Clinical trial NCT03222856
Conditions: Breast Cancer
Sponsor: MedSIR
Start date: 2017-12-14; Completion date: 2020-12-23
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane and prior anti-hormonal therapy is mandatory.

The number of patients to be included is 44 patients at 11 sites. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle.

Detailed description:
This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. Prior anti-hormonal therapy is mandatory.

The number of patients to be included is 44 patients at 11 sites. The primary objective is to assess the efficacy -as determined by the clinical benefit rate (CBR) (total number of objective responses plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab) in combination with eribulin.

Primary endpoint is CBR based on RECIST v.1.1. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose.

Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy since last progression of a metastatic tumor lesion not previously irradiated is requested for this study.

Translational research of this protocol involves the collection, processing, temporary storage, and shipment of samples from consenting patients enrolled in centers selected for participation in the study. The study plan includes collection and initial processing of tumor tissues and blood samples to the central laboratory of Institut Hospital del Mar d"Investigacions Mèdiques (IMIM), that will be used to identify dynamic biomarkers that may be predictive of response to MK3475 (pembrolizumab) and eribulin treatment.

Arms: arm 1: All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose.
Interventions: intervention 1: Pembrolizumab intervention 2: Eribulin
Intervention descriptions: intervention 1: MK3475 (pembrolizumab) will be supplied directly as a solution for infusion in a single-use vial. Each vial contains 100 mg of MK3475 (pembrolizumab) in 4 ml of solution. intervention 2: Eribulin will be supplied as a clear and colourless aqueous solution for injection provided in glass vials containing 2 ml. Each 2 ml vial contains eribulin mesylate equivalent to 0.88 mg eribulin.

Protocol documents:
Prot_000.pdf: 
 
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Clinical Study Protocol 
 
 
A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-
negative metastatic breast cancer previously treated with anthracyclines and taxanes 
KELLY study (KEytruda and EribuLin in Luminal breast cancer) 
 
Protocol number: MedOPP127 
 
Study drug(s):  
 
Halaven®; Keytruda® 
 
 
 
 
 
EudraCT#: 
 
 
2016-004513-27 
Protocol No.:   
 
MedOPP127 
 
 
Protocol date:   
 
23rd October 2019 
 
Protocol Revision History: 
Initial approved Version:  
23rd June 2017 
Amendmend I:   
 
14th November 2017 
Amendment II:  
 
23rd January 2018 
Amendment III:  
 
 23rd October 2019 
 
 
 


 
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SPONSOR’S SIGNATURE PAGE 
 
Study title: A phase II study of pembrolizumab and eribulin in patients with HR-
positive/HER2-negative metastatic breast cancer previously treated with anthracyclines 
and taxanes. KELLY study (KEytruda and EribuLin in Luminal breast cancer) 
 
Study code: MedOPP127 
 
Version number and date: 4.0 dated 23rd October 2019 
 
 
 
Sponsor  
 
Signature 
 
Signature date 
 (DD-Mmm-YYYY) 
 
 
   
Scientific Global Coordinator  
 
 
Signature 
 
Signature date 
 (DD-Mmm-YYYY) 
 


 
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KEY CONTACT DETAILS 
Sponsor   
Name:  
 
Medica Scientia Innovation Research (MedSIR) 
Contact person:  
 
Address: 
 
Rambla Cataluña, 2-4, 2D, 08007-Barcelona, Spain 
Phone:  
 
 
E-mail:  
 
 
 
Scientific Global Coordinator 
Name:  
 
 
Address: 
 
E-mail:  
 
 
 
Medical Study Manager 
Name:  
 
 
Address:  
 
Rambla Cataluña, 2-4, 2D, 08007-Barcelona, Spain 
E-mail:  
 
 
 
Safety Management 
Name:  
 
Experior S.L 
Address:  
 
Vicente Galmés 1a, 46139 La Pobla de Farnals-Valencia, Spain. 
Phone:  
 
 
Fax: 
 
 
 
E-mail:  
 
 
 
Reference Central Laboratory for Translational Reseach 
Name:   
 
Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) 
Contact person:  
 
Address:  
 
Carrer del Dr. Aiguader, 88, 08003 Barcelona 
E-mail:   
 
 
 
 


 
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Reference Central Laboratory for 
 
Name:   
 
 
Contact person:  
 
Address:  
 
  
E-mail:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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DECLARATION OF INVESTIGATORS 
 
Protocol Title: A phase II study of pembrolizumab and eribulin in patients with HR-
positive/HER2-negative metastatic breast cancer previously treated with anthracyclines 
and taxanes 
 
Version date:  23rd October 2019 
 
Protocol number: MedOPP127 
 
I have received, reviewed and understood the following: 
 
a) 
Protocol: A phase II study of pembrolizumab and eribulin in patients with HR-
positive/HER2-negative metastatic breast cancer previously treated with anthracyclines 
and taxanes. 
b) 
Summary of Product Characteristics (SmPC) of eribulin and Investigator Brochure (IB) of 
MK3475(Pembrolizumab) containing clinical and non-clinical data on investigational product that 
are relevant to the study of the product on human subjects. 
I have been adequately informed as to the development to date of the investigational product. I 
will acknowledge receipt of the updated SmPC. I have read this study protocol and agree that it 
contains all the information required to conduct the study. I agree to conduct this study as set out 
in this protocol. 
I understand that any change made by the Investigator(s) not previously agreed  by the Sponsor 
may constitute a protocol non-compliance, including all of the ancillary studies or procedures 
performed on study patients (other than those procedures needed to ensure the patients’ well-
being). I am aware that I can only deviate from or apply changes to the protocol without prior 
approval or the favorable opinion of the Ethics Committee (EC) and/or before Sponsor approval 
to avoid immediate risk to the trial patients. Should this occur, I agree to inform the Sponsor as to 
the deviation or changes in writing and their reasons, as soon as possible. 
I will not begin recruiting patients to the study until I am authorized to do so by the appropriate 
EC and after meeting all legal and regulatory requirements of this country. 
The study will be conducted in accordance with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and its amendments, the 


 
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International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines (ICH 
E6 GCP), and applicable laws and regulations. 
I agree to receiving, as described in this protocol and in the ICH E6 guidelines for GCP, written 
informed consent from the patient or their legally authorized representative or the witnessed 
verbal informed consent from all patients who have been asked to participate in this study, before 
performing any study procedure. 
I will ensure that the study drug(s) provided by the Sponsor will only be used as described in this 
protocol. 
I am aware of the requirements for the correct reporting of serious adverse events, and I commit 
to document and to report such events as required by the Sponsor and in accordance with Health 
Authority Regulatory requirements. 
I agree to provide the Sponsor or Sponsor’s representative, upon request, with evidence of 
current laboratory accreditation, the name and address of the laboratory, and a list of normal 
values and ranges. 
I agree to the use of study results for national and international registration, publication, and 
information for medical and pharmaceutical professionals. 
I agree to keep all source documents and case report forms (CRF) as specified in the relevant 
sections of this protocol. 
I agree to submit all the forms required by the Health Authorities and my updated curriculum vitae 
and those of the sub-Investigators and all of the members of my team (if applicable) before the 
start of this study, which may be submitted, in turn, to the Health Authorities. 
I am aware that the Sponsor or their representative may perform audits and that the Health 
Authorities may carry out inspections as part of the conduct of this study. I will permit monitoring, 
audit and inspection and provide direct access to source data, documents and reports for these 
purposes. 
In light of the foregoing, I hereby consent to the inclusion by the Sponsor of my contact details 
and professional profile in their electronic database to be used for internal purposes and for 
submission to Health Authorities worldwide. 
Name:  
 
_____________________________________________________________________ 
Signature: _________________________ 
Date:  ___________________________ 


 
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Protocol synopsis 
Investigational drug: 
Halaven®; Keytruda® 
Protocol number: 
MedOPP127 
Eudract Number: 
2016-004513-27 
Protocol Title: 
A phase II study of pembrolizumab and eribulin in patients with HR-
positive/HER2-negative metastatic breast cancer previously treated 
with anthracyclines and taxanes. 
Target disease: 
Hormone receptor-(HR)positive/HER2-negative metastatic breast 
cancer (MBC) previously treated with at least one, but not more than 
two, prior chemotherapeutic regimens for treatment of locally 
recurrent and/or metastatic disease. Prior therapy must have included 
an anthracycline and a taxane in any combination or order and either 
in the early or metastatic disease setting unless contraindicated for a 
given patient. Prior anti-hormonal therapy in the metastatic disease 
setting is mandatory. 
Subjects: 
Female patients age ≥ 18 years with advanced HR-positive/HER2-
negative breast cancer previously treated with anthracyclines and 
taxanes.  
Number of patients: 
44 patients.  
Screening criteria: 
Inclusion criteria: 
Patients will be included in the study only if they meet ALL of the 
following criteria: 
1. Written informed consent prior to beginning specific protocol 
procedures. 
2. Female patients ≥ 18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) performance 
status must be 0 or 1 which the Investigator believes is stable 
at the time of screening. 
4. Life expectancy ≥ 12 weeks. 


 
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5. Patients have a histologically and/or cytologically confirmed 
diagnosis of breast cancer. 
6. Patients have radiologic evidence of inoperable locally 
recurrent or MBC. 
7. Patients have HER2-negative breast cancer (based on most 
recently analyzed biopsy) defined as a negative in situ 
hybridization (ISH) test or an immunohistochemistry (IHC) 
status of 0, 1+, or 2+ (if IHC 2+, a negative ISH test is 
required) by local laboratory testing. 
8. Patients have HR-positive breast cancer defined as estrogen 
receptor (ER) and/or progesterone receptor (PR) with >1% of 
tumor cells positive for ER and/or PR by IHC irrespective of 
staining intensity. 
9. Available tumor tissue for PD-L1 biomarker analysis from a 
newly obtained core or excisional biopsy since last 
progression of a metastatic tumor lesion not previously 
irradiated. 
Note: Subjects for whom tumor biopsies cannot be obtained (e.g., 
inaccessible tumor or subject safety concern) may submit an 
archived metastatic tumor specimen only upon agreement from 
the Sponsor. 
10. Patients have measurable disease based on Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria version 
1.1 as assessed by site Investigator and local radiology 
review. 
11. Patients have received at least one, but not more than two, 
prior chemotherapeutic regimens for locally recurrent and/or 
metastatic disease. Prior therapy must have included an 
anthracycline and a taxane in any combination or order and 
either in the early or metastatic disease setting unless 
contraindicated for a given patient. Prior anti-hormonal 
therapy in the metastatic disease setting is mandatory.  
12. Patients have adequate bone marrow and organ function as 
defined by the following laboratory values: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.  
• 
Platelets ≥ 100 x 109/L. 
• 
Hemoglobin ≥ 9 g/dL. 


 
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• 
Potassium, calcium (corrected for serum albumin), 
and magnesium within normal limits for the 
institution. 
• 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN). 
• 
Alanine aminotransferase (AST) and aspartate 
aminotransferase (ALT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN 
if liver metastases are present).  
• 
Total serum bilirubin within normal range (or ≤ 1.5 x 
ULN if liver metastases are present). Patients with 
known Gilbert disease who have serum bilirubin ≤ 3 
x ULN may be enrolled. 
13. Patients must be accessible for treatment and follow-up. 
Exclusion criteria: 
Any patient meeting ANY of the following criteria will be excluded from 
the study: 
1. Patients have received previous treatment with eribulin 
and an/or anti-PD1 or anti-PD-L1 agents. 
2. Patients have a known hypersensitivity to any of the 
excipients of MK3475 (pembrolizumab) or eribulin. 
3. Patients who have received chemotherapy, targeted 
small molecule therapy, or radiotherapy within two 
weeks of first dose of study treatment. 
4. Patients who have received monoclonal antibodies for 
direct antineoplastic treatment or an investigational 
agent/device within four weeks of first dose of study 
treatment. 
5. Patients have known active central nervous system 
(CNS) metastases and/or carcinomatous meningitis. 
Note: Known brain metastases are considered active, if any of the 
following criteria is applicable: 
a. 
Brain imaging during screening demonstrates progression of 
existing metastases and/or appearance of new lesions 
compared to brain imaging performed at least four weeks 
earlier. 


 
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b. 
Neurological symptoms attributed to brain metastases have 
not returned to baseline. 
c. 
Steroids were used for brain metastases within 28 days of first 
dose of study treatment. 
6. Patients have peripheral neuropathy grade 2 or more. 
7. Patients have a concurrent malignancy or malignancy 
within five years of study enrollment (with the exception 
of adequately treated, basal or squamous cell skin 
carcinoma or curatively resected cervical cancer). 
8. Patients have not recovered to grade 1 or better (except 
alopecia) from related side effects of any prior 
antineoplastic therapy. 
9. Patients have had a major surgical procedure within 28 
days prior to starting study drug. 
10. Patients have an active cardiac disease or a history of 
cardiac dysfunction including any of the following: 
• 
Unstable angina pectoris or documented myocardial 
infarction within six months prior to study entry. 
• 
Symptomatic pericarditis. 
• 
History of documented congestive heart failure (New 
York Heart Association functional classification III-
IV). 
• 
Patients have a left ventricular ejection fraction 
(LVEF) < 50% as determined by multiple gated 
acquisition 
(MUGA) 
scan 
or 
echocardiogram 
(ECHO). 
11. Patients have any of the following cardiac conduction 
abnormalities: 
• 
Ventricular arrhythmias except for benign premature 
ventricular contractions. 
• 
Supraventricular and nodal arrhythmias requiring a 
pacemaker or not controlled with medication. 
• 
Conduction abnormality requiring a pacemaker.  
• 
Other cardiac arrhythmia not controlled with 
medication.  


 
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12. Uncontrolled hyper/hypothyroidism or type 1 diabetes 
mellitus (T1DM). Patients with hypothyroidism stable on 
hormone replacement will not be excluded from the trial. 
Patients with controlled T1DM on a stable insulin 
regimen may be eligible for this study. 
13. Active autoimmune disease that has required systemic 
treatment in past 2 years (i.e., with use of disease 
modifying 
agents, 
corticosteroids, 
or 
immunosuppressive drugs). 
Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic 
steroid replacement therapy (≤ 10 mg prednisone daily) for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
14. Prior allogenic stem cell or solid organ transplantation.  
15. Active/history of pneumonitis requiring treatment with 
steroids or active/history of interstitial lung disease. 
16. Active uncontrolled infection at the time of screening  
17. Active tuberculosis. 
18. Current known infection with HIV. 
19. Active hepatitis B (HBV) [patients with negative hepatitis 
B surface antigen (HBsAg) test and a positive antibody 
to HBsAg (anti-HBsAg) test at screening are eligible] or 
hepatitis C (HCV) [patients with a positive antibody to 
hepatitis C (anti-HCV) are eligible only if polymerase 
chain reaction (PCR) is negative for virus hepatitis C 
RNA]. 
20. Patients have any other concurrent severe and/or 
uncontrolled medical condition that would, in the 
Investigator’s 
judgment 
contraindicate 
patient 
participation in the clinical study. 
21. Treatment 
with 
systemic 
steroids 
(standard 
premedication for chemotherapy/contrast reactions, 
inhaled steroids, and local applications are allowed) or 
another immunosuppressive agent within seven days 
prior to study treatment initiation.  


 
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22. Has received  live vaccines within 30 days prior to first 
dose of study treatment.  
23. Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, are not 
allowed to participate in this study unless they are using 
highly effective methods of contraception during dosing 
and up to 120 days after study drugs discontinuation.  
Study objectives: 
Primary objective: 
• To assess the efficacy -as determined by the clinical benefit 
rate (CBR) (total number of objective responses plus stable 
disease for at least 24 weeks) based on RECIST v.1.1- of 
MK3475 (pembrolizumab) in combination with eribulin in 
patients with HR-positive/HER2-negative MBC who have 
previously received an anthracycline and a taxane (for either 
early or advanced disease), unless contraindicated, and 
between one to two lines of chemotherapy in the metastatic 
setting.  
Secondary objectives: 
• To determine the CBR based on RECIST v.1.1 in subjects with 
programmed death ligand-1 (PD-L1) positive tumors. 
• To determine the progression-free survival (PFS) based on 
RECIST v.1.1. 
• To determine the PFS based on RECIST v.1.1 in subjects with 
PD-L1 positive tumors. 
• To determine the overall survival (OS) (OS will be determined 
at the end of the study). 
• To determine the OS in subjects with PD-L1 positive tumors. 
• To determine the overall response rate (ORR) based on 
RECIST v.1.1. 
• To determine the ORR based on RECIST v.1.1 in subjects with 
PD-L1 positive tumors. 
• To determine the duration of response (DoR) based on 
RECIST v.1.1. 
• To determine the DoR based on RECIST v.1.1 in subjects with 
PD-L1 positive tumors. 


 
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• To 
assess 
the 
safety 
and 
tolerability 
of 
MK3475 
(pembrolizumab) in combination with eribulin according to the 
US National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.3. 
 
Exploratory objectives: 
 
 
 
 
 
 
 
 
 
 
Type of study: 
Multicenter, open-label, phase II clinical trial 
Study Treatment: 
All eligible patients will be treated with MK3475 (pembrolizumab) 200 
mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent 
to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day 
cycle. Treatment with MK3475 (pembrolizumab)  and eribulin will 
continue based on physician criteria. Study follow-up will be 
performed  12 months after last study dose.  
A participant must be discontinued from study treatment but continue 
to be monitored in the study for any of the following reasons: 
• Completion of 35 treatments (approximately 2 years) with 
pembrolizumab. Please see the specific conditions at section 
5.3.2 of the protocol. 
Note: The number of treatments is calculated starting with the first 
dose.  Participants who stop the combination or pembrolizumab after 
receiving 35 doses may be eligible for retreatment if they progress 
after stopping study treatment provided they meet the requirements 
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Course Phase (Retreatment) for up to an additional 17 cycles 
(approximately 1 year). 
After 35 dose administrations, patients can continue on treatment with 
eribulin alone.  
Safety and efficacy 
assessments: 
Efficacy assessments:  
Disease assessments [computerized tomography (CT) of the chest, 
abdomen, and pelvis or magnetic resonance imaging (MRI) of the 
abdomen and pelvis with a non-contrast CT scan of the chest in 
patients for whom CT scans with contrast are contraindicated] will be 
performed using RECIST v.1.1 every 9 weeks (± 7 days) from the first 
dose of study treatment up to one year (more frequently if clinically 
indicated). All subjects who remain on treatment for a year will 
subsequently have imaging performed every 12 weeks (± 7 days). 
Imaging should continue to be performed until radiologic evidence of 
disease progression, treatment discontinuation, the start of new anti-
cancer treatment, withdrawal of consent, death, or the end of the 
study, whichever occurs first. 
Bone scans will also be used to assess bone metastases. If a subject 
has a known history of bone metastases or has new bone pain during 
screening, a bone scan should be obtained prior to study entry. A 
bone scan at follow-up is required only if they develop new or 
worsening symptoms or if the site believes they have attained a 
complete response. If a subject has no known metastatic disease in 
the bone or active symptoms, a bone scan at baseline is not needed.  
Brain imaging during the trial should be performed in subjects with 
known brain metastases (every nine weeks for first year, then every 
12 weeks) and those with worsening and/or new neurological 
symptoms. 
After disease progression by RECIST v.1.1, if the site Investigator 
determines the subject is clinically stable and will benefit from 
continued treatment, the subject will then be managed by irRECIST. 
Each assessment will be performed as scheduled according to the 
calendar regardless of any dosing delay to prevent the introduction of 
bias into the assessment of efficacy. Failure to perform any of the 


 
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required disease assessments will result in the inability to determine 
disease status for that time point.  
Safety assessments:  
The occurrence and maximum grade of adverse events (AEs) 
observed throughout the study will be listed. . Any AEs that the 
Investigator reports as unrelated to the drug will also be reported. In 
this study, AEs will be assessed according to the NCI CTCAE v.4.0.3. 
Endpoints 
Primary endpoint:  
• CBR based on RECIST v.1.1. 
Secondary endpoints: 
• CBR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
• PFS based on RECIST v.1.1. 
• PFS based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
• OS (OS will be determined at the end of the study). 
• OS in subjects with PD-L1 positive tumors. 
• ORR based on RECIST v.1.1. 
• ORR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
• DoR based on RECIST v.1.1. 
• DoR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
• Safety. 
Exploratory endpoints: 
 
 
 
 


 
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Planned Study period: 
Recruitment period is planned to be opened for 11 months. 
The end of study will be 12 months after last study dose in the first 
course of pembrolizumab phase treatment, or after the last study dose 
in the second course in all patients. 
 
by the Sponsor, whichever is earlier. This data point will be 
considered: 
• 
LPLV (Last Patient Last Visit).  
• 
End of Recruitment (LPI) (11 months): August 2018 
• 
Last Patient Last Visit (LPLV): Dec 2020 
• 
Final Study Report: Feb 2021 
 
 


 
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List of abbreviations 
Absolute neutrophil count 
 ANC 
Adverse event 
 AE 
Alanine aminotransferase 
 ALT 
Alkaline phosphatase 
 ALP 
Anaplastic lymphoma kinase 
 ALK 
Antibody to hepatitis B surface antigen 
 Anti-HBsAg 
Antibody to hepatitis C virus 
 Anti-HCV 
Aspartate aminotransferase 
 AST 
Body surface area 
 BSA 
Case report form 
 CRF 
Central nervous system 
 CNS 
Circulating tumor cell 
 CTC 
Clinical benefit rate 
 CBR  
Committee for Medicinal Products for Human 
Use 
 CHMP 
Common terminology criteria for adverse 
events 
 CTCAE 
Computerized tomography 
 CT 
Confidence interval 
 CI 
Cytochrome P450 
 CYP 
Dose administration record 
DAR 
Duration of response 
 DoR 
Eastern Cooperative Oncology Group 
 ECOG 
Echocardiography 
 ECHO 
Electrocardiogram 
 ECG 
Electronic data capture 
 EDC 
End of recruitment date 
 LPI 
Epidermal growth factor receptor 
 EGFR 


 
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Erythropoiesis-stimulating agents 
 ESA 
Estrogen receptor 
 ER 
Ethics committee 
 EC 
Event of clinical interest 
 ECI 
Food and drug administration 
 FDA 
False-Discovery Rate 
 FDR 
Formalin fixed paraffin-embedded 
 FFPE 
Gamma-glutamyl transferase 
 GGT 
Good clinical practice 
 GCP 
Granulocyte-colony stimulating factor 
 G-CSF 
Health Authority 
 HA 
Hepatitis B surface antigen 
 HBsAg 
Hepatitis B virus 
 HBV 
Hepatitis C virus 
 HCV 
Hormone receptor 
 HR 
Immune-related Response Evaluation Criteria 
In Solid Tumors 
 irRECIST 
Immune-related adverse event 
 irAE 
Immunohistochemistry 
 IHC 
International Human Microbiome Standards 
 IHMS 
In situ hybridization 
 ISH 
Interferon 
 IFN 
International Committee of Medical Journal 
Editors 
 ICMJE 
International Conference on Harmonization 
 ICH 
Intention To Treat 
 ITT 
Intrauterine device 
 IUD 
Intrauterine system 
 IUS   


 
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Intravenous 
 IV 
Investigational medicinal product 
 IMP 
Last patient last visit 
 LPLV 
Left ventricular ejection fraction 
 LVEF 
Magnetic resonance imaging 
 MRI 
Maximum tolerated dose 
 MTD 
Metastatic breast cancer 
 MBC 
Multiple-gated acquisition 
 MUGA 
National Cancer Institute 
 NCI 
National Comprehensive Cancer Network 
 NCCN 
Non-small cellu lung cancer 
 NSCLC 
Non-steroidal anti-inflammatory drugs 
 NSAIDS 
Overall response rate 
 ORR 
Overall survival 
 OS 
 Operational Taxonomic Units 
 OTUs 
Polymerase chain reaction 
 PCR 
Progesterone receptor 
 PR 
Programmed cell death 1 
 PD-1 
Programmed cell death 1-ligand 
 PD-L1 
Programmed cell death 2-ligand 
 PD-L2 
Progression-free survival 
 PFS 
Recommended phase 2 dose 
 RP2D 
Response criteria in solid tumors 
 RECIST 
Receiver operating characteristic 
ROC 
Serious adverse events 
 SAEs 
Start recruitment date 
 FPI 
Summary of Product Characteristics 
 SmPC 


 
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Thyroid-stimulating hormone 
 TSH 
Treatment emergent adverse event 
 TEAE 
Treatment of physician´s choice 
 TPC 
Triple-negative breast cancer 
 TNBC 
Tumor-infiltrating lymphocytes 
 TILs 
Tumor proportion score 
 TPS 
Type 1 diabetes mellitus 
 T1DM 
Unique patient number 
 UPN 
Upper limit of normal 
 ULN 
US Food and Drug Administration 
 FDA 
White blood cell 
 WBC  
 
 


 
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INDEX 
KEY CONTACT DETAILS ............................................................................................................ 3 
PROTOCOL SYNOPSIS ............................................................................................................... 7 
LIST OF ABBREVIATIONS ........................................................................................................ 17 
1 
STUDY BACKGROUND AND RATIONALE ....................................................................... 27 
1.1 
INTRODUCTION ............................................................................................................................... 27 
1.2 
ANTIMICROTUBULE AGENTS ............................................................................................................... 29 
1.3 
CLINICAL EFFICACY OF ERIBULIN .......................................................................................................... 30 
1.3.1 
Phase I trials ....................................................................................................................... 30 
1.3.2 
Phase II trials ...................................................................................................................... 30 
1.3.3 
Phase III trials ..................................................................................................................... 31 
1.4 
CLINICAL SAFETY OF ERIBULIN ............................................................................................................. 32 
1.4.1 
Neutropenia ........................................................................................................................ 32 
1.4.2 
Peripheral neuropathy ........................................................................................................ 32 
1.4.3 
Hepatotoxicity .................................................................................................................... 33 
1.5 
PROGRAMMED CELL DEATH-1 (PD-1) CHECKPOINT INHIBITION AND CANCER TREATMENT .............................. 33 
1.6 
PRECLINICAL STUDIES WITH PD-1 IMMUNE CHECKPOINT INHIBITORS.......................................................... 33 
1.7 
CURRENT APPROVED INDICATIONS FOR MK3475 (PEMBROLIZUMAB)  AS PER UNITED STATES PRESCRIPTION 
INFORMATION'S .......................................................................................................................................... 34 
1.8 
ROLE OF IMMUNOTHERAPY IN BREAST CANCER ...................................................................................... 34 
1.9 
CLINICAL EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN ER-POSITIVE MBC............................................ 36 
1.10 
CLINICAL SAFETY OF IMMUNE CHECKPOINT INHIBITORS ............................................................................ 36 
1.10.1 
Dermatologic toxicity .......................................................................................................... 37 
1.10.2 
Diarrhea/colitis ................................................................................................................... 37 
1.10.3 
Hepatotoxicity .................................................................................................................... 37 
1.10.4 
Endocrinopathies ................................................................................................................ 37 
1.10.5 
Less common irAEs ............................................................................................................. 37 
1.11 
RATIONALE FOR DOSE SELECTION OF MK3475 (PEMBROLIZUMAB)  AND ERIBULIN ....................................... 38 
1.12 
STUDY RATIONALE ........................................................................................................................... 39 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 39 
2.1 
PRIMARY OBJECTIVE ......................................................................................................................... 39 
2.2 
PRIMARY ENDPOINT ......................................................................................................................... 39 
2.3 
SECONDARY OBJECTIVES .................................................................................................................... 39 
2.4 
SECONDARY ENDPOINTS .................................................................................................................... 40 
2.5 
EXPLORATORY OBJECTIVES ................................................................................................................. 40 


 
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2.6 
EXPLORATORY ENDPOINTS ................................................................................................................. 41 
3 
STUDY DESIGN .................................................................................................................. 41 
3.1 
DESCRIPTION OF STUDY DESIGN .......................................................................................................... 41 
3.2 
PD-L1 STATUS DETERMINATION ......................................................................................................... 42 
3.3 
STUDY SCHEDULE SUMMARY .............................................................................................................. 42 
3.3.1 
Screening phase .................................................................................................................. 42 
3.3.2 
Treatment phase................................................................................................................. 43 
3.3.3 
End of treatment visit ......................................................................................................... 43 
3.3.4 
End of study ........................................................................................................................ 43 
3.3.5 
............................................................................................................ 43 
4 
PATIENT SELECTION ........................................................................................................ 44 
4.1 
STUDY POPULATION ......................................................................................................................... 44 
4.2 
INCLUSION CRITERIA ......................................................................................................................... 44 
4.3 
EXCLUSION CRITERIA ........................................................................................................................ 45 
5 
TREATMENT ....................................................................................................................... 47 
5.1 
FORMULATION, PACKAGING, AND HANDLING ........................................................................................ 47 
5.1.1 
Eribulin ................................................................................................................................ 48 
5.1.2 
MK3475 (pembrolizumab) .................................................................................................. 48 
5.2 
DOSAGE AND ADMINISTRATION .......................................................................................................... 48 
5.2.1 
Eribulin ................................................................................................................................ 48 
5.2.2 
MK3475 (pembrolizumab) .................................................................................................. 49 
5.3 
TREATMENT MODIFICATION ............................................................................................................... 49 
5.3.1 
Modification of the amount of study drug administered due to changes in patient’s weight
 
49 
5.3.2 
Eribulin ................................................................................................................................ 50 
5.3.3 
MK3475 (pembrolizumab) .................................................................................................. 51 
5.3.4 
Supportive care guidelines for MK3475 (pembrolizumab)-related AEs .............................. 56 
5.3.5 
Second Course * .................................................................................................................. 59 
5.3.6 
Chemotherapy extravasation ............................................................................................. 60 
5.4 
GENERAL CONCOMITANT MEDICATION AND ADDITIONAL ASSISTANCE GUIDELINES ......................................... 60 
5.5 
PROHIBITED CONCOMITANT MEDICATIONS ............................................................................................ 61 
5.6 
MEDICATION ERRORS AND OVERDOSE .................................................................................................. 62 
5.7 
TREATMENT COMPLIANCE ................................................................................................................. 62 
6 
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 62 


 
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6.1 
INFORMED CONSENT FORM ............................................................................................................... 62 
6.2 
VISIT SCHEDULE ............................................................................................................................... 63 
6.3 
DEMOGRAPHIC DATA AND MEDICAL HISTORY......................................................................................... 64 
6.4 
EFFICACY ASSESSMENTS .................................................................................................................... 65 
6.4.1 
Tumor and response evaluations ........................................................................................ 65 
6.4.2 
Objective response assessment .......................................................................................... 65 
6.4.3 
OS and PFS definitions ........................................................................................................ 66 
6.4.4 
irRECIST ............................................................................................................................... 66 
6.5 
SAFETY AND TOLERABILITY ASSESSMENTS .............................................................................................. 68 
6.5.1 
Laboratory assessments ..................................................................................................... 68 
6.5.2 
Pregnancy and assessment of fertility ................................................................................ 68 
6.5.3 
Cardiac function monitoring ............................................................................................... 69 
6.5.4 
Physical examination .......................................................................................................... 69 
6.5.5 
Vital signs............................................................................................................................ 69 
6.5.6 
ECOG performance status ................................................................................................... 70 
6.6 
TRANSLATIONAL RESEARCH ................................................................................................................ 70 
6.6.1 
Tumor tissue samples ......................................................................................................... 70 
6.6.2 
Blood samples ..................................................................................................................... 71 
6.6.3 
Storage ............................................................................................................................... 71 
6.7 
.................................................................................................................. 72 
6.8 
DISCONTINUATION OF PATIENT, STUDY, OR SITE PARTICIPATION ................................................................ 72 
6.8.1 
Patient discontinuation ....................................................................................................... 72 
6.8.2 
Study and site discontinuation ............................................................................................ 72 
7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .......................................... 73 
7.1 
AES DEFINITIONS ............................................................................................................................. 73 
7.1.1 
SAEs .................................................................................................................................... 75 
7.1.2 
Events of Clinical Interest (ECI) ........................................................................................... 76 
7.2 
AES REPORTING AND OTHER SAFETY RELATED ISSUES REPORTING .............................................................. 77 
8 
STATISTICAL CONSIDERATIONS AND STATISTICAL ANALYSIS PLAN .................... 80 
8.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................................ 80 
8.2 
STATISTICAL PLAN ............................................................................................................................ 81 
8.2.1 
Primary efficacy endpoint ................................................................................................... 81 
8.2.2 
Secondary efficacy endpoints ............................................................................................. 81 
8.2.3 
Exploratory endpoints ......................................................................................................... 81 
8.2.4 
Analysis sets ........................................................................................................................ 81 


 
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8.2.5 
Analysis of baseline and demographic variables ................................................................ 82 
8.2.6 
Primary efficacy analysis .................................................................................................... 82 
8.2.7 
Decision rules and adjustment of alpha for primary endpoint ........................................... 82 
8.2.8 
Secondary and exploratory analysis ................................................................................... 82 
8.2.9 
Biomarkers analysis ............................................................................................................ 83 
8.3 
SAFETY ANALYSIS ............................................................................................................................. 83 
8.4 
MISSING DATA MANAGEMENT ........................................................................................................... 83 
8.5 
SCIENTIFIC COMMITTEE REVIEW .......................................................................................................... 84 
9 
ETHICAL CONSIDERATIONS ............................................................................................ 84 
9.1 
REGULATORY AND ETHICAL COMPLIANCE .............................................................................................. 84 
9.2 
EC ................................................................................................................................................ 84 
9.3 
INFORMED CONSENT ........................................................................................................................ 85 
9.4 
DATA PROTECTION ........................................................................................................................... 85 
10 ORIGINAL DOCUMENTS, STUDY MONITORING AND QUALITY ASSURANCE ........... 86 
10.1 
SOURCE DATA RECORD ...................................................................................................................... 86 
10.2 
STUDY MONITORING AND SOURCE DATA VERIFICATION ............................................................................ 87 
10.3 
RECORD RETENTION ......................................................................................................................... 87 
10.4 
DATA QUALITY ASSURANCE ................................................................................................................ 88 
11 DATA MANAGEMENT ........................................................................................................ 89 
11.1 
DATA ENTRY AND PROCESSING ........................................................................................................... 89 
11.2 
DATA CLARIFICATION ........................................................................................................................ 89 
11.3 
DATA CODING PROCEDURES ............................................................................................................... 89 
12 STUDY MANAGEMENT ...................................................................................................... 89 
12.1 
STUDY DISCONTINUATION ................................................................................................................. 89 
12.2 
PROTOCOL AMENDMENTS ................................................................................................................. 89 
12.3 
PUBLICATION POLICY AND PROTECTION OF TRADE SECRETS ....................................................................... 90 
12.4 
INSURANCE..................................................................................................................................... 90 
13 REFERENCES ..................................................................................................................... 91 
14 APPENDIX ........................................................................................................................... 93 
Appendix 1: Schedule of study assessments and procedures ............................................................. 93 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Criteria for evaluating 
response in solid tumors ..................................................................................................................... 98 


 
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Appendix 3: Imaging and treatment after first radiologic evidence of disease progression.  Table 
r e presents irRECIST ............................................................................................................................ 99 
 
1 
 
 
2 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
List of tables  
Table 1. Tumor subtype according to St. Gallen 2013 International Expert Consensus ............ 27 
Table 2. Eribulin dose adjustments for hematologic AEs ............................................................ 51 
Table 3. Eribulin dose adjustments for non-hematologic AEs ..................................................... 51 


 
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Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab ................................................................................................. 52 
Table 5. Infusion reactions treatment guidelines......................................................................... 57 
Table 6. ECOG performance status scale .................................................................................. 70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1 
STUDY BACKGROUND AND RATIONALE 
1.1 
Introduction 
Breast cancer is the most common cancer and the second leading cause of cancer death among 
women worldwide. Breast cancer is a heterogeneous disease with multiple clinical presentations 
and tumor characteristics.  
Gene expression profiling studies have classified breast tumors into a number of distinct biological 
and intrinsic subtypes with prognostic and therapeutic implications, thus providing a new 
molecular classification of breast cancer [1]. According to this classification, four main molecular 
subtypes have been identified: luminal A, luminal B, HER2-enriched, and basal-like. In contrast 
to basal-like breast cancers, which do not express estrogen receptor (ER), progesterone receptor 
(PR), and ER-related genes, luminal tumors express luminal cytokeratins and have the highest 
levels of ER expression. On the other hand, HER2-enriched tumors overexpress HER2-
associated genes but do not express genes that define the luminal subtype.  
To distinguish between these molecular subtypes is essential in the clinical practice. Although the 
best way to perform breast tumor intrinsic subtyping is to use microarrays for gene expression 
analysis, molecular profiling is not ready for use in clinical decision-making. Therefore, a 
combination of immunohistochemical surrogate markers, using ER and PR status, HER2 status, 
and Ki67 levels, has been validated for molecular subtyping (Table 1) [2]. However, even though 
there is high agreement between biomarker scoring by protein immunohistochemistry (IHC) and 
gene expression, the concordance is not absolute. In this way, as an example, only around 50% 
of HER2-enriched tumors are ER-negative/HER2-positive by IHC, and approximately 70% of ER-
negative/HER2-positive tumors by IHC are classified as the HER2-enriched subtype [3]. 
 
Table 1. Tumor subtype according to St. Gallen 2013 International Expert Consensus 
Tumor subtype 
Definition 
Luminal A 
ER- and PR-positive  
HER2-negative  
KI67 low (< 20%) 
Recurrence risk ‘low’ based on multi-gene-expression assay 
Luminal B 
Luminal B-like (HER2-negative) 
ER-positive  
HER2-negative  
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PR-negative or low (< 20%) 
or 
KI67 high (≥ 20%) 
or  
Recurrence risk ‘high’ based on multi-gene-expression assay  
Luminal B-like (HER2-positive) 
ER- and HER2-positive 
Basal-like 
ER- and PR-negative 
HER2-negative 
HER2-enriched 
ER- and PR-negative 
HER2-positive 
ER: Estrogen receptor; PR: Progesterone receptor. 
Moreover, recent advances in breast cancer research have allowed the deconstruction of the 
molecular profiles of these breast cancer subtypes [4]. This has led to an increase in treatment 
options, including more personalized therapy and considerable improvements in patient 
outcomes. However, there are only a few targeted therapies approved for metastatic breast 
cancer (MBC), with special focus on the HER2-positive subtype, although several novel targeted 
therapies are currently under evaluation. 
Optimal treatment for patients with MBC is dependent upon the risks and benefits associated with 
each treatment option, as well as with the stage of disease and performance status of each patient 
[5]. Anthracyclines and taxanes are frequently used as (neo) adjuvant therapy, and therefore the 
number of patients previously exposed to these agents by the time they develop MBC is 
increasing. Current available chemotherapeutic options for third-line or later treatment of MBC 
include the vinca alkaloids, gemcitabine, capecitabine, and ixabepilone, as well as new 
formulations of older drugs, such as liposomal anthracyclines and nanoparticle albumin-bound 
paclitaxel. Despite the large number of treatment options, until 2010 in the United States and 2011 
in Europe the only approved monotherapies for late-line treatment of MBC were capecitabine and 
ixabepilone. Capecitabine is approved in the United States and Europe for patients who are 
resistant to both taxane and anthracycline regimens, and for patients who experience taxane 
resistance or in whom anthracycline therapy is not indicated. On the other hand, ixabepilone is 
only approved in the United States for use in combination with capecitabine in patients who do not 
respond to anthracyclines and taxanes, or as a single agent for patients who have failed on 
anthracyclines, taxanes, and capecitabine. 
The management of MBC is complex due to the absence of clear evidence-based guidelines for 
clinicians and the large number of clinical studies developed with several compounds. Moreover, 
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of different cumulative toxicities and development of drug resistance, limiting the current treatment 
options available. Despite these risks, overall survival (OS) in patients with MBC is increasing, and 
many patients with MBC still benefit from three or more lines of treatment [6]. For this reason, 
additional treatment options are needed for heavily pretreated MBC patients. 
 
1.2 
Antimicrotubule agents 
Microtubules are polymers  made  from  proteins called α- and ß-tubulin and are part of the 
cytoskeleton within  the cytoplasm of the cell. In addition to providing structural support, 
microtubules take part in many other cellular processes. During the early stages of mitosis, many 
microtubules increase in length by attachment of more tubulin dimers to one end, and grow out 
from the spindle for long distances (10 
m) into the cell, searching for an unattached 
chromosome. If none is found, the microtubule loses dimers and shrinks again. This expansion and 
retraction is repeated many times until eventually it meets and becomes chemically attached to a 
chromosome. When every chromosome has been captured by a microtubule, they are collected 
into the correct order and are then separated into two halves to divide the cell in two parts. With 
this division, apoptosis is induced. 
The central role of antimicrotubular agents in the treatment of common epithelial cancers is further 
highlighted by their ability to induce remission in patients with classic drug-resistant epithelial 
cancers. Taxanes, vinca alkaloids, and epothilones are all microtubule-targeted agents which bind 
to tubulin with varying affinities and target different binding sites, with subsequent disruption of 
microtubule dynamics [7]. This disruption occurs during mitosis with the induction of G2/M phase 
cell-cycle arrest that eventually leads to cell death by apoptosis. Among these agents, there are 
microtubule-stabilizing (paclitaxel, nab-paclitaxel, docetaxel, and the epothilones, eg, 
ixabepilone) and microtubule-destabilizing drugs (vinca alkaloids, eg, vincristine, vinblastine, 
and vinorelbine). However, current microtubule-targeted treatment is often limited by the 
development of drug resistance and common side effects, frequently based on high incidences 
of chronic peripheral sensory and motor neuropathy, with some studies reporting up to 20–30% 
for patients experiencing grade 3/4 neuropathic symptoms. 
Eribulin mesylate (E7389) is a structurally simplified synthetic analog of the natural marine 
product, halichondrin B, a non-taxane microtubule dynamics inhibitor extracted from the marine 
sponge Halichondria okadai which inhibits microtubules via a novel mechanism of action [8]. 
Eribulin works by binding to microtubule polymerization, without affecting depolymerization, 
and with the additional sequestration of tubulin into nonfunctional aggregates. By inhibiting 
mitotic spindle formation, eribulin causes irreversible mitotic block, which leads to cell cycle 
arrest in the G2/M phase and apoptosis. Moreover, eribulin binds to a limited number of high 
affinity sites at the plus ends of the microtubules, and there is some evidence against its binding 
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mechanistically from other antimicrotubule agents, such as paclitaxel, ixabepilone,  and 
vinblastine. 
Eribulin, which retains the potency of halichondrin B against human cancer cell lines, has a mean 
terminal half-life of 40 hours, and minimal renal excretion have been shown in preclinical studies. 
Although it has been noted that this compound is metabolized by cytochrome P450 (CYP) 3A4, 
preclinical research established that it does not affect the metabolism of other therapeutic agents, 
such as diazepam, paclitaxel, midazolam, or tamoxifen, which are also metabolized by this 
system. Eribulin has shown antiproliferative effects against a broad range of human cancer cell 
lines, including breast, prostate, melanoma, and colorectal cancer, has been associated with 
tumor regression and elimination in a variety of well established human tumor xenograft 
models,and has demonstrated activity against paclitaxel-resistant cell lines, including those with 
mutations in ß-tubulin [9]. 
 
1.3 
Clinical efficacy of eribulin 
1.3.1 
Phase I trials 
Various phase I clinical trials have evaluated eribulin in a variety of dose regimens in patients with 
different types of advanced solid tumors [10, 11]. Briefly, eribulin was administered on days 1, 8, and 15 
of a 28-day cycle in the weekly regimen studies and the maximum tolerated dose (MTD) was reported 
to be 1.4 mg/m2 and 1 mg/m2 (as eribulin mesylate) with further dose escalation limited by 
neutropenia and fatigue. On the other hand, a MTD of 2 mg/m2 as eribulin mesylate was established 
on day 1 of a 21-day cycle schedule with additional dose escalation limited by neutropenia.  
Interestingly, significant antitumor activity was observed in these trials with radiological responses 
and disease stabilizations in several tumor types, with an special interest in breast cancer 
patients. These data led to the initiation of phase II studies in patients with MBC, as well as in 
other types of solid tumors. 
1.3.2 
Phase II trials 
Several phase II studies have assessed the antitumor activity of eribulin in heavely pretreated 
MBC patients. The first study (study 201) was published by Vahdat et al. who investigated the 
efficacy and safety of eribulin in 103 patients with MBC who had received prior treatment with an 
anthracycline and taxanes [12]. Based on the results of previous phase I studies, eribulin mesylate 
1.4 mg/m2 was initially administered as a 2–5-minute intravenous (IV) infusion on days 1, 8, and 15 of 
a 28-day cycle. After an assessment of tolerability data, which indicated that many patients were 
experiencing severe neutropenia on day 15, a protocol amendment was made, and a second 
group of patients received eribulin mesylate 1.4 mg/m2 administered as an IV infusion over 2 to 5 
minutes on days 1 and 8 of a 21-day cycle. In this study, eribulin demonstrated in the per-protocol 
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interval [CI], 5.7–20.1, all partial responses) and achieved a clinical benefit rate (CBR) of 17.2% 
(95%CI, 10.0–26.8). The median duration of response (DoR), median progression-free survival 
(PFS), and median OS were 5.6 months (95%CI, 1.4–11.9), 2.6 months (95%CI, 0.03–14.9), and 
9 months (95%CI, 0.5–27.2), respectively.  
In the second phase II study (study 211), reported by Cortes et al., a total of 291 patients with 
locally advanced disease or MBC who had received prior treatment with anthracyclines, taxanes, 
and capecitabine were included [13]. The patients received eribulin mesylate 1.4 mg/m2 as a 2–5-
minute IV infusion on days 1 and 8 of a 21-day cycle. In this study, eribulin showed an ORR by 
independent review of 9.3% (95%CI, 6.1–13.4, all partial responses) and a CBR of 17.1% (95%CI, 
12.8–22.1). The median DoR, median PFS, and median OS were 4.1 months (95%CI, 1.4–11.9), 
2.6 months (95%CI, 0.03–13.1), and 10.4 months (95%CI, 0.6–19.9), respectively.  
Finally, in other phase II trial, reported by Aogi et al., the safety and efficacy of eribulin was 
investigated in 80 japanese patients with MBC who had previously been treated with an 
anthracycline and a taxane [14]. The study used the same dosing regimen and mode of 
administration as that of the study by Cortes et al. In this study, eribulin demonstrated an ORR by 
independent review of 21.3% (95%CI, 12.9–31.8, all partial responses) and a CBR of 27.5% 
(95%CI, 18.1–38.6). The median DoR, median PFS, and median OS were 3.9 months (95%CI, 
2.8–4.9), 3.7 months (95%CI, range 2–4.4), and 11.1 months (95%CI, range 7.9–15.8), 
respectively. 
1.3.3 
Phase III trials 
The encouraging pharmacokinetic and pharmacodynamic results observed in the phase I trials and 
the antitumor activity without severe adverse events (AEs) objectived in the phase II trials in 
patients with extensively pretreated MBC led to the design of the EMBRACE (Eisai Metastatic 
Breast Cancer Study Assessing Physician’s Choice Versus E7389) phase III randomized trial (also 
known as study 305) [15]. The dosing regimen of the pivotal study [eribulin mesylate at 1.4 
mg/m2 (equivalent to eribulin at 1.23 mg/m2) on days 1 and 8 of a 21-day cycle] was selected 
based on results of two completed phase II studies (study 201 and 202) which were both initiated 
with a dosing regimen of 1.23 mg/m2 eribulin on days 1, 8, and 15 every 28 days. In this trial, a 
total of 762 patients with locally recurrent disease or MBC previously treated with 2–5 prior 
chemotherapy regimens (including anthracyclines and taxanes) were randomly assign (2:1 ratio) 
to receive eribulin or treatment of physicians’ choice (TPC). Randomisation was stratified by 
geographical region, previous capecitabine treatment, and HER2 status. The primary endpoint 
was OS in the intention-to-treat set. Eribulin significantly improved median OS compared with 
TPC (13.1 vs. 10.6 months, HR = 0.81; p = 0.041). Median PFS was 3.7 and 2.2 months (HR = 
0.87; p = 0.14), for the eribulin and TPC groups, respectively. The objective response rate was 
12% in the eribulin group and 5% in the TPC group (p =  0.005). The results of the EMBRACE trial 
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who have received at least two previous chemotherapeutic regimens in the advanced setting, 
including an anthracycline and a taxane. 
A second phase III randomized trial (study 301) compared the efficacy and safety of eribulin with 
capecitabine. In this trial, a total of 1,102 patients with MBC who had received prior anthracycline- 
and taxane-based therapy were randomly assigned (1:1 ratio) to receive eribulin or capecitabine 
as their first-, second-, or third-line chemotherapy for metastatic disease [16]. Stratification factors 
were HER2 status and geographic region. Coprimary endpoints were OS and PFS. Median OS 
was 15.9 and 14.5 months (HR = 0.88; p = 0.056), for the eribulin and capecitabine groups, 
Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR = 
1.08; p = 0.30). Objective response rates were 11% for eribulin and 11.5% for capecitabine. 
Based on the results of this study, eribulin is currently indicated in Europe for the treatment of 
patients with locally advanced or MBC who have progressed after at least one chemotherapeutic 
regimen for advanced disease, including an anthracycline and a taxane in either the adjuvant or 
metastatic setting unless patients were not suitable for these treatments. 
 
1.4 
Clinical safety of eribulin 
The most commonly reported adverse reactions related to eribulin are bone marrow suppression 
manifested as neutropenia, leucopenia, anemia, and thrombocytopenia. New onset or worsening 
of pre-existing peripheral neuropathy has also been described in patients treated with eribulin. 
Gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhea, constipation, and 
stomatitis are among reported undesirable effects. Other adverse effects include fatigue, 
alopecia, increased liver enzymes, sepsis, and musculoskeletal pain syndrome [17]. 
1.4.1 
Neutropenia  
Neutropenia observed with eribulin was reversible and not cumulative; the mean time to nadir 
was 13 days and the mean time to recovery from severe neutropenia was eight days. Neutropenia 
was reported as a Treatment Emergent Adverse Event (TEAE) in 902/1,559 (57.9% for all grades) 
in the breast cancer population. However, neutropenia resulted in discontinuation in only < 1% of 
patients receiving eribulin.  
Although the incidence is very low (< 1%), fatal cases of febrile neutropenia, neutropenic sepsis, 
sepsis, and septic shock have been reported with eribulin.  
Severe neutropenia may be managed by the use of granulocyte-colony stimulating factors (G-
CSF) or equivalent at the physician’s discretion in accordance with relevant guidelines.  
1.4.2 
Peripheral neuropathy  
In the 1,559 breast cancer patients, the most common adverse reaction resulting in treatment 
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peripheral neuropathy was 12.6 weeks. Development of grade 3 or 4 peripheral neuropathy 
occurred in 7.4% of breast cancer patients.  
In clinical trials, patients with pre-existing neuropathy were as likely to develop new or worsening 
symptoms as those who entered the study without this condition. In breast cancer patients with 
pre-existing grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent grade 3 
peripheral neuropathy was 14%.  
1.4.3 
Hepatotoxicity  
In some patients with normal/abnormal liver enzymes prior treatment with eribulin, increased 
levels of liver enzymes have been reported with initiation of eribulin treatment. Such elevations 
appeared to have occurred with eribulin treatment in the first two cycles for the majority of these 
patients. This hepatotoxicity is probably due to a phenomenon of adaptation to eribulin treatment 
by the liver and not a sign of significant liver toxicity in most patients. 
 
1.5 
Programmed cell death-1 (PD-1) checkpoint inhibition and cancer treatment 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades. Extensive evidence has demonstrated a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and prognosis in several tumor types.  
The PD-1 receptor-ligand interaction is critical to suppress immune control. The normal function 
of PD-1, expressed on the cell  surface of activated T cells under healthy conditions, is to down-
modulate excessive immune responses. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4, which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [18]. Binding of PD-L1 
to PD-1 inhibits T cell activation triggered through the T cell receptor in peripheral tissues, 
whereas PD-L2 is thought to control immune T cell activation in lymphoid organs.  
PD-L1 and PD-L2 are constitutively expressed or can be induced in a variety of cell types, and 
their interaction with the PD-1 receptor on tumor-specific T cells, plays a decisive role in immune 
evasion by tumors. As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in cancer. 
 
1.6 
Preclinical studies with PD-1 immune checkpoint inhibitors 
Preclinical data from mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction increases infiltration of tumor-specific CD8-positive T cells and finally guides 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities [19, 
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Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses in 
models of squamous cell carcinoma, pancreatic carcinoma, melanoma, breast carcinoma, acute 
myeloid leukemia, and colorectal carcinoma, among others. In these studies, tumor infiltration by 
CD8-positive T cells and increased interferon (IFN)-γ, granzyme B, and perforin expression were 
observed, reflecting that the principal mechanism that probably justify the antitumor activity of PD-
1 checkpoint inhibition involved local infiltration and activation of effector T cell function in vivo.  
 
1.7 
Current approved indications for MK3475 (pembrolizumab)  as per United States 
prescription information's 
MK3475 (pembrolizumab)  is a potent and highly selective humanized monoclonal antibody of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. Pembrolizumab is indicated for the treatment of: 
• 
Patients with unresectable or metastatic melanoma.  
• 
Patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high 
PD-L1 expression [tumor proportion score (TPS) ≥ 50%] as determined by a food and 
drug administration (FDA)-approved test, with no epidermal growth factor receptor 
(EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and no prior 
systemic chemotherapy treatment for metastatic NSCLC.  
• 
Patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%) as determined 
by an FDA-approved test, with disease progression on or after platinum-containing 
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have 
disease progression on FDA-approved therapy for these aberrations prior to receiving 
MK3475 (pembrolizumab). 
• 
Patients with recurrent or metastatic head and neck squamous cell carcinoma with 
disease progression on or after platinum-containing chemotherapy. This indication is 
approved under accelerated approval based on tumor response rate and durability of 
response. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in the confirmatory trials. 
 
1.8 
Role of immunotherapy in breast cancer 
Several lines of evidence support the use of immunotherapy in breast cancer, mainly in triple-
negative breast cancer (TNBC) patients, such as the heterogeinity of this tumor subtype, the 
presence of high PD-L1 expression levels, the role of TILs, and emerging clinical data with 
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In 2011, Lehmann et al. identified six TNBC subtypes including two basal-like, a mesenchymal, 
a mesenchymal stem-like, a luminal androgen receptor, and an immunomodulatory subtype 
[21]. This immunomodulatory subtype is characterized by an elevated expression of immune 
genes suggesting that some patients may benefit from immune-based therapies. Moreover, PD-
L1 expression is higher in breast cancer cell lines bearing a basal-like phenotype as compared 
with luminal subtype, and high PD-L1 expression levels have been associated with negative 
prognostic features such as large tumor size, high grade, ER- and PR-negative status, HER2-
positive status, high proliferation, and basal and HER2-enriched subtypes [22, 23]. 
In addition, over recent years, a large amount of data has also revealed the importance of TILs 
in controlling the clinical progression of various epithelial cancers. In breast cancer, TILs are 
significantly more frequent in TNBC and several studies have addressed the prognostic impact 
of TILs in this tumor subtype in the (neo) adjuvant setting. In patients with primary TNBC, TILs 
have been associated with a more favorable outcome in two adjuvant phase III trials, as well as 
with a higher likelihood of pCR to neoadjuvant chemotherapy [24-26].  
Finally, four phase I studies have evaluated the antitumor activity of MK3475 (pembrolizumab)  
(anti-PD-1), atezolizumab (anti-PD-L1) (alone or in combination with chemotherapy), and 
avelumab (anti-PD-L1) in patients with advanced TNBC. 
The KEYNOTE-012 was a multicenter, non-randomized, and multicohort phase Ib trial of single-
agent MK3475 (pembrolizumab). In the TNBC cohort with PD-L1 expression (≥ 1% in tumor cells), 
a total of 32 heavily pretreated patients were enrolled and assessed for safety and antitumor 
activity (58.6% of screened patients had PD-L1-positive tumors) [27]. Patients received MK3475 
(pembrolizumab)  at 10 mg/kg every two weeks until disease progression or unacceptable toxicity. 
Among the 27 patients who were evaluable for antitumor activity, ORR was 18.5%, the median 
time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median DoR has not yet 
been reached (range, 15.0 to ≥ 47.3 weeks). 
A phase I study also assessed the efficacy of atezolizumab in TNBC patients [28]. A total of 54 
extensively pretreated patients were included irrespective of PD-L1 expression (69% of patients 
tested positive for PD-L1 expression as defined as PD-L1 expression in ≥ 5% of immune cells). 
Among 21 evaluable patients, who were PD-L1-positive, ORR was 19% with a median DoR not 
yet reached (range, 18.0 to 56 weeks). Atezolizumab has also been evaluated in a phase I trial 
in combination with different chemotherapy regimens. The safety and efficacy of the combination 
of atezolizumab and nab-paclitaxel was assessed in a cohort of 32 patients with advanced TNBC. 
Confirmed ORR was 41.7% (66.7% in first-line, 25% in second-line, and 28.6% in subsequent 
lines) [29]. 
Finally, another phase I study evaluated the antitumor activity of avelumab in 168 patients with 
MBC refractory to standard therapy and unselected for PD-L1 expression [30]. Overall, tumor 
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observed in eight patients for an ORR of 4.8%. The median time to response was 11.4 weeks 
(range, 5.7-17.7) and the median DoR was 28.7 weeks. Among TNBC patients, ORR was 8.6% 
(5 of 58). However, in patients with TNBC who had PD-L1-positive immune cells within the tumor, 
44.4% (4 of 9) had a partial response, compared with 2.6% (1 of 39) for TNBC and PD-L1-
negative immune cells. 
 
1.9 
Clinical efficacy of immune checkpoint inhibitors in ER-positive MBC 
Although the presence of TILs and PD-L1 expression is less common in the luminal subtype than 
in TNBC, patients with ER-positive/HER2-negative tumors represent a considerable proportion of 
PD-L1-positive tumors given their high prevalence. Interestingly, PD-L1 expression has been 
detected in circulating tumor cells from patients with luminal breast cancer, and preliminary data 
with immune checkpoint inhibitors have been recently reported in this tumor subtype [31]. 
The KEYNOTE-028 was a multicenter, non-randomized, and multicohort phase Ib trial evaluating 
MK3475 (pembrolizumab)  in patients with PD-L1–positive advanced solid tumors. The breast 
cancer cohort from KEYNOTE-028 included a total of 25 heavily pretreated patients with ER-
positive/HER2-negative MBC with PD-L1 expression (≥ 1% in tumor cells) [32]. Patients received 
MK3475 (pembrolizumab)  at 10 mg/kg every two weeks for up to 24 months or until disease 
progression or unacceptable toxicity. At a median follow-up of 7.3 months, ORR was 12% and 
CBR was 20%. The median time to response was 8 weeks and the median DoR has not yet been 
reached (range, 8.7 to > 44 weeks). 
Avelumab has also been evaluated in advanced ER-positive/HER2-negative breast cancer 
patients in the phase I study mentioned above [30]. Of 168 patients included, 42.9% had ER-
positive/HER2-negative tumors. ORR was only 2.8% in this tumor subtype.  
It is not clear the reasons for why these results varied, including differences in the assays used 
to measure PD-L1 levels, or simply differences depending whether we are targeting the receptor, 
PD-1, as is done with MK3475 (pembrolizumab) , or the ligand, as is done with avelumab.  
 
1.10 Clinical safety of immune checkpoint inhibitors 
Fatigue is the most common side effect observed with immune checkpoint inhibitors, with an 
estimated overall frequency around 20% percent for the anti-PD-1 and anti-PD-L1 agents. 
However, the most relevant toxicities in clinical practice associated with these agents are 
immune-related AEs (irAE) [33]. 


 
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1.10.1 Dermatologic toxicity 
Skin toxicity is the most common irAE related to immune checkpoint inhibitors, and approximately 
30-40% of patients treated with anti-PD-1 and anti-PD-L1 agents will develop dermatologic 
complications. This toxicity usually is the earliest irAE, with a median time to onset of 3.6 weeks 
after treatment initiation. Typical physical examination findings consist of a reticular and 
maculopapular erythematous rash on the trunk or extremities. Severe rashes such as Stevens-
Johnson syndrome/toxic epidermal necrolysis have been also reported in rare cases. 
1.10.2 Diarrhea/colitis 
Diarrhea is a common clinical AE in patients undergoing treatment with immune checkpoint 
inhibitors. The onset of this toxicity occurs later than dermatologic toxicity, approximately six 
weeks after treatment initiation. Diarrhea of any grade has been reported in approximately 10-
20% of patients treated with these agents, although grade 3 and 4 immune-mediated colitis has 
been seen in only 1-2% of cases. Potential risk of gastrointestinal perforation should be taken into 
consideration on patients with immune-related colitis. 
1.10.3 Hepatotoxicity 
Elevations in serum levels of the hepatic enzymes, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), have been observed with anti-PD-1 and anti-PD-L1 agents in less than 
5% of patients with grade 3 and 4 events being extemely rare. Most episodes are asymptomatic 
laboratory abnormalities, but occasionally patients have an associated fever. Increases in total 
and direct bilirubin are exceptional, and usually ocurr in association with a prolonged period of 
AST and ALT elevations. The most frequent time of onset is around two or three months after 
initiation of treatment, although early or delayed events may also be seen. 
1.10.4 Endocrinopathies 
Inflammation of the pituitary, thyroid, or adrenal glands as a result of checkpoint blockade often 
presents with imprecise symptoms such as nausea, headache, fatigue, and vision changes. 
Although it has been difficult to establish the exact incidence of endocrinopathies associated with 
these compounds, clinically significant events are thought to occur in less than 5-10% of patients 
treated with anti-PD-1 and anti-PD-L1 agents. The most common endocrinopathies are 
hypophysitis and autoimmune thyroid disease, principally primary hypothyroidism secondary to a 
destructive thyroiditis. Hyperthyroidism associated with Graves disease and adrenal insufficiency 
have also been reported with these compounds. 
1.10.5 Less common irAEs 
Other less common immune-related toxicities have been attributed to anti-PD-1 and anti-PD-L1 
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• 
Nephritis (renal insufficiency, granulomatous interstitial nephritis, and lupus membranous 
nephropathy). 
• 
Respiratory complications (sarcoidosis, pneumonitis, and organizing inflammatory 
pneumonia). 
• 
Eye disorders (episcleritis, conjunctivitis, uveitis, or ophthalmopathy associated with 
Graves disease). 
• 
Pancreatic alterations [assymptomatic elevated levels of serum amylase and lipase and 
type 1 diabetes mellitus (T1DM)]. 
• 
Neurologic syndromes (myasthenia gravis, Guillain-Barre syndrome, posterior reversible 
encephalopathy syndrome, aseptic meningitis, enteric neuropathy, and transverse 
myelitis). 
• 
Hematologic disorders (red cell aplasia, neutropenia, and thrombocytopenia). 
 
1.11 Rationale for dose selection of MK3475 (pembrolizumab)  and eribulin 
Although the dose of MK3475 (pembrolizumab)  approved for treatment of melanoma subjects is 
2 mg/kg every three weeks, and the dose of MK3475 (pembrolizumab)  studied in the clinical 
trials KEYNOTE-012 and KEYNOTE-028 was 10 mg/kg every two weeks, the dose planned to 
be used in this trial is 200 mg every three weeks. This is because recent studies in other tumor 
types have indicated that 10 mg/kg every two weeks and 200 mg every three weeks are likely to 
be similar with regard to efficacy and tolerability.  
Accordingly, this flat dose is also being used in the phase Ib/II study that is evaluating the safety 
and antitumor activity of MK3475 (pembrolizumab)  and eribulin in 95 patients with advanced 
TNBC refractory to standard therapy and unselected for PD-L1 expression (NCT02513472). 
Preliminary data from the first 39 patients evaluable for efficacy in this trial have been recently 
reported. No dose-limiting toxicities were observed in phase 1b [34]. The recommended phase II 
dose (RP2D) of this combination was defined at eribulin 1.23 mg/m2 on days 1 and 8 of every 21-
day cycle and MK3475 (pembrolizumab)  200 mg on day 1 of each 21-day cycle. Among the 
evaluable analysis set, ORR was 33.3% and CBR was 41%, with no significant differences 
according to PD-L1 status. AEs observed with this combination were comparable to those 
reported historically with either treatment as monotherapy. 
 


 
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1.12 Study rationale 
Significant antitumor activity of anti-PD-1 and anti-PD-L1 agents, alone and in combination with 
chemotherapy, has been reported in patients with advanced TNBC. 
Preliminary data with MK3475 (pembrolizumab)  in refractory ER-positive/HER2-negative and 
PD-L1-positive MBC patients have shown promising antitumor activity, resulting in response rates 
practically similar to those observed with the best chemotherapy agents used in this setting. 
However, no data are available so far with anti-PD-1 and anti-PD-L1 agents in combination with 
chemotherapy in this tumor subtype. 
In order to determine if immunotherapy in combination with chemotherapy could benefit this 
population, this multicenter, open-label, phase II clinical trial will evaluate the efficacy and safety 
of the combination of MK3475 (pembrolizumab)  and eribulin in hormone receptor (HR)-
positive/HER2-negative MBC patients previously treated with anthracyclines and taxanes. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary objective 
To assess the efficacy -as determined by the CBR (total number of objective responses plus 
stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab)  in 
combination with eribulin in patients with HR-positive/HER2-negative MBC who have previously 
received an anthracycline and a taxane (for either early or advanced disease), unless 
contraindicated, and between one to two lines of chemotherapy in the metastatic setting.  
 
2.2 
Primary endpoint  
CBR based on RECIST v.1.1. 
 
2.3 
Secondary objectives  
• To determine the CBR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• To determine the PFS based on RECIST v.1.1. 
• To determine the PFS based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• To determine the OS (OS will be collected at the end of the study). 
• To determine the OS in subjects with PD-L1 positive tumors. 
• To determine the ORR based on RECIST v.1.1. 
• To determine the ORR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 


 
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• To determine the DoR based on RECIST v.1.1. 
• To determine the DoR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• To assess the safety and tolerability of MK3475 (pembrolizumab)  in combination with 
eribulin according to the US National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0.3. 
 
2.4 
Secondary endpoints  
• CBR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• PFS based on RECIST v.1.1. 
• PFS based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• OS (OS will be collected at the end of the study). 
• OS in subjects with PD-L1 positive tumors. 
• ORR based on RECIST v.1.1. 
• ORR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• DoR based on RECIST v.1.1. 
• DoR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
• Safety. 
 
2.5 
Exploratory objectives  
 
 
 
 
 
  
 
 
 
 


 
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2.6 
Exploratory endpoints  
• 
 
• 
 
• 
 
 
3 
STUDY DESIGN 
3.1 
Description of study design 
This is a multicenter, open-label, phase II clinical trial to evaluate the efficacy and safety of the 
combination of MK3475 (pembrolizumab)  and eribulin in HR-positive/HER2-negative MBC 
patients previously treated with anthracyclines and taxanes. 
The study population consists of female patients age ≥ 18 years with advanced HR-
positive/HER2-negative breast cancer who have received at least one, but not more than two, 
prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. 
Prior therapy must have included an anthracycline and a taxane in any combination or order and 
either in the early or metastatic disease setting unless contraindicated for a given patient. 
Previous anti-hormonal therapy in the metastatic disease setting is mandatory.  
In the absence of disease progression or unacceptable toxicity, treatment with MK3475 
(pembrolizumab)  and eribulin will continue based on physician criteria. MK3475 (pembrolizumab)  
and eribulin may be discontinued for toxicity independently of each other in the absence of 
disease progression.  
A participant must be discontinued from study treatment but continue to be monitored in the study 
for any of the following reasons: 
• 
 Completion of 35 treatments (approximately 2 years) with pembrolizumab. Please see 
the specific conditions at section 5.3.5. 
 
Note: The number of treatments is calculated starting with the first dose.  Participants who stop 
the combination or pembrolizumab after receiving 35 doses may be eligible for retreatment if they 
progress after stopping study treatment provided they meet the requirements detailed in section 
5.3.5. Participants may be retreated in the Second Course Phase (Retreatment) for up to an 
additional 17 cycles (approximately 1 year). 
After 35 dose administrations, patients can continue on treatment with eribulin alone.  
 
Tumor assessments per RECIST v.1.1 (see Appendix 2) and irRECIST (see Appendix 3) will 
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weeks (± 7 days) thereafter until disease progression, treatment discontinuation, the start of new 
anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs 
first. Tumor assessments will be performed on the specified schedule regardless of treatment 
delays. 
For estimation of ORR, CBR, DoR, PFS, and OS, tumor response will be based on RECIST v.1.1 
(see Appendix 2). In patients who continue treatment beyond radiographic disease progression 
per RECIST v.1.1, tumor response (ORR and PFS) may continue to be assessed using irRECIST 
criteria (see Appendix 3) until study treatment discontinuation. 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory 
abnormalities graded per the NCI CTCAE v.4.0.3. Laboratory safety assessments will include the 
regular monitoring of hematology, blood chemistry, coagulation, pregnancy test, and thyroid 
function testing. A schedule of assessments is provided in Appendix 1. 
 
3.2 
PD-L1 status determination 
Tumor lesion will be retrospectively evaluated at a central laboratory for PD-L1 expression by IHC 
from a newly obtained core or excisional biopsy of a metastatic tumor lesion not previously 
irradiated (highly recommended). An archived metastatic tumor specimen may be submitted only 
upon agreement from the Sponsor in patients for whom tumor biopsies cannot be obtained. 
PD-L1 positivity will be defined as PD-L1 expression in ≥ 1% tumor cells or in stroma for the 
purposes of this study. 
 
3.3 
Study schedule summary 
The study will consist of a 28-days screening phase, a treatment phase, and a post-treatment 
phase (end of treatment visit and end of study) that includes safety, efficacy, and survival follow-
up. 
3.3.1 
Screening phase 
During this phase, subject eligibility is determined, including the documentation of baseline 
characteristics. This phase of the study will begin once the informed consent is signed by the 
patient and the procedures to be performed are described in Section 6 of the protocol. 
One re-screening is allowed in patients that are screening failure in this study. Patient has to re-
consent Informed Consent Form (ICF) before any study procedure is done. 


 
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3.3.2 
Treatment phase 
Patients will receive study treatment according to the protocol and will be discontinued if one of 
the following situations arises: 
• 
AEs which, according to the protocol or in the opinion of the Investigator, can cause 
serious or permanent damage or which rule out further treatment with the study drug. 
• 
Disease progression is confirmed radiologically and unequivocally assesed according to 
the RECIST criteria version 1.1 and/or irRECIST. 
• 
Major study protocol non-compliance. 
• 
Patient’s withdrawal from the study. 
• 
Death. 
• 
Study is canceled by the Sponsor. 
• 
Completion of 35 treatments (approximately 2 years) with pembrolizumab. Please see 
section 5.3.5 of the protocol for the specific conditions. 
Note: The number of treatments is calculated starting with the first dose.  Participants who stop 
the combination or pembrolizumab after receiving 35 doses may be eligible for retreatment if they 
progress after stopping study treatment provided they meet the requirements detailed in section 
5.3.5. Participants may be retreated in the Second Course Phase (Retreatment) for up to an 
additional 17 cycles (approximately 1 year). 
After 35 dose administrations, patients can continue on treatment with eribulin alone.  
 
3.3.3 
End of treatment visit 
End of treatment visit is within 30 days after the last dose of study treatment.  
3.3.4 
End of study 
The end of study visit will be 12 months after last study dose in the first course of pembrolizumab 
phase treatment, or after the last study dose in the second course in all patients. 
During this visit, status survival and post study anti-cancer therapy evaluation will be collected 
(telephone contact is acceptable).  
LPLV: 12 months after last study dose or progressive disease experienced in all patients or when 
the trial is terminated by the Sponsor, whichever is earlier. 
3.3.5 
 
 
 
 


 
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4 
PATIENT SELECTION 
The following eligibility criteria can be used in the screening of patients for whom the protocol 
treatment is deemed suitable. In order to determine whether this protocol is suitable for a given 
patient, all medical and non-medical criteria should be taken into consideration. 
 
4.1 
Study population 
Female patients age ≥ 18 years with advanced HR-positive/HER2-negative breast cancer 
previously treated with anthracyclines and taxanes. 
The patient’s signed informed consent should be obtained before any trial related activities and 
according to local guidelines. 
4.2 
Inclusion criteria 
Patient eligibility will be reviewed and documented by a suitable member of the Investigator’s 
study team before the patients are enrolled in the study. 
Patients must meet ALL the following inclusion criteria to be enrolled in the study: 
1. Written informed consent prior to beginning specific protocol procedures. 
2. Female patients ≥ 18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which 
the Investigator believes is stable at the time of screening. 
4. Life expectancy ≥ 12 weeks. 
5. Patients have a histologically and/or cytologically confirmed diagnosis of breast cancer. 
6. Patients have radiologic evidence of inoperable locally recurrent or MBC. 
7. Patients have HER2-negative breast cancer (based on most recently analyzed biopsy) 
defined as a negative in situ hybridization (ISH) test or an IHC status of 0, 1+, or 2+ (if 
IHC 2+, a negative ISH test is required) by local laboratory testing. 
8. Patients have HR-positive breast cancer defined as ER and/or PR with >1% of tumor 
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9. Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or 
excisional biopsy since last progression of a metastatic tumor lesion not previously 
irradiated.  
Note: Subjects for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or 
subject safety concern) may submit an archived metastatic tumor specimen only upon 
agreement from the Sponsor. 
10. Patients have measurable disease based on RECIST v.1.1 as assessed by site 
Investigator and local radiology review. 
11. Patients have received at least one, but not more than two, prior chemotherapeutic 
regimens for locally recurrent and/or metastatic disease. Prior therapy must have 
included an anthracycline and a taxane in any combination or order and either in the early 
or metastatic disease setting unless contraindicated for a given patient. Prior anti-
hormonal therapy in the metastatic disease setting is mandatory.  
12. Patients have adequate bone marrow and organ function as defined by the following 
laboratory values: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.  
• 
Platelets ≥ 100 x 109/L. 
• 
Hemoglobin ≥ 9 g/dL. 
• 
Potassium, calcium (corrected for serum albumin), and magnesium within normal 
limits for the institution. 
• 
Serum creatinine ≤ 1.5 x upper limit of normal (ULN). 
• 
AST and ALT ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver metastases are present).  
• 
Total serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are 
present). Patients with known Gilbert disease who have serum bilirubin ≤ 3 x ULN 
may be enrolled. 
13. Patients must be accessible for treatment and follow-up. 
 
 
 
4.3 
Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from the study: 
1. Patients have received previous treatment with eribulin and an/or anti-PD1 or anti-PD-L1 
agents. 
2. Patients have a known hypersensitivity to any of the excipients of MK3475 
(pembrolizumab)  or eribulin. 
3. Patients who have received chemotherapy, targeted small molecule therapy, or 
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4. Patients who have received monoclonal antibodies for direct antineoplastic treatment or 
an investigational agent/device within four weeks of first dose of study treatment. 
5. Patients have known active central nervous system (CNS) metastases and/or  
carcinomatous meningitis. 
Note: Known brain metastases are considered active, if any of the following criteria is 
applicable: 
a. Brain imaging during screening demonstrates progression of existing metastases 
and/or appearance of new lesions compared to brain imaging performed at least 
four weeks earlier. 
b. Neurological symptoms attributed to brain metastases have not returned to 
baseline. 
c. Steroids were used for brain metastases within 28 days of first dose of study 
treatment. 
6. Patients have peripheral neuropathy grade 2 or more. 
7. Patients have a concurrent malignancy or malignancy within five years of study inclusion 
(with the exception of adequately treated basal or squamous cell skin carcinoma or 
curatively resected cervical cancer). 
8. Patients have not recovered to grade 1 or better (except alopecia) from related side 
effects of any prior antineoplastic therapy. 
9. Patients have had a major surgical procedure within 28 days prior to starting study drug. 
10. Patients have an active cardiac disease or a history of cardiac dysfunction including any 
of the following: 
• 
Unstable angina pectoris or documented myocardial infarction within six months 
prior to study entry. 
• 
Symptomatic pericarditis. 
• 
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV). 
• 
Patients have a left ventricular ejection fraction (LVEF) < 50% as determined by 
multiple gated acquisition (MUGA) scan or echocardiogram (ECHO). 
11. Patients have any of the following cardiac conduction abnormalities: 
• 
Ventricular arrhythmias except for benign premature ventricular contractions. 
• 
Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled 
with medication. 
• 
Conduction abnormality requiring a pacemaker.  
• 
Other cardiac arrhythmia not controlled with medication.  


 
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12. Uncontrolled hyper/hypothyroidism or T1DM. Patients with hypothyroidism stable on 
hormone replacement will not be excluded from the trial. Patients with controlled T1DM 
on a stable insulin regimen may be eligible for this study. 
13. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic steroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
14. Prior allogenic stem cell or solid organ transplantation. 
15. Active/history of pneumonitis requiring treatment with steroids or active/history of 
interstitial lung disease. 
16. Active uncontrolled infection at the time of screening.  
17. Active tuberculosis. 
18. Current known infection with HIV. 
19. Active hepatitis B (HBV) [patients with negative hepatitis B surface antigen (HBsAg) test 
and a positive antibody to HBsAg (anti-HBsAg) test at screening are eligible] or hepatitis 
C (HCV) [patients with a positive antibody to hepatitis C (anti-HCV) are eligible only if 
polymerase chain reaction (PCR) is negative for virus hepatitis C RNA]. 
20. Patients have any other concurrent severe and/or uncontrolled medical condition that 
would, in the Investigator’s judgment contraindicate patient participation in the clinical 
study. 
21. Treatment with systemic steroids (standard premedication for chemotherapy/contrast 
reactions and local applications are allowed) or another immunosuppressive agent within 
seven daysprior to study treatment initiation. 
22. Has received  live vaccines within 30 days prior to first dose of study treatment.  
23. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, are not allowed to participate in this study unless they are using 
highly effective methods of contraception during dosing and up to 120 daysafter study 
drugs discontinuation. 
 
5 
TREATMENT 
5.1 
Formulation, packaging, and handling 
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies department and 
bear a label with the identification required by local law, the protocol number, drug identification, 


 
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and dosage. The packaging and labeling of the study drug will be in accordance with Sponsor 
standards and local regulations. Local packaging in some countries may be different. 
The study drug must be stored according to the details on the Product Information. The drug label 
indicates the storage temperature. Upon arrival of investigational products at the site, site 
personnel should check them for damage, verify proper identity, quantity, integrity of seals, and 
temperature conditions, and report any deviations or product complaints upon discovery. 
5.1.1 
Eribulin 
Eribulin will be supplied as a clear and colourless aqueous solution for injection provided in glass 
vials containing 2 ml.. Each 2 ml vial contains eribulin mesylate equivalent to 0.88 mg eribulin. 
The other ingredients are ethanol and water for injections, with hydrochloric acid and sodium 
hydroxide possibly present in very small amounts. 
5.1.2 
MK3475 (pembrolizumab)  
MK3475 (pembrolizumab)  will be supplied directly as a solution for infusion in a single-use vial. 
MK3475 (pembrolizumab)  solution for infusion is a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for IV infusion. Each vial 
contains 100 mg of MK3475 (pembrolizumab)  in 4 ml of solution. Each 1 ml of solution contains 
25 mg of MK3475 (pembrolizumab)  and is formulated in: L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
 
5.2 
Dosage and administration 
The medicinal products should be administered sequentially on day 1 of each cycle (every three 
weeks) as follows: MK3475 (pembrolizumab)  first followed immediately by eribulin. Eribulin will 
also be administered alone on day 8 of each cycle. 
5.2.1 
Eribulin 
The recommended dose of eribulin as the ready to use solution is 1.23 mg/m2 (equivalent to 
eribulin mesylate at 1.4 mg/m2) which should be administered intravenously over 2 to 5 minutes 
on days 1 and 8 of every 21-day cycle. 
Please note: In the European Union the recommended dose refers to the base of the active 
substance (eribulin). Calculation of the individual dose to be administered to a patient must be 
based on the strength of the ready to use solution that contains 0.44 mg/ml eribulin and the dose 
recommendation of 1.23 mg/m2. The dose reduction recommendations shown below are also 
shown as the dose of eribulin to be administered based on the strength of the ready to use 
solution. In the pivotal trials, the corresponding publications and in some other regions e.g., the 


 
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United States and Switzerland, the recommended dose is based on the salt form (eribulin 
mesylate). 
5.2.2 
MK3475 (pembrolizumab)   
The recommended dose of MK3475 (pembrolizumab)  is 200 mg administered as a 30-minute IV 
infusion on day 1 of each 21-day cycle. Sites should make every effort to target infusion timing to 
be as close to 30 minutes as possible. A window of -5 minutes/+10 minutes is allowed. 
 
5.3 
Treatment modification 
Safety and tolerability of all patients will be closely monitored throughout study treatment and the 
follow-up period using the NCI CTCAE v.4.0.3. Patients will be assessed in order to detect any 
AEs before administering new study treatment during each treatment visit. Treatment will only be 
administered if clinical evaluation and local laboratory test results are acceptable.  
If, in the opinion of the Investigator, a toxicity is considered to be due solely to one component of 
the study treatment (e.g., MK3475 (pembrolizumab)  or eribulin) and the dose of that component 
is delayed or modified in accordance with the guidelines below, the other component may be 
administered if there is no contraindication. When treatment is temporarily interrupted because of 
toxicity caused by MK3475 (pembrolizumab)  or eribulin, the treatment cycles will be restarted 
such that the MK3475 (pembrolizumab)  and eribulin infusions remain synchronized. Patients who 
have both treatments withheld for more than 21 days must discontinue study treatment and are 
considered off study. Patients whose treatment is interrupted or permanently discontinued due to 
an AE, including abnormal laboratory value, must be followed until resolution or stabilization of 
the event, whichever comes first, which includes all study assessments appropriate to monitor 
the event. 
 
5.3.1 
Modification of the amount of study drug administered due to changes in patient’s 
weight 
MK3475 (pembrolizumab)  is administered as a fixed dose irrespective of the patient´s body 
weight.  
The amount of eribulin is calculated according to the patient’s body surface area (BSA). Weight 
and height should be recorded at baseline and the BSA calculated, thereafter at every scheduled 
visit for all patients should be re-weighed. The amount to be administered must be recalculated if 
the patient’s body weight has changed by > 10% (increased or decreased) from baseline. Re-
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5.3.2 
Eribulin 
Dose delay: The administration of eribulin should be delayed on day 1 or day 8 of each cycle for 
any of the following: 
• 
ANC < 1 x 109/L complicated or not by fever or infection. 
• 
Platelets < 75 x 109/L. 
• 
Grade 3 or 4 non-hematologic toxicities. 
Retreatment following treatment interruption for toxicity may not occur until all of the following 
parameters have been met: 
• 
ANC ≥ 1 x 109/L and no fever. 
• 
Platelets ≥ 75 x 109/L. 
• 
Grade 3 or higher non-hematologic AEs have recovered to grade ≤ 1 or baseline (or, at 
the Investigator’s discretion, grade ≤ 2 if not considered a safety risk for the patient). 
Dose reduction: Dose reduction recommendations for eribulin retreatment are shown in the 
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Table 2. Eribulin dose adjustments for hematologic AEs 
Adverse reaction after previous eribulin administration 
Recommended dose 
of eribulin 
ANC < 0.5 x 109/L lasting more than 7 days 
0.97 mg/m2 
ANC < 1 x 109/L neutropenia complicated by 
fever or infection 
Platelets < 25 x 109/L  
Platelets < 50 x 109/L and complicated by haemorrhage 
or requiring platelet transfusion 
Reoccurrence of any hematologic adverse reactions 
as specified   above 
Despite dose reduction to 0.97 mg/m2 
0.62 mg/m2 
Despite dose reduction to 0.62 mg/m2 
Consider 
Absolute neutrophil count: ANC. 
 
Table 3. Eribulin dose adjustments for non-hematologic AEs 
Adverse 
reaction 
after 
previous 
eribulin 
administration
Recommended dose of 
eribulin
Any grade 3 or 4 in the previous cycle 
0.97 mg/m2 
Reoccurrence of any non-hematologic adverse 
reactions as specified above 
Despite dose reduction to 0.97 mg/m2 
0.62 mg/m2 
Despite dose reduction to 0.62 mg/m2 
Consider discontinuation 
 
Do not re-increase the dose of eribulin after it has been reduced. 
 
5.3.3 
MK3475 (pembrolizumab)  
AEs (both non-serious and serious) associated with MK3475 (pembrolizumab)  exposure may 
represent an immunologic etiology. These AEs may occur shortly after study treatment initiation 
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for certain drug-related toxicities and severe or life-threatening AEs as per Table 4 below. Dose 
reduction of MK3475 (pembrolizumab)  is not permitted. 
MK3475 (pembrolizumab)  should be permanently discontinued: 
• 
For grade 4 toxicity except for endocrinopathies that are controlled with replacement 
hormones. 
• 
If steroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 
12 weeks. 
• 
If a treatment-related toxicity does not resolve to grade 0-1 within 12 weeks after last 
dose of MK3475 (pembrolizumab) . 
• 
If any event occurs a second time at grade ≥ 3 severity (also for recurrent grade 2 
pneumonitis). 
 
 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and 
continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be 
resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve 
within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first 
followed by oral steroid. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids. 
 
Immune-
related 
AEs 
Toxicity 
grade or 
condition
s 
(CTCAEv
4.0) 
Action 
taken to 
pembroliz
umab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumon
itis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor participants for 
signs and symptoms of 
pneumonitis 
• 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
Grade 3 
or 4, or 
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recurrent 
Grade 2 
discontinu
e 
and initiate corticosteroid 
treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
Diarrhea / 
Colitis  
Grade 2 
or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
• 
Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis.  
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion. 
Grade 4 
Permanent
ly 
discontinu
e 
AST / 
ALT 
elevation 
or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 0.5- 
1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable 
Grade 3 
or 4  
Permanent
ly 
discontinu
e 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
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Type 1 
diabetes 
mellitus 
(T1DM) 
or 
Hypergly
cemia 
 
Newly 
onset 
T1DM or  
Grade 3 
or 4 
hyperglyc
emia 
associate
d with 
evidence 
of -cell 
failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophy
sitis 
Grade 2 
Withhold 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
• 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 
or 4  
Withhold 
or 
permanent
ly 
discontinu
e1  
Hyperthyr
oidism  
Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 
or 4  
Withhold 
or  
permanent
ly 
discontinu
e1 
Hypothyr
oidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis 
and 
Renal 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of renal 
function 
 
Grade 3 
or 4  
Permanent
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dysfuncti
on 
discontinu
e 
Myocardit
is 
Grade 1 
or 2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 
or 4 
Permanent
ly 
discontinu
e 
All other 
immune-
related 
AEs 
Intolerable
/ 
persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE 
administer 
corticosteroids  
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 
Withhold 
or 
discontinu
e based on 
the type of 
event.  
Events 
that 
require 
discontinu
ation 
include 
and not 
limited to:  
Gullain-
Barre 
Syndrome, 
encephaliti
s 
Grade 4 
or 
recurrent 
Grade 3  
Permanent
ly 
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1. Withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of 
pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ 
Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM).   
 
5.3.4 
Supportive care guidelines for MK3475 (pembrolizumab)-related AEs 
Pneumonitis: Steroids should be administered for grade ≥ 2 events (initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper continued over no less than four weeks). MK3475 
(pembrolizumab)  should be withheld for grade 2 pneumonitis, and permanently discontinued for 
grade 3, grade 4, or recurrent grade 2 pneumonitis. Consider adding prophylactic antibiotics for 
opportunistic infections in the case of prolonged steroid administration. 
Diarrhea/colitis: Subjects should be carefully monitored for signs and symptoms of enterocolitis 
such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever. The potential 
risk of gastrointestinal perforation should be taken into consideration.  
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via 
IV infusion.  
Steroids should be administered for grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone 
or equivalent followed by a taper continued over no less than four weeks). MK3475 
(pembrolizumab)  should be withheld for grade 2 or 3 colitis, and permanently discontinued for 
grade 4 colitis. 
T1DM (if new onset) or hyperglycemia: Insulin should be administered for T1DM and 
hyperglycemia, and MK3475 (pembrolizumab)  should be withheld in cases of grade 3 or 4 
hyperglycaemia until metabolic control is achieved. MK3475 (pembrolizumab)  will be resumed 
when subjects are clinically and metabolically stable. 
Hypophysitis: Steroids should be administered for grade ≥ 2 events (initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper continued over no less than four weeks). 
Replacement of appropriate hormones should be administered as clinically indicated, and 
MK3475 (pembrolizumab)  should be withheld for symptomatic hypophysitis until the event is 
controlled with hormone replacement.  
Hepatotoxicity: Steroids should be administered [initial dose of 0.5-1 mg/kg/day (for grade 2 
events) and 1-2 mg/kg/day (for grade 3 or 4 events) prednisone or equivalent followed by a taper 
continued over no less than four weeks]. MK3475 (pembrolizumab)  should be withheld for grade 


 
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2 immune-related hepatitis, and permanently discontinued for grade 3 or 4 immune-related 
hepatitis. 
Renal failure or nephritis: Steroids should be administered for grade ≥ 2 events (initial dose of 
1-2 mg/kg/day prednisone or equivalent followed by a taper continued over no less than four 
weeks). MK3475 (pembrolizumab)  should be withheld for grade 2 immune-related nephritis, and 
permanently discontinued for grade 3 or 4 immune-related nephritis. 
Hyperthyroidism or hypothyroidism: Hypothyroidism may be managed with replacement 
therapy without treatment interruption and without steroids. Hyperthyroidism must be managed 
symptomatically and steroids should be administered for grade ≥ 2 events (initial dose of 1-2 
mg/kg/day prednisone or equivalent followed by a taper continued over no less than four weeks). 
MK3475 (pembrolizumab)  should be withheld for grade 2 hyperthyroidism, and permanently 
discontinued for grade 3 or 4 hyperthyroidism. 
Management of infusion reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of 
infusion.Treatment guidelines for subjects who experience an infusion reaction associated with 
administration of MK3475 (pembrolizumab)  are described in Table 5. 
 
Table 5. Infusion reactions treatment guidelines 
NCI CTCAE v.4.0.3 grade 
Treatment 
Premedication at 
subsequent dosing 
 
Grade 1 
 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the Investigator 
 
None 
 
Grade 2 
 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, and IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours 
 
Stop infusion and monitor 
symptoms. Additional 
appropriate medical therapy 
may include but is not limited 
to: Antihistamines, NSAIDS, 
acetaminophen, narcotics, 
and IV fluids. 
 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the Investigator. 
 
Subject may be 
premedicated 1.5 
hours (± 30 minutes) 
prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 
mg orally (or 
equivalent dose of 
antihistamine) 
 
Acetaminophen 500-
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NCI CTCAE v.4.0.3 grade 
Treatment 
Premedication at 
subsequent dosing 
 
If symptoms resolve within 
one hour of stopping drug 
infusion, the infusion may be 
restarted at 50% of the 
original infusion rate (e.g., 
from 100 ml/hour to 50 
ml/hour). Otherwise, dosing  
will be held until symptoms 
resolve and the subject 
should be premedicated for 
the next scheduled dose. 
 
Subjects who develop grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
equivalent dose of 
antipyretic) 
 
Grades 3- 4 
Grade 3 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates). 
 
Grade 4 
Life-threatening; pressor or 
ventilatory support 
indicated. 
Stop infusion and monitor 
symptoms. Additional 
appropriate medical therapy 
may include but is not limited 
to: Antihistamines, NSAIDS, 
acetaminophen, narcotics, IV 
fluids, oxygen pressors, 
steroids, and epinephrine. 
 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the Investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
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Common terminology criteria for adverse events: CTCAE; Intravenous: IV; National Cancer 
Institute: NCI; Non-steroidal anti-inflammatory agents: NSAIDS. 
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
 
5.3.5 Second Course * 
All participants who stop study treatment with SD or better may be eligible for up to an additional 
17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping study 
treatment from the initial treatment phase.  This retreatment is termed the Second Course Phase 
of this study and is only available if the study remains open and the participant meets the following 
conditions: 
Either 
• 
Stopped initial treatment with study treatment after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and 
o 
Was treated with at least 8 cycles of study treatment before discontinuing treatment, 
and 
o 
Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared 
OR 
• 
Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability 
AND 
• 
Experienced 
an 
investigator-determined 
radiographic 
disease 
progression 
by 
RECIST 1.1 after stopping initial treatment, and 
o 
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o 
The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and 
o 
The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for a 
participant will not be counted as an event for the primary analysis of either endpoint in this study. 
 
5.3.6 
Chemotherapy extravasation 
As a general recommendation, in the event of extravasation, the following advice should be 
considered: 
• 
Stop the infusion immediately. 
• 
Do not remove the needle or cannula. 
• 
Aspirate with the same needle as much infiltrated drug as possible from the subcutaneous 
site. 
• 
Apply ice to area for 15 to 20 minutes every four to six hours for the first 72 hours. 
• 
Paint the skin over the extravasated site with 100% DMSO (or hyaluronidase) four  times 
daily for two weeks. 
Watch the area closely during the following days in order to determine whether a surgical excision 
and skin graft is necessary 
 
5.4 
General concomitant medication and additional assistance guidelines 
Concomitant treatment and prior medication are defined as non-investigational medicinal product 
(IMP). Concomitant treatment includes any prescribed medication or phytotherapy between the 
28 days prior to the administration of the first treatment dose and the last safety visit during 
treatment period. All concomitant treatments will be recorded. After this time, information will only 
be collected on any anti-cancer drugs taken by the patient until end of study. 
Information on concomitant medication will include start date, end date, brand or generic name, 
route of administration, dose, and treatment indication. The following concomitant treatments are 
permitted during the study: 
• 
Erythropoiesis-stimulating agents (ESA) (such as Procrit®, Aranesp®, Epogen®) for the 
supportive treatment of anemia. Blood transfusions are permitted during the study. 
• 
The prophylactic use of G-CSF is not allowed during the first treatment cycle, but can be 
used for cases of neutropenia arising during treatment, in accordance with the National 
Comprehensive Cancer Network (NCCN) guidelines.  


 
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• 
Bisphosphonates and denosumab for the prevention of skeletal events.  
• 
Prophylactic or therapeutic anticoagulation therapy such as low-molecular weight heparin 
or warfarin at a stable dose level. 
• 
Mineralcorticoids (e.g., fludrocortisone). 
• 
Medications for the treatment of diarrhea, nausea, anorexia, or vomiting. 
• 
Any medications deemed necessary to ensure patient safety and well-being may be 
administered at the discretion of the Investigator with the excepcion of prohibited 
therapies contained in Section 5.5. 
 
5.5 
Prohibited concomitant medications 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
phase of this trial: 
• 
Immunotherapy not specified in the protocol. 
• 
Chemotherapy not specified in the protocol. 
• 
Endocrine therapy. 
• 
Radiation therapy. 
Note: Radiation therapy is allowed during screening, as long as it is completed at least two weeks 
prior to first dose of study treatment, and may be allowed to treat a symptomatic bone lesion or 
the brain after consultation with Sponsor. 
• 
Herbal supplements. 
• 
Live vaccines within 30 days prior to first dose of study treatment and while participating 
in the trial. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella, herpes zoster, yellow fever, rabies, BCG, and typhoid 
(oral) vaccines. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines, and are not allowed. 
• 
Immunosupresive agents within seven days prior to first dose of study treatment. 
• 
Steroids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  
Note: The use of physiologic doses of steroids (≤ 10 mg prednisone daily) is allowed and does 
not require Sponsor consultation. 
Note: The use of systemic steroids to premedicate patients for whom computerized tomography 
(CT) scans with contrast are contraindicated is allowed. Magnetic resonance imaging (MRI) of 


 
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abdomen and pelvis with a non-contrast CT scan of the chest may also  be performed in these 
patients. 
Note:  Local applications and inhaled steroids for management of asthma.are allowed.  
Subjects who, per Investigator’s assessment, require any of the aforementioned medications for 
clinical management should be discontinued from study treatment. There are no prohibited 
therapies during the post-treatment follow-up phase. 
 
5.6 
Medication errors and overdose 
Medication errors in this study may arise when the drug is administered at the wrong time or when 
the wrong dose strength is taken. Patient medication errors should be recorded on the relevant 
section in the case report form (CRF). In the event of an error in the administration of the 
medication, the Sponsor should be informed immediately. 
Medication errors must be reported irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the IMP. 
• 
Any possible medication errors or use of the medication not defined in the protocol which 
implicate the participating patient or not. 
Regardless of whether the medication error is accompanied by an AE or not, in the judgment of 
the Investigator, the medication error should be recorded in the dose administration record page 
(DAR). 
5.7 
Treatment compliance 
Patients will receive treatment under physician supervision. Personnel will check the 
administration volume and total administered dose. The administered dose of each treatment will 
be recorded in the source data and the appropriate CRF. 
 
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Informed consent form  
Written informed consent from the patient must be signed before performing any study procedure. 
However, tumor assessments available and performed as part of clinical practice prior to 
obtaining informed consent and within 28 days prior to treatment start may be used; 
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By giving their consent, patients will be informed as to the nature of the study drug and will receive 
pertinent information regarding the study objectives, possible benefits, and potential AEs. They 
will also receive information on the follow-up procedures and possible risks they will be exposed 
to. This document also informs patients about how biological samples will be obtained and 
collected and its legal implications. After receiving the document, the patient will read it (or receive 
information verbally before witnesses) and will sign the previously approved informed consent. 
The patient will receive a signed copy of the informed consent. The patient can withdraw her 
consent and discontinue the study, this will not affect any future medical treatment. One re-
screening is allowed in patients that are screening failure in this study. Patient has to re-consent 
ICF before any study procedure is done. 
At inclusion: 
• 
The Sponsor will request the patient’s demographic and clinical data related to screening 
criteria. . 
• 
Each patient will be given a Unique Patient Number (UPN) for this study, provided by the 
Sponsor. All data will be recorded in the appropriate CRF using this identification number. 
This number will be provided to the central laboratory to ensure traceability of study 
samples. 
Confirmation of patient’s eligibility for study participation will be recorded on the CRF. The 
Investigator is responsible for safeguarding patient information (e.g., age, name, address, 
telephone number, social security number, and study identification number), ensuring access to 
this information by HAs if necessary. These records will remain confidential for the period of time 
stipulated by current legislation.  
 
6.2 
Visit schedule  
All screening tests and evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria within 28 days prior to the first administration of study medication (dosing).  
Tumor assessments available and performed as part of clinical practice prior to obtaining 
informed consent and within 28 days prior to treatment start may be used; such evaluations do 
not need to be repeated for screening. 
The Investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
Visits are organized in programmed cycles of 21 days (if there are no delays in treatment owing 
to the occurrence of an AE). All visits must occur within ± 2 working days (± 1 working day in day 
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Assessments scheduled for day 1 (before treatment) of all cycles must be performed within 48 
hours prior to study treatment administration and day 8 (before treatment) of all cycles must be 
performed within 24 hours prior to study treatment administration,  unless otherwise indicated in 
the schedule of assessments, to confirm to the patient if treatment can be followed up. If a 
mandatory procedure described in the protocol falls on a bank holiday and/or weekend, this 
procedure should be performed on the day before or after the holiday (i.e. within a period of ± 2 
working days). The summary of all study assessments are included in Appendix 1. 
Day 8 visits can be omitted, at the Investigator’s discretion,in those patients that permanently 
discontinue eribulin treatment and continue with pembrolizumab as single agent. 
End of treatment visit (EOT) will be performed within 30 days after last study dose and End of 
Study Visit (including survival status and post-study anticancer therapy evaluation) will take place 
12 months after last study dose in the First Course of pembrolizumab phase treatment (± 14 
days). Telephone contact is acceptable.  
Participants who are eligible for retreatment/crossover with pembrolizumab (as described in 
Section 5.3.5) may have up to two EOT visits, one after the Initial Treatment Period and one after 
the Second Course Treatment. 
Participants who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 5.3.5 will move to the Second Course Phase when they experience disease 
progression. The same visits and evaluation calendar of the First Course will be followed during 
the Second Course Phase. 
Follow-up visits 
A follow up visit is required  as per protocol to be performed to patients that finish the First Course 
Phase and are candidates to enter to the Second Course Phase of re-treatment with 
pembrolizumab, once disease progression is confirmed. A eCRF page will have to be completed 
in order to confirm the progression date.  The tumor evaluation performed to confirm the 
progression disease before entering the Second Course Treatment will also be recorded at the 
eCRF. 
During the period between the First and Second Course phases, it is highly recommended to 
perform safety follow up visits every 6 weeks and efficacy assessments every 12 weeks. 
However, patient’s follow up during this period will be done as per local practice and at the 
Investigator criteria.    
6.3 
Demographic data and medical history 
Demographic data include age, sex, and self-reported race/ethnicity. Medical history comprises 
clinically significant diseases, surgical interventions, history of cancer (including prior 
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as any medications (e.g., prescribed drugs, over-the-counter drugs, medicinal plants, 
homeopathic remedies, or food supplements) used by the patient in the 28 days prior to screening 
visit.  
6.4 
Efficacy assessments 
6.4.1 
Tumor and response evaluations 
All measurable and evaluable lesions should be assessed and documented at the screening visit 
and re-assessed at each subsequent tumor evaluation. Tumor assessments will be performed at 
screening, every 9 weeks (± 7 days) for the first 12 months following first dose of study treatment, 
and every 12 weeks (± 7 days) thereafter until disease progression, treatment discontinuation, 
withdrawal of consent, the start of new anticancer treatment, death, or study termination by the 
Sponsor, whichever occurs first. The same radiographic procedures and technique must be used 
throughout the study for each patient. 
Radiologic imaging performed during the screening period should consist of 1) CT scan of the 
chest, abdomen, and pelvis (MRI of the abdomen and pelvis with a non-contrast CT scan of the 
chest in patients for whom CT scans with contrast are contraindicated), 2) bone scan if a subject 
has a known history of bone metastases or has new bone pain during screening, and 3) any other 
imaging studies as clinically indicated by the treating physician [brain imaging during the trial 
should be performed in subjects with known brain metastases (every nine weeks for first year, 
then every 12 weeks) and those with worsening and/or new neurological symptoms].   
Tumor assessments performed after the screening period should consist of 1) CT scan of the 
chest, abdomen, and pelvis (MRI of the abdomen and pelvis with a non-contrast CT scan of the 
chest in patients for whom CT scans with contrast are contraindicated), 2) bone scan if a subject 
develops new or worsening symptoms or if the site believes they have attained a complete 
response, and 3) any other imaging studies felt to be clinically indicated by the treating physician. 
All known sites of disease documented at screening should be re-assessed at each subsequent 
tumor evaluation.  
After disease progression by RECIST v.1.1, if the site Investigator determines the subject is 
clinically stable and will benefit from continued treatment, the subject will then be managed by 
irRECIST as described in Section 6.4.4 of the protocol. 
6.4.2 
Objective response assessment 
CBR is defined as the proportion of the subjects in the analysis set who have a complete 
response, partial response, and stable disease using RECIST v.1.1 for at least 24 weeks. 
ORR is defined as the proportion of the subjects in the analysis set who have a complete response 
or partial response based on RECIST  v.1.1: 


 
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• 
Complete response: Complete disappearance of all targets lesions. Any pathological 
lymph nodes (target or non-target) must have reduction in short axis to < 10 mm. 
• 
Partial response: At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.  
• 
Stable disease: Neither sufficient shrinkage to qualify for partial response, nor sufficient 
increase to qualify for disease progression, taking as reference the smallest sum 
diameters while on study. 
• 
Disease progression: At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum diameters while on study. The development of new, 
previously undetected lesions, is also considered progression. 
DoR is defined as the time from documentation of tumor response until disease progression or 
death from any cause. 
6.4.3 
OS and PFS definitions 
OS is defined as the time from first dose of study treatment to death due to any cause. Subjects 
without documented death at the time of the final analysis will be censored at the date of the last 
follow-up.  
PFS is defined as the time from first dose of study treatment to the first documented disease 
progression based on RECIST v.1.1 or death due to any cause, whichever occurs first. 
6.4.4 
irRECIST 
Immunotherapeutic agents such as MK3475 (pembrolizumab)  may induce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns observed 
with these compounds may be different to the typical time course of responses seen with classical 
cytotoxic agents, and can manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Standard RECIST v.1.1 may, therefore, not provide a 
precise response assessment of immunotherapeutic agents such as MK3475 (pembrolizumab) . 
irRECIST is RECIST v.1.1 adapted to account for the unique tumor response seen with 
immunotherapeutic agents. In this way, in subjects who have initial evidence of radiological 
disease progression by RECIST v.1.1, it is at the discretion of the Investigator whether to continue 
a subject on study treatment until repeat imaging is obtained. Subjects may receive study 
treatment and tumor asessment should be repeated at least four weeks later in order to confirm 
disease progression by irRECIST. Any subject deemed clinically unstable should be discontinued 
from trial treatment at first
 
radiologic evidence of disease progression and is not required to have 
repeat imaging for disease progression confirmation. Clinical stability is defined as the following: 
• 
Absence of symptoms and signs indicating clinically significant disease progression, 
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• 
No decline in ECOG performance status. 
• 
Absence of rapid progression of disease. 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
In determining whether or not the tumor burden has increased or decreased per irRECIST, the 
local site Investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s). Scenarios where disease progression is confirmed at repeat imaging if any of the 
following occur by irRECIST: 
• 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir. 
• 
Non-target disease resulting in initial disease progression is worse (qualitative assessment). 
• 
New lesion resulting in initial disease progression is worse (qualitative assessment). 
• 
Additional new lesion(s) since last evaluation. 
• 
Additional new non-target progression since last evaluation. 
 
If repeat imaging confirms disease progression due to any of the scenarios listed above, subjects 
will be discontinued from study therapy. If repeat imaging does not confirm disease progression 
by irRECIST and the subject continues to be clinically stable, treatment may continue and follow 
the regular imaging schedule. 
 
Note: If a subject with confirmed radiographic progression per irRECIST, but the subject is 
achieving a clinically meaningful benefit, and there is no further increase in the tumor burden at 
the confirmatory tumor imaging, an exception to continue treatment may be considered following 
consultation with the Sponsor. In this case, if treatment is  continued,  tumor imaging  should  
continue  to  be  performed  following  the  intervals  as  outlined  in Appendix 1. 
Note: In subjects who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
following  the  intervals  as  outlined  in Appendix 1 until the start of new anti-cancer treatment, 
disease progression, death, or the end of the study, whichever occurs first. 
 


 
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6.5 
Safety and tolerability assessments 
 
6.5.1 
Laboratory assessments 
Laboratory tests will be performed in accordance to local standard treatment and clinical 
indications. These values will include:  
• 
Hematological test [hemoglobin, hematocrit, red blood cell count, platelet count, white 
blood cell (WBC) with differential count (ANC, lymphocytes, monocytes, eosinophils and 
basophils)], coagulation, chemistry with renal function analysis (serum creatinine), liver 
function [AST, ALT, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), 
total and direct bilirubin], glucose, sodium, potassium, calcium, chloride, magnesium, uric 
acid, total protein, albumin, and lactate dehydrogenase. 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood). 
• 
Thyroid function testing [thyroid-stimulating hormone (TSH), free T3, and free T4]. 
• 
HIV serology. 
• 
HBV serology [HBsAg, anti-HBsAg]. 
• 
HCV serology (anti-HCV). In patients with a positive anti-HCV, HCV RNA detection and 
quantification by PCR will be additionally performed. 
6.5.2 
Pregnancy and assessment of fertility 
MK3475 (pembrolizumab)  and eribulin may have adverse effects on a fetus in utero. Only female 
patients of childbearing potential must undergo a pregnancy test at screening (serum pregnancy 
test within 14 days before Cycle 1, Day 1) to confirm eligibility in the trial and thereafter every two 
cycles (cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.)  (urine pregnancy test) and at EOT visit. 
In case an additional pregnancy test is indicated during the trial, a serum test should be performed.  
Post-menopausal status is defined as: 
• 
Prior bilateral oophorectomy. 
• 
Age ≥ 60 years. 
• 
Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, 
tamoxifen, toremifen, or ovarian suppression), and with a documented estradiol level in 
the postmenopausal range according to local institutional/laboratory standard. 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use a highly 
effective, non-hormonal form of contraception (such as surgical sterilization, total abstinence or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or two effective forms of 
non-hormonal contraception, or are considered highly unlikely to conceive (post-menopausal; not 


 
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heterosexually active for the duration of the study) [35]. The following non-hormonal methods of 
contraception are acceptable: 
• 
Condom with spermicidal foam/gel/film/cream/suppository. 
• 
Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository. 
Subjects should start using birth control from screening throughout the study period up to 120 
days after the last dose of treatment with MK3475 (pembrolizumab) . 
In case of pregnancy, the patient must permanently stop study treatment immediately, withdraw 
from the trial, and the pregnancy must be reported within 24 hours to the Sponsor. The site will 
contact the subject at least monthly and documented the subject´s status until the pregnancy has 
been completed or terminated. The outcome of pregnancy will be reported to the Sponsor without 
delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or newborn). 
The study Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. 
6.5.3 
Cardiac function monitoring 
Cardiac function monitoring will consist of LVEF measurement, standard 12-lead ECG, and 
cardiac signs or symptoms collection. All patients must have a standard 12-lead ECG and an 
LVEF measurement of at least 50% by (preferably) ECHO or MUGA scan, a maximum of 28 days 
prior to first dose of study treatment. Additional LVEF assessments or ECGs can be performed if 
clinically are indicated. 
6.5.4 
Physical examination 
A complete physical examination will include an examination of head, eyes, ears, nose, and 
throat, breast and locoregional lymph nodes, as well as cardiovascular, dermatological, 
musculoskeletal, respiratory, digestive, genitourinary, and neurological systems. A limited 
physical exam will consist of a symptom-directed physical examination.  
Changes to abnormalities identified during the baseline period should be recorded at all 
subsequent physical examinations. New or worsening abnormalities should be recorded as AEs, 
if applicable. 
6.5.5 
Vital signs 
These will include the measurement of height (only during screening), weight, respiratory rate, 
heart rate, blood pressure, and body temperature. Abnormal or significant changes in vital signs 
from baseline should be recorded as AEs, if appropriate. 


 
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6.5.6 
ECOG performance status 
Performance status will be determined using the ECOG performance status scale (see Table 6). 
Wherever possible, the patient’s performance status should always be assessed by the same 
personnel throughout the study. 
Table 6. ECOG performance status scale 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead. 
(http://www.ecog.org/general/perf_stat.html) 
 
6.6 
Translational research 
The molecular study involves the collection, processing, temporary storage, and shipment of 
samples from consenting patients enrolled in centers selected for participation in the study. The 
study plan includes collection and initial processing of tumor tissues and blood samples to the 
central laboratory of Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), that will be used 
to identify dynamic biomarkers that may be predictive of response to MK3475 (pembrolizumab)  
and eribulin treatment.   
Since the identification of new markers that correlate with disease activity and the efficacy or 
safety of treatment is rapidly developing, the definitive list of analyses remains to be determined, 
but may include determination of markers of tumor genesis pathways or mechanisms of response 
to immunotherapies. 
6.6.1 
Tumor tissue samples 
Tumor samples from the metastatic tumor (biopsy) will be collected for analysis of PD-L1 status 
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prediction (gene expression profiles and mutational profile through a genes’ panel study will be 
evaluated).  
Formalin-fixed paraffin-embedded (FFPE) tissue biopsies will be analyzed for PD-L1 expression 
by IHC at a central laboratory from a newly obtained core or excisional biopsy since last 
progression of a metastatic tumor lesion not previously irradiated.  
PD-L1 positivity will be defined as PD-L1 expression in ≥ 1% tumor cells or in stroma for the 
purposes of this study. 
For PD-L1 evaluation, it would be preferable to use the FFPE blocks. 
Subjects for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety 
concern) may submit an archived metastatic tumor specimen only upon agreement from the 
Sponsor. An archival tumor block or 30 slides can be submitted to the central lab (IMIM- Institut 
Hospital del Mar d’Investigacions Mèdiques). 
6.6.2 
Blood samples 
Three blood (plasma and serum) samples for translational study will be obtained at each time 
point; at screening, every three cyles of treatment (Cycle 4 day 1, cycle 7 day 1, Cycle 10 day 1, 
etc), and at the end of the study treatment in the first course in order to monitor the mutations 
detected in tumor samples.  
- 
One sample (approx. 8-10 mL) will be collected in a non-EDTA, SST gel containing tube 
(biochemistry) for serum processing. 
- 
Two samples (approx. 8 mL) will be collected in Cell-free DNA BCT tubes (STRECK) for 
plasma processing. 
The processing of blood samples at the participating centers will be performed according to the 
protocol described into the laboratory manual (in a separate document). 
6.6.3 
Storage 
Sample collection, storage, distribution, and destination Samples (tumor tissue and blood 
samples for the translational research will be sent to a central sample storage facility 
(MARBiobanc) located at IMIM (Hospital del Mar Medical Research Institute, Barcelona). These 
samples will be used for the analysis planned in the study. In addition, as scientific discoveries 
could happen in the future, samples collected now could be useful for future studies.  
For this reason, if the patient consents, samples not used on the analysis planned in the present 
study will be maintained in a research line collection. In this case, patient’s samples can be used 
for future research in breast cancer for analysis not strictly related to the objectives of the current 
research, sensivity to cancer or other diseases.  
Samples will be maintained up to 15 years. When (or before) the 15-year period ends, patient’s 
samples will be either destroyed or transferred to a biobank. The biobank to be used in this study 


 
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(MARBiobanc) is a public non-profit organization that gathers various biological samples 
collections for biomedical research purposes. 
 
6.7 
 
 
 
 
 
  
 
 
 
 
6.8 
Discontinuation of patient, study, or site participation 
6.8.1 
Patient discontinuation 
Patients have the right to withdraw from the study at any time for any reason. The Investigator 
also has the right to withdraw patients from the study in the event of intercurrent illness, AEs, and 
treatment failure after a prescribed procedure, protocol violation, administrative reasons, or for 
other reasons. An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Should a patient decide to withdraw, all efforts should be made to complete and report the 
observations as thoroughly as possible. The Investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as completely as possible 
the reason for the withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made with an explanation of why the patient is withdrawing from the study. If the reason 
for removal of a patient from the study is an AE, the principal specific event will be recorded on 
the CRF. 
In the case that the patient decides to prematurely discontinue study treatment, she should be 
asked if she can still be contacted for further information. The outcome of that discussion should 
be documented in both the medical records and in the CRF. 
6.8.2 
Study and site discontinuation 
The Sponsor reserves the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 


 
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• 
The incidence or seriousness of AEs in this or other studies indicates a potential health 
risk to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
• 
Excessively slow recruitment. 
• 
Poor protocol adherence. 
• 
Non-compliance with the International Conference on Harmonization (ICH) guideline for 
Good Clinical Practice (GCP). 
 
7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording protocol-defined AEs,)events of 
Clinical Interest (ECI), and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to competent authorities, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonization (ICH) guidelines, , and/or local regulatory 
requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the study drug(s) to the regulatory agencies and competent 
authorities within seven calendar days after being notified of the event. The Sponsor or its 
designee will report other relevant SAEs associated with the use of the study medication to the 
appropriate competent authorities (according to local guidelines), investigators, by a written safety 
report within 15 calendar days of notification. 
7.1 
AEs definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IMP, regardless of whether it is considered related to the IMP or 
not. 
An abnormal test finding should only be reported as an AE if meets any of the following criteria: 


 
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• 
Is associated with accompanying symptoms and a general diagnostic term, including the 
symptoms and the abnormal test finding, cannot be defined. 
• 
Requires additional diagnostic testing or medical/surgical intervention, leads to a change 
in study drug(s) dosing or discontinuation from the study. 
• 
Needs additional concomitant drug treatment. 
• 
Is considered to be an AE by the investigator or by the Sponsor. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE 
 
The causal relationship between an AE and the IMP will be defined as follows: 
• 
Unrelated: The temporal association between the AE and the administration of the IMP 
makes a causal relationship unlikely, or the subject/patient’s clinical state or the study 
procedure/conditions provide a sufficient explanation for the AE. 
• 
Related: The temporal association between the AE and the administration of the IMP 
makes a causal relationship possible, and the subject/patient’s clinical state or the study 
procedure/conditions do not provide a sufficient explanation for the AE. 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP. 
The descriptions and grading scales found in the revised NCI CTCAE v.4.0.3 will be utilized for 
all toxicity reporting. A copy of the NCI CTCAE v.4.0.3 can be downloaded from the CTEP 
website: (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_5x7.pdf).  
The intensity (severity) of an AE will be recorded as one of the following:  
• 
Mild-easily tolerated: It does not interfere with normal daily activities. CTCAE grade 1. 
• 
Moderate: It causes some interference with daily activities; may require intervention or 
treatment. CTCAE grade 2. 
• 
Severe: Normal daily activities are substantially impaired; hospitalization and/or 
intervention or treatment is required. CTCAE grade 3 or 4. 
• 
Fatal-death. CTCAE grade 5. 
• 
Not applicable: Clinically significant and asymptomatic laboratory test abnormalities or 
abnormal assessments, for which no CTCAE grading guidance is applicable but which 
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A mild, moderate, or severe AE may or may not be serious (see definition below). These terms 
are used to describe the intensity of a specific AE. However, a severe AE (such as severe 
headache) may be of relatively minor medical significance and is not necessarily serious. For 
example, nausea lasting several hours may be rated as severe, but may not be clinically serious. 
Fever of 39°C that is not considered severe may become serious if it prolongs hospital discharge 
by a day. Seriousness rather than severity serves as a guide for defining regulatory reporting 
obligations. 
 
7.1.1 
SAEs 
Per definition, a SAE is defined as any AE that either: 
• 
Results in death (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening (i.e., the AE, in the view of the investigator, places the subject/patient 
at immediate risk of death when it occurs). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person ability to conduct normal life functions). 
• 
Constitutes a congenital anomaly/birth defect (in a neonate/infant born to a mother 
exposed to the investigational product(s). 
Definition of life-threatening: An AE is life-threatening if the subject/patient was at immediate risk 
of death from the event as it occurred, i.e. does not include an event that might have caused 
death if it had occurred in a more serious form. For instance, drug induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life-threatening even though drug 
induced hepatitis can be fatal. 
Definition of hospitalization: AEs requiring hospitalization should be considered serious. In 
general, hospitalization means that the subject/patient has been detained (usually involving an 
overnight stay) at the hospital or emergency ward for observation and/or treatment which would 
not have been appropriate at the study site. When in doubt as to whether hospitalization occurred 
or was necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, do not need to be notified according to immediate reporting criteria. If anything untoward is 
reported during any procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
According to immediate reporting criteria, a hospitalization or prolongation of hospitalization in 
the absence of a precipitating clinical AE, do not need to be notified. Some examples include: 


 
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• 
Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (i.e., for work-up of persistent 
pre treatment lab abnormality). 
• 
Social admission (i.e., subject/patient has no place to sleep). 
• 
Administrative admission (i.e., for yearly physical examination). 
• 
Protocol-specified admission during a study (i.e., for a procedure required by the study 
protocol). 
• 
Optional admission not associated with a precipitating clinical AE (i.e., for elective 
cosmetic surgery). 
• 
Hospitalization for observation without a medical AE. 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation and/or for the individual subject/patient. 
• 
Admission exclusively for the administration of blood products. 
Definition of clinically/medically significant event: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject/patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. Clinically/medically significant events 
MUST be reported as SAEs. 
In this clinical trial and as defined in this protocol, SAEs and hospitalizations unequivocally and 
solely related to established tumour disease progression will NOT be treated as SAEs for 
reporting obligations. 
7.1.2 
Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor. 
For the time period beginning when the consent form is signed until treatment allocationfirst dose 
of study treatment, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result 
of a protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocationfirst dose of study treatment through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
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Events of clinical interest for MK3475 (pembrolizumab)  include: 
1.  An overdose of MK3475 (pembrolizumab)  product; defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose), that is not associated with clinical symptoms or abnormal 
laboratory results. 
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal 
and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of 
normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
All SAEs/ECIs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject/patient's participation in the study, must be followed until any of 
the following occurs: 
• 
The event resolves. 
• 
The event stabilizes. 
• 
The event returns to baseline, if a baseline value/status is available. 
• 
The event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct. 
• 
It becomes unlikely that any additional information can be obtained (subject/patient or 
health care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts). 
 
7.2 
AEs reporting and other safety related issues reporting 
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides informed consent. .  
Reporting period for SAEs/ECIs that are NOT related with the study IMPs (MK3475 
(pembrolizumab)  and/or eribulin) and also all non-serious AEs is as follows: 
If patient discontinues treatment during the study, until 30 calendar days after the last 
administration of any of the study IMP. 
All study patients will be carefully monitored for the occurrence of AEs (including SAEs and ECIs) 
during the above specified adverse event reporting period. 
 
If the investigator becomes aware of a SAE/ECI at any time after the end of administration of 
study treatment and believes that it is POSSIBLY RELATED to MK3475 (pembrolizumab)  


 
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and/or eribulin (a serious adverse reaction to MK3475 (pembrolizumab)  and/or eribulin), the 
investigator should notify the serious adverse reaction to the Sponsor immediately irrespective 
of the time elapsed since last administration of the study IMP. 
 
For all ≥ grade 3 AEs with causal relationship to the investigational product, a follow-up by the 
Investigator may be required until the event or its sequelae resolve or stabilize at the acceptable 
level to the Investigator, and the Sponsor concurs with that assessment. 
Clearly related signs, symptoms, and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. Any additional 
events that fall outside this definition should also be reported separately. 
All AEs must be recorded in the CRF. 
SAE reporting and timeframe 
Reporting requirements will comply with all EU safety reporting requirements as detailed in 
current legislation and all applicable local regulations for safety reporting. 
The investigator or investigator’s team will report all protocol defined SAEs and ECIs to the 
Sponsor (MedSIR) no later than 24 hours of any site study team staff becoming aware of the 
event as follows: 
• 
The full details of the SAE and/or ECI should be collected and fully documented using 
the SAE form and sent to the Sponsor (MedSIR). 
• 
Follow-up information, copies of any relevant test results, event outcome and the opinion 
of the investigator as to the relationship between the IMP and the SAE and ECI, 
accompanied by other applicable documentation when it is requested, will be sent along 
with the SAE form, if available on the day the event is reported or as soon as possible if 
it is not. 
• 
The original SAE reporting form and the confirmation from the Sponsor must be kept with 
the CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MedSIR) 
according to the reporting instructions provided by MedSIR at the site initiation visit and filed in 
the Investigator’s File. 
SAEs and ECIs will be followed until resolved, a stable outcome is reached, subject/patient is lost 
to follow-up, or dies. 
As sponsor, MedSIR will be responsible for ensuring that events are reported within the mandated 
timeframe to the European Medicines Agency (EMA), other competent authorities, IRBs/ECs, and 
investigator(s), as necessary and in accordance with all applicable guidelines, approved 
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Expedited reporting to HAs, investigators, IRBs, and ECs 
To determine reporting requirements for single AAE cases, MedSIR (as Sponsor) or its designee 
will assess the expectedness of these events using the following reference documents: 
- 
MK3475 (pembrolizumab)  Investigator Brochure (IB). 
- 
Halaven® Summary of Product Characteristics (SmPC). 
MedSIR (as Sponsor) or its designee will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency reported in the applicable 
reference document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Within seven calendar days after being notified of the event, MedSIR (as Sponsor) or its designee 
will report unexpected fatal or life-threatening events associated with the use of the study drug to 
the regulatory agencies and competent authorities, to the investigators and Ethics Committees 
(ECs). MedSIR (as Sponsor) or its designee will report other unexpected SAEs associated with 
the use of the study medication to the appropriate competent authorities (according to local 
guidelines), investigators, and Ethics Committees (ECs) by a written safety report within 15 
calendar days of notification. All safety expedited reports will be reported in accordance to all 
regulatory reporting obligations (including timelines) and local regulatory requirements. 
Other safety-related reports 
As Sponsor, MedSIR will assess constantly the benefit/risk rate of the trial, that means a 
continuous evaluation of the safety profile of the drugs under investigation will be done using all 
available information. MedSIR will provide the regulatory agencies and competent authorities and 
the investigators with any relevant information that may affect the benefit/risk rate of the trial. An 
annual DSUR safety report for study IMPs  (the combination of MK3475 (pembrolizumab)  and 
eribulin) will be prepared and distributed by MedSIR or its designee in accordance to all regulatory 
reporting obligations and local regulatory requirements. 
In order to ensure the correct and necessary exchange of safety related information between 
MedSIR (as Sponsor), MSD and Eisai (as the Marketing Authorization Holders of the IMPs), a 
contract will be established and signed between MedSIR and these companies. 
MedSIR or its designee will report any finding of noncompliance (as failure to follow any applicable 
regulation or institutional policies that govern human subjects’ research) and/or serious 
noncompliance (as noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants) 
according to any reporting obligation and local regulatory requirements. 
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Irrespective of the treatment received by the subject/patient, any subject/patient’s or 
subject/patient’s partner pregnancy occurring during study treatment or during the 7 months 
following study drug discontinuation must be reported within 24 hours of investigator’s knowledge 
of the event. 
Pregnancies will be treated as SAEs and the investigator will complete a pregnancy form, and 
forward it to the sponsor according to the reporting instructions provided by MedSIR at the site 
initiation visit and filed in the Investigator’s File. 
The subject/patient will be asked to provide follow-up information on the outcome of the 
pregnancy, including premature termination should the case arise. Spontaneous miscarriage and 
congenital abnormalities will also be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined at 12 months of the infant’s life. 
Additional follow up information on any MK3475 (pembrolizumab) /eribulin-exposed pregnancy 
and infant will be requested at specific time points (i.e., after having received the initial report, at 
the end of the second trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 
months of the infant’s life). 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
8 
STATISTICAL CONSIDERATIONS AND STATISTICAL ANALYSIS PLAN 
8.1 
Determination of sample size 
A sample size of 44 evaluable patients will be accrued, with an exact single-stage phase II design. 
The primary endpoint for this study is the CBR. CBR will be evaluated according to the RECIST 
criteria v.1.1. The CBR of MK3475 (pembrolizumab)  in combination with eribulin will be assessed 
with the exact binomial test. In designing the trial, a CBR of 30% is deemed to be unacceptable 
in this patient population [16]. In contrast, a CBR of 50% would be considered to be successful. 
At least 17 patients with clinical benefit among 39 patients will be adequate to justify the 
investigation of this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample 
size of 44 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. 
 


 
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8.2 
Statistical plan 
8.2.1 
Primary efficacy endpoint  
The primary endpoint is to evaluate the CBR. The CBR is defined as the number of patients with 
complete response, partial response, or stable disease for at least 24 weeks divided by the  
number of patients in the analysis set. Tumor response will be assessed every nine weeks for the 
first 12 months following first dose of study treatment, and every 12 weeks thereafter. Tumor 
response will be defined as best response, based on local Investigator’s assessment according 
to the RECIST criteria v.1.1. 
8.2.2 
Secondary efficacy endpoints 
The secondary efficacy variables are PFS, OS, ORR, and DoR. These secondary efficacy 
endpoints have been previously defined in Sections 6.4.2 and 6.4.3. 
8.2.3 
Exploratory endpoints 
 
  
 
 
 
 
 
 
8.2.4 
Analysis sets 
Full analysis set 
All patients that accomplish selection criteria and receive at least one drug exposure. 
Per-protocol set 
All patients that accomplish selection criteria, receive at least one drug exposure, and receive the 
protocol required study drug exposure and processing. Criteria for determining the “per protocol” 
group assignment would be established by the Steering Committee before the statistical analysis 
begins. 
This analysis will only occur if this set differs by ≥ 10% from the full analysis set. 
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All patients with PD-L1 positive tumors that accomplish selection criteria and receive at least one 
drug exposure. 
Safety set 
The safety set includes patients who receive at least one dose of study medication. 
8.2.5 
Analysis of baseline and demographic variables 
The demographics and baseline characteristics will be summarized using descriptive statistics. 
8.2.6 
Primary efficacy analysis 
We will describe number and proportion of patients with clinical benefit. We will estimate the 
proportion of patients with clinical benefit with the 95% Pearson-Clopper CI (95%CI). 
In order to assess the robustness of the primary analysis based on the full analysis set, the 
primary analysis will be repeated for the per-protocol set. 
8.2.7 
Decision rules and adjustment of alpha for primary endpoint 
• 
The study will be declared positive in the analysis of CBR if the one-sided p-value 
estimated in accordance with exact binomial test is ≤ 0.05. With this criteria, we will reach a 
positive finding if ≥ 17 patients achieve a clinical benefit among 39 patients. 
• 
With this design, there is an 80% power of a positive finding if the true CBR is ≥ 50%. 
The one-sided type I error is 0.05. 
8.2.8 
Secondary and exploratory analysis 
 
 
 
 
 
 
 
 
 
 


 
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8.2.9 
Biomarkers analysis 
Markers will be evaluated on a univariate level regarding their potential for prediction of the clinical 
endpoints (CBR and ORR). Biomarker and response correlations with clinical covariates will be 
investigated. It will be checked whether covariates can improve the prediction and whether there 
is an interaction with the biomarkers. Relevant covariates could become a part of the statistical 
prediction model. Further multivariate techniques (i.e., Multiple Logistic Regression, Cox 
regression, Principal Component Analysis with Rotation, Cluster Analysis) will be considered in 
order to study combinations of markers. Techniques to control false discovery rate and overfitting 
(cross-validation) will be deliverated. 
 
8.3 
Safety analysis 
Analysis of safety-related data will be considered at three levels: 
• 
First, the degree of exposure (dose, duration, number of patients) will be assessed to 
determine the degree to which study safety can be assessed. 
• 
Second, clinically relevant tests, concomitant medications, and reported AEs will be 
described. For AEs, severity, expectedness, causality, relationship, body system, action 
taken, and outcome will be reported. 
• 
Third, SAEs, deaths, and study discontinuations for each study group will be described 
and assessed. 
Analysis will he performed on the safety set. 
 
8.4 
Missing data management 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. 
We will report reasons for withdrawal. Patient with missing in binary outcomes will considered as 
non-responders. The analysis of timed endpoints are based on a Kaplan-Meier methods, 
therefore, not affected by patient withdrawals (as they are censored) provided that dropping out 
is unrelated to prognosis. The other variables will be managed with simple imputations methods 
(last observation carried forward). The effect that any missing data might have on results will be 
assessed via sensitivity analysis of study sets. 
 


 
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8.5 
Scientific committee review 
A Steering Committee has been established for this study. Initially, it is composed of the 
Investigators, the study medical monitor, the Scientific Global Coordinator, and two physicians 
expert in MK3475 (pembrolizumab)  management.  
The Steering Committee will meet on demand to review, discuss, and evaluate all of the gathered 
safety data. In case of any arising safety concern, these meetings can also be called at any time 
at request of a participating Investigator. At these meetings, MedSIR and the participating 
Investigators must reach a consensus on safety data. MedSIR will prepare minutes from these 
meetings and circulate them to each Investigator for comments prior to finalization.  
The study site Investigators and MedSIR will review patient data at least every four months. Each 
study site Investigator will monitor patients data for serious toxicities on an ongoing basis.  
 
9 
ETHICAL CONSIDERATIONS 
9.1 
Regulatory and ethical compliance 
The study will be conducted and reported in accordance with the protocol, the ICH guidelines, the 
ethical principles laid down in the Declaration of Helsinki, European Clinical Trials Regulation 
[Regulation (EU) No. 536/2014], and any applicable regulatory requirement.  
 
9.2 
EC 
The conduct of the study must be authorized by a duly constituted EC. Authorization is required 
for study protocol, protocol amendments, informed consent forms, patient information sheets, and 
promotional materials. The EC must also be contacted in the event of any major protocol violation 
or any SAE. 
Wherever necessary, the Investigator and/or Sponsor should contact the EC to ensure that 
accurate and timely information is being provided at every phase of the study. 
The principal Investigator and/or Sponsor are responsible for providing, when required, written 
summaries of the study status to the EC annually or more frequently, in accordance with the 
requirements, policies and procedures set out by the EC. The Investigators are also responsible 
for immediately informing the EC of any protocol amendment. 
In addition to reporting the AEs defined in the protocol to the Sponsor, the Investigators must 
immediately report any unexpected issues that entail a risk to patients to their respective ECs. 
Some ECs may request immediate reporting of all SAEs, while others may only require reporting 
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provide the Investigators with written safety reports or other safety-related reports. Safety reports 
should be made available to the EC for review and processing in accordance with the regulatory 
requirements and policies and procedures established by the EC and kept on file at the study 
site. 
 
9.3 
Informed consent 
Before any protocol-related activity, the signed informed consent should be obtained from each 
patient. As part of this procedure, the study site Investigator or his/her representative should 
explain verbally and in writing, the nature, duration, and purpose of the study, as well as the action 
of the drugs so that the patient is aware of the possible risks, discomfort, and adverse effects that 
may occur. Study patients will be informed of their right to withdraw from the study at any time 
and without any reason. The patient will receive all the information required by local regulations 
and ICH guidelines. 
Consent forms must be signed and dated by the patient or their authorized legal representative 
before starting their participation in the study. Each patient’s medical history or medical records 
should include an entry detailing the process of obtaining informed consent and that it was 
obtained in writing before the patient’s participation in the study. 
One copy of the signed consent form should be provided to the patient or the patient’s authorized 
legal representative. 
Signed and dated consent forms should be kept in each patient’s study file. They should be made 
available to study monitors who may request them for review at any time. 
Consent forms should be reviewed whenever changes have been made to the procedures 
described in the informed consent or when new information becomes available that may affect 
the patient’s willingness to participate. 
In case of review or update of consent forms, each patient’s medical history should include an 
entry detailing the process of obtaining informed consent and that it was obtained in writing using 
the updated/reviewed consent form in order to continue their participation in the study. The final 
informed consent form approved by the EC should be provided to the Sponsor for regulatory 
purposes. 
 
9.4 
Data protection 
The Sponsor will ensure confidentiality of the patient’s medical information, in accordance with 
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The study Sponsor, as data controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of such data 
confirms herewith compliance with Directive 95/46/EC, Organic Law 15/1999, and Royal Decree 
1720/2007 in all stages of data management. 
The data generated by this study will be made available to the representatives of national and 
local HAs, Sponsor monitors, Sponsor representatives, and partners, as well as the EC of each 
study site for review, as needed. 
 
10 ORIGINAL DOCUMENTS, STUDY MONITORING AND QUALITY ASSURANCE 
10.1 Source data record 
Source data refers to all the information found in source files and certified copies of source files 
containing clinical findings, observations, or other activities that are part of the clinical study and 
which are necessary for study reconstruction and assessment. Source data is contained in source 
documents (comprising source documents and certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, medical 
histories and office records, laboratory notes, memoranda, patients' diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, patients files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
study). 
The Sponsor’s quality assurance group may assist in determining whether electronic records 
generated using computerized medical record systems used at investigational sites can be 
considered source documentation for the purposes of this protocol. 
If the site computerized medical record system has not been adequately validated for the 
purposes of clinical research (instead of general clinical practice), all paper source documentation 
should be kept on file to ensure that important protocol data entered on the CRFs can be verified. 
At a minimum, source documentation must be available to substantiate patient identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study drug receipt/dispensing/return records; study drug administration information; 
and date of completion and reason. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original documents, laboratory reports, medical records) in order to ensure data 


 
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completeness and accuracy as required by study protocol. The Investigator and/or site staff must 
make CRFs and source documents of patients enrolled in this study available for inspection by 
Sponsor or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as 
required by regulations, officials of the regulatory HAs (e.g., FDA, EMA, and others), and/or ECs. 
The study Investigator and site staff must comply with applicable privacy, data protection, and 
medical confidentiality laws for use and disclosure of information related to the study and enrolled 
patients. 
The patient must also allow access to the patient's medical record. Each patient should be 
informed of this requirement prior to study start. 
 
10.2 Study monitoring and source data verification 
Sponsor or its representative will monitor study progress as frequently as necessary to ensure: 
- 
Protection of study patients’ rights and well-being. 
- 
Study data are accurate, complete, and verifiable from the source documents. 
- 
Conduct of the trial is in compliance with the approved protocol/amendment, GCP 
guidelines, and applicable regulatory requirements. 
Study staff contact details are included in a document located on the Investigator site file  
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(i.e., all original documents, laboratory reports, medical records, patients’ diaries) in order to 
ensure data completeness and accuracy as required by study protocol. The Investigator and/or 
site staff must make CRFs and source documents of patients enrolled in this study available for 
inspection by the Sponsor or its representative at the time of each monitoring visit. 
 
10.3 Record retention 
Investigators should retain all study records in a secure place with restricted access as per 
applicable regulatory requirements. The Investigator must consult a Sponsor representative 
before disposal of any study records and must notify the Sponsor (of any change in the location, 
disposition, or custody of the study files. 
Essential documents must be retained by the Investigator for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least two years have elapsed since 
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documents” are defined as those documents which individually and collectively allow for the 
assessment of the conduct of the study and the quality of the resulting data. These documents 
must be retained for a longer period if required by the applicable regulatory requirements or as a 
result of an agreement with the Sponsor. The Committee for Medicinal Products for Human Use 
(CHMP) requires retention for the maximum period of time permitted by the institution, but not 
less than 15 years (ICH E6, 4.9.5). It is the responsibility of the Sponsor to inform the Investigator 
or site when these documents no longer need to be retained (ICH E6, 4.9.5). 
The study site Investigator should not dispose of records belonging to this study without either (1) 
obtaining written approval from the Sponsor or (2) offering the Sponsor an opportunity to collect 
these records. The study site Investigator will be responsible for retaining suitable and accurate 
electronic or paper copies of source documentation containing observations and data collected 
from this study. Such documentation is subject to inspection by the Sponsor and the FDA and/or 
EMA (or respective individual EU country regulatory authorities). 
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
 
10.4 Data quality assurance 
During the study or upon its completion, the quality assurance auditor(s) designated by Sponsor 
or the competent authorities may wish to perform an audit of the sites. Investigators are expected 
to cooperate in these audits, offering their assistance, and providing auditors with the 
documentation they require (including source documents). 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator in order 
to inspect the facilities and, upon request, to inspect clinical trial records (e.g., CRF and other 
pertinent data), provided that patient confidentiality is respected. 
The Investigator agrees to cooperate with the monitor to ensure that all issues detected during 
these monitoring visits are resolved, including delays in completing CRFs. 
In accordance with the ICH E6 R2 Guideline for GCP and the Sponsor’s audit plans, the Sponsor’s 
Department of Quality Assurance or its representatives may perform an audit of this study. An 
inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-
related records will be carried out in order to assess the conduct of the study and compliance with 
the protocol, the ICH guidelines for GCP (ICH E6 R2), and relevant regulatory requirements. 
 


 
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11 DATA MANAGEMENT 
11.1 Data entry and processing 
In this study, the Investigator and/or site staff will regularly enter all data into the CRFs.The 
Investigator must also review all data included in the CRF to ensure its accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the end of the study, any 
protocol non-compliances will be identified and recorded as part of the clinical database. Once all 
of these tasks are complete and the accuracy and completeness of the database has been 
verified, it will be locked and the data will become available for data statistical analysis. 
11.2 Data clarification 
As part of the conduct of the trial, Sponsor may have questions about the data entered by the 
site, referred to as queries. Queries can be generated by the monitors, data managers and the 
Sponsor   
11.3 Data coding procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries described in the Data Management Plan. 
 
12 STUDY MANAGEMENT 
12.1 Study discontinuation 
MedSIR reserves the right to discontinue the study at any time for safety or administrative 
reasons. If the study is discontinued and/or the site is closed for any reason, all of the 
investigational study drugs can be destroyed locally at the site according local law regarding 
radioactive products) . All of the actions needed to assess or maintain study patient safety will 
continue as required, despite study discontinuation. 
 
12.2 Protocol amendments 
Any change or addition to the protocol requires a written protocol amendment or administrative 
letter that must be approved by Sponsor, the Scientific Global Coordinator, the study site 
Investigator, and the EC/HAs when applicable. This requirement should not, under any 
circumstances, prevent any immediate action taken by the study site Investigator or Sponsor to 
ensure the safety of all the patients enrolled in the study. If, in the opinion of the study site 
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this process should be reported to Sponsor as soon as possible (within 24 hours) and the EC will 
be informed, as needed. 
 
12.3 Publication policy and protection of trade secrets 
All of the data generated by this study should be considered highly confidential and should not 
be disclosed to persons who are not directly related to the study without prior written permission 
from the Scientific Global Coordinator and Sponsor. Nevertheless, full access is granted to 
authorized officials of HAs, the Scientific Global Coordinator or study site Investigator, and 
Sponsor staff (or their representatives) for record inspection and copying. All of the investigational 
products, patient body fluids and/or other collected materials will only be used in accordance with 
this protocol, unless otherwise agreed in writing between the global scientific coordinator or study 
site Investigator and Sponsor. 
The Sponsor will ensure that, as far as possible, the study results are published in the form of 
scientific/clinical articles in prestigious scientific peer-reviewed journals. These documents will be 
prepared with the full participation of the principal Investigators and in accordance with applicable 
guidelines for Good Publication Practice and with international recommendations, such as those 
from the International Committee of Medical Journal Editors (ICMJE) and all elements of the 
Consort Statement (2010). 
The Sponsor will be notified of any attempt to publish data obtained during the study and 
permission to do so must first be obtained from the Sponsor before publication. 
 
12.4 Insurance 
The Sponsor contracts an insurance policy to cover the responsibilities of the Investigator and 
other parties participating in the study, according to the applicable Spanish legislation. 
 
 
 


 
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13 REFERENCES 
1. 
Perou, C.M., et al., Molecular portraits of human breast tumours. Nature, 2000. 
406(6797): p. 747-52. 
2. 
Goldhirsch, A., et al., Personalizing the treatment of women with early breast cancer: 
highlights of the St Gallen International Expert Consensus on the Primary Therapy of 
Early Breast Cancer 2013. Ann Oncol, 2013. 24(9): p. 2206-23. 
3. 
Prat, A. and C.M. Perou, Deconstructing the molecular portraits of breast cancer. Mol 
Oncol, 2011. 5(1): p. 5-23. 
4. 
Comprehensive molecular portraits of human breast tumours. Nature, 2012. 490(7418): 
p. 61-70. 
5. 
Cardoso, F., et al., ESO-ESMO 2nd international consensus guidelines for advanced 
breast cancer (ABC2). Breast, 2014. 23(5): p. 489-502. 
6. 
Cardoso, F., et al., International guidelines for management of metastatic breast cancer: 
combination vs sequential single-agent chemotherapy. J Natl Cancer Inst, 2009. 101(17): 
p. 1174-81. 
7. 
Jordan, M.A. and L. Wilson, Microtubules as a target for anticancer drugs. Nat Rev 
Cancer, 2004. 4(4): p. 253-65. 
8. 
Munoz-Couselo, E., J. Perez-Garcia, and J. Cortes, Eribulin mesylate as a microtubule 
inhibitor for treatment of patients with metastatic breast cancer. Onco Targets Ther, 2011. 
4: p. 185-92. 
9. 
Cortes, J., A.J. Montero, and S. Gluck, Eribulin mesylate, a novel microtubule inhibitor in 
the treatment of breast cancer. Cancer Treat Rev, 2012. 38(2): p. 143-51. 
10. 
Goel, S., et al., A phase I study of eribulin mesylate (E7389), a mechanistically novel 
inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin 
Cancer Res, 2009. 15(12): p. 4207-12. 
11. 
Tan, A.R., et al., Phase I study of eribulin mesylate administered once every 21 days in 
patients with advanced solid tumors. Clin Cancer Res, 2009. 15(12): p. 4213-9. 
12. 
Vahdat, L.T., et al., Phase II study of eribulin mesylate, a halichondrin B analog, in 
patients with metastatic breast cancer previously treated with an anthracycline and a 
taxane. J Clin Oncol, 2009. 27(18): p. 2954-61. 
13. 
Cortes, J., et al., Phase II study of the halichondrin B analog eribulin mesylate in patients 
with locally advanced or metastatic breast cancer previously treated with an 
anthracycline, a taxane, and capecitabine. J Clin Oncol, 2010. 28(25): p. 3922-8. 
14. 
Aogi, K., et al., A phase II study of eribulin in Japanese patients with heavily pretreated 
metastatic breast cancer. Ann Oncol, 2012. 23(6): p. 1441-8. 
15. 
Cortes, J., et al., Eribulin monotherapy versus treatment of physician's choice in patients 
with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. 
Lancet, 2011. 377(9769): p. 914-23. 
16. 
Kaufman, P.A., et al., Phase III open-label randomized study of eribulin mesylate versus 
capecitabine in patients with locally advanced or metastatic breast cancer previously 
treated with an anthracycline and a taxane. J Clin Oncol, 2015. 33(6): p. 594-601. 
17. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002084/WC500105112.pdf. 
18. 
Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer, 2012. 12(4): p. 252-64. 
19. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 


 
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20. 
Iwai, Y., et al., Involvement of PD-L1 on tumor cells in the escape from host immune 
system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A, 2002. 
99(19): p. 12293-7. 
21. 
Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes and 
preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 2750-
67. 
22. 
Sabatier, R., et al., Prognostic and predictive value of PDL1 expression in breast cancer. 
Oncotarget, 2015. 6(7): p. 5449-64. 
23. 
Ali, H.R., et al., PD-L1 protein expression in breast cancer is rare, enriched in basal-like 
tumours and associated with infiltrating lymphocytes. Ann Oncol, 2015. 26(7): p. 1488-
93. 
24. 
Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant 
chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-
positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91. 
25. 
Denkert, C., et al., Tumor-associated lymphocytes as an independent predictor of 
response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol, 2010. 28(1): p. 
105-13. 
26. 
Adams, S., et al., Prognostic value of tumor-infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 
and ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66. 
27. 
Nanda, R., et al., Pembrolizumab  in Patients With Advanced Triple-Negative Breast 
Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol, 2016. 
28. 
Emens, L.A., et al., Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients 
with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual 
Meeting; April 18-22; Philadelphia, PA. Abstract 6317. 
29. 
Adams, S., et al., Phase Ib trial of atezolizumab in combination with nab-paclitaxel in 
patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 34, 2016 
(suppl; abstr 1009). 
30. 
Dirix, L.Y., et al., Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with 
locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. In: 
Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer 
Symposium: 2015 Dec 8-12; San Antonio, TX. Abstract S1-04. 
31. 
Mazel, M., et al., Frequent expression of PD-L1 on circulating breast cancer cells. Mol 
Oncol, 2015. 9(9): p. 1773-82. 
32. 
Rugo, H., et al., Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients 
with PD-L1–positive estrogen receptor–positive/HER2-negative advanced breast cancer 
enrolled in KEYNOTE-028. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San 
Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Abstract S5-07. 
33. 
Postow, M.A., M.K. Callahan, and J.D. Wolchok, Immune Checkpoint Blockade in Cancer 
Therapy. J Clin Oncol, 2015. 33(17): p. 1974-82. 
34. 
Tolaney, S., et al., Phase 1b/2 study to evaluate eribulin mesylate in combination with 
pembrolizumab in patients with metastatic triple-negative breast cancer In: Proceedings 
of the Thirty-Nihth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2016 
Dec 6-10; San Antonio, TX. Abstract P5-15-02. 
35. 
Recommendations related to contraception and pregnancy testing in clinical trials (CTFG) 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


 
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14 APPENDIX 
Appendix 1: Schedule of study assessments and procedures 
 
Assessment Window 
(Days) 
Screening 
 
All cycles (First and 
Second Course Phase) 
End Of 
Treatment 
visit (EOT)13 
Follow up visit 
to confirm 
patient 
progression 
to Sponsor14 
End Of Study 
(EOS) 
12 months after 
last study 
dose in the first 
course of 
pembrolizumab 
phase 
treatment, or 
after the last 
study dose in 
the second 
course in all 
patients. 
Days –28 
to –1 
1 
(± 2 days) 
812 
(± 1 
day) 
≤ 30 days 
after last 
dose  
At patient’s disease 
progression after 
First Treatment 
Course 
Signed informed consent form(s)  
x 
Review of eligibility criteria 
x 
Demographic data and medical history1 
x 
HIV, HBV, HCV serology (± HCV RNA 
PCR t
t)
x 
Concomitant medications  
x 
x 
x 
x 
x 
Complete physical examination  
x 
x 
x 


 
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Limited physical examination (symptom-
di
t d)
 
x 
Assessment of symptoms 
x 
x 
x 
x 
ECOG performance status 
x 
x  
x 
Vital signs2  
x 
x 
x 
x 
Weight 
x 
x 
x 
Height 
x 
Newly obtained and/or archival tissue for 
biomarker analysis  
x 
Tumor assessment3 
x 
 
See footnote (4) 
12-lead electrocardiogram 
x 
 
Performed as clinically indicated 
FEVI assesstment (ECHO or MUGA) 
x 
 
Performed as clinically indicated 
Hematology5 
x 
x(6) 
x 
x 
Serum chemistry5  
x 
x(6) 
x 
x 
TSH, free T3, free T4 
x 
Every two cycles8 
 
 
 
Coagulation panel (aPTT, INR) 
x 
x 
Urinalysis7 
x 
Every two cycles8 
 
Pregnancy test (women of childbearing 
potential only)9 
x(9) 
Every two cycles8 
x 
Blood samples for translational research10 
x 
Every three cycles 
x 


 
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Adverse events  
x 
x 
x 
x 
x 
MK3475 (pembrolizumab)  infusion  
 
x 
 
 
Eribulin administration 
 
x 
x 
   
X (if applicable) 
 
Suvival and anti-cancer therapy follow-up  
 
 
x 
x 
 
Anti-therapeutic antibody: ATA; Eastern  Cooperative Oncology Group: ECOG; Echocardiography: ECHO; Hepatitis B virus: HBV; Hepatitis C virus: HCV; 
Left ventricular ejection fraction: LVEF; Multiple-gated acquisition: MUGA; Pharmacokinetic: PK; Pharmacodynamic: PD; Thyroid-stimulating hormone: 
TSH. 
 
1. Demographic data include age, sex, and self-reported race/ethnicity. Medical history comprises clinically significant diseases, surgical interventions, 
history of cancer (including prior antineoplastic treatments and procedures), history of smoking, alcoholism, drug addiction, as well as any medications 
(e.g., prescribed drugs, over-the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the patient in the 28 days prior 
to screening visit.  
2. Vital signs include: respiratory rate, heart rate, blood pressure, and body temperature 
3. All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic imaging performed during the screening 
period should consist of 1) CT of  the chest, abdomen, and pelvis or MRI of the abdomen and pelvis with a non-contrast CT scan of the chest in patients 
for whom CT scans with contrast are contraindicated, 2) bone scan if a subject has a known history of bone metastases or has new bone pain during 
screening, and 3) any other imaging studies as clinically indicated by the treating physician [brain imaging during the trial should be performed in 
subjects with known brain metastases (every nine weeks for first year, then every 12 weeks) and those with worsening and/or new neurological 
symptoms]. Tumor assessments will be performed at baseline, every 9 weeks (± 7 days) for the first 12 months following first dose of study treatment, 
and every 12 weeks (± 7 days) thereafter, with additional scans as clinically indicated. All known sites of disease documented at screening should be 
re-assessed at each subsequent tumor evaluation. The same radiographic procedures and technique must be used throughout the study for each 
patient (bone scan will be performed only if a subject develops new or worsening symptoms or if the site believes they have attained a complete 


 
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response). 
4. In subjects who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease 
status by tumor imaging following  the  intervals  as  outlined  in footnote 3 until the start of new anti-cancer treatment, disease progression, death, or 
the end of the study, whichever occurs first. However, tumor evaluation will be done by the Investigator criteria and local practice according to the 
technical sheet of pembrolizumab during the suspension of the First Course Phase and during the Second Course Phase.  
5. Blood test will be performed as per local standard of care and clinical indication before treatment administration. These values should be included: 
hemoglobin, hematocrit, red blood cell count, platelet count, and WBC count with differential count (ANC, lymphocytes, monocytes, eosinophils, and 
basophils), coagulation, chemistry with renal function analysis (serum creatinine), liver function (AST, ALT, ALP, GGT, total and direct bilirubin), glucose, 
sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, albumin, and lactate dehydrogenase. 
6. Not repeat in Cycle 1, Day 1 if done in day -3 to day 1. 
7. Urinalysis include: Specific gravity, pH, glucose, protein, ketones, and blood 
8. Every 2 cycles: Cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc, before study treatment administration.   
9. Serum pregnancy test within 14 days before Cycle 1, Day 1. Urine pregnancy test every two cycles thereafter. 
10. Samples for translational study will be obtained at each time point; at screening, every three cyles of treatment (Cycle 4 day 1, cycle 7 day 1, Cycle 
10 day 1, etc), and at the end of the study treatment ony in the first course. 
 
 
12. Day 8 visits can be omitted, at the Investigator’s discretion, in those patients that permanently discontinue eribulin treatment and continue with 
pembrolizumab as single agent. 


 
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13. End of treatment visit (EOT) will be performed within 30 days after last study dose. Participants who are eligible for retreatment/crossover with 
pembrolizumab (as described in Section 5.3.5) may have up to two EOT visits, one after the Initial Treatment Period and one after the Second Course 
Treatment. 
14. A follow up visit is required  as per protocol to be performed to patients that finish the First Course Phase and are candidates to enter to the Second 
Course Phase of re-treatment with pembrolizumab, once disease progression is confirmed. A eCRF page will have to be completed in order to confirm 
the progression date.  
During the period between the First and Second Course phases, it is highly recommended to perform safety follow up visits every 6 weeks and 
efficacy assessments every 12 weeks. However, patient’s follow up during this period will be done as per local practice and at the Investigator 
criteria.    
 


 
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Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Criteria for evaluating response in solid tumors 
 
RECIST v.1.1* will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST v.1.1, CT is the preferred imaging technique in this study. 
 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47 
 
 


 
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Appendix 3: Imaging and treatment after first radiologic evidence of disease 
progression.  Table r e presents irRECIST 
 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First 
radiologic 
evidence of 
disease 
progression 
by RECIST 
v.1.1 
Repeat 
imaging at ≥ 4 
weeks at site 
to confirm 
disease 
progression 
May continue 
study 
treatment at 
the local site 
Investigator’s 
discretion 
while awaiting 
confirmatory 
tumor imaging 
by site by 
irRECIST 
Repeat 
imaging at ≥ 
4 weeks to 
confirm 
disease 
progression 
per 
physician 
discretion 
only 
Discontinue 
treatment 
Repeat tumor 
imaging 
confirms 
disease 
progression  
by irRECIST 
No additional 
imaging 
required 
Discontinue 
treatment 
(exception is 
possible upon 
consultation 
with Sponsor) 
No 
additional 
imaging 
required 
Not applied 
Repeat tumor 
imaging 
shows stable 
disease or 
partial or 
complete 
response by 
irRECIST
Continue 
regularly 
scheduled 
assessments 
Continue 
study 
treatment at 
the local site 
Investigator´s 
discretion 
Continue 
regularly 
scheduled 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per local site 
Investigator´s 
discretion
Immune-Related Response Evaluation Criteria In Solid Tumors: irRECIST; Response criteria in 
solid tumors: RECIST. 
 
 
 
 
 
 


 
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SAP_001.pdf: 
MedSIR 
Confidential 
Page 1 of 32 
MEDOPP127 Statistical Analysis Plan 
Version 2.0 
Date: Apr 15, 2020 
EudraCT number: 2016-004513-27 
Mod.141; Version 02 dated 8/21/2012 
SOP BS004 
 
 
 
 
A phase II study of pembrolizumab and eribulin in patients with HR-
positive/HER2-negative metastatic breast cancer previously treated 
with anthracyclines and taxanes 
KELLY study (KEytruda and EribuLin in Luminal breast cancer) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Medica Scientia Innovation Research (MedSIR). 
Author: 
Document type: 
Statistical Analysis Plan
Eudract number: 
2016-004513-27 
Phase: 
II 
Version: 
2.0 
Release date: 
15/Apr/2020 
 
Notice: Part or all the information included in this document may be unpublished material and it should be 
treated as confidential and property of the sponsor. It may not be disclosed to any unauthorized person, 
including publications and presentations, without the written consent of the Sponsor. 
 
 
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MedSIR 
Confidential 
Page 2 of 32 
MEDOPP127 Statistical Analysis Plan 
Version 2.0 
Date: Apr 15, 2020 
EudraCT number: 2016-004513-27 
Mod.141; Version 02 dated 8/21/2012 
SOP BS004 
 
 
 
 
SIGNATURE PAGE FOR THE STATISTICAL ANALYSIS PLAN 
MEDOPP127 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Medica Scientia Innovation Research (MedSIR) 
Author: 
Sponsor contact person: 
Sponsor, signature and date:
 
Author, signature and date: 
 
 
 
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MedSIR 
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MEDOPP127 Statistical Analysis Plan 
Version 2.0 
Date: Apr 15, 2020 
EudraCT number: 2016-004513-27 
Mod.141; Version 02 dated 8/21/2012 
SOP BS004 
1. Synopsis 
Type of application 
Clinical Trial 
Sponsor 
Medica Scientia Innovation Research (MedSIR) 
Rambla Cataluña, 2-4, 2D, 08007-Barcelona, Spain 
Tel.: + 34 93 221 41 35; Fax: + 34 93 299 23 82 
Clinical trial title 
“A phase II study of pembrolizumab and eribulin in patients with 
HR-positive/HER2-negative metastatic breast cancer previously 
treated with anthracyclines and taxanes. KELLY study 
(KEytruda and EribuLin in Luminal breast cancer).” 
Protocol number 
MEDOPP127 
Study Coordinator and 
Principal Investigator 
Expected sites 
11 
Central Ethics 
Committee/Institutional Review 
Board 
CEIC Hospital Arnau de Vilanova de Valencia 
Name and qualification of the 
persons in charge of 
Monitoring 
Experior, S.L. 
C/ Vicente Galmés, 1A; 46139 La Pobla de Farnals (Valencia) 
Tel.: 902.105.255; Fax: 96.145.21.91 
Investigational drug 
Halaven®; Keytruda®. 
Trial phase 
II 
Objectives 
Primary objective: 
 To assess the efficacy -as determined by the clinical 
benefit rate (CBR) (total number of objective responses 
plus stable disease for at least 24 weeks) based on 
RECIST 
v.1.1- 
of 
MK3475 
(pembrolizumab) 
in 
combination 
with 
eribulin 
in 
patients 
with 
HR-
positive/HER2-negative MBC who have previously 
received an anthracycline and a taxane (for either early or 
advanced disease), unless contraindicated, and between 
one to two lines of chemotherapy in the metastatic setting.  
Secondary objectives: 
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MEDOPP127 Statistical Analysis Plan 
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 To determine the CBR based on RECIST v.1.1 in subjects 
with programmed death ligand-1 (PD-L1) positive tumors. 
 To determine the progression-free survival (PFS) based 
on RECIST v.1.1. 
 To determine the PFS based on RECIST v.1.1 in subjects 
with PD-L1 positive tumors. 
 To determine the overall survival (OS) (OS will be 
determined at the end of the study). 
 To determine the OS in subjects with PD-L1 positive 
tumors. 
 To determine the overall response rate (ORR) based on 
RECIST v.1.1. 
 To determine the ORR based on RECIST v.1.1 in subjects 
with PD-L1 positive tumors. 
 To determine the duration of response (DoR) based on 
RECIST v.1.1. 
 To determine the DoR based on RECIST v.1.1 in subjects 
with PD-L1 positive tumors. 
 To assess the safety and tolerability of MK3475 
(pembrolizumab) in combination with eribulin according to 
the US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 
4.0.3. 
 
Exploratory objectives: 
 
 
 
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MEDOPP127 Statistical Analysis Plan 
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SOP BS004 
Design 
Multicenter, open-label, phase II clinical trial. 
Primary endpoint 
The primary endpoint of this study is to assess the CBR based 
on RECIST v.1.1. 
Study population and total 
number of subjects 
Female patients age ≥ 18 years with advanced HR-
positive/HER2-negative breast cancer previously treated with 
anthracyclines and taxanes. 
A total of 44 patients will be enrolled into this trial. 
Approximate duration of 
subject participation 
All 
eligible 
patients 
will 
be 
treated 
with 
MK3475 
(pembrolizumab) 200 mg on day 1 of each 21-day cycle and 
eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 
mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with 
MK3475 (pembrolizumab) and eribulin will continue based on 
physician criteria.  
No maximum duration of treatment is specified. Study follow-up 
will be performed 12 months after last study dose. 
Calendar and estimated 
completion dates 
Recruitment period is planned to be opened for 11 months. 
The end of study will be 12 months after last study dose or 
progressive disease experienced in all patients or when the 
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MEDOPP127 Statistical Analysis Plan 
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trial is terminated by the Sponsor, whichever is earlier. This 
data point will be considered: 
 
End of Recruitment (LPI) (11 months): August 2018 
 
Last Patient Last Visit (LPLV): August 2019 
 
Final Study Report: December 2019 
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MEDOPP127 Statistical Analysis Plan 
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2. Table of contents 
1. 
Synopsis ................................................................................................................................... 3 
2. 
Table of contents ..................................................................................................................... 7 
3. 
Abbreviations ........................................................................................................................... 8 
4. 
Study objectives and variables ............................................................................................ 10 
4.1 
Primary objective(s) and primary variable(s) .............................................................. 10 
4.2 
Secondary objective(s) and secondary variables ....................................................... 10 
4.3 
Exploratory objective(s) and exploratory variables .................................................... 11 
4.4 
Safety evaluation ............................................................................................................ 11 
4.5 
Determination of sample size ....................................................................................... 12 
4.6 
................................................................................................. 13 
4.7 
................................................................... 15 
4.7.1 
Sample size calculated .................................................................................................. 15 
4.7.2 
Justification of sample size .......................................................................................... 15 
5. 
Study populations .................................................................................................................. 17 
5.1 
Protocol deviations ........................................................................................................ 17 
6. 
Statistical strategy ................................................................................................................. 19 
6.1 
Primary analysis ............................................................................................................. 19 
6.1.1 
Summary statistics ........................................................................................................ 19 
6.1.2 
Statistical inference ....................................................................................................... 19 
6.2 
Secondary analysis ........................................................................................................ 19 
6.2.1
Summary statistics ........................................................................................................19
6.2.2 
Statistical inference ....................................................................................................... 21 
6.3 
Exploratory analysis ...................................................................................................... 21 
6.3.1 
Summary statistics ........................................................................................................ 21 
6.4 
Statistical methods for Caladrio sub-study ................................................................. 23 
6.5 
Safety analysis ............................................................................................................... 23 
6.6 
Demographic and baseline characteristics ................................................................. 23 
6.7 
Statistical model assumptions ..................................................................................... 24 
6.8 
Transformation of expected variables ......................................................................... 24 
6.9 
Handling of missing data .............................................................................................. 25 
6.10 
Description of the softwares to be used for data analysis ........................................ 25 
6.11 
Interim analysis protocol ............................................................................................... 25 
6.12 
List of tables and figures ............................................................................................... 26 
7. 
References .............................................................................................................................. 30 
 
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MEDOPP127 Statistical Analysis Plan 
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3. Abbreviations 
AE:
Adverse Event.
AF: 
Absolute frequency. 
ATC: 
Anatomical Therapeutic Chemical. 
C1D1: 
Cycle 1 Day 1. 
CBR: 
Clinical benefit rate. 
CI:
Confidence Interval.
CR: 
Complete Response. 
CTCs: 
Circulating Tumor Cells. 
CTCAE: 
Common Terminology Criteria for Adverse Events. 
DoR: 
Duration of Response. 
ECG:
Electrocardiogram.
eCRF: 
electronic Case Report Form. 
ECOG: 
Eastern Cooperative Oncology Group. 
ER: 
Estrogen Receptor. 
EOT: 
End Of Treatment. 
FDA:
Food and Drug Administration.
HBV: 
Hepatitis B Virus. 
HCV: 
Hepatitis C Virus. 
HIV: 
Human Immunodeficiency Virus. 
HR: 
Hormone Receptor. 
IC:
Informed Consent.
irRECIST: 
immune-related Response Evaluation Criteria in Solid Tumors. 
ITT: 
Intention To Treat. 
LPI: 
End of recruitment date. 
LPLV: 
Last patient last visit. 
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LVEF: 
Left Ventricular Ejection Fraction. 
MBC: 
Metastatic Breast Cancer. 
MEDDRA: 
Medical Dictionary for Regulatory Activities. 
NA: 
Not available. 
NCI: 
National Cancer Institute. 
ORR: 
Overall Response Rate. 
OS: 
Overall Survival. 
PD-L1: 
Programmed cell Death 1-Ligand. 
PFS: 
Progression Free Survival. 
PR: 
Partial Response. 
PR: 
Progesterone Receptor. 
PT: 
Preferred Term. 
Q1: 
First quartile. 
Q3: 
Third quartile. 
RECIST: 
Response Criteria In Solid Tumors. 
SD: 
Stable Disease. 
SDev: 
Standard Deviation. 
SAE: 
Serious Adverse Event. 
SOC: 
System Organ Class. 
 
 
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MEDOPP127 Statistical Analysis Plan 
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4. Study objectives and variables 
4.1
Primary objective(s) and primary variable(s)
Primary objective: 
To assess the efficacy -as determined by the CBR (total number of objective responses 
plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 
(pembrolizumab)  in combination with eribulin in patients with HR-positive/HER2-negative 
MBC who have previously received an anthracycline and a taxane (for either early or 
advanced disease), unless contraindicated, and between one to two lines of 
chemotherapy in the metastatic setting. 
Primary endpoint: 
To determine the CBR based on RECIST v.1.1. 
4.2 
Secondary objective(s) and secondary variables 
Secondary objectives: 
 
To determine the CBR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
 
To determine the PFS based on RECIST v.1.1. 
 
To determine the PFS based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
 
To determine the OS (OS will be collected at the end of the study). 
 
To determine the OS in subjects with PD-L1 positive tumors. 
 
To determine the ORR based on RECIST v.1.1. 
 
To determine the ORR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
 
To determine the DoR based on RECIST v.1.1. 
 
To determine the DoR based on RECIST v.1.1 in subjects with PD-L1 positive 
tumors. 
 
To assess the safety and tolerability of MK3475 (pembrolizumab) in combination 
with eribulin according to the US National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.3. 
 
 
 
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MEDOPP127 Statistical Analysis Plan 
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Secondary endpoints: 
 
CBR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
 
PFS based on RECIST v.1.1. 
 
PFS based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
 
OS (OS will be collected at the end of the study). 
 
OS in subjects with PD-L1 positive tumors. 
 
ORR based on RECIST v.1.1. 
 
ORR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
 
DoR based on RECIST v.1.1. 
 
DoR based on RECIST v.1.1 in subjects with PD-L1 positive tumors. 
 
Safety. 
4.3 
Exploratory objective(s) and exploratory variables 
Exploratory objectives: 
 
Exploratory endpoints: 
4.4 
Safety evaluation 
The safety evaluation has been included in secondary objective (see 4.2). 
 
 
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4.5 
Determination of sample size 
The accrual objective are 44 patients, with an exact single-stage phase II design. The 
primary endpoint for this study is the CBR. CBR will be evaluated according to the 
RECIST criteria v.1.1. The CBR of MK3475 (pembrolizumab) in combination with eribulin 
will be assessed with the exact binomial test. In designing the trial, a CBR of 30% is 
deemed to be unacceptable in this patient population [16]. In contrast, a CBR of 50% 
would be considered to be successful. At least 17 patients with clinical benefit among 39 
patients will be adequate to justify the investigation of this strategy in further clinical trials. 
Considering a drop-out rate of 10%, a sample size of 44 patients will be needed to attain 
80% power at nominal level of one-sided alpha of 0.05. 
 
 
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4.6 
 
 
 
 
 
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MEDOPP127 Statistical Analysis Plan 
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MEDOPP127 Statistical Analysis Plan 
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MEDOPP127 Statistical Analysis Plan 
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SOP BS004 
 
 
 
 
 
 
 
 
 
 
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MEDOPP127 Statistical Analysis Plan 
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5. Study populations 
The analysis sets will be defined as follows:  
Full analysis set 
Full analysis set will include all patients that accomplish selection criteria and receive at 
least one drug exposure. 
Per-protocol set 
Per-protocol set will include all patients that accomplish selection criteria, receive at least 
one drug exposure, and receive the protocol required study drug exposure and 
processing. Criteria for determining the “per protocol” group assignment would be 
established by the Steering Committee before the statistical analysis begins. 
This analysis will only occur if this set differs by ≥ 10% from the full analysis set. 
Experior will send a list of protocol deviations (major and minor) to establish the per-
protocol set after the close out of data base (see section 5.1). 
Intent-to-treat (ITT) set with PD-L1 positive tumors 
ITT set will include all patients with PD-L1 positive tumors that accomplish selection 
criteria and receive at least one drug exposure. 
 
Safety set 
The safety set includes patients who receive at least one dose of study medication. 
5.1 
Protocol deviations 
Major deviation is defined as a breach that may significantly affect the safety and rights of 
the trial subjects or the reliability and robustness of the data generated in the clinical trial. 
Minor deviation is defined as conditions, practices or processes that indicate a need for 
improvement but are not expected to harm the rights, safety or well-being of the patients 
and/or the quality of the data.
Listings of protocol deviations will be reviewed prior to database lock and them will be send 
to sponsor in the closeout phase. 
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MEDOPP127 Statistical Analysis Plan 
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To determine per protocol set, all major protocol deviations will be check, and a list of exclude 
patients of the statistical analysis will be established by the Steering Committee. 
Data Management unit will review the following protocol deviations according to the data 
registered in the eCRF: 
 Inclusion/exclusion criteria not met. 
 Tumor assessments out of window (according to the protocol). 

Visits out of window (according to the protocol).
 Specific evaluations (ECOG, vital signs, hematology, etc.) not performed. 
 Prohibited medication administered. 
 Adjustments of dose not performed according to the protocol. 
 Study treatment interruptions > 21 days. 
 Study treatment administration out of window. 
Furthermore, Project Manager/CRA will provide a list of major protocol deviations registered 
during the monitoring visits period. 
 
 
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MEDOPP127 Statistical Analysis Plan 
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6. Statistical strategy 
Below are detailed the statistical aspects of the data analysis. 
6.1 
Primary analysis 
Primary analysis will be based primarily on the Full analysis set and secondarily on the 
Per protocol analysis set (if applicable, see section 5). 
6.1.1 Summary statistics 
CBR is defined as the number of subjects with complete response (CR), partial 
response (PR) or stable disease (SD) for at least 24 weeks divided by the number 
of patients in the analysis set. 
CBR= (CR+PR+SD) / Total number of patients 
The CBR results will be presented as number and proportion of patients with clinical 
benefit and 95% CI of the proportion. 
6.1.2 Statistical inference 
 
The study will be declared positive in the analysis of CBR if the one-sided p-value 
estimated in accordance with exact binomial test is ≤ 0.05. With this criterion, we will 
reach a positive finding if ≥ 17 patients achieve a clinical benefit among 39 patients. 
 
With this design, there is an 80% power of a positive finding if the true CBR is ≥ 50%. 
The one-sided type I error is 0.05. 
6.2 
Secondary analysis 
Secondary analysis will be performed on full analysis and per-protocol sets. Safety 
objectives will be based on the safety set. ITT set will be used to analyze the objectives 
based in subjects with PD-L1 positive tumors. 
6.2.1 Summary statistics 
Efficacy: 
 
CBR is defined as the number of subjects with complete response (CR), partial 
response (PR) or stable disease (SD) for at least 24 weeks based on RECIST v.1.1 
divided by the number of patients in the analysis set (in subjects with PD-L1 positive 
tumors). Tumor response will be defined as best response. The CBR results will be 
presented as number and proportion of patients with clinical benefit and 95% CI of 
the proportion. 
 
The radiological PFS is defined as the time from the first dose of treatment until death 
by any cause or objective tumor progression according to RECIST v.1.1. Patients with 
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MEDOPP127 Statistical Analysis Plan 
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no progression or death will be censored at the date of their last evaluable imaging. 
PFS censoring rules will follow FDA guidance in 2007 (see Table 1 - Appendix I). 
 The first dose of treatment is defined as the minimum date of the first 
administration of eribulin and/or pembrolizumab. 
 
The PFS as assessed by investigator is defined as the time from the first dose of 
treatment until death by any cause or objective tumor progression as assessed by 
investigator according to RECIST v.1.1. Patients with no progression or death will be 
censored at the date of their last evaluable imaging. PFS censoring rules will follow 
FDA guidance in 2007 (see Table 2- Appendix I). 
 oThe first dose of treatment is defined as the minimum date of the first 
administration of eribulin and/or pembrolizumab. 
 
The OS is defined as the time from the first dose of treatment until death by any cause 
or the last date the patient was known to be alive. Patients who are lost to follow-up 
and the patients who are alive at the date of data cut-off will be censored at the date 
the patient was last known alive (censoring rules are specified in Table 3 - Appendix 
I). 
A Kaplan-Meier survival analysis will be carried out to analyse PFS and OS. Number 
of events, median survival time and the corresponding 95% CI will be provided. 
Survival curves will be reported. 
 

The ORR is defined as the number of patients with CR and PR divided by the number
of patients in the analysis population. Tumor response will be defined as best 
response, based on local investigator’s assessment according to RECIST v.1.1. ORR 
will be reported as a proportion with the corresponding 95% CI. 
 
The DoR is defined as the time from first documented CR or PR until disease 
progression or death from any cause, according to RECIST v.1.1. In case of the 
patient first reaching PR and later CR, the duration of CR will be measured and 
reported separately, starting from the date when first documented and ending when 
a progressive disease is diagnosed, or the patient dies. 
Patients without PD or death will be censored and patients who has not documented 
neither CR nor PR response will be considered as not available in the Kaplan Meier 
analysis. 
Number of events, median survival time, 95% CI of median and survival curves 
calculated with Kaplan Meier analysis will be provided. 
Safety: 
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The degree of exposure (dose, duration of treatment, number of patients) will be 
assessed to determine the degree to which study safety can be assessed. These 
results will be presented with descriptive statistics (n, NA, mean, standard
deviation, median and range). 
 
Adverse events (AEs) and serious AEs (SAEs) will be classified using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be presented by preferred 
term (PT) and by system organ class (SOC). Severity, relationship to study drug 
(eribulin and pembrolizumab), action taken and outcome will be reported as 
frequency tables. 
 
Concomitant medications will be coded to the appropriate Anatomical-
Therapeutic-Chemical (ATC) code indicating 1st to 4th levels. The results will be 
reported by frequency tables. 
 
Deaths and study discontinuations will be described and assessed. It will be 
reported by frequency tables. 
6.2.2 Statistical inference 
A Kaplan-Meier survival analysis will be performed to analyze PFS, OS and DoR. 
The number of events and the median survival time with corresponding 95% CI will 
be provided.  
1- and 2-year survival rates with corresponding 95%CI will be calculated. 
Comparisons using log rank test or model of Cox proportional hazards multivariate 
analysis will be used if needed, and P values of 0.05 or less will be considered to 
indicate statistical significance. 
6.3 
Exploratory analysis 
6.3.1
Summary statistics
 
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6.4 
Subgroup analysis 
Subgroup analysis for CBR, ORR, PFS, OS and DoR will be performed outside the 
indications of the study protocol. The following variables will be part of this analysis to 
explore differences between subgroups of subjects: 
 
Ki67 ranges (≤ 13% (low), 14-19% (medium), ≥ 20% (high)) 
 
Previous treatment with CDK4/6 inhibitor 
 
Previous treatment with PI3K inhibitor 
The next variables will be used for the PFS, CBR and ORR subgroup analysis: 
 
Previous treatment with mTOR inhibitor 
 
ECOG (0 vs. 1) 
 
Number of organs involved (< 3 organs vs. ≥ 3 organs) 
 
Number of chemotherapy lines in metastatic setting (1 line vs. 2 lines) 
 
Endocrine sensitivity. Defined according to either of the following criteria: 
 Relapse that occurred after at least 24 months while the patient was 
receiving adjuvant endocrine therapy.  

Progression that occurred after at least 24 weeks while the patient was
receiving endocrine therapy in the context of metastatic disease. 
 
Neutrophil/Lymphocyte, ratio (<3 vs >=3) 
 
 
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6.5 
Statistical methods 
 
6.6 
Safety analysis 
The safety analysis has been included in secondary analysis (see 6.2.1). 
6.7 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be analyzed using the full analysis set. 
Descriptive statistics will use for the analysis: continuous variables will be summarized 
as n, number of not available data (NA), mean, standard deviation (SDev), median, first 
and third quartiles, minimum and maximum values. For categorical variables frequency 
tables will be presented (n and %). 
Demographic and baseline variables are: 
 
Age (at the IC signature) 
 
Race 
 
Clinically significant disease and surgical interventions (they will be coded with 
MedDRA) 
 
Toxic habits 
 
History of cancer 
 Number of relapses 
 Hormone receptors: ER and PR values 
 Ki67 
 HER2 status 
 Patients treated with anthracyclines, taxanes and antihormone therapy. 
 
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 Previous antineoplastic treatment for breast cancer. They will be classified 
as: 
§ 
Chemotherapty: 
Antracycline, 
Taxanes, 
Capecitabine, 
Vinorelbine, Other 
§ 
Endocrine therapy: Tamoxifen, Aromatase Inhibitors, Fulvestrant. 
§ 
Target therapy: CDK4/6 inhibitors, ParP inhibitors, mTOR 
inhibitors. 
 Previous procedure for breast cancer (surgery/radiotherapy). 
 HIV, HBV, HCV serology. 

Physical examination and ECOG status.
 Vital signs / ECG / LVEF. 
 Hematology and coagulation. 
 Biochemistry and thyroid function. 
 Evolution tables will be presented for laboratory values (hematology, 
biochemistry, coagulation, thyroid function). Data will be summarized with 
descriptive statistics for baseline and post-dose values. 
 Frequencies for toxicities related to clinically significant laboratory values 
will be presented (for 2-5 CTCAE grades). 
6.8 
Statistical model assumptions 
The proportional hazards assumption in the Cox model will be checked. 
6.9 
Transformation of expected variables 
 
The CBR is defined as the proportion of subjects who have best overall response 
of CR, PR or SD (by RECIST v.1.1): 
CBR= (CR+PR+SD)/Total of subjects 
 
The ORR is defined as the proportion of subjects who have best overall 
response of CR or PR (by RECIST v.1.1): 
ORR= (CR+PR)/Total of subjects 
 
The time to progression is defined as the difference between start of study drug 
(C1D1) and the progression date or death (whichever occurs first) or the last 
tumor assessment documented. 
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The time to death is defined as the difference between start of study drug and the 
date of death. 
 
Duration of response (DoR) is defined as the difference between first documented 
CR or PR and the disease progression date (by RECIST v.1.1) or death. 
 
Duration of treatment is defined as the difference between the first dose 
administrated of study drug (eribulin and/or pembrolizumab) and the date of EOT 
visit. If no date of EOT is available, the last administration of study drug will be 
used. 
6.10 Handling of missing data 
There is no planned procedure of imputation of missing values in other variables. The 
analysis will be performed with the available data. 
6.11
Description of the softwares to be used for data analysis
Statistical programming and analyses will be performed using the R statistical software 
version 3.1.3. 
6.12 Interim analysis protocol 
No interim analysis is planned. 
 
 
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MEDOPP127 Statistical Analysis Plan 
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6.13 List of tables and figures 
The tables below are an approximated list of the tables and figures that will be shown 
in the statistical analysis. They will be able to modify as required.
List of tables: 
Descriptive statistics for the age at the informed consent signature 
Absolute and relative (%) frequencies for the race 
Absolute and relative (%) frequencies for significant disease and surgical intervention 
(registered in medical history). 
Absolute and relative (%) frequencies for toxic habits 
Descriptive statistics for number of relapses 
Absolute and relative (%) frequencies for hormonal receptors (ER, PR) and HER2 
status 
Descriptive statistics for Ki67 
Absolute and relative (%) frequencies for patients treated with anthracyclines, taxanes 
and antihormone therapy (previous treatments) 
Absolute and relative (%) frequencies for patients treated with chemotherapy, 
endocrine therapy and target therapy. 
Absolute and relative (%) frequencies for previous procedure for breast cancer 
(surgery/radiotherapy) 
Absolute and relative (%) frequencies for HIV, HBV HCV 
Absolute and relative (%) frequencies for physical examination and ECOG status at 
screening visit 
Descriptive statistics for vital signs, ECG and LVEF at screening visit 
Descriptive statistics for laboratory tests (hematology, biochemistry and thyroid 
function) 
Absolute and relative (%) frequencies for toxicities (2 to 5 CTCAE grades) related to 
clinically significant laboratory values 
Absolute and relative (%) frequencies for the best response according to RECIST v1.1 
criteria. 
Results of CBR (proportion, % and 95% CI) 
Results for CBR vs. Ki67 ranges 
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Results for CBR vs. previous treatment with CDK4/6 inhibitor 
Results for CBR vs. previous treatment with PI3K inhibitor 
Results for CBR vs. previous treatment with mTOR inhibitor 
Results for CBR vs. PD-L1 
Results for CBR vs. ECOG 
Results for CBR vs. number of organs involved 
Results for CBR vs. lines of chemotherapy in metastatic setting 
Results for CBR vs. endocrine sensitivity 
Results for CBR vs. Neutrophil/Lymphocyte, ratio (<3 vs >=3) 
Absolute and relative (%) frequencies for progression disease events and/or deaths
Descriptive statistics for PFS (according to RECIST v1.1 criteria) 
Results for PFS (according to RECIST v1.1 criteria) vs. Ki67 ranges 
Results for PFS (according to RECIST v1.1 criteria) vs. previous treatment with CDK4/6 
inhibitor 
Results for PFS (according to RECIST v1.1 criteria) vs. previous treatment with PI3K 
inhibitor 
Results for PFS (according to RECIST v1.1 criteria) vs. previous treatment with mTOR 
inhibitor 
Results for PFS (according to RECIST v1.1 criteria) vs. PD-L1 
Results for PFS (according to RECIST v1.1 criteria) vs. ECOG 
Results for PFS (according to RECIST v1.1 criteria) vs. number of organs involved 
Results for PFS (according to RECIST v1.1 criteria) vs. lines of chemotherapy in 
metastatic setting 
Results for PFS (according to RECIST v1.1 criteria) vs. endocrine sensitivity 
Results for PFS (according to RECIST v1.1 criteria) vs. Neutrophil/Lymphocyte, ratio 
(<3 vs >=3) 
Descriptive statistics for PFS (according to investigator criteria) 
Results for PFS (according to investigator criteria) vs. Ki67 ranges 
Results for PFS (according to investigator criteria) vs. previous treatment with CDK4/6 
inhibitor 
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SOP BS004 
Results for PFS (according to investigator criteria) vs. previous treatment with PI3K 
inhibitor 
Results for PFS (according to investigator criteria) vs. previous treatment with mTOR 
inhibitor 
Results for PFS (according to investigator criteria) vs. PD-L1 
Results for PFS (according to investigator criteria) vs. ECOG 
Results for PFS (according to investigator criteria) vs. number of organs involved 
Results for PFS (according to investigator criteria) vs. lines of chemotherapy in 
metastatic setting 
Results for PFS (according to investigator criteria) vs. endocrine sensitivity
Results for PFS (according to investigator criteria) vs. Neutrophil/Lymphocyte, ratio (<3 
vs >=3) 
Descriptive statistics for PFS (according to irRECIST v1.1 criteria) 
Descriptive statistics for OS 
Results for OS vs. Ki67 ranges 
Results for OS vs. previous treatment with CDK4/6 inhibitor 
Results for OS vs. previous treatment with PI3K inhibitor 
Results for OS vs. PD-L1 
Results of ORR (proportion, % and 95% CI) (according to RECIST v1.1 criteria) 
Results for ORR vs. Ki67 ranges 
Results for ORR vs. previous treatment with CDK4/6 inhibitor 
Results for ORR vs. previous treatment with PI3K inhibitor 
Results for ORR vs. previous treatment with mTOR inhibitor 
Results for ORR vs. PD-L1 
Results for ORR vs. ECOG 
Results for ORR vs. number of organs involved 
Results for ORR vs. lines of chemotherapy in metastatic setting 
Results for ORR vs. endocrine sensitivity 
Results for ORR vs. Neutrophil/Lymphocyte, ratio (<3 vs >=3) 
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MEDOPP127 Statistical Analysis Plan 
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SOP BS004 
Results of ORR (proportion, % and 95% CI) (according to irRECIST v1.1 criteria) 
Descriptive statistics for DoR 
Results for DoR vs. Ki67 ranges 
Results for DoR vs. previous treatment with CDK4/6 inhibitor 
Results for DoR vs. previous treatment with PI3K inhibitor 
Results for DoR vs. PD-L1 
Descriptive statistics for dose of study treatment 
Descriptive statistics for duration of treatment 
Absolute and relative (%) frequencies for adverse events (coded as PT and SOC terms 
from MedDRA): severity, relationship to study drugs, action taken and outcome
Absolute and relative (%) frequencies for concomitant medication (coded using ATC) 
Absolute and relative (%) frequencies for deaths and discontinuations 
List of figures 
Kaplan-Meier curves for PFS (according to RECIST v1.1 criteria) and subgroups 
Kaplan-Meier curves for PFS (according to investigator criteria) and subgroups 
Kaplan-Meier curves for PFS (according to irRECIST v1.1 criteria) 
Kaplan-Meier curves for OS and subgroups 
Kaplan-Meier curves for DoR and subgroups 
 
 
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MEDOPP127 Statistical Analysis Plan 
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7. References 
1. R Core Team (2015). R: A language and environment for statistical computing. R Foundation 
for Statistical Computing, Vienna, Austria. URL (http://www.R-project.org/).
2. Guidance for Industry: Clinical Trail Endpoints the Approval of Cancer Drugs and Biologics 
(May 2007). 
 
 
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MEDOPP127 Statistical Analysis Plan 
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SOP BS004 
Appendix I 
Table 1. Censoring rules for PFS 
 
Situation 
Date of progression or censoring 
Outcome 
Progression documented 
between scheduled visits  
Earliest of: 
 
Date of radiological assessment showing new 
lesion (if progression is based on new lesion); 
or 

Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions);  
Or 
Progressed  
Death before first progression 
disease assessment 
Date of death 
Progressed  
Death between adequate 
assessment visits  
Date of death  
Progressed  
No progression 
Date of last radiological assessment of measured 
lesions 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment of measured 
lesions
Censored 
Treatment discontinuation for
toxicity or other reason* 
Date of last radiological assessment of measured 
lesions 
Censored 
Death or progression after 
more than one missed visit * 
Date of last radiological assessment of measured 
lesions 
Censored 
* In accordance with these criteria death after the end of treatment visit will be considered as censored 
with the date of last radiological assessment of measured lesions. 
 
 
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SOP BS004 
Table 2. Censoring rules for PFS as assessed by investigator. 
 
Situation
Date of progression or censoring
Outcome
No baseline assessment 
Randomization + 1 day 
Censored 
Progression documented* 
between scheduled visits 
Next scheduled visit 
Progressed 
No progression 
Date of last visit with adequate assessment 
Censored 
Investigator’s claim of 
progression* 
Scheduled visit (or next scheduled visit if between 
visits) 
Progressed 
Treatment discontinuation for
toxicity or other reason ** 
Date of last visit with adequate assessment 
Censored 
New anticancer treatment 
started with no claim of 
progression 
Date of last visit with adequate assessment 
Censored 
Death before first progression 
disease assessment 
Date of death 
Progressed  
Death between adequate 
assessment visits  
Date of death  
Progressed  
Death after an extended lost-
to-followup time (two or more 
missed assessments)** 
Last visit with adequate assessment 
Censored 
* In addition to the progressions confirmed by radiological criteria, also the progressions evaluated by 
the investigator, without a radiological image confirming them, will be considered as PFS events. 
** In accordance with these criteria death after the end of treatment visit will be considered as censored 
with the date of last adequate assessment. 
 
Table 3. Censoring rules for OS 
 
Situation 
Date of death or censoring 
Outcome 
Death during study follow-up 
Date of death 
Death 
The patient is alive at last follow-up Date of last follow-up 
Censored 
 
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