Clinical trial NCT02753595
Conditions: Metastatic Breast Cancer
Keywords: PEGylated Recombinant Human Hyaluronidase Eribulin Mesylate E7389 PEGPH20 Human Epidermal Growth Factor Receptor 2-Negative High-Hyaluronan
Sponsor: Eisai Inc.
Start date: 2016-07-13; Completion date: 2019-08-16
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective for the study is as follows:

For the Phase 1b - to determine safety tolerability and recommended Phase 2 dose (RP2D) of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase (PEGPH20) in participants with Human Epidermal Growth Factor Receptor (HER2)-negative metastatic breast cancer (MBC) previously treated with up to two lines of systemic anticancer therapy in the metastatic setting.

For the Phase 2 - to evaluate objective response rate (ORR) of eribulin mesylate in combination with PEGPH20 in participants with HER2-negative, High-Hyaluronan (HA)-high, MBC previously treated with up to 2 lines of systemic anticancer therapy in the metastatic setting.

Detailed description:
Phase 1b will occur in two parts:

Part 1: Run-in safety cohort(s) (dose levels 1, 0, and -1, as necessary) of 6 participants each will be conducted until the RP2D is determined. The purpose of the run-in safety cohort(s) is to study the safety of the 2-drug combination and determine a RP2D. Dose limiting toxicity (DLT) will be assessed in the first cycle to determine the RP2D of eribulin mesylate in combination with PEGPH20.

Part 2 (Phase 1b "Expansion Part"): A total of 12 additional participants will be enrolled at the RP2D determined in Part 1 (using Phase 1b criteria, i.e., participants previously treated with up to 2 lines of systemic anticancer therapy) in order to assess the safety profile of the combination and identify any potential safety signals and the incidence of thromboembolic events in this population (RP2D determined dosing).

In Phase 2, participants will be stratified by triple negative breast cancer (TNBC) status and randomized 1:1 to receive eribulin mesylate and PEGPH20 at the established RP2D level or eribulin mesylate alone at 1.4 milligrams per square meters (mg/m\^2).

Arms: arm 1: Recommended Phase 2 dose (RP2D) will be determined from the below dose levels:

* Dose level 1: PEGPH20 (3.0 microgram per kilogram (mcg/kg)) followed by eribulin mesylate (1.4 milligrams per square meter (mg/m\^2)) or
* Dose level 0: PEGPH20 (1.6 mcg/kg) followed by eribulin mesylate (1.4 mg/m\^2) or
* Dose level -1: PEGPH20 (1.6 mcg/kg) followed by eribulin mesylate (1.1 mg/m\^2)

Dose level 1 can be selected as the RP2D if no more than 1 out of 6 participants has a DLT; DLT was only observed from the first treatment cycle; otherwise, Dose level 0 will be assessed in a second cohort of 6 subjects and will be selected as the RP2D if no more than 1 subject has a DLT. Otherwise, Dose level - 1 will be assessed in a third cohort of 6 subjects. Upon determination of the RP2D, study Phase 1b Expansion Part will proceed to confirm the RP2D, and thereafter Phase 2 part will proceed. arm 2: Participants will receive eribulin mesylate and PEGPH20 at the established RP2D level achieved in the Phase 1b. arm 3: Participants will receive eribulin mesylate at 1.4 mg/m\^2.
Interventions: intervention 1: Eribulin mesylate intervention 2: Eribulin mesylate intervention 3: Eribulin mesylate intervention 4: Biologic: PEGylated recombinant human hyaluronidase (PEGPH20) intervention 5: Biologic: PEGylated recombinant human hyaluronidase
Intervention descriptions: intervention 1: Eribulin mesylate will be administered at 1.4 mg/m\^2 or 1.1 mg/m\^2 as intravenous (IV) infusion on Day 1 and 8 of 21-day cycle intervention 2: Eribulin mesylate will be administered at 1.4 mg/m\^2 or 1.1 mg/m\^2, depending on RP2D, as IV infusion on Day 1 and 8 of each 21-day cycle intervention 3: Eribulin mesylate will be administered at 1.4 mg/m\^2 as IV infusion on Day 1 and 8 of 21-day cycle intervention 4: PEGPH20 will be administered at 3.0 mcg/kg or 1.6 mcg/kg as IV infusion on Day -1 and 7 of 21-day cycle intervention 5: PEGPH20 will be administered at 3.0 mcg/kg or 1.6 mcg/kg, depending on RP2D, as IV infusion on Day -1 and 7 of each 21-day cycle

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 1 of 42 
CONFIDENTIAL 
Eisai 
 
Test Drug: 
E7389 
Protocol Number: 
E7389-M000-219 
Protocol Title: 
A Randomized, Open-label, Multicenter, Phase 1b/2 Study of 
Eribulin Mesylate in Combination with PEGylated 
Recombinant Human Hyaluronidase (PEGPH20) versus 
Eribulin Mesylate Alone in Subjects with Human Epidermal 
Growth Factor Receptor 2 (HER2)-Negative, High-
Hyaluronan (HA) Metastatic Breast Cancer (MBC) 
 
Date of Original Protocol: 
25 April 2016 
Date of Protocol Amendment 01: 
27 Oct 2016  
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS  
SYNOPSIS  
Approval Date:  V1.0 
25 Apr 2016 (Original 
Protocol) 
Approval 
Date: 
V2.0 
27 Oct 2016 (Amendment 
01) 
Study Period and Phase of Development 
Duration Overall:  Approximately 30 months 
Duration by Subject:  Estimated median treatment 
duration is 8 months, although subjects may remain 
on study treatment as long as the subject 
demonstrates clinical benefit.   
Study Interval:  The study is estimated to begin in 
May 2016 and end in or before October 2018 
(includes enrollment of approximately 18 months). 
 
Study Period and Phase of Development 
Duration Overall:  Approximately 30 36 months 
Duration by Subject:  Estimated median treatment 
duration is 8 months, although subjects may 
remain on study treatment as long as the subject 
demonstrates clinical benefit.   
Study Interval:  The study is estimated to begin in 
May 2016 and end in or before April 2019 
(includes enrollment of approximately 24 months). 
 
Study Interval:  The study is estimated to begin in 
May 2016 and end in or before October 2018 
(includes enrollment of approximately 18 months). 
Reason(s) for the Amendment:   
Administrative 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS AND SECTION 8.1 
SYNOPSIS AND SECTION 8.1 
Objectives 
Primary Objectives  
Objectives 
Primary Objectives  
 
For the Phase 1b part – to determine safety 
tolerability and recommended Phase 2 dose 
(RP2D) of eribulin mesylate in combination 
with PEGPH20 in subjects with HER2-negative 
MBC previously treated with 0 to 1 line of 
systemic anticancer therapy in the metastatic 
setting. 
 
For the Phase 2 part – to evaluate objective 
 
For the Phase 1b part – to determine safety 
tolerability and recommended Phase 2 dose 
(RP2D) of eribulin mesylate in combination 
with PEGPH20 in subjects with HER2-
negative MBC previously treated with 0 to 1 
line up to two lines of systemic anticancer 
therapy in the metastatic setting.  
 
For the Phase 2 part – to evaluate objective 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 2 of 42 
CONFIDENTIAL 
Eisai 
response rate (ORR) of eribulin mesylate in 
combination with PEGPH20 in subjects with 
HER2-negative, HA-high, MBC previously 
treated with 0 to 1 line of systemic anticancer 
therapy in the metastatic setting. 
response rate (ORR) of eribulin mesylate in 
combination with PEGPH20 in subjects with 
HER2-negative, HA-high, MBC previously 
treated with 0 to 1 line up to two lines of 
systemic anticancer therapy in the metastatic 
setting. 
SYNOPSIS AND SECTION 8.3 
SYNOPSIS AND SECTION 8.3 
Exploratory Objectives 
 
To identify and explore tumor and blood 
markers that correlate with clinical outcomes, 
including efficacy 
Exploratory Objectives 
 
To identify and explore tumor and blood 
markers (e.g., Plasma HA levels) that 
correlate with clinical outcomes, including 
efficacy 


 
 
 
 
 
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Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 3 of 42 
CONFIDENTIAL 
Eisai 
Reason(s) for the Amendment: 
 Study design modified to include patients in later lines based on Investigator feedback and allow for the 
combination to be used in a broader patient population. 
Exploratory objectives updated due to addition of HA plasma sample collection 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.1 
SYNOPSIS and Section 9.1 
Study Design 
Study Design 
This is a randomized, open-label, multicenter, 
Phase 1b/2 study of eribulin mesylate in 
combination with PEGPH20 versus eribulin 
mesylate alone in subjects with HER2-negative, 
HA-high, MBC previously treated with 0 to 1 line 
of systemic anticancer therapy (cytotoxic or 
targeted anticancer agents) in the metastatic setting. 
 
This is a randomized, open-label, multicenter, 
Phase 1b/2 study of eribulin mesylate in 
combination with PEGPH20 versus eribulin 
mesylate alone in subjects with HER2-negative, 
HA-high, MBC previously treated with  0 to 1 line 
up to 2 lines  of systemic anticancer therapy 
(cytotoxic drugs or targeted anticancer agents)in 
the metastatic setting.  
CDK4/6 inhibitors and mTOR inhibitors will 
not be considered as prior lines of therapy.  Any 
single agents or combination of scheduled pre-
planned treatments (given concomitantly, 
sequentially, or both) is considered as one 
regimen.  Hormonal therapy and bone 
metastases treatment (eg, bisphosphonates, 
denosumab, etc) are not considered forms of 
systemic anticancer therapy. 
 
The Phase 1b part will have dose-limiting toxicity 
(DLT) assessed in the first cycle….. 
 
Phase 1b occurs in two parts:  
Part 1: Conduct run-in safety cohorts (dose 
levels 1, 0, and -1, as necessary) of 6 subjects 
each, until RP2D is determined as follows:  
 
The Phase 1b part 1 will have dose-limiting 
toxicity (DLT) assessed in the first cycle….. 
 
Otherwise, alternative doses will be explored prior 
to the start of Phase 2. 
 
 
 
 
 
 
 
…Otherwise, alternative doses will be explored 
prior to the start of Phase 2. 
Part 2:  Upon determination of the RP2D, begin 
Phase 1b "Expansion Part" by enrolling 12 
additional subjects (using Phase 1b criteria, ie, 
subjects previously treated with up to 2 lines of 
systemic anticancer therapy) at the RP2D. This 
will result in a total of 18 subjects at RP2D for 
further safety analysis.  
Following completion of one treatment cycle by 
the Expansion Part subjects, a safety evaluation 
of all Phase 1b subjects, focusing on incidence 
of TE events, will be conducted prior to 
proceeding with the Phase 2 part of the study.  
If ≤ 1 out of 18 subjects experience a TE event, 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 4 of 42 
CONFIDENTIAL 
Eisai 
 
 
 
 
the upper limit of the 1-sided 80% exact CI for 
the true TE rate will not be greater than 15.7%.  
If ≤ 2 out of 18 subjects experience a TE event, 
the upper limit of the 1-sided 80% exact CI for 
the true TE rate will not be greater than 22.3%. 
If more than 2 TE events occurs in 18 subjects 
in Phase 1b, then the sponsor in collaboration 
with Halozyme will decide on further required 
changes to the study conduct. 
 
Pharmacokinetic (PK) assessments of eribulin 
mesylate and PEGPH20 will be performed in all 
subjects in the Phase 1b part of the study. Only 
subjects receiving combination treatment with 
PEGPH20 and eribulin mesylate (Arm A) in the 
Phase 2 part will undergo sparse PK sampling for 
population 
pharmacokinetic 
/pharmacodynamic 
(PK/PD) analysis, where feasible. 
Pharmacokinetic (PK) assessments of eribulin 
mesylate and PEGPH20 will be performed in all 
subjects in the Phase 1b part of the study for all 12 
subjects in the Phase 1b Expansion Part.  Only 
subjects receiving combination treatment with 
PEGPH20 and eribulin mesylate (Arm A) in the 
Phase 2 part will undergo sparse PK sampling for 
population pharmacokinetic/pharmacodynamic 
(PK/PD) analysis, where feasible. 
Reason(s) for the Amendment:   
Study design modified to include patients in later lines based on Investigator feedback and allow for the 
combination to be used in a broader patient population. 
Added additional details to further clarify definition of systemic anticancer therapy.  
Rationale of adding the Phase 1b expansion part is based on safety considerations                         
(discussed and required by Eisai Sr Management and GSO). 
PK being done only in expansion part patients since all these patients will be treated at RP2D and PK 
sampling data from 12 patients is adequate.  


 
 
 
 
 
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Amendment 01 (27 Oct 2016) 
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Page 5 of 42 
CONFIDENTIAL 
Eisai 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.3.1   
SYNOPSIS and Section 9.3.1   
Inclusion Criteria 
3. Human epidermal growth factor receptor 2-
negative (defined as immunohistochemistry [IHC] 
<2+ or fluorescence in situ hybridization [FISH] 
negative) breast cancer previously treated 
with 0 to 1 line 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. 
 
Inclusion Criteria 
3. Human epidermal growth factor receptor 2-
negative (defined as immunohistochemistry [IHC] 
<2+ or fluorescence in situ hybridization [FISH] 
negative) breast cancer previously treated with 0 to 
1 line 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. 
 Metastatic breast cancer meeting the following 
criteria:  
a. Human epidermal growth factor 
receptor 2-negative, defined as 
immunohistochemistry (IHC) <2+ or 
fluorescence in situ hybridization (FISH) 
negative. 
 
b. Previously treated with up to two lines of 
systemic anticancer therapy (cytotoxic 
drugs or targeted anticancer agents) in 
the metastatic setting. CDK4/6 inhibitors 
and mTOR inhibitors will not be 
considered as prior lines of therapy.   
Any single agents or combination of 
scheduled pre-planned treatments (given 
concomitantly, sequentially, or both) is 
considered as one regimen.  Hormonal 
therapy and bone metastases treatment 
(eg, bisphosphonates, denosumab, etc) 
are not considered forms of systemic 
anticancer therapy. 
 
 
4. Archived tissue sample or new biopsy sample: 
Metastatic breast cancer tissue with HA-high levels 
based on available tumor tissue in 
formaldehyde fixed-paraffin embedded (FFPE) 
block or minimum of 5 (10 preferred) 
unstained core biopsy slides that meet specific 
tissue sample requirements. Fine needle 
aspirates (FNA) or brushing biopsies will not be 
acceptable. 
4. Archived tissue sample or new biopsy sample: 
Metastatic breast cancer tissue with HA-high 
levels based on available tumor tissue in 
formaldehyde fixed-paraffin embedded (FFPE) 
block or minimum of 5 (10 preferred) 10  
unstained core biopsy slides that meet specific 
tissue sample requirements.  Fine needle aspirates 
(FNA), or brushing biopsies or bone metastasis 
tumor samples will not be acceptable. 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 6 of 42 
CONFIDENTIAL 
Eisai 
 
 
Reason(s) for the Amendment:   
For Inclusion Criteria #3: Study design modified to include patients in later lines based on Investigator 
feedback and to allow for the combination to be used in a broader patient population. Added additional 
details to further clarify definition of systemic anticancer therapy.  
For Inclusion Criteria #4: Provide further clarification regarding the minimum number of unstained 
biopsy slides being requested (10)   
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.3 
SYNOPSIS and Section 9.3 
Number of Subjects 
A total of approximately 96 adult female or male 
subjects previously treated with 0 to 1 line of 
systemic anticancer therapy in the metastatic 
setting will be enrolled (approximately 6 to 18 in 
the Phase 1b  and 84 randomized in Phase 2 to 
obtain 80 evaluable in Phase 2). 
Number of Subjects 
A total of approximately 96 114 adult female or 
male subjects previously treated with 0 to 1 line 
up to 2 lines of systemic anticancer therapy in the 
metastatic setting will be enrolled (comprising of 
up to 30 in Phase 1b [approximately 6 to 18 in 
the safety run-in cohort plus 12 in the 
Expansion part] and 84 randomized in Phase 2 to 
obtain 80 evaluable in Phase 2). 
Reason(s) for the Amendment:   
Number of subjects revised due to addition of 12 subjects in the Phase 1b expansion part. 
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.4.1.3 
SYNOPSIS and Section 9.4.1.3 
Study Treatments 
Dose Delays and Modifications for Eribulin 
Mesylate:  
Table 2: Eribulin Mesylate Dose Adjustments for 
Toxicity 
Occurrence of any event 
requiring permanent dose 
reduction while receiving 
0.7 mg/m2 
Unable to administer a 
scheduled dose of eribulin 
mesylate for more than 21 days 
of study 
Discontinue 
eribulin 
mesylate 
 
 
Study Treatments 
Dose Delays and Modifications for Eribulin 
Mesylate:  
Table 2: Eribulin Mesylate Dose Adjustments for 
Toxicity 
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 
 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 7 of 42 
CONFIDENTIAL 
Eisai 
Reason(s) for the Amendment:   
To further clarify the language and added requirement to seek Sponsor agreement prior to continuing 
treatment following dose delay of Eribulin Mesylate for more than 21 days.  
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.4.1 
SYNOPSIS and Section 9.4.1 
Duration of Treatment 
Those subjects who will be treated with eribulin 
mesylate and PEGPH20 can remain on eribulin 
mesylate only or both study drugs in the presence 
of clinical benefit until unacceptable toxicity or 
disease progression occurs, or until the subject 
withdraws consent. Subjects who experience any 
TE event requiring full dose anti-coagulation while 
on PEGPH20 treatment will be discontinued from 
PEGPH20 treatment but may continue to receive 
eribulin mesylate and remain on the study. 
Duration of Treatment 
Those subjects who will be treated with eribulin 
mesylate and PEGPH20 can remain on eribulin 
mesylate only or both study drugs in the presence 
of clinical benefit until unacceptable toxicity or 
disease progression occurs, or until the subject 
withdraws 
consent. 
Discontinuing 
either 
eribulin or PEGPH20 only will be considered 
as study treatment discontinuation. Subjects 
who experience any TE event requiring full dose 
anti-coagulation while on PEGPH20 treatment 
will be discontinued from PEGPH20 treatment but 
may continue to receive eribulin mesylate and 
remain on the study. 
Reason(s) for the Amendment:   
Added language to clarify the end of treatment definition.  
 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.4.4 
Section 9.4.4 
 
Added text: 
The  RP2D will be selected as a dose which 
does not exceed 1 DLT per 6 patients or 3 
DLTs per 18 patients (during the DLT 
assessment period) and will also include 
assessment of the entirety of safety data 
including dose reductions or discontinuations 
that occur for either study drug during or after 
the DLT period. 
Reason(s) for the Amendment: 
To further clarify rationale behind RP2D selection.   
 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
E7389-M000-219 
Page 8 of 42 
CONFIDENTIAL 
Eisai 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.4.7.1 
Section 9.4.7.1 
Dexamethasone may be used to attenuate 
musculoskeletal symptoms that may occur in 
subjects treated with PEGPH20. 
Dexamethasone may be used is being given 
as part of the study dosing regimen in 
order to attenuate musculoskeletal symptoms 
that may occur in subjects treated with 
PEGPH20. 
Reason(s) for the Amendment:  
To further clarify that Dexamethasone is a mandated concomitant medication in this study.   
 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.4.7.3 
Section 9.4.7.3 
Subjects who, in the assessment by the 
investigator, require the use of any of the 
aforementioned treatments for clinical 
management should be removed from the trial. 
Subjects may receive other medications that 
the investigator deems to be medically 
necessary. 
For sSubjects 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 should be removed from the 
trial.  Subjects may receive other medications 
that the investigator deems to be medically 
necessary. 
 
Reason(s) for the Amendment:  
To further specify need of Sponsor approval prior to provision of any prohibited therapies to study 
subjects.   
 
 
 


 
 
 
 
 
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Amendment 01 (27 Oct 2016) 
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Page 9 of 42 
CONFIDENTIAL 
Eisai 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.5.1.2 
Section 9.5.1.2 
 
Added text: 
Additional screening assessments for Phase 
1b and Phase 2 subjects will include blood 
samples collected for potential biomarker 
and plasma-HA analyses (see Section 
9.5.1.6.3, Table 7, Table 8, and Table 9). 
 
Reason(s) for the Amendment:  
For consistency with additions made in the synopsis and schedule of events  
 
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.5.1.3 
SYNOPSIS and Section 9.5.1.3 
Assessments 
Definition of Dose-Limiting Toxicity: 
Hematologic Toxicities: 
 
Any Grade 4 thrombocytopenia or 
neutropenia lasting >7 days.  
Nonhematologic Toxicities: 
 
Any Grade PE or stroke.  
 
Any Grade 4 toxicity. 
 
Any Grade 3 toxicity EXCLUDING: 
o Nausea, vomiting, or diarrhea 
controlled by medical 
intervention within 72 hours. 
 
Discontinuation or delay of more than 
2 weeks of either study drug due to 
treatment-related AE will be 
considered as a DLT. 
 
Assessments 
Definition of Dose-Limiting Toxicity: 
Hematologic Toxicities: 
 
Any Grade 4 thrombocytopenia or 
neutropenia lasting >7 days.  
 
Neutropenia Grade 3 or 4 
complicated by fever and/or 
infection (ANC <1.0 x 109/L, fever 
≥38.5°C). 
 
Thrombocytopenia Grade 3 
complicated by bleeding and/or 
requiring platelet or blood 
transfusion. 
Nonhematologic Toxicities: 
 
Any Grade DVT, PE or stroke.  
 
Any Grade 4 toxicity. 
 
Any clinically significant* Grade 3 
toxicity EXCLUDING: 
o Nausea, vomiting, or diarrhea 
controlled by medical 
intervention within 72 hours. 
 
Hypersensitivity reactions Grade 3 
or 4 including allergy reactions or 
anaphylaxis symptomatic  
bronchospasm requiring parenteral 
medication(s) with or without 
urticaria; allergy-related 


 
 
 
 
 
Clinical Study Protocol Amendment 
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edema/angioedema. 
 
Discontinuation or delay of more than 
2 weeks of either study drug due to 
treatment-related AE will be 
considered as a DLT. 
*An abnormal lab value should be 
deemed clinically significant if either of 
the following conditions is met: 
• The abnormality suggests a 
disease and/or organ toxicity 
that is new or has worsened from 
baseline. 
• The abnormality is of a degree 
(severity)  that requires 
additional active management, 
e.g., Study drug withdraw, dose 
delay or omission or dose 
reduction, close observation and 
monitoring, more frequent 
follow-up assessments, or further 
diagnostic investigation. 
Therefore, a clinically significant lab 
value is one that indicates a new disease 
process, an exacerbation or worsening 
of an existing condition, or requires 
further action(s) to be taken. 
 
Reason(s) for the Amendment:   
1) Include a “standard definition” of DLTs as defined as any of the following using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE Version 4.03),  
2)Include hypersensitivity reactions as DLT , as per the IB brochure Table 35  Adverse Reaction 
Specification (Including Frequencies and Severities) for PEGPH20 Based on Cumulative Clinical Data 
(Through 2 June 2015).  
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS, Section 9.5.1.5, and Section 9.5.1.5.1 
SYNOPSIS, Section 9.5.1.5, and Section 
9.5.1.5.1 
Efficacy Assessments 
The primary endpoint (ORR), secondary endpoint 
(PFS), and exploratory endpoints (CBR, DCR, and 
DOR) will be evaluated based on tumor 
Efficacy Assessments 
The primary endpoint (ORR), secondary endpoint 
(PFS), and exploratory endpoints (CBR, DCR, 
and DOR) will be evaluated based on tumor 


 
 
 
 
 
Clinical Study Protocol Amendment 
Amendment 01 (27 Oct 2016) 
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Page 11 of 42 
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assessments performed by the investigator.  The 
secondary endpoint OS will be assessed throughout 
the study.  All scans for tumor assessments 
performed during the study should be archived in 
accordance with the standard local practice.  The 
scans must be submitted to a central core laboratory 
selected by the sponsor for potential central review. 
 
  
Tumor assessments (CT chest and CT/MRI of 
abdomen, pelvis, and other areas of known disease 
at Screening plus any areas of newly suspected 
disease) should be performed at Screening (within 
21 days prior to first dose of study drugs) and 
every6 weeks ±1 week from the date of first dose 
of study drug, or sooner if clinically indicated, until 
documentation of disease progression. Skin lesions 
will not be included as target lesions, but may only 
be considered as non-target lesions. 
 
 
A brain scan (CT with contrast or MRI pre- and 
post-gadolinium) must be performed at Screening 
(within 21 days prior to first dose of study drugs), 
to assess potential CNS disease and/or metastases. 
For the duration of the study (ie, post-Baseline), 
CT/MRI of the brain will be performed if clinically 
indicated, and within a target of 1 week after a 
subject achieves a complete response (CR). For 
subjects with a history of treated brain metastases, 
brain scans will be performed at tumor assessment 
time points, if clinically indicated. 
 
 
A bone scan (99m-technetium polyphosphonate 
scintigraphy, whole body bone MRI, or 18F-
NaFpositron emission tomography [PET]) to assess 
bone metastases should be performed within 6 
weeks prior to first dose of study drugs (historical 
scans are acceptable) and then every 24 weeks ±1 
week after the date of first dose of study drugs, or 
sooner if clinically indicated. 
 
 
 
assessments performed by the investigator.  The 
secondary endpoint OS will be assessed 
throughout the study.  All scans for tumor 
assessments performed during the study should be 
archived in accordance with the standard local 
practice.  The scans must be submitted to a central 
core laboratory selected by the sponsor for 
potential central review. 
 
Tumor assessments (CT chest and CT/MRI of 
abdomen, pelvis, and other areas of known 
disease at Screening plus any areas of newly 
suspected disease) should be performed at 
Screening (within 21 days prior to first dose of 
study drugs) and every 6 weeks ±1 week from the 
date of first dose of study drug (Phase 1b) or 
randomization (Phase 2), or sooner if clinically 
indicated, until documentation of disease 
progression.  Skin lesions will not be included as 
target lesions, but may only be considered as non-
target lesions. 
 
A brain scan (CT with contrast or MRI pre- and 
post-gadolinium) must be performed at Screening 
(within 21 days prior to first dose of study drugs 
[Phase 1b] or randomization [Phase 2]), to 
assess potential CNS disease and/or metastases.  
For the duration of the study (ie, post-Baseline), 
CT/MRI of the brain will be performed if 
clinically indicated, and within a target of 1 week 
after a subject achieves a complete response (CR).  
For subjects with a history of treated brain 
metastases, brain scans will be performed at all 
tumor assessment time points, if clinically 
indicated. 
 
A bone scan (99m-technetium based 
polyphosphonate scintigraphy, whole body bone 
MRI, or 18F-NaF-positron emission tomography 
[PET]) to assess bone metastases should be 
performed within 6 weeks prior to first dose of 
study drugs (Phase 1b) or randomization (Phase 
2) (historical scans are acceptable) and then every 
24 weeks ±1 week after the date of first dose of 
study drugs (Phase 1b) or randomization (Phase 
2), or sooner if clinically indicated. 
 
 


 
 
 
 
 
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Confirmation is not required for best overall 
response (BOR) of CR or partial response (PR) in 
either Phase 1b or Phase 2 parts of the trial.  Best 
overall response of stable disease (SD) requires at 
least 1 posttreatment assessment that meets the SD 
criteria ≥5 weeks after the start of treatment  
 
  
Confirmation is not required for best overall 
response (BOR) of CR or partial response (PR) in 
either Phase 1b or Phase 2 parts of the trial.  Best 
overall response of stable disease (SD) requires at 
least 1 posttreatment assessment that meets the 
SD criteria ≥5 weeks after the start of treatment 
(Phase 1b) or randomization (Phase 2). 
 
Reason(s) for the Amendment:   
Added language to a. delete contradictory language and b. specify the various intervals of tumor 
assessment apply to both phases of the study. 
 
 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.5.1.6.1 
Section 9.5.1.6.1 
 
Table 1 
Blood Sample Collection for 
Pharmacokinetic Analysis of 
Eribulin and PEGPH20 for 
Phase 1b Subjects 
 
 
 
Cycle / 
Day 
PEGPH20 
Sample 
Timepoints 
(n=8)  
Eribulin Sample 
Timepoints (n=11) 
C1D-1 
Predose (0 h)  
 
Postdose (15 
min) 
 
Postdose (1 h) 
 
Postdose (2 h) 
 
Postdose (4 h) 
 
C1D1a 
Postdose (24 h)  
Predose (0 h) 
 
Postdose (15 min) 
 
Postdose (30 min) 
 
Postdose (1 h) 
 
Postdose (2 h) 
 
Postdose (4 h) 
C1D2a 
Postdose (48 h)  
Postdose (24 h) 
C1D3a 
Postdose (72 h)  
Postdose (48 h) 
C1D4 
 
Postdose (72 h) 
C1D5 
 
Postdose (96 h) 
C1D6 
 
Postdose (120 h) 
C=cycle; D=day; h=hour(s); min=minutes 
 
Table 2 
Blood Sample Collection for 
Pharmacokinetic Analysis of 
Eribulin,andPEGPH20 and 
Plasma HA analysis for Phase 
1b  Expansion Part subjects 
 
 
Cycle / 
Day 
PEGPH20 
Sample 
Timepoints 
(n=8)  
Eribulin Sample 
Timepoints 
(n=11) 
C1D-1 
Predose (0 h) b 
 
Postdose (15 
min) 
 
Postdose (1 h) 
 
Postdose (2 h) 
 
Postdose (4 h) 
 
C1D1a 
Postdose (24 h) 
b 
Predose (0 h) 
 
Postdose (15 min) 
 
Postdose (30 min) 
 
Postdose (1 h) 
 
Postdose (2 h) 
 
Postdose (4 h) 
C1D2a 
Postdose (48 h) 
b 
Postdose (24 h) 
C1D3a 
Postdose (72 h) 
b 
Postdose (48 h) 
C1D4 
 
Postdose (72 h) 
C1D5 
 
Postdose (96 h) 


 
 
 
 
 
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a: 
Note that samples collected at 24, 48 and 72 
hours after the PEGPH20 infusion 
correspond, respectively, with eribulin 
mesylate predose [0 hour] on Cycle 1 Day 1 
[C1D1], as well as 24 and 48 hours after the 
infusion of eribulin mesylate.  Separate 
PEGPH20 and eribulin blood samples will 
be collected at these time points.  Details are 
provided in the Pharmacokinetics Sample 
Collection and Handling Manual for this 
study.  
 
 
C1D6 
 
Postdose (120 h) 
C=cycle; D=day; h=hour(s); min=minutes 
 
a: 
Note that samples collected at 24, 48 and 
72 hours after the PEGPH20 infusion 
correspond, respectively, with eribulin 
mesylate predose [0 hour] on Cycle 1 Day 1 
[C1D1], as well as 24 and 48 hours after the 
infusion of eribulin mesylate.  Separate 
PEGPH20 and eribulin blood samples will 
be collected at these time points.  Details 
are provided in the Pharmacokinetics 
Sample Collection and Handling Manual 
for this study.  
b: For those time points, one PEGPH20 PK 
samples and one Plasma-HA sample will 
be collected (for more details please see 
Section 9.5.1.6.3 Biomarker assessment - 
Pharmacogenomic and 
Pharmacodynamic blood samples) 
 
Reason(s) for the Amendment:  
The plasma HA sample is being added as a PD marker for PEGPH20 activity, and the additional time 
points are added to better characterize the PD response. Changes in plasma HA over the first 24 hours 
would be critical to our understanding of the pharmacological effects of PEGPH20 in this patient 
population. 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.5.1.6.3 
SYNOPSIS and Section 9.5.1.6.3 
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
Tumor Samples 
Archived and/or fresh (if possible) tissue samples 
will be obtained for all subjects at screening for 
assessment of HA levels. At least 5 (preferred 10) 
unstained, consecutive slides of one archival tumor 
block or paraffin block, or a fresh tumor biopsy that 
meet specific tissue sample requirements are 
required. Tumor samples collected via FNA and 
brushing biopsies are not acceptable.  
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
Tumor Samples 
Archived and/or fresh (if possible) tissue samples 
will be obtained for all subjects at screening for 
assessment of HA levels. At least 5 (preferred 10) 
10 unstained, consecutive slides of one archival 
tumor block or paraffin block, or a fresh tumor 
biopsy that meet specific tissue sample 
requirements are required. Tumor samples 
collected via FNA and brushing biopsies are not 
acceptable.  
Pharmacogenomic and Pharmacodynamic blood 
samples 
Where not prohibited by local regulations, blood 
samples for all Phase 2 subjects will be collected 
for potential pharmacogenomic and/or 
Pharmacogenomic and Pharmacodynamic blood 
samples 
Where not prohibited by local regulations, blood 
samples for Phase 1b and all Phase 2 subjects will 
be collected for potential pharmacogenomic 


 
 
 
 
 
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pharmacodynamic analyses.  
 
 
 
 
 
 
 
 
 
 
 
and/or pharmacodynamic analyses as defined in 
the schedule of assessments.  
Phase 1b 
Blood samples from all Phase 1b Expansion 
Part subjects will be collected at the PEGPH20 
predose on Day -2 or C1 Day -1 for potential 
pharmacogenomics (PGx) analyses.  
Blood samples for potential 
pharmacodynamics (PD) for biomarkers 
analyses will be collected from the Phase 1b 
Expansion Part subjects at the screening visit, 
at the PEGPH20 predose on Day -2 or C1 Day -
1, C1 Day 7, C2 Day -1, Day -1 of every other 
cycle (C3, C5, C7, etc.), and at the End of 
Treatment Visit, or whenever a subject is 
withdrawn from study treatment. 
A sample for plasma-HA analysis of PEGPH20 
will be collected from the Phase 1b expansion 
Part subjects on Cycle 1 Day -1 (C1 Day -1) at 
predose (0 hour). Additional sample will be 
collected at 24, 48, and 72 hours after the 
PEGPH20 infusion (which will correspond, 
respectively, with eribulin mesylate predose [0 
hour] on C1D1, 24 and 48 hours after the 
infusion of eribulin mesylate). 
 
A single blood sample on Cycle 1 Day -1 will be 
collected at PEGPH20 pre-dose (for Phase 2/Arm 
A subjects) and a single sample on Cycle 1 Day 1 
will be collected at eribulin mesylate pre-dose…… 
Phase 2 
A single blood sample on Day -2 or Cycle 1 Day 
-1 will be collected at PEGPH20 pre-dose (for 
Phase 2/Arm A subjects) and a single sample on 
Day -1 or Cycle 1 Day 1 will be collected at 
eribulin mesylate pre-dose…… 


 
 
 
 
 
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For Phase 2/Arm A subjects (samples collected at 
PEGPH20 pre-dose on C1 Day -1 and at the End of 
Treatment Visit or whenever a subject is withdrawn 
from the study), pharmacodynamic evaluations (eg, 
to study blood biomarkers and total HA 
disaccharide in plasma [plasma-HA]) may be 
performed using global proteomic methods, 
enzyme-linked immunosorbent assay (ELISA), 
multiplex bead-based immunoassay, validated 
liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) methods, or other assays/methods 
and new technology. Samples may also be analyzed 
for circulating tumor DNA or miRNA. Blood 
biomarker samples may be used for exploratory 
analysis for evaluation of response-related and/or 
safety-related outcomes as well as for potential use 
in diagnostic development. 
For Phase 2/Arm A subjects (samples collected at 
PEGPH20 pre-dose on C1 Day -1 and at the End 
of Treatment Visit or whenever a subject is 
withdrawn from the study), 
For Phase 2/Arm A subjects blood samples for 
potential ADA analyses will be collected at 
PEGPH20 predose on Day -2 or C1 Day -1 and 
at the End of Treatment Visit (or whenever a 
subject is withdrawn from the study).  Blood 
samples for potential pharmacodynamics for 
plasma-HA and biomarkers analyses  will be 
collected during screening, at PEGPH20 pre-
dose on Day -2 or C1 Day -1, C1 Day 7, C2 Day 
-1, Day -1 of every other cycle (C3, C5, C7, 
etc.), and at the End of Treatment Visit or 
whenever a subject is withdrawn from the 
study).  
For Phase 2/Arm B subjects (samples collected at 
eribulin mesylate pre-dose on C1 Day 1 and at the 
End of Treatment Visit or whenever a subject is 
withdrawn from the study), pharmacodynamics 
evaluations (blood biomarkers, only) may be 
performed as described above. 
 
For  Phase 2/Arm B blood samples for 
potential pharmacodynamics for plasma-HA 
and biomarkers analyses will be collected 
during screening, at eribulin mesylate pre-dose 
on C1 Day 1, C1 Day 8, C2 Day 1, Day 1 of 
every other cycle (C3, C5, C7, etc.), and at the 
End of Treatment Visit or whenever a subject 
is withdrawn from the study). 
Pharmacodynamic evaluations (eg, to study blood 
biomarkers and total HA disaccharide in plasma 
[plasma-HA]) may be performed using global 
proteomic methods, enzyme-linked 
immunosorbent assay (ELISA), multiplex bead-
based immunoassay, validated liquid 
chromatography-tandem mass spectrometry (LC-
MS/MS) methods, or other assays/methods and 
new technology. Samples may also be analyzed 
for circulating tumor DNA or miRNA. Blood 
biomarker samples may be used for exploratory 
analysis for evaluation of response-related and/or 
safety-related outcomes as well as for potential 
use in diagnostic development. 
(samples collected at eribulin mesylate pre-dose 
on C1 Day 1 and at the End of Treatment Visit or 
whenever a subject is withdrawn from the study), 
pharmacodynamics evaluations (blood 
biomarkers, only) may be performed as described 
above 
Reason(s) for the Amendment:   


 
 
 
 
 
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Phase 1b: PGx sample added for pharmacogenomics analysis. Plasma HA sample is being added as a 
PD marker for PEGPH20 activity, and the additional time points are added to better characterize the 
PD response. Changes in plasma HA over the first 24 hours would be critical to the understanding of 
the pharmacological effects of PEGPH20 in this patient population. PD biomarker samples added to 
better characterize the PD response. 
Phase 2 Arm A and Arm B: Plasma HA and Biomarkers - Additional time points added to better 
characterize the PD response. 
 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.1.1 
Section 9.1.1 
Pretreatment/Prerandomization Phase 
The Baseline Period includes randomization (Phase 
2 subjects only) and the Baseline Visit (all 
subjects). Specifically, Phase 1b and Phase 2/Arm 
A subjects, will have their safety and efficacy 
assessments performed on or before designated 
Study Day -1 or C1D-1, prior to administration of 
their first dose of PEGPH20 (see Schedule of 
Procedures/Assessments, Table 7 and Table 8); 
Phase 2/Arm B subjects will have their safety and 
efficacy assessments performed on or before 
designated Study Day 1, prior to administration of 
their first dose of eribulin mesylate (Table 7 see 
Schedule of Procedures/Assessments, Table 9). 
Pretreatment/Prerandomization Phase 
The Baseline Period includes randomization 
(Phase 2 subjects only) and the Baseline Visit (all 
subjects).  Specifically, Phase 1b and Phase 
2/Arm A subjects, will have their safety and 
efficacy Baseline assessments performed on or 
before designated Study Day -2 1 or C1D-1, prior 
to administration of their first dose of PEGPH20 
(see Schedule of Procedures/Assessments, Error! 
Reference source not found. and Error! 
Reference source not found.); Phase 2/Arm B 
subjects will have their safety and efficacy 
Baseline assessments performed on Day -1 or on 
Cycle 1 Day 1 or before designated Study Day 1, 
prior to administration of their first dose of 
eribulin mesylate (Table 7 see Schedule of 
Procedures/Assessments, Error! Reference 
source not found.).   
Reason(s) for the Amendment:   
For added clarity 
 
 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
Section 9.2 
Section 9.2 
Discussion of Study Design, Including Choice of 
Control Groups 
HA-high is considered to be a poor prognostic 
factor for patients with metastatic disease (Tammi 
RH et al, Kultti A et al). Therefore, a two-arm 
study design is used to allow evaluation of a 
potential synergistic effect of the combination 
therapy over single agent eribulin mesylate in this 
patient population. 
 
Discussion of Study Design, Including Choice of 
Control Groups 
HA-high is considered to be a poor prognostic 
factor for patients with metastatic disease (Tammi 
RH, et al., 2008; Kultti A, et al., 2012) Therefore, 
a two-arm study design is used to allow evaluation 
of a potential synergistic effect of the combination 
therapy over single agent eribulin mesylate in this 
patient population. 
Following establishment of RP2D at the Phase 
1b Safety run-in part of the study, a Phase 1b 
Expansion part consisting of 12 subjects will 
provide additional safety data prior to 
initiating the Phase 2 part of the study. This is 
in order to assess the safety profile of the 
combination and identify any potential safety 
signals and the incidence of thromboembolic 
events in this population. 
Reason(s) for the Amendment:   
Language added to further explain rationale for adding the Phase 1b expansion part.  
 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
Section 7.1.3.2  
Section 7.1.3.2 
Clinical Experience with PEGPH20 
PEGPH20 is being developed as an investigational, 
novel therapeutic agent for use in combination with 
chemotherapy or other agents for the treatment of 
patients with cancers that accumulate HA. As of 02 
June 2015, a total of 197 subjects have been 
exposed to PEGPH20 as a single agent or in the 
following 
combinations: 
1) 
gemcitabine; 
2) 
gemcitabine and nab-paclitaxel; 3) modified 
FOLFIRNOX; or 4) docetaxel. …… In an ongoing 
Phase 2 study in subjects with pancreatic cancer 
(Study 
HALO-109-202), 
111 
subjects 
were 
randomized to receive 1000 mg/m2 gemcitabine IV 
once weekly, 125 mg/m2 nab-paclitaxel IV once 
weekly, and 3.0 μg/kg PEGPH20 IV twice weekly 
in the first cycle and once weekly thereafter. In an 
ongoing Phase 1b/2 study in subjects with 
advanced NSCLC (Study HALO-107-201), 4 
subjects have received 75 mg/m2 docetaxel and 
PEGPH20 3.0 μg/kg IV once every 21 days.  
 
 
 
 
Halozyme Therapeutics has sponsored a total of 
three completed studies of PEGPH20 in subjects 
with solid tumor malignancies (2 monotherapy and 
one in combination with gemcitabine), as well as 
one ongoing clinical study with PEGPH20 in 
combination with nab-paclitaxel and gemcitabine 
in subjects with advanced pancreatic cancer, and 
one ongoing clinical study with PEGPH20 in 
combination with docetaxel in subjects with 
metastatic NSCLC. 
 
 
 
 
Clinical Experience with PEGPH20 
PEGPH20 is being developed as an 
investigational, novel therapeutic agent for use in 
combination with chemotherapy or other agents 
for the treatment of patients with cancers that 
accumulate HA.  As of 02 June 2015 13 
February 2016, a total of 197 272 subjects have 
been exposed to PEGPH20 as a single agent or in 
the following combinations: 1) gemcitabine; 2) 
gemcitabine and nab-paclitaxel; 3) modified 
FOLFIRNOX; or 4) docetaxel or 5) 
pembrolizumab. ……In an ongoing Phase 2 
study in subjects with pancreatic cancer (Study 
HALO-109-202), 111 156 subjects were 
randomized to receive 1000 mg/m2 gemcitabine 
IV once weekly, 125 mg/m2 nab-paclitaxel IV 
once weekly, and 3.0 µg/kg PEGPH20 IV twice 
weekly in the first cycle and once weekly 
thereafter.  In an ongoing Phase 1b/2 study in 
subjects with advanced NSCLC (Study HALO-
107-201),  4  10 subjects have received 75 mg/m2 
docetaxel and various doses of PEGPH20 1.6-
3.0 µg/kg IV once every 21 days.  In an ongoing 
Phase 1b/2 study in subjects with advanced 
NSCLC or gastric cancer (Study HALO-107-
101), 4 subjects have received 2 mg/kg IV 
pembroluzimab and 1.6 µg/kg IV of PEGPH20 
3.0 μg/kg once every 21 days.… 
Halozyme Therapeutics has sponsored a total of 
three completed studies of PEGPH20 in subjects 
with solid tumor malignancies (2 monotherapy 
and one in combination with gemcitabine), as well 
as one ongoing clinical study with PEGPH20 in 
combination with nab-paclitaxel and gemcitabine 
in subjects with advanced pancreatic cancer, and 
one ongoing clinical study with PEGPH20 in 
combination with docetaxel in subjects with 
metastatic NSCLC and one ongoing clinical 
study with PEGPH20 in combination with 
pembroluzimab in subjects with metastatic 
NSCLC or gastric cancer.As of the data cutoff 
date of the current IB, 255 subjects (156 
subjects in the PAG arm versus 99 in the AG 
arm) have been dosed in Study HALO-109-202. 
Among the PAG subjects, 74 subjects were 
dosed in Stage 1 and 82 in Stage 2. Among the 


 
 
 
 
 
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AG subjects, 61 were dosed in Stage 1 and 38 
in Stage 2.  
Halozyme has also developed, in collaboration 
with a leading diagnostic company, a novel 
investigational co-developed diagnostic product  
assay which may potentially be used to identify 
subjects who might benefit most, based on HA 
tumor content, from the administration of 
PEGPH20 in conjunction with other cancer 
therapeutics. This assay uses an affinity-
histochemistry-based staining method to 
evaluate HA levels in tumor biopsies. The CDx 
assay was developed in parallel with the 
clinical program and was used to 
retrospectively analyze PDA tumor samples for 
HA levels in Study HALO-109-202, to 
determine its predictive value. A tumor is 
determined to be HA-high when the 
extracellular tumor matrix, over the entire 
tumor surface stained at ≥50%. 
Final efficacy data (with a data cut of 
December 2014) for subjects in Stage 1 of 
Study HALO-109-202 using the Ventana HA 
CDx assay and scoring algorithm are presented 
below: 
A total of 135 subjects were treated (74 PAG, 
61 AG), of which 118 subjects 
(66 PAG and 52 AG) had evaluable HA data. 
PFS results are shown below (median follow-up 
was 7 months). In HA-high subjects receiving 
PAG versus AG, ORR was 55% (1 CR) versus 
33%. 
 
mPFS, mo 
 
Population 
PAG 
AG 
Hazard 
Ratio 
[95% CI] 
Treated  
5.5 
(n=74) 
5.2 
(n=61) 
0.73 
[0.46-
1.15] 
HA-High 
(n=43 
w/ 
evaluable 
9.2 
(n=22) 
6.3 
(n=21) 
0.48 
[0.16-
1.48] 


 
 
 
 
 
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Preliminary efficacy data for subjects in Stage 1 of 
Study HALO-109-202 in 146 total patients were 
presented at the American Society of Clinical 
Oncology Meeting in May 2015. A total of 41% of 
PAG subjects and 34% of AG subjects have had a 
complete or partial response, with a median 
duration of response at 7.4 months on PAG and 4.2 
months on AG. Subjects with HA-high tumors on 
PAG had a 15% higher response rate than those 
with HAlow tumors with a duration of response at 
8.1 months, versus 5.8 months, respectively. There 
was no difference in response rate between HA-
high or HA-low for subjects on AG. 
In regards to PFS, PAG subjects had a median PFS 
of 5.7 months versus 5.2 months for AG. When 
assessing for subjects with HA data, there was a 
statistically significant difference in PFS between 
subjects with HA-high on PAG (9.2 months) vs AG 
(4.3 months). Subjects on PAG with HA-high 
tumors had an almost 4 month increase in PFS as 
compared to those with HA-low tumors (9.2 
months vs 5.3 months, respectively). In regards to 
AG subjects, there was no significant difference 
between the two HA scores (HA-high: 4.3 months 
vs HA-low: 5.6 months). Preliminary overall 
survival from 23 subjects on PAG and 21 on AG is 
12 months and 9 months, respectively. 
 
 
 
HA data) 
HA-Low 
(n=75 
w/ 
evaluable 
HA data) 
5.3 
(n=44) 
4.3 
(n=31) 
0.69 
[0.38-
1.25] 
In conclusion, clinically meaningful 
improvements in PFS, and ORR was observed 
in subjects with HA-high tumors receiving 
PAG versus AG. 
Final safety and efficacy analyses including 
Stage 2 patients is pending data maturation.  
Preliminary efficacy data for subjects in Stage 1 
of Study HALO-109-202 in 146 total patients 
were presented at the American Society of 
Clinical Oncology Meeting in May 2015. A total 
of 41% of PAG subjects and 34% of AG subjects 
have had a complete or partial response, with a 
median duration of response at 7.4 months on 
PAG and 4.2 months on AG. Subjects with HA-
high tumors on PAG had a 15% higher response 
rate than those with HAlow tumors with a 
duration of response at 8.1 months, versus 5.8 
months, respectively. There was no difference in 
response rate between HA-high or HA-low for 
subjects on AG. 
In regards to PFS, PAG subjects had a median 
PFS of 5.7 months versus 5.2 months for AG. 
When assessing for subjects with HA data, there 
was a statistically significant difference in PFS 
between subjects with HA-high on PAG (9.2 
months) vs AG (4.3 months). Subjects on PAG 
with HA-high tumors had an almost 4 month 
increase in PFS as compared to those with HA-
low tumors (9.2 months vs 5.3 months, 
respectively). In regards to AG subjects, there was 
no significant difference between the two HA 
scores (HA-high: 4.3 months vs HA-low: 5.6 
months). Preliminary overall survival from 23 
subjects on PAG and 21 on AG is 12 months and 
9 months, respectively. 
A total of 238 subjects (93%) have experienced 
a treatment-emergent AE (TEAE) up to 13 Feb 
2016 (Data cutoff for the Investigator’s 
brochure) and 230 subjects (90%) have 
experienced at least 1 TEAE related to study 


 
 
 
 
 
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In terms of safety, the most common PEGPH20 
treatment-related AEs (≥10%) by preferred term 
(PT) were muscle spasms (53%), fatigue (51%), 
peripheral edema (37%), myalgia (23%), nausea 
(23%), arthralgia (21%), diarrhea (20%), decreased 
appetite 
(19%), 
vomiting 
(16%), 
alanine 
aminotransferase (ALT) increased (15%), aspartate 
aminotransferase (AST) increased (14%), anemia 
(14%), 
dysgeusia 
(14%), 
asthenia 
(14%), 
dysphonia 
(12%), 
thrombocytopenia 
(12%), 
platelet count decreased (11%), neutropenia (11%), 
and hypoalbuminemia (10%). 
 
In Stage 2 of the study, after the protocol was 
amended to include prophylaxis with enoxaparin, 
the TE event rate was reduced. An analysis of TE 
events as of May 2015 in the ongoing Stage 2 
portion indicated a TE event rate of 28% (n = 18) 
in the PAG group vs 29% (n = 7) in the AG group 
for subjects who either initiated enoxaparin at 40 
mg/day or initiated at 40 mg/day and increased to 1 
mg/kg/day; and no TE events for subjects who 
initiated enoxaparin at 1 mg/kg/day were reported 
in the PAG group (n = 20) vs 10% in the AG group 
(n = 10). 
drug. Overall, the most commonly reported 
SOCs were gastrointestinal disorders (221 
subjects [87%]), general disorders and 
administration site conditions (216 subjects 
[85%]), metabolism and nutritional disorders 
(175 subjects [69%]), and musculoskeletal and 
connective tissue disorders (164 subjects 
[64%]). 
In terms of safety, the most common PEGPH20 
treatment-related AEs (≥10%) by preferred 
term (PT) were muscle spasms (79 subjects 
[51%]), fatigue (72 subjects [46%]), peripheral 
edema (56 subjects [36%]), myalgia (34 
subjects [22%]), nausea (30 subjects [19%]), 
arthralgia (29 subjects [19%]), decreased 
appetite (27 subjects [17%]), diarrhea (27 
subjects (17%)], vomiting (22 subjects (14%)], 
dysgeusia (20 subjects [13%], abdominal pain 
(16 subjects [10%]) ALT increased (16 subjects 
[10%]), and asthenia (15 subjects [10%]).   
In terms of safety, the most common PEGPH20 
treatment-related AEs (≥10%) by preferred term 
(PT) were muscle spasms (53%), fatigue (51%), 
peripheral edema (37%), myalgia (23%), nausea 
(23%), 
arthralgia 
(21%), 
diarrhea 
(20%), 
decreased appetite (19%), vomiting (16%), 
alanine aminotransferase (ALT) increased (15%), 
aspartate 
aminotransferase 
(AST) 
increased 
(14%), anemia (14%), dysgeusia (14%), asthenia 
(14%), 
dysphonia 
(12%), 
thrombocytopenia 
(12%), 
platelet 
count 
decreased 
(11%), 
neutropenia (11%), and hypoalbuminemia (10%). 
 
In Stage 2 of the study, after the protocol was 
amended to include prophylaxis with enoxaparin, 
the TE event rate was reduced.  An analysis of TE 
events as of May 2015 February 2016 in the 
ongoing Stage 2 portion indicated a TE event rate 
of 28% (n = 18) in the PAG group vs 29% (n = 7) 
in the AG group for subjects who either initiated 
enoxaparin at 40 mg/day or initiated at 40 mg/day 
and increased to 1 mg/kg/day; the incidence for 
subjects who have started on enoxaparin at 1 
mg/kg/day was 9% for PAG subjects (n=68) vs 
5% versus for AG subjects (n=38) and no TE 
events for subjects who initiated enoxaparin at 1 
mg/kg/day were reported in the PAG group (n = 


 
 
 
 
 
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20) vs 10% in the AG group (n = 10). 
As of 13 February 2016, 10 subjects have been 
dosed with PEGPH20 (6 subjects with 1.6 
μg/kg of PEGPH20 and 4 subjects with 3.0 
μg/kg of PEGPH20) and docetaxel once every 
21 days.  All subjects (N=10) have experienced 
at least one TEAE.  Overall, the most 
commonly reported SOCs (SOCs experienced 
by ≥50% of subjects) were musculoskeletal and 
connective tissue disorders (90%), general 
disorders and administration site conditions 
(80%), respiratory, thoracic, and mediastinal 
disorders (80%),  blood and lymphatic system 
disorders (60%), gastrointestinal disorders 
(60%), and nervous system disorders (60%). 
The most common treatment emergent adverse 
events (by preferred term) were myalgia 
(70%), fatigue (70%), muscle spasms (50%), 
and nausea (50%).   
 
Phase 1b/2 Study HALO-107-101: This an 
ongoing Phase 1b/2 study to evaluate the 
combination of pembrolizumab and PEGPH20 
in previously treated Stage IIIB or IV NSCLC 
subjects having failed at least 1 previous 
platinum containing chemotherapy regimen for 
locally advanced or metastatic disease and 
subjects with recurrent locally advanced or 
metastatic gastric adenocarcinoma having 
failed at least 1 previous chemotherapy 
regimen. In Phase 1b pembrolizumab in 
combination with a fixed dose of 
pembrolizumab (2mg/kg) will be investigated 
starting at 1.6 μg/kg with increasing cohorts of 
2.2, 3.0, and 4.0 μg/kg per standard dose 
escalation design.  The Phase 2 portion of the 
study will further study the recommended 
Phase 2 dose of pembrolizumab combined with 
PEGPH20 in the 2 study populations 
separately in order to assess additional safety 
and preliminary efficacy.  The study is 
currently enrolling in Phase 1b.  A total of 4 
patients were enrolled as of the date of cutoff of 
the current IB.   
Reason(s) for the Amendment:   
Amended per recent data from Halozyme studies on PEGPH20 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
Section 9.2.1.1 
Section 9.2.1.1.1 
 
Section 9.2.1.1.1 Thromboembolic Events  
Added following sub-section 
Section 9.2.1.1.1 THROMBOEMBOLIC EVENTS IN 
BREAST CANCER 
The clinical evidence for the use of enoxaparin 
prophylaxis in outpatients with breast cancer 
is not sufficiently proven, and carries a risk of 
additional safety for the risk of bleeding. 
When deciding whether to use primary 
antithrombotic prophylaxis in ambulatory 
cancer patients receiving chemotherapy, a 
clinician needs to determine the patient’s 
baseline risk of VTE and weigh the magnitude 
of benefit with antithrombotic prophylaxis, 
especially on major clinical endpoints, against 
the risk of bleeding.  
Breast cancer was associated with the lowest 
risk of VTE among average-risk groups (5 per 
1,000 person-years), but among those at high 
risk of VTE, this rose to 55 per 1,000 person-
years. Approximately 1% of breast cancer 
patients developed VTE within 2 years, with 
the highest incidence in the first 6 months 
after diagnosis. Metastatic disease and 
comorbidities were the strongest predictors. 
The diagnosis of VTE was associated with a 
higher risk of death within 2 years. 
Specifically, a higher incidence of VTE has 
been reported in patients receiving tamoxifen 
therapy (0.9%), chemotherapy (2.1%), and 
the combination (4% to 13%), in either early 
stage1-4 or advanced breast cancer (4.4%) 
(Chew, et al., 2007) 
Routine thromboprophylaxis is not 
recommended for patients with cancer in the 
outpatient setting. It may be considered for 
selected high-risk patients. LMWH is 
recommended for the initial 5 to 10 days of 
treatment for DVT and PE as well as for long-
term secondary prophylaxis (at least 6 
months). Use of novel oral anticoagulants is 
not currently recommended for patients with 
malignancy and VTE because of limited data 


 
 
 
 
 
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in patients with cancer. Anticoagulation 
should not be used to extend survival of 
patients with cancer in the absence of other 
indications. (Lyman, et al., 2013).  
Reason(s) for the Amendment:   
Added additional data regarding incidence of TE in mBC and the rationale a. for including expansion 
part in Phase 1b and b. for not mandating prophylaxis in this population.  
 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.2.1.4 Risk Mitigation Plans 
Section 9.2.1.4 Risk Mitigation Plans 
To reduce the potential for TE events during the 
study, subjects will be excluded during screening if 
they have prior history or current evidence of DVT, 
PE, CVA, TIA, hereditary thrombophilic 
syndromes, or active carotid artery disease 
requiring treatment. Also, subjects who experience 
any TE event requiring full dose anti-coagulation 
while on PEGPH20 treatment will be discontinued 
from PEGPH20 treatment but may continue to 
receive eribulin mesylate and remain on study. 
Since the risk for MSEs are previously known to be 
low in various eribulin mesylate MBC studies 
(Studies 301, 305, and 206), dexamethasone 
premedication will be required for the combination 
treatment arm (eribulin mesylate and PEGPH20), 
only. To reduce the potential for 
immunosuppressive effects that might lead to 
hematologic toxicity and/or infections, 
pretreatment with dexamethasone will be limited to 
the same day as PEGPH20 infusion (2 hours before 
and 8 to 12 hours after). 
To reduce the potential for TE events during the 
study, subjects will be excluded during screening 
if they have prior history or current evidence of 
DVT, PE, CVA, TIA, atrial fibrillation, hereditary 
thrombophilic syndromes, or active carotid artery 
disease requiring treatment. Subjects with prior 
history and/or clinical evidence of venous 
thromboembolism (VTE) during screening or 
venous thromboembolism High Clinical Risk 
Khorana score ≥3 will also be excluded from 
the study.  An Expansion Part of 12 subjects in 
the phase 1b part of the study will allow 
further monitoring of the TE events and other 
risks. Following completion of one treatment 
cycle by the Expansion Part subjects, a safety 
evaluation of all Phase 1b subjects, focusing on 
incidence of TE events, will be conducted prior 
to proceeding with the Phase 2 part of the 
study. If  more than 2  TE events occurs in 18 
subjects in Phase 1b  then the sponsor in 
collaboration with Halozyme will decide on 
further  required changes to the study conduct.  
Also, but may continue to receive eribulin 
mesylate and remain on studySince the risk for 
MSEs are previously known to be low in various 
eribulin mesylate MBC studies (Studies 301, 305, 
and 206), dexamethasone premedication will be 
required for the combination treatment arm 
(eribulin mesylate and PEGPH20), only. To 
reduce the potential for immunosuppressive 
effects that might lead to hematologic toxicity 
and/or infections, pretreatment with 
dexamethasone will be limited to the same day as 
PEGPH20 infusion (2 hours before and 8 to 12 
hours after). 
Reason(s) for the Amendment:   


 
 
 
 
 
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Added language to further clarify rational for excluding patients with high risk of VTE and reason for 
addition of the Phase 1b Expansion part (appropriate measures to improve the TE risk minimization of 
the combination treatment).  
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.3.2 
SYNOPSIS and Section 9.3.2 
Exclusion Criteria 
5. Previous history or current evidence of deep vein 
thrombosis (DVT), hereditary thrombophilic 
syndromes, pulmonary embolism (PE), cerebral 
vascular attack (CVA), transient ischemic attack 
(TIA), or active carotid artery disease requiring 
treatment. 
 
 
 
 
 
 
 
 
 
6. Treatment with hormonal or biological therapy 
within the previous 3 weeks, radiation or small 
molecule targeted therapy within the previous 2 
weeks. 
 
 
18. Females of childbearing potential who: 
contraception (eg, total abstinence [if it is their 
preferred and usual lifestyle], an intrauterine 
device, a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with 
confirmed azoospermia) within 30 days before 
study entry and throughout the entire study period 
or for 28 days after study drug 
discontinuation. 
and usual lifestyle), and who do not agree to 
continue to be totally abstinent during the study 
period or for 28 days after study drug 
discontinuation. 
on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before 
dosing and who do not agree to use the same 
contraceptive during the study or for 28 days after 
study drug discontinuation. 
 
Exclusion Criteria 
 
5. Previous history or current evidence of deep 
vein thrombosis (DVT), hereditary 
thrombophilic syndromes, pulmonary 
embolism (PE), cerebral vascular accident 
attack (CVA), transient ischemic attack (TIA), 
atrial fibrillation [AF] or active carotid 
artery disease requiring treatment. 
 
6. Patients with prior history and or clinical 
evidence of venous thromboembolism 
(VTE) during screening or VTE High 
Clinical Risk Khorana score ≥3 (Appendix 
7)  
 
8. Treatment with chemotherapy, hormonal or 
biological therapy within the previous 3 weeks, 
radiation or small molecule targeted therapy 
within the previous 2 weeks preceding informed 
consent. 
 
   19. Females of childbearing potential who: 
 
Do not agree to use a highly effective 
method of contraception (ie, total 
abstinence [if it is their preferred and 
usual lifestyle], an intrauterine device 
(IUD) or intrauterine system (IUS), 
a contraceptive implant, an oral 
contraceptive, or have a vasectomized 
partner with confirmed azoospermia) 
within 30 days before study entry and 
throughout the entire study period or 
and for 3 months 28 days after study 
drug discontinuation.   
For sites outside of the EU, it is 
permissible that if a highly effective 
method of contraception is not 
appropriate or acceptable to the 
subject, then the subject must agree 
to use a medically acceptable 
method of contraception, i.e., 
double barrier methods of 


 
 
 
 
 
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19. Males who have not had a successful 
vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above 
(ie, not of childbearing potential or using effective 
contraception throughout the study period or for 28 
days after study drug discontinuation). No sperm 
donation is allowed during the study period or for 
28 days after study drug discontinuation. 
 
contraception such as a condom 
plus diaphragm or cervical vault 
cap with spermicide. 
 
Are currently totally abstinent (as 
their preferred and usual lifestyle), 
and who do not agree to continue to 
be totally abstinent during the study 
period or and for 3 months 28 days 
after study drug discontinuation. 
 
Are using hormonal contraceptives 
but are not on a stable dose of the 
same hormonal contraceptive product 
for at least 4 weeks before dosing and 
who do not agree to use the same 
contraceptive during the study or and 
for 3 months 28 days after study drug 
discontinuation.  
 
         20. Males who have not had a successful 
vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria 
above (ie, not of childbearing potential or using 
effective contraception throughout the study 
period or for 28 days and for 3 months after 
study drug discontinuation). No sperm donation is 
allowed during the study period or for 28 days 
and for 3 months after study drug 
discontinuation. 
 
Reason(s) for the Amendment:  
For Exclusion Criteria #5: Subjects with history of atrial fibrillation [AF] is added for safety 
consideration 
For Exclusion Criteria #6: Exclude Patients with VTE High Clinical Risk based on the Khorana score1 
for safety consideration 
For Inclusion Criteria #8: prior chemotherapy is added, as standard definition of population in this 
setting 
For Inclusion Criteria #19: For outside EU sites, permissible method of contraception is added.  
According to the EMA CTFG recommendations on contraception in clinical trials, for authorised 
products the period of time that contraception is required should match the SmPC which recommends 3 
months. 
For Inclusion criteria #20: Male contraception is usually not required for eribulin monotherapy studies. 
For this protocol male contraception is recommended for PEGPH20. 
 
 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
 
 
SYNOPSIS and Section 9.7.2 
SYNOPSIS and Section 9.7.2 
Statistical Methods (Analysis Sets) 
 
Definitions of Analysis Sets 
The evaluable analysis set (EAS) includes all 
subjects randomized to Phase 2 who had at least 1 
dose of the study drug and had both an evaluable 
baseline tumor assessment and an evaluable 
postbaseline tumor assessment, unless discontinued 
early because of disease progression or death 
(within 91 days of randomization). It is the primary 
analysis set for the primary efficacy endpoint, 
ORR. 
Statistical Methods (Analysis Sets) 
 
Definitions of Analysis Sets 
The evaluable analysis set (EAS) includes all 
subjects randomized to Phase 2 who had at least 
1 dose of the study drug and had both an 
evaluable baseline tumor assessment and an 
evaluable postbaseline tumor assessment, unless 
discontinued early or death (within 91 days of 
randomization).  It is the primary analysis set for 
the primary efficacy endpoint, ORR. 
Reason(s) for the Amendment:  
Using the modified evaluable analysis set will more accurately estimate the primary efficacy endpoint 
(ORR). 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.5.4.2 
Section 9.5.4.2 
Any pregnancy in which the estimated date of 
conception is either before the last visit or within 
28 days of last study treatment, or any exposure to 
study drug through breastfeeding during study 
treatment or within 28 days of last study treatment, 
must be reported. 
Any pregnancy (including pregnancy in the 
partner of a male subject) in which the 
estimated date of conception is either before the 
last visit or within 3 months 28 days of last study 
treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 28 
days of last study treatment, must be reported. 
Reason(s) for the Amendment:  
Language added to align with the safety reporting plan for the study 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
Section 9.7.1.1.1 
Section 9.7.1.1.1 
• 
The primary endpoint of Phase 1b is the 
RP2D of the eribulin mesylate and PEGPH20 
combination.  The efficacy endpoint(s) described 
below will be summarized and listed by dose level 
based on the safety analysis set (SAS).  No 
statistical comparison will be performed. 
 
• 
The primary endpoint of Phase 1b is the 
RP2D of the eribulin mesylate and PEGPH20 
combination.  The efficacy endpoint(s) described 
below will be summarized and listed by dose 
level based on the safety analysis set (SAS).  No 
statistical comparison will be performed. 
Reason(s) for the Amendment:  
Administrative 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.7.1.2 
SYNOPSIS and Section 9.7.1.2 
• 
The DLT Evaluable Set includes subjects 
enrolled in Phase 1b who complete the first 
treatment cycle (ie, take at least 2 doses of eribulin 
mesylate and PEGPH20 with no more than 1 dose 
reduction) and have sufficient safety evaluation.  
Subjects who had a DLT event will be considered 
evaluable for the DLT as well.  It is the analysis 
set for DLT evaluation in the Phase 1b part of the 
study. 
• 
The 
Evaluable 
Analysis 
Set 
(EAS) 
includes all subjects randomized to Phase 2 who 
had at least 1 dose of the study drug and had both 
an evaluable baseline tumor assessment and an 
evaluable postbaseline tumor assessment, unless 
discontinued because of disease progression or 
death (within 91 days of randomization). It is the 
primary analysis set for the primary efficacy 
endpoint, ORR. 
 
The DLT Evaluable Set includes subjects enrolled 
in Phase 1b who complete the first treatment 
cycle (ie, take at least 2 doses of eribulin mesylate 
and PEGPH20 with no more than 1 dose 
reduction) and have sufficient safety evaluation.  
Subjects who had a DLT event will be considered 
evaluable for the DLT as well.  It is the analysis 
set for DLT evaluation in the Phase 1b part of the 
study. 
• 
The Evaluable Analysis Set (EAS) 
includes all subjects randomized to Phase 2 who 
had at least 1 dose of the study drug and had both 
an evaluable baseline tumor assessment and an 
evaluable postbaseline tumor assessment, unless 
discontinued early because of disease progression 
or death (within 91 days of randomization). It is 
the primary analysis set for the primary efficacy 
endpoint, ORR. 
Reason(s) for the Amendment:  
Using the modified evaluable analysis set will more accurately estimate the primary efficacy endpoint 
(ORR). 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.7.1.6.1 
SYNOPSIS and Section 9.7.1.6.1 
Primary Efficacy Analysis 
Phase 1b  
The study will include at least 1 safety run-in 
cohort in which 6 metastatic subjects (any HA 
level) will receive PEGPH20 3 μg/kg on Days -1 
and 7 of a 21-day cycle followed approximately 24 
(±4) hours later by eribulin mesylate 1.4 mg/m2 
(dose level 1).  Subjects will be observed for DLT 
in the first cycle.  The purpose of the safety run-in 
cohort(s) is to study safety of the 2-drug 
combination.  Phase 2 will proceed with dose level 
1 when no more than 1 subject has a DLT.  
Otherwise, an eribulin mesylate dose of 1.4 mg/m2 
and PEGPH20 1.6 µg/kg will be evaluated in 
another cohort of 6 subjects.  If no more than 1 
subject has a DLT, the Phase 2 part will proceed 
with dose level 0 as the RP2D.  Otherwise, 
alternative doses (eg dose level -1: eribulin 
mesylate 1.1 mg/m2 and PEGPH20 1.6µg/kg) will 
be explored prior to the start of the Phase 2 part.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Efficacy Analysis 
Phase 1b  
The study will include at least 1 safety run-in 
cohort in which 6 metastatic subjects (any HA 
level) will receive PEGPH20 3µg/kg on Days -1 
and 7 of a 21-day cycle followed approximately 
24 (± 4) hours later by eribulin mesylate 1.4 
mg/m2 (dose level 1).  Subjects will be observed 
for dose-limiting toxicity in the first cycle.  The 
purpose of the safety run-in cohort(s) is to study 
the safety of the 2-drug combination and 
determine a recommended Phase 2 dose 
(RP2D).  The Phase 2 1b Expansion Part will 
proceed with dose level 1 when no more than 1 
subject has a DLT.  Otherwise, an eribulin 
mesylate dose of 1.4 mg/m2 and PEGPH20 1.6 
µg/kg will be evaluated in another cohort of 6 
subjects.  If no more than 1 subject has a DLT, 
the Phase 2Phase 1b Expansion Part will 
proceed with dose level 0 as the RP2D.  
Otherwise, alternative doses (eg, dose level -1: 
eribulin mesylate 1.1 mg/m2 and PEGPH20 
1.6µg/kg) will be explored prior to the start of the 
Phase 2 Phase 1b Expansion part.  
Following completion of one treatment cycle 
by the Expansion Part subjects, a safety 
evaluation of all Phase 1b subjects, focusing on 
incidence of TE events, will be conducted prior 
to proceeding with the Phase 2 part of the 
study 
If ≤1 out of 18 subjects experience a DLT, the 
upper limit of the 1-sided 80% exact CI for the 
true DLT rate will not be greater than 15.7%. 
If ≤2 out of 18 subjects experience a TE event, 
the upper limit of the 1-sided 80% exact CI for 
the true TE rate will not be greater than 
22.3%.    If more than 2 TE events occurs in 18 
subjects in Phase 1b, then the sponsor in 
collaboration with Halozyme will decide on 
further required changes to the study conduct. 
 
Phase 2 


 
 
 
 
 
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Phase 2 
The null hypotheses of no difference in ORR (H0: 
ORREP=ORRE) will be tested using normal 
approximation to binomial test with a two-sided 
significance level of 0.05, where ORREP and ORRE 
are the ORR in eribulin and PEGPH20 
combination and eribulin arm, respectively.  It is 
the primary test for ORR. 
Two-sided 95% confidence intervals (CI) of the 
ORR differences will be calculated using normal 
approximation to binomial distribution.  The 
superiority of combination arm will be 
demonstrated if the lower bound of the 95% CI is 
above zero. Clopper-Pearson 95% CIs of ORR will 
be constructed for each arm 
The null hypotheses of no difference in ORR (H0: 
ORREP=ORRE) will be tested using normal 
approximation to binomial test with a two one-
sided significance level of  0.05 0.10, where 
ORREP and ORRE are the ORR in eribulin and 
PEGPH20 combination and eribulin arm, 
respectively.  It is the primary test for ORR. 
Two-sided 95%80% confidence intervals (CI) of 
the ORR differences will be calculated using 
normal approximation to binomial distribution.  
The superiority of combination arm will be 
demonstrated if the lower bound of the 95%80% 
CI is above zero. Clopper-Pearson 95%80% CIs 
of ORR will be constructed for each arm 
Reason for Amendment:  
Language revised to align section with changes in the study design 
ORIGINAL TEXT 
AMENDED TEXT 
Section 9.7.1.7.2 
Section 9.7.1.7.2 
PHARMACODYNAMIC, 
PHARMACOGENOMIC, AND OTHER 
BIOMARKER ANALYSES 
Pharmacodynamic and other biomarker 
analyses may be performed and reported 
separately.  Details of these analyses may be 
described in a separate analysis plan.  
PHARMACODYNAMIC, 
PHARMACOGENOMIC, 
AND 
OTHER 
BIOMARKER ANALYSES 
Pharmacodynamic and other biomarker 
analyses may be performed and reported 
separately. Pharmacodynamic and other 
biomarker analyses including soluble 
and/or tissue exploratory biomarkers 
(baseline and/or post-treatment) will be 
summarized using descriptive statistics 
and may be correlated with PK, and 
clinical outcomes-related endpoints for 
safety and/or efficacy as appropriate. 
Details of these analyses may will be 
described in a separate analysis plan. 
Reason for Amendment:  
To add more clarity regarding Pharmacodynamic and other biomarker analyses. 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.7.2 
SYNOPSIS and Section 9.7.2 
Statistical Methods (Analysis Sets) 
 
Definitions of Analysis Sets 
• 
The DLT Evaluable Set includes subjects 
enrolled in Phase 1b who complete the first 
treatment cycle (ie, take at least 2 doses of eribulin 
mesylate and PEGPH20 with no more than 1 dose 
reduction) 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 evaluable analysis set (EAS) includes all 
subjects randomized to Phase 2 who had at least 1 
dose of the study drug and had both an evaluable 
baseline tumor assessment and an evaluable 
postbaseline 
tumor 
assessment, 
unless 
discontinued early because of disease progression 
or death (within 91 days of randomization). It is 
the primary analysis set for the primary efficacy 
endpoint, ORR. 
The SAS includes subjects who received at least 1 
dose of the study drug in either Phase 1b or Phase 
2.  This is the analysis set for all safety 
evaluations. 
 
Statistical Methods (Analysis Sets) 
 
Definitions of Analysis Sets 
• 
The DLT Evaluable Set includes subjects 
enrolled in Phase 1b who complete the first 
treatment cycle (ie, take at least 2 doses of 
eribulin mesylate and PEGPH20 with no more 
than 1 dose reduction) 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 evaluable analysis set (EAS) includes all 
subjects randomized to Phase 2 who had at least 1 
dose of the study drug and had both an evaluable 
baseline tumor assessment and an evaluable 
postbaseline 
tumor 
assessment, 
unless 
discontinued because of disease progression or 
death (within 91 days of randomization) or death ) 
early or death.  It is the primary analysis set for 
the primary efficacy endpoint, ORR. 
The Safety Analysis Set SAS includes subjects 
who received at least 1 dose of the study drug in 
either Phase 1b or Phase 2.  This is the analysis set 
for all safety evaluations. 
 
Reason(s) for the Amendment:  
Using the modified evaluable analysis set will more accurately estimate the primary efficacy endpoint 
(ORR). 
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.7.2 
SYNOPSIS and Section 9.7.2 
The sample size calculation is based on the 
comparisons of the primary endpoint ORR. 
Assuming ORREP =0.63 and ORRE =0.29, 40 
evaluable subjects per arm provide a power of 
0.877 in testing of ORREP vs ORRE when using 
normal approximation to binomial test with a two-
sided significance of 0.05. For the testing of PFS, it 
is assumed that HR of PFS in combination arm vs 
single arm eribulin mesylate is 0.5 (median PFS 6.8 
months vs 13.6 months). Assuming a uniform 
The sample size calculation is based on the 
comparisons of the primary endpoint ORR. 
Assuming ORREP =0.63 0.35 and ORRE =0.29 
0.15, 40 evaluable subjects per arm provide a 
power of 0.877 0.800 in testing of ORREP vs 
ORRE when using normal approximation to 
binomial test with a two one-sided significance of 
0.05 0.10. For the testing of PFS, it is assumed 
that HR of PFS in combination arm vs single arm 
eribulin mesylate is 0.5 (median PFS 6.8 months 


 
 
 
 
 
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enrollment rate of 80 evaluable subjects over 18 
months, 58 PFS events are expected after 9 month 
follow-up which shows a power of 0.84 in a log 
rank test with one-sided alpha of 0.05. 
Approximately 96 subjects will be enrolled in the 
trial, including 12 in the Phase 1b part and 84 in the 
Phase 2 part. 
 
 
 
 
vs 13.6 months). Assuming a uniform enrollment 
rate of 80 evaluable subjects over 18 months, 58 
PFS events are expected after 9 month follow-up 
which shows a power of 0.84 in a log rank test 
with one-sided alpha of 0.05. Approximately 96 
subjects will be enrolled in the trial, including 12 
in the Phase 1b part and 84 in the Phase 2 part. 
A total of up to 114 subjects will be enrolled in 
the trial, comprising of up to 30 in the Phase 1b 
part (6 to 18 in the safety run-in cohort plus 12 
in the Expansion part) and 84 in the Phase 2 
part (to obtain 80 evaluable subjects).  
 
 
 
Reason(s) for the Amendment:  
The protocol was revised to include  third line patients; hence, the null and alternative hypotheses were 
adjusted correspondingly. Sample size determination was updated according to the new hypotheses.  
 
ORIGINAL TEXT 
AMENDED TEXT 
SYNOPSIS and Section 9.7.3 
SYNOPSIS and Section 9.7.3 
Interim Analysis 
In the EAS, at least two more responders in the 
combination arm are required to cross the interim 
threshold.  Using Bayesian predictive power, a 
minimum difference of 2 responders corresponds to 
an average predictive probability of 0.294 when 
observed ORREP is between 0.33 and 0.66.  
Simulation results show that the probabilities of 
passing interim analysis threshold are 0.912 under 
Ha and 0.278 under H0.  
 
Interim Analysis 
In the EAS, at least two one more responders in 
the combination arm are is required to cross the 
interim threshold.  Using Bayesian predictive 
power, a minimum difference of 2one responder 
corresponds to an average predictive probability 
of 0. 294 0.149 when observed ORREP is between 
0. 33 0.26 and 0. 66 0.40.  Simulation results 
show that the probabilities of passing interim 
analysis threshold are 0. 912 0.8583 under Ha and 
0. 278 0.3913 under H0.  
 
If fewer than 2 additional responders are observed 
in the combination arm, enrollment will be halted 
and assessment of other efficacy and safety 
parameters will be carried out before making the 
final interim decision, ie, restarting enrollment or 
terminating the trial.  This scenario renders a 
predictive power of 0.147.  The estimated 
probabilities of observing ≥1 responder difference 
between two treatment arms are 0.962 under Ha and 
If fewer than 2 additional responders are observed 
in the combination arm, enrollment will be halted 
and assessment of other efficacy and safety 
parameters will be carried out before making the 
final interim decision, ie, restarting enrollment or 
terminating the trial.  The predictive probability is 
0.160 0.1505 if only one additional responder is 
observed in the combination arm. The estimated 
probabilities of observing ≥1 responder difference 
between two treatment arms are 0. 946 0.9402 


 
 
 
 
 
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0.419 under H0.  
under Ha and 0. 405 0.3933 under H0.  
Reason(s) for the Amendment:  
The protocol was revised to include the second and third line patients; hence, the null and alternative 
hypotheses were adjusted correspondingly. Sample size determination was updated according to the new 
hypotheses. 
 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
Table 7 Schedule of Procedures/Assessment 
Table 7 Schedule of Procedures/Assessment 
 
Two additional rows added within the schedule of 
procedures/assessment: 
(1) Blood samples for potential PGx in Phase 
1b Expansion Parts 
(2) Blood sample for plasma-HA analysis in 
Phase 1b Expansion Parts  
(3) Blood samples for PD (biomarkers) in 
Phase 1b  Expansion Part s 
Footnotes were revised after adding new footnote 
s. 
Footnote g: At least 5 (preferred 10) unstained, 
consecutive slides of one archival tumor block or 
paraffin block, or a fresh tumor biopsy that meet 
specific tissue sample requirements are required.  
Any remaining tumor tissues not used for 
determination of HA level 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. 
Footnote g: At least 5 (preferred 10) 10 unstained, 
consecutive slides of one archival tumor block or 
paraffin block, or a fresh tumor biopsy that meet 
specific tissue sample requirements are required.  
Any remaining tumor tissues not used for 
determination of HA level 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. 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1, C1 Day 8, and as clinically 
indicated during the study. Electrocardiograms 
obtained at C1 Day1 and C1 Day 8 should be 
performed just prior to and immediately after 
receiving the eribulin mesylate infusion. Subjects 
must be in the recumbent position for a period of 5 
minutes prior to the ECG. 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1, C1 Day 8, and as 
clinically indicated during the study. 
Electrocardiograms obtained at C1 Day1 and C1 
Day 8 should be performed just prior to and 
immediately after receiving the eribulin mesylate 
infusion. Subjects must be in the recumbent 
position for a period of 5 minutes prior to the 
ECG. 
 
 
 
 
 
New Footnote s:   
Blood samples for all Phase 1b subjects will be 
collected at the PEGPH20 predose on Day -2 or 
C1 Day -1 for potential pharmacogenomics 
(PGx) analyses. Blood samples for potential 
pharmacodynamics (PD) biomarkers analyses 
will be collected during screening, at the 
PEGPH20 predose on Day -2 or C1 Day -1, C1 
Day 7, C2 Day -1, Day -1 of every other cycle 
(C3, C5, C7, etc), and at the End of Treatment 


 
 
 
 
 
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Visit, or whenever a subject is withdrawn from 
study treatment. A sample for plasma-HA 
analysis of PEGPH20 will be collected from the 
Phase 1b expansion Part subjects on Cycle 1 
Day -1 (C1 Day -1) at predose (0 hour). 
Additional sample will be collected at 24, 48, 
and 72 hours after the PEGPH20 infusion 
(which will correspond, respectively, with 
eribulin mesylate predose [0 hour] on C1D1, 24 
and 48 hours after the infusion of eribulin 
mesylate).   
Footnote v: 
Tumor 
assessments 
will 
be 
performed using RECIST 1.1.  Assessments are to 
be performed at the site by appropriately qualified 
personnel at each time point and results of the site 
interpretation are to be recorded on the 
appropriate CRFs.  Historical standard of care 
scans 
that 
are 
performed 
with 
scanning 
parameters consistent with the requirements for 
this protocol within 21 days prior to dosing are 
acceptable.  Tumor assessments (CT chest and 
CT/MRI of abdomen, pelvis, and other areas of 
known disease at Screening plus any areas of 
newly suspected disease) should be performed at 
Screening (within 21 days prior to first dose of 
study drugs and every 6 weeks  ±1 week from the 
date of enrollment or sooner if clinically 
indicated, 
until 
documentation 
of 
disease 
progression. 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 6 weeks, until (1) the start of new 
anticancer treatment, (2) disease progression (3) 
death, or (4) the end of the study, or withdrawal of 
consent, whichever occurs first.  Confirmation is 
not required for best overall response (BOR) of 
CR or PR in either Phase 1b or Phase 2 parts of 
the trial. 
Footnote v w: Tumor assessments will be 
performed using RECIST 1.1.  Assessments are to 
be performed at the site by appropriately qualified 
personnel at each time point and results of the site 
interpretation are to be recorded on the 
appropriate CRFs.  Historical standard of care 
scans that are performed with scanning parameters 
consistent with the requirements for this protocol 
within 21 days prior to dosing are acceptable.  
Tumor assessments (CT chest and CT/MRI of 
abdomen, pelvis, and other areas of known 
disease at Screening plus any areas of newly 
suspected disease) should be performed at 
Screening (within 21 days prior to first dose of 
study drugs [Phase 1b] or randomization [Phase 
2]) and every 6 weeks  ±1 week from the date of 
enrollment first dose of study drugs (Phase 1b) 
or randomization (Phase 2), or sooner if 
clinically indicated, until documentation of 
disease progression. 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 6 weeks, until (1) the 
start of new anticancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, 
or withdrawal of consent, whichever occurs first.  
Confirmation is not required for best overall 
response (BOR) of CR or PR in either Phase 1b or 
Phase 2 parts of the trial. 
Footnote w:   
A bone scan (99m-technetium polyphosphonate 
scintigraphy, whole body bone MRI, or 18F-NaF-
PET) to assess bone metastases should be 
performed within 6 weeks prior to first dose of 
study drugs and then every 24 weeks ±1 week after 
the date of the first dose of study drugs, or sooner if 
clinically indicated.  In subjects whose body 
CT/MRI scans indicates CR has been achieved, a 
bone scan will be performed within 2 weeks to 
exclude bone metastases.  The same methodology 
and acquisition techniques used at screening should 
Footnote w x: A bone scan (99m-technetium 
polyphosphonate based scintigraphy, whole body 
bone MRI, or 18F-NaF-PET) to assess bone 
metastases should be performed within 6 weeks 
prior to first dose of study drugs (Phase 1b) or 
randomization (Phase 2) and then every 24 
weeks ±1 week after the date of the first dose of 
study drugs (Phase 1b) or randomization (Phase 
2), or sooner if clinically indicated.  In subjects 
whose body CT/MRI scans indicates CR has been 
achieved, a bone scan will be performed within 2 
weeks to exclude bone metastases.  The same 


 
 
 
 
 
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be used throughout the study to ensure 
comparability. Lesions detected on bone scans  
must be followed with cross-sectional CT/MRI 
imaging.    
 
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 
CT/MRI imaging.    
Footnote x: 
A brain scan (CT with contrast or 
MRI pre- and post- gadolinium) must be 
performed at Screening (within 21 days prior to 
first dose of study to assess potential CNS disease 
and/or metastases.  For the duration of the study 
(ie, post-Baseline), CT/MRI of the brain will be 
performed if clinically indicated, and within a 
target of 1 week after a subject achieves a CR.  
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. 
Footnote x y: 
A brain scan (CT with contrast or 
MRI pre- and post- gadolinium) must be 
performed at Screening (within 21 days prior to 
first dose of study drugs  [Phase 1b] or 
randomization [Phase 2]) to assess potential 
CNS disease and/or metastases.  For the duration 
of the study (ie, post-Baseline), CT/MRI of the 
brain will be performed if clinically indicated, and 
within a target of 1 week after a subject achieves a 
CR.  For subjects with history of treated brain 
metastases, brain scans will be performed at all 
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. 
Reason(s) for the Amendment:  
Footnote i: Since ECG is being done before and after Eribulin administration use of the word Single at 
the start was deleted to avoid confusions. 
Other footnotes: To align footnote definitions with changes in the protocol content and other sections.  
 
ORIGINAL TEXT 
AMENDED TEXT 
Table 8 Schedule of Procedures and Assessments 
Table 8 Schedule of Procedures and Assessments 
Blood samples for potential PGx, PD (plasma-HA; 
biomarkers), and safety (ADA) analysesj 
 
Two additional rows added: 
(1) Blood samples for potential PGxj   
(2) Blood samples for potential ADA 
analysesj 
Revised row:  
Blood samples for potential PGx, PD (plasma-
HA; biomarkers), and safety (ADA) analysesj 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1, C1 Day 8, and as clinically 
indicated during the study. Electrocardiograms 
obtained at C1 Day 1 and C1 Day 8 should be 
performed just prior to and immediately after 
receiving the eribulin mesylate infusion. Subjects 
must be in the recumbent position for a period of 5 
minutes prior to the ECG. 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1, C1 Day 8, and as 
clinically 
indicated 
during 
the 
study.  
Electrocardiograms obtained at C1 Day 1 and C1 
Day 8 should be performed just prior to and 
immediately after receiving the eribulin mesylate 
infusion. Subjects must be in the recumbent 
position for a period of 5 minutes prior to the 
ECG. 


 
 
 
 
 
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Footnote J: Blood samples for all Phase 2/Arm A 
subjects will be collected at the PEGPH20 predose 
on Day -2 or C1 Day -1 for potential 
pharmacogenomics analyses. Blood samples for 
potential pharmacodynamic (plasma-HA and 
biomarkers) and safety (ADA) analyses will be 
collected at both the PEGPH20 predose on Day -2 
or C1 Day -1 and at the End of Treatment Visit, or 
whenever a subject is withdrawn from study 
treatment. 
 
 
 
 
 
 
 
 
 
Footnote J: Blood samples for all Phase 2/Arm A 
subjects will be collected at the PEGPH20 
predose on Day -2 or C1 Day -1 for potential 
pharmacogenomics analyses. Blood samples for 
potential ADA analyses will be collected at 
PEGPH20 predose on Day -2 or C1 Day -1 and 
at the End of Treatment Visit (or whenever a 
subject is withdrawn from the study).  Blood 
samples for potential pharmacodynamics (PD) 
for plasma-HA and biomarkers analyses will 
be collected during screening, at  the PEGPH20 
predose on Day -2 or C1 Day -1, C1 Day 7, C2 
Day -1,  Day 1 of every other cycle (C3, C5, C7, 
etc.), Blood samples for potential 
pharmacodynamic (plasma-HA and biomarkers) 
and safety (ADA) analyses will be collected at 
both the PEGPH20 predose on Day -2 or C1 Day -
1 and at the End of Treatment Visit, or whenever 
a subject is withdrawn from study treatment. 
Footnote x:  bone scan (99m-technetium 
polyphosphonate scintigraphy, whole body bone 
MRI, or 18F-NaF-PET) to assess bone metastases 
should be performed within 6 weeks prior to first 
dose of study drugs and then every 24 weeks ±1 
week after the date of the first dose of study drugs, 
or sooner if clinically indicated.  In subjects whose 
body CT/MRI scans indicates CR has been 
achieved, a bone scan will be performed within 2 
weeks to exclude 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 
CT/MRI imaging.    
 
Footnote x; A bone scan (99m-technetium 
polyphosphonate based scintigraphy, whole body 
bone MRI, or 18F-NaF-PET) to assess bone 
metastases should be performed within 6 weeks 
prior to first dose of study drugs and then every 24 
weeks ±1 week after the date of the first dose of 
study drugs, or sooner if clinically indicated.  In 
subjects whose body CT/MRI scans indicates CR 
has been achieved, a bone scan will be performed 
within 2 weeks to exclude 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 CT/MRI imaging.    
Reason(s) for the Amendment:  
Footnote i: Since ECG is being done before and after Eribulin administration use of the word Single at 
the start was deleted to avoid confusions. 
Other footnotes: To align footnote definitions with changes in the protocol content and other sections. 
 
ORIGINAL TEXT 
AMENDED TEXT 
Table 9 Schedule of Procedures and Assessments 
Table 9 Schedule of Procedures and Assessments 
Blood samples for potential PGx and PD 
biomarkers) analysesj 
Blood samples for potential PGx and PD 
biomarkers) analysesj 
 
Revised row: 
Blood samples for potential PGx and PD 


 
 
 
 
 
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(biomarkers) analysesj 
Added new row:  
Blood samples for potential PD (plasma-HA; 
biomarkers) analyses j 
 
Procedures/ 
Assessments 
Screening 
Baselined 
Treatment 
Cycle 1 
12-lead 
ECGi 
X 
X 
X 
 
 
Procedures/ 
Assessments 
Screening 
Baselined 
Treatment 
Cycle 1 
12-lead 
ECGi 
X 
X 
X 
 
Footnote g: 
At least 5 (preferred 10) unstained, consecutive 
slides of one archival tumor block or paraffin 
block, or a fresh tumor biopsy that meet specific 
tissue sample requirements are required.  Any 
remaining tumor tissues not used for determination 
of HA level 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. 
Footnote g: 
At least 10 At least 5 (preferred 10) unstained, 
consecutive slides of one archival tumor block or 
paraffin block, or a fresh tumor biopsy that meet 
specific tissue sample requirements are required.  
Any remaining tumor tissues not used for 
determination of HA level 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. 
 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1 (or Baseline), C1 Day 8, 
and as clinically indicated during the study. 
Electrocardiograms obtained at C1 Day 1 and C1 
Day 8 should be performed just prior to and 
immediately after receiving the eribulin mesylate 
infusion.Subjects must be in the recumbent position 
for a period of 5 minutes prior to the ECG. 
 
Footnote i: Single 12-lead ECG will be performed 
at screening, C1 Day 1 (or Baseline), C1 Day 8, 
and as clinically indicated during the study. 
Electrocardiograms obtained at C1 Day 1 and C1 
Day 8 should be performed just prior to and 
immediately after receiving the eribulin mesylate 
infusion. Subjects must be in the recumbent 
position for a period of 5 minutes prior to the 
ECG. 
 
Footnote j: Blood samples for all Phase 2/Arm B 
subjects will be collected at the eribulin mesylate 
predose on Day -1 or C1 Day 1 for potential 
pharmacogenomic analyses. Blood samples for 
potential pharmacodynamics (biomarkers) analyses 
will be collected at both the eribulin mesylate 
predose on Day -1 or C1 Day 1 and at the End of 
Treatment Visit, or whenever a subject is 
withdrawn from study treatment. 
 
Footnote j: Blood samples for all Phase 2/Arm B 
subjects will be collected at the eribulin 
mesylate predose on Day -1 or C1 Day 1 for 
potential pharmacogenomics (PGx) analyses. 
Blood samples for potential 
pharmacodynamics (PD) for plasma-HA and 
biomarkers analyses will be collected during 
screening, at  the eribulin mesylate predose on 
Day -1 or C1 Day 1, C1 Day 8, C2 Day 1, Day 1 
of every other cycle (C3, C5, C7, etc.) and at 
the End of Treatment Visit, or whenever a 


 
 
 
 
 
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subject is withdrawn from study treatment 
Footnote t:  bone scan (99m-technetium 
polyphosphonate scintigraphy, whole body bone 
MRI, or 18F-NaF-PET) to assess bone metastases 
should be performed within 6 weeks prior to first 
dose of study drugs and then every 24 weeks ±1 
week after the date of the first dose of study drugs, 
or sooner if clinically indicated.  In subjects whose 
body CT/MRI scans indicates CR has been 
achieved, a bone scan will be performed within 2 
weeks to exclude 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 
CT/MRI imaging 
Footnote t: A bone scan (99m-technetium 
polyphosphonate based scintigraphy, whole body 
bone MRI, or 18F-NaF-PET) to assess bone 
metastases should be performed within 6 weeks 
prior to first dose of study drugs and then every 24 
weeks ±1 week after the date of the first dose of 
study drugs, or sooner if clinically indicated.  In 
subjects whose body CT/MRI scans indicates CR 
has been achieved, a bone scan will be performed 
within 2 weeks to exclude 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 CT/MRI imaging.    
 
Reason(s) for the Amendment:  
To align tables with changes in the protocol content and other sections. 
 
ORIGINAL TEXT 
AMENDED TEXT 
Appendix 1 Overview of RECIST v1.1 for 
Evaluation of Tumors Response 
Appendix 1 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 
 
 
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).”   
The sole modification to RECIST 1.1 to be 
implemented in this study is that chest x-
rays may not be used to follow disease; only 
CT scans may be used to follow chest 
disease. Best overall response of stable 
disease (SD) requires at least 1 
posttreatment assessment that meets the SD 
criteria ≥5 weeks after the start of 
treatment. 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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Baseline Tumor Assessment 
Subjects are required to have measurable disease, 
defined as the presence of at least 1 measurable lesion, 
to be eligible for entry into the study. 
Measurable……………………………………………
…………. …………………………………………… 
The clinical relevance of the duration of SD varies for 
different tumor types and grades.  For this protocol, 
duration of SD is not being measured. 
 
Baseline Tumor Assessment 
Subjects are required to have measurable 
disease, defined as the presence of at least 1 
measurable lesion, to be eligible for entry into 
the study. 
Measurable……………………………………
…………………. 
…………………………………………… 
The clinical relevance of the duration of SD 
varies for different tumor types and grades.  
For this protocol, duration of SD is not being 
measured. 
Response Review 
For this Phase 2 study, response review will be 
performed at the site by appropriately qualified 
personnel (radiologist in conjunction with clinical 
investigator). 
Response Review 
For this Phase 2 study, response review will be 
performed at the site by appropriately qualified 
personnel (radiologist in conjunction with 
clinical investigator). 
Reporting of Results 
All subjects included in the study should be assessed 
for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. 
Reporting of Results 
All subjects included in the study should be 
assessed for response to treatment, even if there 
are major protocol treatment deviations or if 
they are ineligible.  
Reason(s) for the Amendment:  
Administrative change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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ORIGINAL TEXT 
AMENDED TEXT 
12 Appendices 
12 Appendices 
 
Added Appendix 1 Khorana's risk assessment score 
 
 
Reason(s) for the Amendment:  
As a reference for updates to the eligibility criteria  
 


 
 
 
 
 
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Study Protocol Number: E7389-M000-219 
 
Study Protocol Title: 
A Randomized, Open-label, Multicenter Phase 1b/2 Study of 
Eribulin Mesylate in Combination with PEGylated Recombinant 
Human Hyaluronidase (PEGPH20) versus Eribulin Mesylate 
Alone in Subjects with Human Epidermal Growth Factor 
Receptor (HER2)-negative, High-Hyaluronan (HA) Metastatic 
Breast Cancer (MBC) 
 
Investigational Product 
Names: 
E7389/eribulin mesylate and PEGylated recombinant human 
PH20 hyaluronidase (PEGPH20)  
 
IND Numbers: 
113851 (eribulin mesylate), 102770 (PEGPH20) 
 
EudraCT Number 
2015-004740
 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
Date 
 
 
 
 
Oncology Business Group 
Eisai Inc.  
 
Date 
 
 
 
 
Oncology Business Group 
Eisai Inc. 
 
Date 
 
Eisai Inc. 
 
 
Date 
 
PPD
PPD
PPD
PPD


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E7389-M000-219 - Protocol Summary of Changes Amendment 01
Clinical Approval
07-Nov-2016 10:32 GMT-05
PPD

SAP_001.pdf: 
Statistical Analysis Plan 
E7389-M000-219 
 
 
Eisai 
DRAFT (Version 0.4): 
07 Dec 2018 
Confidential 
Page 1 of 23 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7389-M000-219 
Study Protocol 
Title: 
A Randomized, Open-label, Multicenter, Phase 1b/2 Study of Eribulin 
Mesylate in Combination with PEGylated Recombinant Human 
Hyaluronidase (PEGPH20) versus Eribulin Mesylate Alone in 
Subjects with Human Epidermal Growth Factor Receptor 2 (HER2)-
Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC) 
Date: 
07 Dec 2018 
Version: 
Draft Version 0.4 


Statistical Analysis Plan 
E7389-M000-219 
 
 
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DRAFT (Version 0.4): 
07 Dec 2018 
Confidential 
Page 2 of 23 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................6 
3.1 
Study Objectives ......................................................................................................6 
3.1.1 
Primary Objectives.........................................................................................6 
3.1.2 
Secondary Objectives.....................................................................................6 
3.1.3 
Exploratory Objective(s) ................................................................................6 
3.2 
Overall Study Design and Plan ................................................................................7 
3.2.1 
Phase 1b and Phase 2 .....................................................................................7 
3.2.2 
Study Drugs Administration ..........................................................................8 
3.2.3 
Subject Study Phases .....................................................................................8 
3.2.4 
Tumor, Safety and PK Assessments ..............................................................9 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ............................................................................................10 
5.1 
Study Endpoints .....................................................................................................10 
5.1.1 
Primary Endpoints .......................................................................................10 
5.1.2 
Secondary Endpoints (Phase 2) ...................................................................10 
5.1.3 
Exploratory Endpoints (Phase 2) .................................................................10 
5.2 
Study Subjects ........................................................................................................11 
5.2.1 
Definitions of Analysis Sets.........................................................................11 
5.2.2 
Subject Disposition ......................................................................................11 
5.2.3 
Protocol Deviations ......................................................................................11 
5.2.4 
Demographic and Other Baseline Characteristics .......................................11 
5.2.5 
Prior and Concomitant Therapy ...................................................................12 
5.2.6 
Treatment Compliance .................................................................................12 
5.3 
Data Analysis General Considerations ..................................................................12 
5.3.1 
Pooling of Centers........................................................................................12 
5.3.2 
Adjustments for Covariates..........................................................................12 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................12 
5.3.4 
Examination of Subgroups ...........................................................................13 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................13 
5.3.6 
Other Considerations ...................................................................................13 
5.4 
Efficacy Analyses ..................................................................................................13 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................14 


Statistical Analysis Plan 
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5.6 
Safety Analyses ......................................................................................................14 
5.6.1 
Extent of Exposure .......................................................................................14 
5.6.2 
Adverse Events ............................................................................................15 
5.6.2.1 
Death ..................................................................................................16 
5.6.3 
Laboratory Values ........................................................................................16 
5.6.4 
Vital Signs ....................................................................................................17 
5.6.5 
Electrocardiograms ......................................................................................17 
5.6.6 
Other Safety Analyses..................................................................................17 
5.6.6.1 
Dose-limiting Toxicity in Phase1b Study ..........................................17 
5.6.6.2 
ECOG Performance Status ................................................................18 
5.7 
Other Analyses .......................................................................................................18 
5.8 
Exploratory Analyses .............................................................................................18 
6 
INTERIM ANALYSES ...................................................................................................18 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................19 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................19 
8.1 
Data Report ............................................................................................................19 
8.2 
Baseline ..................................................................................................................19 
8.3 
Study Day...............................................................................................................19 
8.4 
Day to Month to Year ............................................................................................19 
8.5 
Censoring Rule.......................................................................................................19 
8.6 
Missing Date Handling ..........................................................................................20 
8.7 
Unscheduled Visit ..................................................................................................21 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................21 
10 STATISTICAL SOFTWARE ..........................................................................................21 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................21 
12 REFERENCES ................................................................................................................21 
13 APPENDICES .................................................................................................................22 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....22 
 


Statistical Analysis Plan 
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Page 4 of 23 
 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
BOR 
best overall response  
CBR  
clinical benefit rate  
CR 
complete response 
CRF 
case report form  
CSR 
clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events  
DCR 
disease control rate  
DLT 
dose-limiting toxicity  
DOR 
duration of response  
E 
Eribulin Mesylate alone 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EP 
Eribulin Mesylate in combination with PEGylated Recombinant 
Human Hyaluronidase (PEGPH20) 
HA 
hyaluronan  
HER2 
human epidermal growth factor receptor 2  
IV 
intravenous  
MBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSE 
musculoskeletal events 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PE 
pulmonary embolism 
PEGPH20 
PEGylated recombinant human hyaluronidase 
PFS 
progression-free survival 


Statistical Analysis Plan 
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Page 5 of 23 
 
Abbreviation 
Term 
PK 
pharmacokinetic  
PK/PD 
pharmacokinetic/pharmacodynamic 
PR 
partial response 
PT 
preferred term 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors (version 1.1) 
RP2D 
recommended Phase 2 dose 
RR 
response rate, respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
system organ class 
TE 
thromboembolic 
TEAE 
treatment-emergent adverse event 
TNBC 
triple negative breast cancer 
US 
United States 
WHO DD 
World Health Organization Drug Dictionary 
 


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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E7389-
M000-219 (Amendment 01, dated as 27Oct2016). This was an originally planned, 
Randomized, Open-label, Multicenter, Phase 1b/2 Study of Eribulin Mesylate in 
Combination with PEGylated Recombinant Human Hyaluronidase (PEGPH20) versus 
Eribulin Mesylate Alone in Subjects with Human Epidermal Growth Factor Receptor 2 
(HER2)-Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC). This study was 
carried out only for Phase 1b as planned during the study process due to its early termination. 
Therefore, this SAP is only focused on statisical methods and analyses that will be performed 
in the final for the data of Phase 1b, but the information on the original study design (overall 
for both Phase 1b and Phase 2) is explained first in Section 3.1 for Study Objectives, in 
Section 3.2 for Overall Design and Plan, in Section 4 for Sample Size Determination, and in 
Section 5.1 for Study Endpoints.  
This SAP will be finalized and approved before the database lock of the study. 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
 For the Phase 1b part – to determine safety tolerability and recommended Phase 2 
dose (RP2D) of eribulin mesylate in combination with PEGPH20 in subjects with 
HER2-negative MBC previously treated with up to  two lines of systemic anticancer 
therapy in the metastatic setting.  
 For the Phase 2 part – to evaluate objective response rate (ORR) of eribulin mesylate 
in combination with PEGPH20 in subjects with HER2-negative, HA-high, MBC 
previously treated with up to two lines of systemic anticancer therapy in the 
metastatic setting.  
 
3.1.2 
Secondary Objectives 
 To evaluate progression-free survival (PFS) 
 To evaluate overall survival (OS) 
 
To evaluate the safety and tolerability 
 
3.1.3 
Exploratory Objective(s) 
 To explore clinical benefit rate (CBR) 
 To explore disease control rate (DCR)  
 To explore duration of response (DOR) 
 To explore efficacy for subjects enrolled in Phase 1b 


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 To evaluate exposure-response relationship 
 To explore pharmacokinetics of PEGPH20 and eribulin mesylate when co-
administered  
 To identify and explore tumor and blood markers (e.g. Plasma HA levels) that 
correlate with clinical outcomes, including efficacy 
 
3.2 
Overall Study Design and Plan 
This was a randomized, open-label, multicenter, Phase 1b/2 study of eribulin mesylate in 
combination with PEGPH20 versus eribulin mesylate alone in subjects with HER2-negative, 
HA-high, MBC previously treated with  up to two lines  of systemic anti-cancer therapy 
(cytotoxic drugs or targeted anti-cancer agents) in the metastatic setting.  CDK4/6 inhibitors 
and mTOR inhibitors would not be considered as prior lines of therapy. Any single agents or 
combination of scheduled pre-planned treatments (given concomitantly, sequentially, or 
both) would be considered as one regimen.  Hormonal therapy and bone metastases treatment 
(eg, bisphosphonates, denosumab, etc) would not be considered forms of systemic anti-
cancer therapy. 
3.2.1 
Phase 1b and Phase 2 
Study Phase 1b would occur in two parts (Part 1 and Part 2 ("Expansion Part")):  
Part 1: would conduct run-in safety cohorts (dose levels 1, 0, and -1, as necessary) of 6 
subjects each, until RP2D to be determined as followed:  
 The part 1 would have dose-limiting toxicity (DLT) assessed in the first cycle, and 
would include at least 1 initial safety run-in cohort in which the first 6 enrolled 
subjects (with any hyaluronan [HA] level) would receive PEGPH20 at a dose of 3 
μg/kg intravenously (IV) on Days -1 and 7 of a 21-day cycle, each dose followed 
approximately 24 (±4) hours later with eribulin mesylate 1.4 mg/m2 IV on Days 1 
and 8 (dose level 1).   
 Dose level 1 could be selected as the RP2D if no more than 1 subject had a DLT; 
otherwise, a second cohort of 6 subjects would receive a lower dose of PEGPH20 at 
1.6 μg/kg on Days -1 and 7, each dose followed approximately 24 (±4) hours later 
with eribulin mesylate 1.4 mg/m2 IV on Days 1 and 8 (dose level 0).   
 Dose level 0 could be selected as the RP2D if no more than 1 subject of this second 
cohort had a DLT; otherwise, a third cohort of 6 subjects would receive PEGPH20 
1.6 μg/kg on Days -1 and 7, each dose followed approximately 24 (±4) hours later 
with eribulin mesylate at a lowered dose of 1.1 mg/m2 IV on Days 1 and 8 (dose 
level - 1).   
 If no more than 1 of 6 subjects in this third cohort had a DLT, the Phase 2 part would 
proceed with dose level -1 as the RP2D.  Otherwise, alternative doses would be 
explored prior to the start of Phase 2. 
 


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Part 2 ("Expansion Part"):  Upon determination of the RP2D, would begin Phase 1b 
"Expansion Part" by enrolling 12 additional subjects (using Phase 1b criteria, ie subjects 
previously treated with up to 2 lines of systemic anticancer therapy) at the RP2D. This 
would result in a total of 18 subjects at RP2D for further safety analysis.   
 
Following completion of one treatment cycle by the Phase 1b "Expansion Part" subjects, a 
safety evaluation of all Phase 1b subjects, focusing on incidence of TE events, would be 
conducted prior to proceeding with the Phase 2 part of the study. If ≤ 1 out of 18 subjects 
experienced a TE event, the upper limit of the 1-sided 80% exact CI for the true TE rate 
would not be greater than 15.7%.  If ≤ 2 out of 18 subjects experienced a TE event, the upper 
limit of the 1-sided 80% exact CI for the true TE rate would not be greater than 22.3%. If 
more than 2 TE events occurred in 18 subjects in Phase 1b, then the sponsor in collaboration 
with Halozyme would decide on further required changes to the study conduct. 
In the Phase 2 part, approximately 84 subjects (with HA-high levels only) would be stratified 
by triple negative breast cancer (TNBC) status and randomized 1:1 to receive eribulin 
mesylate and PEGPH20 (Arm A) at the established RP2D level (defined below) or eribulin 
mesylate alone (Arm B) at 1.4 mg/m2:     
 RP2D level 1: PEGPH20 (3 μg/kg) plus eribulin mesylate (1.4 mg/m2) or 
 RP2D level 0: PEGPH20 (1.6 μg/kg) plus eribulin mesylate (1.4 mg/m2) or 
 RP2D level -1: PEGPH20 (1.6 μg/kg) plus eribulin mesylate (1.1 mg/m2) 
 
3.2.2 
Study Drugs Administration 
On Days -1 and 7 of each 21-day cycle, Phase 1b subjects and Phase 2 (Arm A, only) 
subjects would receive PEGPH20 via IV injection over 10 minutes, approximately 1 
mL/minute (a window of +2 minutes would be allowed, ie, infusion could be 10 to 12 
minutes). On the following day, approximately 24 (±4) hours after Day -1 and Day 7 doses of 
PEGPH20, eribulin mesylate via IV injection over 2 to 5 minutes would be administered. 
Phase 2 subjects in Arm B would receive eribulin mesylate alone on Day 1 and Day 8 of each 
21-day cycle.  
For the subjects of Phase 1b and Phase 2 Arm A, dexamethasone 8 mg twice daily would be 
administered orally in each treatment cycle to alleviate musculoskeletal toxicities. Subjects 
would take dexamethasone orally within 2 hours prior to the beginning of each PEGPH20 
and 8 to 12 hours after the completion of the infusions. The investigator might adjust the 
dose of dexamethasone based on the clinical presentation of each subject. 
3.2.3 
Subject Study Phases 
For subjects in the study there would be the following three study phases: 
 The Pre-treatment phase: consisted of the 21-day Screening Period and Baseline 
Period. The Baseline Period would include the Baseline Visit (all subjects), 


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performed on or before designated Study Day -2 or C1D-1, prior to administration of 
their first dose of PEGPH20 (see Schedule of Procedures/Assessments, Table 7 in 
Protocol). 
 Treatment phase:  would begin with the first dose of study drug administration in 
Cycle 1 and would continue in 21-day cycles until completion of the End of 
Treatment visit (within 30 days of the last study drug administration) or subject 
discontinuation of study, whichever occurred first.  In the presence of clinical benefit, 
subjects would remain on study treatment until unacceptable toxicity (excluding 
Thromboembolic (TE) events which required discontinuation of PEGPH20 yet 
subjects might continue on eribulin mesylate alone), or disease progression occurred, 
or the subject withdrew consent. 
 Follow-up phase: would start at the End of Treatment visit and would continue as 
long as the subject was alive or until the subject withdrew consent or lost to follow-up.     
Subjects who discontinued study treatment before disease progression would continue 
to undergo disease assessment every 6 weeks ±1 week until documentation of disease 
progression or start of another anticancer therapy. Follow-up assessment for survival 
would be performed every 12 weeks ±1 week. 
 
3.2.4 
Tumor, Safety and PK Assessments 
Tumor assessments would be performed every 6±1 weeks from the date of first dose of study 
drugs or sooner if clinically indicated, until documentation of disease progression. In subjects 
who discontinued study therapy without documented disease progression, every effort would 
be made to continue monitoring their disease status by radiologic imaging every 6 weeks, 
until (1) the start of new anticancer treatment, (2) disease progression (3) death, or (4) the 
end of the study, or withdrawal of consent, whichever occurred first.  
Pharmacokinetic (PK) assessments of eribulin mesylate and PEGPH20 would be performed 
for all 12 subjects in the Phase 1b Expansion Part.  Only subjects receiving combination 
treatment with PEGPH20 and eribulin mesylate (Arm A) in the Phase 2 part would undergo 
sparse PK sampling for population pharmacokinetic/pharmacodynamic (PK/PD) analysis, 
where feasible. 
Safety assessments would be by monitoring and recording of all adverse events (AEs), 
including all CTCAE v4.03 grades (both increasing and decreasing severity) and serious AEs 
(SAEs), regular monitoring of hematology, and clinical chemistry, urinalysis, regular 
measurement of vital signs, 12-lead ECGs, and ECOG and detail schedules would be found 
in protocol Table 7 (Schedule of Procedures/Assessments). 
4 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation was based on the comparisons of the primary endpoint ORR. 
Assuming ORREP =0.35 and ORRE =0.15, forty evaluable subjects per arm would provide a 
power of 0.800 in testing of ORREP vs ORRE when using normal approximation to binomial 


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test with a one-sided significance of 0.10.  Up to 114 subjects would be enrolled in the trial, 
comprising of up to 30 in the Phase 1b part (6 to 18 in the safety run-in cohort plus 12 in the 
Expansion part) and 84 in the Phase 2 part (to obtain 80 evaluable subjects). 
 
5 
STATISTICAL METHODS 
5.1 
Study Endpoints 
In this study, all the primary, secondary, and exploratory endpoints on tumor related 
measurement/definition would be from the investigator assessment per RECIST 1.1. 
5.1.1 
Primary Endpoints 
 The primary endpoint of Phase 1b was the RP2D of the eribulin mesylate and 
PEGPH20 combination.  
 The primary efficacy endpoint of Phase 2 was ORR defined as the proportion of 
subjects who had a best overall response (BOR) of complete response (CR) or partial 
response (PR). 
 
5.1.2 
Secondary Endpoints (Phase 2) 
 Progression-Free Survival (PFS) – defined as the time from date of randomization to 
date of first documentation of disease progression or death, whichever occurred first 
 Overall Survival (OS) – defined as the time from the date of randomization until date 
of death from any cause 
 
5.1.3 
Exploratory Endpoints (Phase 2)  
 Clinical Benefit Rate (CBR) was the proportion of subjects who had a BOR of CR or 
PR or durable stable disease (SD). Stable disease must be maintained at ≥ 23 weeks after 
randomization to be considered durable SD, and any stable disease required at least 1 
post-treatment assessment that met the SD criteria ≥5 weeks after the start of treatment 
(Phase 1b) or randomization (Phase 2).   
 Disease Control Rate (DCR) was the proportion of subjects who had a BOR of CR, 
PR, or SD. 
 Duration of Response (DOR) was defined as the time from the date that the criteria 
were met for CR or PR (whichever was recorded first) to the date that progressive 
disease (PD) was objectively documented or death, whichever occurred first. 
 


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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
 DLT Evaluable Set will include subjects enrolled in Phase 1b who completed the first 
treatment cycle (ie, took at least 2 doses of eribulin mesylate and PEGPH20 with no 
more than 1 dose reduction) and had sufficient safety evaluation. This will be the 
analysis set for DLT evaluation in the Phase 1b Part 1 of the study.  
 Safety Analysis Set will include subjects who received at least 1 dose of the study 
drug. This will be the analysis set for both safety and efficacy evaluations. 
 Pharmacokinetic (PK) Analysis Set will include all eribulin mesylate and PEGPH20-
treated subjects with at least 1 quantifiable eribulin concentration with a documented 
related dosing history. This will be the analysis set for PK data. 
 
Enrolled subjects will also be considered in the final, and they are the subjects who signed 
the informed consent form. 
5.2.2 
Subject Disposition 
The number (percentage) of subjects enrolled (ie, signed informed consent form), treated, 
discontinued from study/treatment (with reasons according to the categories in the CRF) will 
be summarized. The study status at the end of study or data cutoff will be summarized using 
the data from the survival follow-ups. The data will be listed as well. 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and reviewed before the database lock. Major protocol 
deviations by each category will be summarized. The data will be listed as well. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized. Continuous 
demographic and baseline variables will include age, weight, height, BMI (BMI (kg/m2) = 
Weight in Kilograms / (Height in Meters)
2 ), and BSA; categorical variables will include sex, 
age group (<65, ≥65 years), race, race group (White and Non-White), ethnicity, geographic 
region, enrollment strata (Triple Negative Breast Cancer, Other HER2 negative Metastatic 
Breast Cancer), estrogen status, progesterone status, Eastern Cooperative Oncology Group 
(ECOG) Performance Status, New York Heart Association (NYHA) classification, and 
pregnancy test. The data will be listed as well. 
Medical History 
The number (percentage) of subjects reporting a history of any medical condition and current 
medical condition, as recorded on the CRF, will be summarized. Medical History will be 


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coded using MedDRA (version 19.1 or newer), and summarized by System Organ Class 
(SOC) and Preferred term (PT). The data will be listed as well. 
Disease History 
Disease history and characteristics data at study entry will be summarized as recorded on 
eCRF. The data will be listed as well.  
5.2.5 
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). The 
number (percentage) of subjects who took prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) 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 any study drugs and were continuing at the time of the first dose of any study drugs, 
or (2) started on or after the date of the first dose of any study drugs up to 28 days after the 
subject’s last dose. Medications that cannot be determined to be prior/concomitant/post-
treatment due to missing or incomplete dates will be regarded as concomitant.  
Previous anti-cancer medications and previous anti-cancer procedures will be summarized 
similarly. Previous radiotherapies will also be summarized per the CRF data category.  
The data summarized will be listed as well. 
5.2.6 
Treatment Compliance 
Dose modifications (i.e., reduction and missing) will be summarized (see Section 5.6.1).  
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Data from all centers will be pooled in analyses.  
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 


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5.3.4 
Examination of Subgroups 
No subgroup analyses will be performed. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
Rules of handling full/partial missing dates and the censoring rules for PFS are explained in 
Section 8. Handling missing data in analyses of ORR, CBR and DCR is explained in Section 
5.4. Any potential outlier values will be investigated and they will be analyzed as originally 
reported in the locked database.  
5.3.6 
Other Considerations 
No other consideration. 
5.4 
Efficacy Analyses 
All the efficacy endpoints defined in the protocol for Phase 2 (in Section 5.1), except OS and 
the duration of response, will be summarized for Phase 1b data. Their definitions will use the 
first date of any study drugs instead of the date of randomization, and the BOR will be 
determined from the confirmed CR or PR (after 28 days starting at the initial CR or PR 
observed) per RECIST 1.1. 
In the efficacy analyses,  
• Number (percentage) of subjects involved in objective response rate (CR or PR), disease 
control rate (CR, PR or SD), clinical benefit rate (CR, PR or durable SD), and durable SD 
rate will be reported together with their 95% confidence intervals (using the exact method 
of binomial distribution). Each BOR category will also be summarized in number 
(percentage) of subjects. In the analyses of ORR, CBR and DCR, subjects with missing 
data will be considered as non-responders and will be included in the denominator when 
calculating ORR, CBR and DCR. The figure of percent change of sum of target lesions’ 
diameters from baseline and the figure of subjects’ timepoint overall responses will be 
presented as well. The data and the tumor timepoint assessments (on target lesions, non-
target lesions, new lesions) from the CRF will be listed as well. 
• The Kaplan-Meier (KM) estimated PFS (month) at median, Q1 and Q3, and the KM 
estimated  rates of PFS at the timepoints of 3, 6 and 12 months will be reported together 
with their 95% confidence intervals (the methods of generalized Brookmeyer and 
Crowley for survivals and Greenwood Formula for rates). The KM estimated PFS will 
also be plotted. The censoring rules for PFS calculation are explained in Section 8. The 
data will be listed as well.   
 


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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
Available PK data will be summarized, plotted and listed.  
No pharmacodynamic, pharmacogenomic, and other biomarker data will be available. 
5.6 
Safety Analyses 
5.6.1 
Extent of Exposure 
First and last dosing dates will be derived, separately, for each of study drugs (i.e.  
PEGHPH20 and Eribulin) and overall:  
Study Drug 
First Dosing date 
Last Dosing date 
Eribulin 
first non-missing eribulin dosing 
date 
last non-missing eribulin dosing date   
PEGPH20 
first non-missing PEGPH20 
last non-missing PEGPH20 dosing 
date   
Overall 
Minimum of 2 study drugs’ first 
dosing dates  
Maximum of 2 study drugs’ last 
dosing dates 
 
In the analyses, the number of cycles/weeks/doses on treatment, cycle length, cumulative 
dose received, average dose intensity, relative dose intensity, and the number of subjects with 
dose reduction/missing, will be summarized by study drug. The data will be listed as well.  
Per protocol, one cycle would be 21 days of treatment. The following calculations will be 
carried out in the analyses: 
• The duration of treatment (weeks) for each study drug will be calculated as:  
◦ 
 (First dosing date of the study drug in the final cycle  - first dosing date of the  
study drug in the first cycle + 21)/7. 
• The duration of overall treatment (weeks) will be calculated as:  
◦ 
(First dosing date of any study drugs in the final cycle - First dosing date of any 
study drugs in the first cycle + 21)/7 (note: ‘+21’ if the first PEGPH20 dose in 
final cycle was not missing, and ‘+20’ if the first PEGPH20 dose in final cycle 
was missing and first eribulin dose in the final cycle was not missing). 
• The average cycle length of each study drug: will be calculated as the duration of each 
drug treatment divided by its corresponding number of cycles received in the study.    


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• Cumulative dose per subject (mg for eribulin, µg for PEGPH20), average dose intensity 
per subject (mg/m2/week for eribulin and µg/kg/week for PEGPH20), and relative dose 
intensity per subject (percentage of cumulative dose relative to planned dose):   
◦ 
Average dose intensity (mg/m2/week) for eribulin = total dose (mg)/ baseline 
BSA(m2)/duration of eribulin treatment (weeks)  
◦ 
Average dose intensity (µg/ kg/week) for PEGPH20= total dose (µg)/baseline  
weight(kg)/duration of PEGPH20 treatment (weeks)  
◦ 
Relative dose intensity (%)=average dose intensity (mg/m2/week for eribulin,  
µg/kg/week for PEGPH20)/planned dose intensity, where the planned eribulin 
dose intensity is 0.933 mg/m2/week and the planned PEGPH20 dose intensity is  
2 ug/kg/week for dosing level 1 (3 ug/kg) and  1.067 ug/kg/week for dosing  level 
0 (1.6 ug/kg)      
 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 19.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database. The CTCAE grading 
(Version 4.03 or higher) will be considered in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged during 
treatment (i.e., AE onset or worsening is on or after first dose date of any study drugs, or up 
to 28 days following last dose of any study drugs), having been absent at pretreatment 
(Baseline) or  
• Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• Worsened in severity during treatment relative to the pretreatment state, when the AE 
was continuous. 
Only those AEs that are treatment emergent will be summarized in tables. A subject will be 
counted only once within each category (ie, SOC, PT, grade, or other specific category to be 
summarized in table) even if the subject experienced more than 1 TEAE within the category. 
All AEs, treatment emergent or otherwise, will be presented in subject data listings. 
The following TEAE summary analyses will be performed: 
• An overview summary table will include number (percentage) of subjects with any 
TEAE, with any treatment-related TEAE, with any TEAE of grade 3 or above, with any 
TEAE of grade 3 or grade 4, with any serious TEAE, with any TEAE leading to study 
drug withdrawal, with any TEAE leading to study drug dose reduction, with any TEAE 


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leading to study drug interruption, and with any TEAE of special interest.  This overall 
summary will be repeated similarly for treatment-related TEAEs. 
• TEAEs will be summarized by SOC, PT and grade in number (percentage) of subjects. 
Repeat this analysis for the TEAEs that are treatment-related, serious, serious and 
treatment-related, leading to death/dose modification/dose discontinuation, separately. 
• TEAEs will be summarized by PT and grade in number (percentage) of subjects. 
• Fatal TEAEs will be summarized by SOC and PT in number (percentage) of subjects. 
Repeat this analysis for non-fatal TEAEs, for TEAEs leading to study dose withdrawn, 
and for TEAEs leading to study dose reduction/interruption, separately.  
• TEAEs of special interest will also be summarized in number (percentage) of subjects for 
each type of special interest by PT and grade. Repeat this analysis for treatment-related 
TEAEs, for serious TEAEs, and for treatment-related and serious TEAEs, separately.   
 
5.6.2.1 
Death 
All deaths, deaths within 28 days of last dose, and deaths >28 days of last dose will be 
summarized. Deaths will be listed as well.  
5.6.3 
Laboratory Values 
Clinical laboratory test parameters, per category, are listed in Table 1. The test results will be 
standardized using System International (SI) units and categorized according to CTCAE 
grade (v4.03 or higher) (see protocol Appendix 6).  
Each laboratory test parameter will be summarized by visit, on the actual value observed, and 
on its change from baseline (except the parameters from Urinalysis). Grade shifting table 
from baseline to the worst during treatment period will also be summarized per parameter. 
The data will be listed as well. 
 


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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, Coagulationa (PT, PTT, INR) 
Clinical Chemistry 
 
     Electrolytes 
Sodium, potassium, chloride, calcium, magnesium 
     Liver Function Tests 
ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin 
     Renal Function 
BUN, serum creatinine 
     Pregnancy 
Serum or urine β-hCG 
     Other 
Albumin, glucoseb, LDH, total protein, uric acid 
Urinalysis (urine dipstick) 
Glucose, ketones, pH, protein, blood RBCs, leukocytes, specific gravity.  Urine 
microscopy (if clinically indicated), culture, and sensitivity in case of UTI 
ALT = alanine aminotransferase, ANC = absolute neutrophil count, AST = aspartate aminotransferase, 
β-hCG = beta-human chorionic gonadotropin, BUN = blood urea nitrogen, LDH = lactate dehydrogenase, 
PT=prothrombin time, PTT=partial thromboplastin time, INR=international normalized ratio, RBC = red 
blood cells, UTI=urinary tract infection, WBC = white blood cells. 
a: Coagulation tests at screening visit and when clinically indicated 
b: Fasting glucose at screening only 
 
 
5.6.4 
Vital Signs 
Each parameter of vital signs assessments (diastolic and systolic BP, pulse rate, respiratory 
rate, temperature, weight, body surface area) will be summarized by visit on actual value 
observed and on its change from baseline. The data will be listed as well.  
5.6.5 
Electrocardiograms 
Each parameter of electrocardiogram (ECG) assessments (heart rate, QT interval, QTcB 
interval, QTcF interval, RR interval) will be summarized by visit on actual value observed 
and on its change from baseline (or from the first assessment observed during study if no 
baseline available). The data will be listed as well. 
ECG findings (normal, abnormal-not clinically significant, abnormal-clinically significant) 
will also be summarized on shifting from baseline to the worst during treatment period. The 
data will be listed as well. 
5.6.6 
Other Safety Analyses 
5.6.6.1 
Dose-limiting Toxicity in Phase1b Study 
Per protocol, Part 1 Phase 1b subjects would get dose-limiting toxicity (DLT) assessed in the 
first treatment cycle to determine the RP2D during the study. The DLTs will be summarized 
and the data will be listed as well.  


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Per the protocol, the definition of DLT would be 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 
- 
Neutropenia Grade 3 or 4 complicated by fever and/or infection (ANC < 1.0 x 109/L, 
fever ≥ 38.5°C). 
- 
Thrombocytopenia Grade 3 complicated by bleeding and/or requiring platelet or 
blood 
- 
transfusion 
• Nonhematologic Toxicities: 
- 
Any Grade DVT, PE or stroke.  
- 
Any Grade 4 toxicity. 
- 
Any clinically significant Grade 3 toxicity EXCLUDING: 
- 
Nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours. 
- 
Hypersensitivity reactions Grade 3 or 4 including allergy reactions or anaphylaxis 
symptomatic bronchospasm requiring parenteral medication(s) with or without 
urticaria; allergy-related edema/angioedema. 
- 
Discontinuation or delay of more than 2 weeks of either study drug due to treatment-
related AE will be considered as a DLT. 
 
5.6.6.2 
ECOG Performance Status 
ECOG performance status will be summarized on shifting from baseline to the worst during 
treatment period. The data will be listed as well. 
5.7 
Other Analyses 
No other analysis will be performed. 
5.8 
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. 
6 
INTERIM ANALYSES 
Not applicable. 
 


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7 
CHANGES IN THE PLANNED ANALYSES 
Final analyses will be focused on the analyses planned in this document based on Phase 1b 
data due to the early termination of this study. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Data Report 
Data reporting for both safety and efficacy analyses will use Safety Analysis Set, data 
reporting for PK analyses will use PK Analysis Set, and the DLT reporting will use DLT 
Evaluable Set. All the data reporting (tables, listings, figures) will be performed by dosing 
level. All descriptive statistics for continuous variables will be reported in mean, standard 
deviation (SD), median, Q1, Q3, minimum and maximum. Unless otherwise specified, all 
categorical variables will be summarized and reported in number (percentage) of subjects. 
The data summarized will be listed as well.  Some data will only be listed if listing is enough 
for data reporting. 
8.2 
Baseline 
Baseline is defined as the non-missing value most recently collected prior to the first dose of 
any study drugs.  
8.3 
Study Day 
Study Day is defined as days from the first dosing date of any study drugs (i.e., PEGPH20 
and Eribulin), in detail as   
• For a date on or after the first dosing date, Study Day= event date – first dosing date of 
any study drugs+1, 
• For a date prior to the first dosing date, Study Day= event date – first dosing date of any 
study drugs. 
 
8.4 
Day to Month to Year  
1 month = 30.4375 days; 1 year = 365.25 days.  
8.5 
Censoring Rule 
Table 2 shows the primary censoring rules for the derivation of PFS based upon 
investigator’s tumor assessment and the Food and Drug Administration (FDA) “Guidance for 
Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007)”.    
   


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Table 2 Censoring Rules for Analysis of Progression-Free Survival  
No. 
Situation 
Date of Progression or Censoring 
Outcome 
1 
No 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 or 
withdrawal from study 
Date of last adequate radiologic 
assessment prior to or on date of data 
cut-off or withdrawal from study 
Censored 
4 
New anti-cancer treatment started 
Date of last adequate radiologic 
assessment prior to or on date of new 
anti-cancer 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 
2 
No post-baseline tumor assessments but known 
to be alive 
Date of the first dose  
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.  
** More than two missed visits is defined if the duration between the last tumor assessment and death or PD is 
longer than 84 days (12 weeks) for subjects on the every 6 week scanning schedule during treatment /follow up 
phase 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 died or had clinical progression within 84 days (12 weeks) after the first 
dose and did not receive new anti-cancer treatment, the date of death or clinical progression will be the 
PFS event date (not censored). 
 
If a subject had new anti-cancer treatment before PD or death (No.  4), the subject will be censored on the 
date of the last tumor assessment prior to or on the date of new anti-cancer treatment. 
 
If a subject missed two assessments before PD or death (No.  7), the subject will be censored on the date of 
the last tumor assessment before PD or death.  Note that if a subject is censored by both this criterion and 
the anti-cancer treatment criteria, the earliest 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, or No. 7). 
 
8.6 
Missing Date Handling 
• Adverse Event with missing or partial missing date : 
Adverse Event with incomplete start date will be considered as treatment emergent if: 


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a. Day and month are missing and the year is equal to or after the year of the first 
dosing 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 dosing date and the 
month is equal to or after the month of the first dosing date; 
d. Year is missing; or 
e. Complete date is missing. 
 
• Therapy (medication, procedure, radiotherapy) date missing or partial missing: 
See Section 5.2.5 for the missing date handling in determination of prior and concomitant 
medications. For the case of missing efficacy data, see Section 5.4. For other cases, detail 
of handling will be provided in a separate document (analysis datasets specification). 
 
8.7 
Unscheduled Visit 
Data from unscheduled visits (eg, vital signs or laboratory tests) will be excluded from the 
by-visit summary but will contribute to the worst value in required summary tables. Listings 
will include all, the scheduled and unscheduled.  
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications will be provided in separate 
document (analysis datasets specification).  
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS version 9 or higher. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
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. 
12 REFERENCES 
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute, Washington, DC, USA, May 28, 2009. 
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; 45:228-47. 


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13 APPENDICES 
13.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results  
See Protocol Appendix 6. 


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SIGNATURE PAGE 
Remove table rows that are not applicable.  For example, if there is only 1 author delete the 
table rows for the second author. 
Author(s):  If there is 1 author, remove “(s)” in the heading; if there 
is more than 1 author, remove the parentheses around the “s.” 
 
 
 
Study Statistician signs here 
 
 
 
<Name, degree(s)> 
<title> 
 
Date 
 
(Note:  There may be more than 1 SAP author, eg, a CRO 
statistician may also be an author of the SAP.) 
If applicable, the second author signs here 
 
 
 
<Name, degree(s)> 
<title> 
<legal name of non-Eisai company>(if applicable) 
 
Date 
Approval: 
 
 
 
The biostatistics head signs here 
 
 
 
Biostatistics Head of <insert therapeutic area> 
<Name, degree(s)> 
<title, department> 
 
Date 
 
The study director signs here 
 
 
 
Study Director 
<Name, degree(s)> 
<title, department> 
 
Date 
 
Additional approver(s) as per local SOP or as otherwise 
required. 
 
 
 
<Function title> 
<Name, degree(s)> 
<title, department> 
 
Date