
sum of all of the doses received during study.

Average dose intensity per subject (mg/m2/week for eribulin) and relative dose intensity per 
subject (percent of total dose received relative to total planned dose (including the missed 
doses)) will be summarized by descriptive statistics for eribulin.  
Average dose intensity (mg/m2/week) for eribulin = total dose (mg/m2)/ duration of treatment 
in weeks.  
Relative dose intensity (RDI)(%)  for eribulin= total dose (mg/m2)/ total planned 
dose(mg/m2).   
Total dose (mg/m2), average dose intensity and relative dose intensity will be calculate based on BSA 
at each visit. If BSA is missing, the last BSA before missing will be carried forward as the BSA for 
the visit. 
Subject data listings will be provided for all dosing records, and for the summary statistics calculated 
above.
6.6.3
Adverse Events
All Adverse Events (AE) will be graded by the investigators using CTCAE v4.03. The AE verbatim 
descriptions (investigator terms from the CRF) will be classified into standardized medical 


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terminology using the Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events will 
be coded to the MedDRA (Version 22.0) lower level term (LLT) closest to the verbatim term.  The 
linked MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database.
The incidence of TEAEs will be summarized descriptively. A TEAE is defined as an AE that 
emerged during treatment or up to 30 days (90 days for SAEs and /or events of clinical interest) 
following last dose of study drug, having been absent at pretreatment (Baseline) or 
●
Reemerged during treatment or up to 30 days (90 days for SAEs and /or events of clinical 
interest) following last dose of study drug, having been present at pretreatment (Baseline) but 
stopped before treatment, or 
●
Worsened in severity during treatment or up to 30 days (90 days for SAEs and /or events of 
clinical interest)  following last dose of study drug relative to the pretreatment state, when the 
AE was continuing.
Per protocol amendment 1, Events of clinical interest (ECI) for this trial include: an elevated
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than or 
equal to 3 × ULN and an elevated total bilirubin lab value that is greater than or equal to 2× ULN and, 
at the same time, an alkaline phosphatase lab value that is less than 2 × ULN, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing. 
We used the following AE PT terms to identify ECI above:  

ALT increased  

AST increased

Blood bilirubin increased

Blood alkaline phosphatase increased 
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, treatment 
emergent or otherwise, will be presented in subject data listings.
An overview table, including the incidence of and the number of subjects with TEAEs, TEAEs with 
grade 3 or above, serious adverse events (SAEs), deaths, and TEAEs that led to death, treatment 
discontinuation, dose reduction, or dose interruption will be provided.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC 
and PT.  A subject will be counted only once within a SOC and PT, even if the subject experienced 
more than one TEAE within a specific SOC and PT.  TEAEs by preferred term, and CTCAE Grade 
will be summarized in descending frequency order.
The number (percentage) of subjects with treatment-related TEAEs including Eribulin, 
Pembrolizumab, both Eribulin and Pembrolizumab will be summarized by SOC and PT.  Treatment-
related TEAEs include those events considered by the investigator to be possibly or probably related 
to study treatment or with missing assessment of the causal relationship.  


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The number (percentage) of subjects with TEAEs leading to death, TEAEs with grade 3 or above, 
SAEs, TEAEs leading to discontinuation from study drugs, TEAEs leading to study drug dose 
reduction of eribulin and TEAEs leading to study drug interruption of study drugs will be summarized 
by MedDRA SOC and PT in separate tables. Separate subject data listings of all AEs, all AEs leading 
to death, treatment-related AE, grade 3 or above AEs, SAEs, and AEs leading to discontinuation from 
study drug will be provided. 
6.6.4
Treatment-Emergent Adverse Events of Special Interest
Potential immune-related adverse events (irAE) are the primary events of clinical interest (ECIs) in 
addition to the adverse event specific to eribulin (peripheral neuropathy and neutropenia, etc).  The 
listings of ECI potentially related to Pembrolizumab, Eribulin or both are documented in separate 
files.  
Standardized MedDRA Queries (SMQ) of treatment-emergent ECI will be summarized by MedDRA 
preferred term and CTCAE grade. 
6.6.5
Laboratory Values
Clinical laboratory tests to be performed, including hematology, chemistry and urinalysis are 
summarized in Table 1.
Laboratory results will be standardized and summarized using Système International (SI) units, as 
appropriate.  For all quantitative parameters listed in Table 1, the actual value and the change from 
baseline to each postbaseline visit and to off treatment visit (end of treatment defined as the last value 
within 30 days of the last study dose) will be summarized by visit using descriptive statistics.  
Laboratory parameters will be categorized according to CTCAE v4.03 grades. Shift tables of 
laboratory values by CTCAE grade from baseline to worst grade will be provided. Percentages will 
be based on the number of subjects with non-missing baseline and relevant postbaseline results.


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Table 1.
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), ANC
Clinical Chemistry
     Electrolytes
Sodium, potassium, chloride, calcium, magnesium
     Liver Function Tests
ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin
     Renal Function
BUN, serum creatinine
     Thyroid Function
TSH, T4a
     Serum pregnancy
Serum β-hCG
     Other
LDH, total protein, glucose (fastingb)
Urinalysis
Glucose, ketones, pH, protein, RBCs, WBCs, specific gravity
ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, 
β-hCG = beta-human chorionic gonadotropin, BUN = blood urea nitrogen, LDH = lactate 
dehydrogenase, RBC = red blood cells, T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = 
white blood cells
a:  Thyroid function will be assessed at the Screening Visit and then every 2 cycles (starting at C2) 
throughout the study.
b: Fasting glucose at Screen, only
6.6.6
Vital Signs
Descriptive statistics for vital signs parameters (i.e., diastolic and systolic BP, resting pulse rate, 
respiratory rate, temperature) and changes from baseline will be presented by visit and dosing cohort.
6.6.7
Electrocardiograms 
ECG findings (categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant) at baseline and unscheduled visit will be summarized.
In addition, the number (percentage) of subjects with at least one postbaseline abnormal ECG result 
in QTc Fridericia values during the treatment period will be summarized.   Clinically abnormal ECG 
results in Fridericia values will be categorized as follows:
Change from baseline in QTc interval:
•
At least one postbaseline increase of  >30 ms
•
At least one postbaseline increase of  >60 ms
•
At least one postbaseline value of  >450 ms


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•
At least one postbaseline value of  >480 ms
•
At least one postbaseline value of  >500 ms
6.6.8
Other Safety Analyses
ECOG performance status will be summarized descriptively by visit and by shift from baseline to 
worst postbaseline.
6.7
Other Analyses
No other analysis is planned.
6.8
Exploratory Analyses
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are performed 
will be appropriately titled/labeled as exploratory and will be clearly distinguished from planned 
analyses when results are reported in the Clinical Study Report.
7
INTERIM ANALYSES
The Interim Analysis Set includes all subjects treated at RP2D level who have either completed two 
post-baseline tumor assessments or discontinued early.  The planned interim analysis will be 
performed when there are 38 such subjects. If the number of subjects in the Interim Analysis Data Set 
is not exactly 38 at the time of the interim analysis, the Bayesian stopping boundaries will be adjusted 
based upon the current information (Appendix 13.1)
Interim decisions can be made on the basis of the expected response rate at the end of the study, 
which compromises the current information with the future sample size via predictive probability 
approach.  The Bayesian design can continuously update the predictive probability of the study 
outcome, such that early termination of a study is possible for either superiority or futility.  The pre-
specified Bayesian stopping boundaries are included in Appendix 13.1.  
The study statistician will work with the clinical study managers and data managers to define the 
datasets for the interim analysis.  The study statistician will assess the impact of any issues such as 
unsolved data queries, missing data or data entry delays on the interim results.  
If the protocol needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will be 
documented and described in the clinical study report.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
Baseline
Baseline is defined as the non-missing value most recently collected before the first dose of any study 
drug.


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In the analyses of ORR, CBR and DCR, subjects without baseline or postbaseline tumor assessment 
will be considered as non-responders and will be included in the denominator when calculating ORR, 
CBR and DCR. Non-responders will be excluded in the analysis of DOR.
Study Day 1
Study Day 1 is defined as the day of the first dose of any study drug administrated. 
By-visit analysis
All by-visit analyses will be performed using assessment at corresponding scheduled visits recorded 
in the eCRF (not including unscheduled).  
The unscheduled visits will be included in the analyses that involve definition of worst post-baseline 
assessment. 
Definition of BOR by RECIST 1.1
The definition of BOR by RECIST 1.1 will follow Appendix 3 in protocol. In particular, 
Tumor assessments after any new anti-caner therapy, including the palliative radiotherapy, 
will be deleted in defining BOR.  
Tumor assessment after PD defined by RECIST 1.1 will be deleted in defining BOR.  
The following BOR responses are defined based on the timepoint-level response
Complete Response (CR):A BOR of CR requires two timepoint assessments of CR, with 
the second at least 4 weeksafter the initial CR. An intervening timepoint assessment of 
PR, SD, or PD prevents confirmation. BOR of CR cannot be preceded by PD.
Partial Response (PR):A BOR of PR requires a first assessment of PR and a second 
assessment of PR (or CR) at least 4 weeks after the initial PR. An intervening timepoint 
assessment of PD prevents confirmation. BOR of PR cannot be preceded by PD.
Stable Disease (SD):A BOR of SD is assessed if the criteria for BOR of CR, orPRare 
not met and if,in addition, an assessment of SD (or better) has been documented at least 
once ≥  8 weeks from the first dose of study treatment.
Progressive Disease (PD): A BOR of PD is defined by any timepoint assessment of PD 
with no prior BOR qualifying as SD, PR, or CR.
Not evaluable (NE): A BOR of NE refers to subjects with either no postbaseline tumor 
assessment(s) or with postbaseline tumor assessment(s) that are not evaluable [i.e., due to 
insufficient data for assessment of response per applied response criteria RECIST 1.1 or 
an early SD with duration < 8 weeks]. 
Unknown response (UNK): A BOR of UNK refers to subjects with no baseline tumor 
assessment


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Definition of BOR by irRECIST 

Investigator Review
Subjects who experience PD defined by RECIST1.1 will have a confirmation scan at least 4 weeks 
apart to confirm PD (irPD). Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable. If a subject discontinued study treatment without 
confirmation of irPD, the subject will be counted as irPD. 
Tumor assessments after any new anti-caner therapy, including the palliative radiotherapy, will be 
deleted in defining BOR. The overall time point tumor response data collected via both the CRF of 
the irRECIST and the CRF of the RECIST 1.1 will be used. Simply add prefix ‘ir’ to 
CR/PR/SD/PD/NE from RECIST 1.1 and follow the definition of BOR per RECIST 1.1 to define 
BOR per irRECIST (irCR/irPR/irSD/irPD/irNE). Table 2 describes the scenarios of PD by RECIST 
1.1 followed by different confirmation scans. 
Table 2.  BOR by irRECIST for Scenarios with PD (defined by RECIST 1.1) Followed by 
Subsequent Scans
Timepoint 1
Overall 
Response
Timepoint 2
(≥ 4 weeks since 
Timepoint 1)
Overall Response
BOR by irRECIST
PD
CR a
If subject has been followed for ≥4 weeks and 
CR is confirmed, BOR is irCR. If CR not 
confirmed, then follow same rule as BOR by 
definition of RECIST 1.1. 
PD
PR a
If subject has been followed for ≥4 weeks and 
PR is confirmed, BOR is irPR. If PR not 
confirmed, then follow same rule as BOR by 
definition of RECIST 1.1.
PD
SD b
irSD
PD
PD c
irPD
PD
NE
irPD
PD
irPD, if no confirmation scan.  
a The subject should be followed for ≥ 4 weeks to confirm the CR/PR.
b The subject is on the study treatment and followed for further tumor assessments.
c PD is confirmed. The subjects should be discontinued from the study treatment, and no further 
tumor response assessments will be performed.
                                                                                                                                                                                             


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Other exploratory endpoints using irRECIST: ORR, PFS, DOR, CBR and DCR will be derived 
similarly as those using RECIST1.1; but the derivation will be based on irCR, irPR, irSD and irNE 
instead of CR, PR, SD and NE.

Independent Imaging Review 
BOR by irRECIST for IIR data will follow the same principle as above except tumor 
assessments by mRECIST 1.1(modified RECIST 1.1) criteria for the time points up to PD are 
used.
Censoring rule for OS
Subjects who are lost to follow-up or withdrawal from study will be censored at the last date the 
subject was known to be alive, and subjects who remained alive will be censored at the time of data 
cutoff.
Censoring rule for PFS by RECIST 1.1
The PFS derivation rules in this SAP follow the sensitivity of analyses described in Food and Drug 
Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (2007)”.   
Definition of Progression Date:  Progression date is assigned to the first time at which radiological 
progression can be declared.
For progression based on a new lesion, the progression date is the date of the initial detection of the 
new lesion, if there were multiple new lesions detected, then the earliest date of initial detection will 
be used.  
Table 3 shows the primary censoring rules for the derivation of PFS based upon investigator’s tumor 
assessment.  
Censoring rule for irPFS by irRECIST
Definition of progression date by irRECIST (i.e., irPD):

For the subjects who experience PD by RECIST 1.1 and then confirmed by irPD (> or <28 
days) or not confirmed due to any reasons, the first documented PD date by RECIST 1.1  is 
the date of irPD.

For the subjects who experience PD by RECIST1.1 and then followed by irCR/irPR/irSD, the 
first documented progression date is the date of first irPD defined by irRECIST.

If the subject had new lesion earlier than overall timepoint response of PD in irRECIST, the 
date of new lesion is not counted as irPD date.   (this is different from PD by RECIST 1.1 for 
which, as soon as subject developed new lesions, subject is considered as PD and PD date is 
the date of new lesion). 


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Censoring rule will be same as RECIST1.1 except that for the second rule in Table 3.
“Date of first radiologic PD assessment” means the irPD Date determined as above.
Duration of Response
Duration of Response (DOR) – defined as the time from the date that a confirmed objective response 
is first documented to the date of PD or death due to any cause for those subjects with a confirmed PR 
or CR. For subjects who did not experience PD or death by the end of data cut off, the date of last 
adequate radiologic assessment before missing tumor assessments or new anti-cancer therapy will be 
used as censoring date.
BOR, PFS and DOR will be defined separately for IIR data and for investigator reviewed data 
following the same rules. 


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Table 3. Censoring Rules for Analysis of Progression-Free Survival
No.
Situation
Date of Progression or Censoring
Outcome
1
No baseline or post-baseline tumor 
assessments
Date of the first dose 
Censored
2
Progression documented between 
scheduled visits
Date of first radiologic PD 
assessment 
Progressed
3
No progression at the time of data cut-off 
Date of last adequate radiologic 
assessment prior to or on date of 
data cut-off
Censored
4
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of 
new anticancer treatment 
Censored
5
Death before first PD assessment
Date of death
Progressed
6
Death between adequate assessment 
visits*
Date of death
Progressed
7
Death or progression after two or more 
missed visit**
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease,
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as 
determined by investigators. 
New anticancer treatment includes palliative radiotherapy. Any tumor assessments after new 
anticancer treatment started will be removed in the definition of PFS. 
** More than two missed visits is defined if  the duration between the last tumor assessment
(including NE) and death or PD is longer than 126 days (18  weeks) or 168 days (e.g. 24 weeks) for 
subjects on the every 9 or 12 week scanning schedule in this study:
The priority of the censoring rules is as follows:
1. If the subject had PD or death, the following sequence will be applied:

If a subject did not have baseline tumor assessment (No.  1), the subject will be censored on 
date of the first dose.  However, if the subject did not have baseline tumor assessment and 
died within 126 days (18 weeks) after the first dose and did not receive new anticancer 
treatment, the date of death will be the PFS event date (not censored).

If a subject had new anticancer treatment before PD or death (No.  4), the subject will be 
censored on the date of the last adequate tumor assessment prior to or on the date of new 
anticancer treatment.

If a subject missed two assessments before PD or death (No.  7), the subject will be 
censored on the date of the last adequate tumor assessment before PD or death.  Note that if 
a subject is censored by both this criterion and the anticancer treatment criteria, the earliest 


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censoring date will be used.

Otherwise, if a subject had an event (No.  2, No.  5, or No.  6), the earliest event date will 
be used.
2.
If a subject did not have PD or death, the censoring date will be the earliest censoring date if the 
subject met multiple censoring criteria (No.  1, No.  3, No.  4, No.  7).
Rules for missing dates:
In case of dates missing in adverse event and concomitant medication collection following rules will 
be followed.

Adverse Events
Adverse Events with incomplete start dates will be considered treatment emergent if:
a.
Day and month are missing and the year is equal to or after the year of the first dose date; 
b.
Day is missing, and the year is after the year of the first dose; 
c.
Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date;
d.
Year is missing; or
e.
Complete date is missing.

Concomitant Medications
Medications will be considered concomitant if:
a.
Day and month are missing and the year is equal to or after the year of the first dose date; 
b.
Day is missing, and the year is after the year of the first dose; 
c.
Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date; or
d.
Year is missing; or complete date is missing.
Pharmacokinetics/Pharmacodynamic Data Handling

Lower Limit of Quantification of Eribulin Plasma Concentration
The Lower Limit of Quantification (LLOQ) of eribulin plasma concentration is 0.200 ng/mL.

Below Limit of Quantification Handling for Calculation of Pharmacokinetic Parameters


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While calculating PK parameters in Phoenix/WinNonlin, BLQ values will be handled according to 
the NCA-MNL. 

BLQ Handling for Developing Concentration-Time Profiles
When developing individual concentration-time profiles, BLQ values will be handled according to the 
NCA-MNL. 

Handling of Anomalous Concentration Values
The handling of anomalous concentration values will follow the guidance in the NCA-MNL.

General Rules for Presentation of Drug Concentrations and PK Parameters
When presenting individual/raw (raw, hereafter) values and summary statistics, the following rule 
will be applied: for drug concentrations and concentration-dependent pharmacokinetic parameters, all 
summary statistics (mean, median, geometric mean, SD, and CV) will have 3 significant digits.  For 
tmax and tlag, raw values and median have fixed 2 decimal places.
Table 4. General Rules for Presentation of Drug Concentrations and PK Parameters
Typical 
variable
Standard 
Unit
(depends on 
compound)
N
Digit rule
Raw
Minimu
m
Maximu
m
Mean
Median
SD
Geometr
ic  Mean
CV
(%)
E2027 
concentration
ng/mL
X
Significant 
digits
3
3
3
-
-
Cmax, Cmin
ng/mL
X
Significant 
digits
3
3
3
3
3
tmax, tlag
a
h
X
Fixed decimal 
places
2
2
-
-
-
λz
1/h
X
Significant 
digits
3
3
3
3
3
t1/2
h
X
Significant 
digits
3
3
3
3
3
AUC
ng·h/mL
X
Significant 
digits
3
3
3
3
3
%AUCex
%
X
Significant 
digits
3
3
3
3
3
CL
L/h
X
Significant 
digits
3
3
3
3
3
Vd
L
X
Significant 
3
3
3
3
3


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Typical 
variable
Standard 
Unit
(depends on 
compound)
N
Digit rule
Raw
Minimu
m
Maximu
m
Mean
Median
SD
Geometr
ic  Mean
CV
(%)
digits
MRT
h
X
Significant 
digits
3
3
3
3
3
a:  Mean, SD, geometric mean and CV will not be calculated for tmax and tlag.
CV(%) = sqrt(exp[SD2 of log transformed data]-1)×100
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate documents.
10 STATISTICAL SOFTWARE
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, NC, 
USA), version 9.3 or higher, and/or other validated statistical software as required. Non-
compartmental analysis (NCA) will be performed using Phoenix 64 WinNonLin (version 7.0 or later).
11 MOCK TABLES, LISTINGS AND GRAPHS (TLGS)
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs in detail.


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12 REFERENCES
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)]. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11 .pdf.
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.  
Washington, DC: United States Food and Drug Administration, 2007.
Yin, G.S. Clinical trial design: Bayesian and frequentist adaptive methods. Wiley: Hoboken, New 
Jersey 2012.
NCA-MNL: 302-104.01-MNL: Non-compartmental pharmacokinetic analysis, June 2018.


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13 APPENDICES
13.1
Bayesian Stopping Boundaries
N
LB
UB
N
LB
UB
N
LB
UB
38
6
16
60
12
22
82
19
27
39
6
16
61
12
22
83
19
27
40
6
17
62
12
23
84
19
27
41
7
17
63
13
23
85
20
27
42
7
17
64
13
23
86
20
27
43
7
18
65
13
23
87
20
28
44
7
18
66
14
23
88
21
28
45
8
18
67
14
24
89
21
28
46
8
18
68
14
24
90
22
28
47
8
19
69
14
24
91
22
28
48
9
19
70
15
24
92
22
28
49
9
19
71
15
25
93
23
28
50
9
20
72
15
25
94
23
28
51
9
20
73
16
25
95
24
28
52
10
20
74
16
25
96
24
28
53
10
20
75
16
25
97
25
28
54
10
21
76
17
26
98
25
28
55
10
21
77
17
26
99
26
28
56
11
21
78
17
26
100
27
28
57
11
21
79
18
26
58
11
22
80
18
26
59
12
22
81
18
27
Footnote:
N=number of subjects included in the predictive probability calculation;
LB=lower bound (futility boundary crossed if # objective response ≤LB);
UB=upper bound (efficacy boundary crossed if # objective response ≥UB).


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SIGNATURE PAGE
Author:  
Signature
Oncology Business Group, Eisai Inc.
Date
Approval:
Signatur
                  Oncology Business Group, Eisai Inc.
Date
Signa
, Eisai Inc.
Date
PPD
PPD
PPD
PPD