Conditions: Metastatic Pancreatic Adenocarcinoma Recurrent Pancreatic Adenocarcinoma Stage IV Pancreatic Cancer AJCC v6 and v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This pilot phase IIb trial studies how well pembrolizumab and CXCR4 antagonist BL-8040 work in treating patients with pancreatic cancer that has spread to other places. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CXCR4 antagonist BL-8040 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and CXCR4 antagonist BL-8040 may work better in treating patients with pancreatic cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the overall response rate (complete response or partial response) after treatment with CXCR4 antagonist BL-8040 (BL-8040) and pembrolizumab.

SECONDARY OBJECTIVES:

I. To determine the ability of BL-8040 by itself and in combination with pembrolizumab to increase T cell infiltration into the tumor.

II. To determine if BL-8040 treatment results in increases in circulating immune cells.

III. To estimate the safety and tolerability of intravenous administration of pembrolizumab in combination with sub-cutaneously injected BL-8040 in subjects with advanced pancreatic cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate overall response rate (ORR) per immune-related (ir) Response Evaluation Criteria in Solid Tumors (RECIST) and duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression free survival (PFS), and overall survival (OS) per RECIST and irRECIST assessed by MD Anderson investigators.

II. To explore the association between PD-L1 expression by immunohistochemistry, shed PD-L1 level, somatic gene expression profiling and antitumor efficacy of pembrolizumab based on RECIST 1.1 imaging criteria as well as overall survival.

III. To explore the relationship between genomic variation and response to the treatment administered.

IV. Tissue and blood immune monitoring will be conducted through our immune platform group as detailed per the biomarker section based on 3 biopsies done at the following time points: 1) pre-treatment, 2) during the third week of cycle 2 or beginning of cycle 3, and 3) voluntary upon end of cycle 1 (BL-8040 \[BL\] monotherapy) on days 10 to 14.

OUTLINE:

Patients receive CXCR4 antagonist BL-8040 subcutaneously (SC) on days 1-5 and 8-12 of cycle 1 and days 1, 4, 8, and 11 of subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab intravenously (IV) over about 30 minutes on day 1. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 10 and 12 weeks.

Arms:
arm 1: Patients receive CXCR4 antagonist BL-8040 SC on days 1-5 and 8-12 of cycle 1 and days 1, 4, 8, and 11 of subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab IV over about 30 minutes on day 1. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: CXCR4 Antagonist BL-8040 intervention 2: Pembrolizumab intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given SC intervention 2: Given IV intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Product:  Pembrolizumab 
1 
Protocol/Amendment No.:  2016-0410 
M.D. Anderson Cancer Center 
 
 
 
 
 
 
Version: November 11, 2016 
 
 
SPONSOR:  M.D. Anderson Cancer Center 
SUPPORTERS:  Merck, BiolineRx. 
 
TITLE:  A Phase IIb Pilot study to assess the efficacy, safety and pharmacodynamics effects of 
Pembrolizumab and BL-8040 in Patients with Metastatic Pancreatic Cancer. 
 
IND NUMBER:  131, 637 
 
 
Principal Investigator: 
 
David Fogelman, MD, Assistant Professor,  
1515 Holcombe Blvd, Unit 426, Department of GI Medical Oncology, Houston, TX 77030, 
Phone: 713-792-2828 
 
Email : dfogelman@mdanderson.org 
 
 
 
 
 
Statistician:                         J. Jack Lee, MS, PhD 
                                           Professor, Quantitative Research, Biostatistics 
                                           MD Anderson Cancer Center      
                                                T. Boone Pickens Academic Towe (FCT4.6018) 
                                                1515 Holcombe Blvd., Unit 1411 
                                                Houston, TX 77030  
                                                Phone (713) 794-4158 office  
 
 
 


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CONTENTS 
1.0 
TRIAL ABSTRACT ................................................................................................... 9 
Statist   Statisical Analysis Plan ....................................................................................... 10 
Corre    Correlative Studies ............................................................................................. 10 
2.0 
TRIAL DESIGN........................................................................................................ 10 
2.1 
Trial Design ........................................................................................................... 10 
2.2 
Trial Diagram ........................................................................................................ 12 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................. 12 
3.1 
Primary Objective(s) & Hypothesis(es) .............................................................. 12 
3.2 
Secondary Objective(s) & Hypothesis(es)........................................................... 12 
3.3 
Exploratory Objectives ......................................................................................... 13 
4.0 
BACKGROUND & RATIONALE .......................................................................... 13 
4.1 
Background ........................................................................................................... 13 
4.1.1 Pharmaceutical and Therapeutic Background – BL-8040 .................................. 14 
4.1.2 Pharmaceutical and Therapeutic Background – Pembrolizunab ........................ 15 
4.1.3 Preclinical and Clinical Trial Data ...................................................................... 16 
4.1.4 Ongoing Clinical Trials ....................................................................................... 17 
4.2 
Rationale ................................................................................................................ 17 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 19 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 19 
4.2.3 Rationale for Endpoints ...................................................................................... 22 
4.3 
Benefit/Risk ........................................................................................................... 28 
5.0 
METHODOLOGY ................................................................................................... 28 
5.1 
Entry Criteria ........................................................................................................ 28 


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5.1.2 Subject Exclusion Criteria ..................................................................................... 30 
5.2 
Trial Treatments ................................................................................................... 32 
5.2.1 Dose Selection .................................................................................................... 33 
5.2.2 Dose Modification (Escalation/Titration/Other) ................................................. 33 
5.2.3 Timing of Dose Administration .......................................................................... 35 
5.2.4 Trial Blinding/Masking ....................................................................................... 35 
5.3 
Treatment Assignment ......................................................................................... 35 
5.4 
Stratification .......................................................................................................... 35 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 36 
5.5.1 Acceptable Concomitant Medications ................................................................ 36 
5.5.2 Prohibited Concomitant Medications.................................................................. 37 
5.6 
Rescue Medications & Supportive Care ............................................................. 38 
5.6.1 Rescue Medications ............................................................................................ 38 
5.6.2 Supportive Care Guidelines ................................................................................ 38 
5.7 
Diet/Activity/Other Considerations ..................................................................... 41 
5.7.1 Diet ...................................................................................................................... 41 
5.7.2 Contraception ...................................................................................................... 41 
5.7.3 Use in Pregnancy ................................................................................................ 43 
5.7.4 Use in Nursing Women ....................................................................................... 43 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 43 
5.8.1 Discontinuation of Study Therapy after CR ....................................................... 44 
5.8.2 Treatment after Initial Radiologic Progression (irRECIST-based Management) 45 
5.9 
Subject Replacement Strategy ............................................................................. 47 
5.10 
Beginning and End of the Trial ........................................................................... 47 


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5.11 
Clinical Criteria for Early Trial Termination ................................................... 47 
6.0 
TRIAL FLOW CHART ........................................................................................... 47 
6.1 
Study Flow Chart .................................................................................................. 47 
7.0 
TRIAL PROCEDURES ........................................................................................... 49 
7.1 
Trial Procedures ................................................................................................... 49 
7.1.1 Administrative Procedures .................................................................................. 49 
7.1.2 Clinical Procedures/Assessments ........................................................................ 51 
7.1.3 Laboratory Procedures/Assessments .................................................................. 53 
7.1.4 Efficacy Measurements ....................................................................................... 55 
7.1.5 Other Procedures ................................................................................................. 60 
7.1.6 Visit Requirements .............................................................................................. 60 
7.2 
Investigator Communication with Merck and BiolineRx for Overdose, Pregnancy, 
Lactation, Serious Adverse Events, Events of Clinical Interest (ECI), and non-
serious Events of Clinical Interest. ...................................................................... 62 
7.2.1 Adverse Events ................................................................................................... 63 
7.2.2 Definition of an Overdose ................................................................................... 63 
7.2.3 Reporting of Pregnancy and Lactation to Merck and BioLineRx ...................... 64 
7.2.4 Immediate Reporting of Adverse Events to the Merck and BioLineRx ...... Error! 
Bookmark not defined. 
7.2.5 Evaluating Adverse Events ................................................................................. 69 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 71 
8.1 
Statistical Analysis Plan Summary ..................................................................... 71 
8.2 
Responsibility for Analyses .................................................................................. 73 
8.3 
Hypotheses/Estimation ......................................................................................... 73 
8.4 
Analysis Endpoints ............................................................................................... 73 
8.4.1 Efficacy Endpoints .............................................................................................. 73 


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8.4.2 Safety Endpoints ................................................................................................. 74 
8.5 
Analysis Populations ............................................................................................. 74 
8.5.1 Efficacy Analysis Populations ............................................................................ 74 
8.5.2 Safety Analysis Populations ............................................................................... 74 
8.6 
Statistical Methods ................................................................................................ 74 
8.6.1 Statistical Methods for Efficacy Analyses .......................................................... 74 
8.6.2 Statistical Methods for Safety Analyses ............................................................. 77 
8.6.3 Demographic and Baseline Characteristics ........................................................ 77 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
..................................................................................................................................... 77 
9.1 
Investigational Product ........................................................................................ 77 
9.2 
Packaging and Labeling Information ................................................................. 78 
9.3 
Storage and Handling Requirements .................................................................. 78 
9.4 
Returns and Reconciliation .................................................................................. 78 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 79 
10.1 
Confidentiality ....................................................................................................... 79 
10.1.1 Confidentiality of Data ........................................................................................ 79 
10.1.2 Confidentiality of Subject Records...................................................................... 79 
10.1.3 Confidentiality of Investigator Information ......................................................... 79 
10.1.4 Confidentiality of IRB/IEC Information ............................................................. 80 
11.0 
APPENDICES ........................................................................................................... 80 
11.1 
Merck Code of Conduct for Clinical Trials ........................................................ 80 
11.2 
Common Terminology Criteria for Adverse Events ......................................... 83 
11.3 
List of Abbreviations      ............................................ Error! Bookmark not defined. 
11.4 
ECOG Performance Status .................................................................................. 85 


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11.5 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors .................................................................................... 86 
11.6     Tip sheet for Resist 1.1 and irRESIST …………………………………………86 
12.0     REFERENCES .................................................................................................... 888 
 
 


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LIST OF TABLES 
 
Table 1 Adequate Organ Function Laboratory Values 
29 
Table 2  Trial Treatment 
32 
Table 3 Dose Modification Guidelines for Drug-Related Adverse Events 
33 
Table 4 Infusion Reaction Treatment Guidelines 
40 
Table 5 Imaging and Treatment after First Radiologic Evidence of PD (irRECIST-based 
Management) 
46 
Table 6 Study Flow Chart 
47 
Table 7 Laboratory Tests 
55 
Table 8 Imaging and Treatment after First Radiologic Evidence of PD 
60 
Table 9 Evaluating Adverse Events 
72 
Table 10 Key Elements of the Statistical Analysis Plan 
75 
Table 11 Analysis Stratgey for Efficacy Variables 
78 
Table 12 Statistical Methods Per Endpoint Anaylsis 
79 
Table 13 Censoring Rules for DOR 
80 
Table 14  Product Descriptions 
81 
Table 15 List of Abbreviations 
92 
Table 16  ECOG Performance 
94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF FIGURES 
 
 
Figure 1 Trial Design 
12 
Figure 2 Imaging and Treatment for Clinically Stable Subjects after First Radiologic Evidence of     
Progressive Disease Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease 
59 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 TRIAL ABSTRACT 
Abbreviated Title 
Pembrolizumab and BL8040 in Pancreatic Cancer 
Trial Phase 
Phase II study 
Clinical Indication 
Metastatic Pancreatic cancer 
Trial Type 
IIb, Pilot Study 
Type of control 
None 
Route of administration 
Pembrolizumab IV; Bioline 8040 Subcutaneous (SC) 
Trial Blinding 
None 
Treatment Groups  
Single arm 
Number of trial subjects 
15 
Estimated enrollment period 
6 months 
Estimated duration of trial 
24 months 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact.  After a 
screening phase of up to 28 days, patients are treated based on three 
week cycles.  In cycle 1, a daily dose of BL-8040 will be administered 
subcutaneously on days 1-5 and 8-12 (e.g. Mon-Fri for the first two 
weeks), week three will be free of treatment.  No pembrolizumab will be 
administered during cycle 1.  Cycles two and beyond will include 
pembrolizumab, administered on day 1 of the cycle, and BL-8040, 
administered BIW on weeks 1 and 2 (e.g. days 1,4, 8, and 11 of the 21 
day cycle).  In week three there will be no dosing. Dose 
Selection/Modification Treatment will continue until progressive disease, 
unacceptable adverse events, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the 
subject, subject withdrawal of consent, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, subject 
receives 17 treatments (approximately 1 year) of pembrolizumab, or 
administrative reasons requiring cessation of treatment.  Subjects who 
discontinue for reasons other than progressive disease will have post-
treatment follow-up visits for monitoring disease status until progressive 
disease, initiating a non-study cancer treatment, withdrawing consent 
from study participation, or becoming lost to follow-up.  All subjects will 
be followed (by telephone or visit) for overall survival until death, 
withdrawal of consent from study participation, or the end of the study.  
After the end of study treatment, each subject will be followed for 30 
days for adverse event monitoring.  Serious adverse events will be 
collected for 30 days after the end of treatment. 
 
Duration of Participation 
12 months 
Estimated average length of 
treatment per patient 
4 months 


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  Statisical Analysis Plan  
 
Simon’s 2-stage design will be used.  The null hypothesis that the true 
response rate is 10% will be tested against a one-sided alternative.  In 
this treatment arm, 15 patients will be accrued.  If there is </= 1 response 
in these 15 patients, research into this combination will be halted.  If we 
see significant activity, we will plan to study (in a subsequent protocol) 
an additional 26 patients, for a total of 41.  The null hypothesis will be 
rejected if 8 or more responses are observed in 41 patients.  This design 
yields a type I error rate of 5% and power of 80% when the true response 
rate is 25%. 
The 15 patients needed for this analysis will be enrolled as one cohort.  
Patients who do not receive study drug, and patients who receive BL 
only (cycle 1) and who withdraw from the study for reasons unrelated to 
safety or efficacy may be replaced in the cohort at the discretion of the 
investigator. 
  Correlative Studies 
Biomarker research to identify factors important for pembrolizumab 
therapy will be pursued.  Tumor and blood samples (including serum and 
plasma) from this study may undergo proteomic, genomic, metabolomic, 
and transcriptional analyses.  Additional research may evaluate factors 
important for predicting responsiveness or resistance to pembrolizumab 
therapy and other immunologic targets. 
We will avail ourselves of the services of the M.D. Anderson Tissue 
Molecular Pathology laboratory – in particular, the immunoprofiling lab 
(TMPIL) directed by Ignacio Wistuba.  Some correlative studies may be 
performed at Merck Research Labs.  Assays may include but are not be 
limited to: 
• 
Tumor PD-L1 Expression by IHC 
• 
Immune-related Gene Expression Profile (GEP) by Nanostring and 
HTG–Edge analysis 
• 
Transcriptional Analyses by global messenger RNA profiling 
• 
Proteomic Analysis by liquid chromatography/mass spectrometry.   
• 
Gene Analyses by next generation sequencing 
• 
Planned Genetic Analysis  
• 
Whole ExoBlood Analysis - Serum Cytokine Analysis; Liquid 
Biopsy Analysis; Flow cytometry 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This will be a pilot study investigating combinations of Pembrolizumab (Keytruda) with BL-8040 
(CXCR4) in patients with metastatic pancreatic cancer.  It will be a single arm trial of 15 patients and is 
designed to test the response rate and biological impact of their combination.  
Patients will initially receive BL-8040 as a single agent, followed by the addition of Pembrolizumab.  A 
biopsy will be performed, preferably from a metastatic site, prior to treatment.  An additional biopsy will 
be performed during the third week of cycle 1.  A third, optional biopsy will be requested during the 
third week of cycle 3. 


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In order to be eligible, subjects must have at least one measurable lesion per RECIST 1.1 criteria.  
Although subjects will be enrolled regardless of PD-L1 status, the pre- and post-treatment biopsis will 
be assessed for PD-L1 expression by IHC.   
Beginning with screening, all imaging assessments will be determined by the investigator's institution 
using RECIST 1.1 criteria. Images will be transferred to Merck for data analysis.  On-study imaging 
assessments will be performed every 9 weeks (63±7 days) calculated from the date of enrollment and 
independent of treatment delays.  RECIST 1.1 will be used by the site for treatment decisions until the 
first radiologic evidence of progressive disease (PD).  Following the first radiologic evidence of PD by 
RECIST 1.1, treatment decisions may be made by the adaptation of RECIST 1.1 as described in 
Sections 4.2.3.2 and 7.1.6.4.1.5 termed immune-related RECIST (irRECIST) to accommodate the tumor 
response patterns seen with pembrolizumab treatment (e.g., tumor flare).  This was first described by 
Nishino, et al. 20131, but is further modified for the PD-1 program.  For a clinically stable subject with 
first radiologic evidence of PD, it will be at the discretion of the investigator to continue treating the 
subject with pembrolizumab until PD is confirmed at least 4 weeks from the date of the first tumor 
imaging suggesting PD.  If radiologic PD is confirmed, the subject should be discontinued from 
treatment unless, in the opinion of the investigator, the subject is achieving a clinically meaningful 
benefit; an exception for continued treatment may be considered following consultation with Merck. 
Subjects may continue to be treated with pembrolizumab until PD is confirmed by modified RECIST, 
unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, 
investigator decides to withdraw the subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, administrative reasons, or the subject has 
received 17 trial treatments (approximately 1 year) with pembrolizumab.  Subjects who discontinue trial 
treatment will move into the Follow-Up Phase and should be assessed every 9 weeks (±3 weeks) by 
radiologic imaging to monitor disease status for up to 12 months calculated  from the date of treatment 
and independent of treatment delays and then every 12 weeks (±3 weeks) thereafter. The follow-up 
phase imaging does not apply to patients who terminate treatment for disease progression.  Disease 
status will continue to be monitored until whichever of the following occurs first:  The start of new anti-
cancer treatment, disease progression, death, or the end of the study.  All subjects, once progressed, will 
be followed every 12 weeks for OS until death, withdrawal of consent from participation in the study, or 
the end of the study, whichever comes first.   
Subjects who attain a complete response (CR) by 2 tumor imaging assessments at least 4 weeks apart 
and who have received at least 8 treatments (approximately 6 months of therapy) with pembrolizumab 
may discontinue treatment at the discretion of the investigator after receiving at least 2 treatments 
beyond the initial determination of a CR.  Such patients would thereafter be allowed to resume treatment 
at the discretion of the investigator in the event of a recurrence. 
Adverse events will be monitored throughout the trial and graded in severity according to the guidelines 
outlined in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (Section 12.11).  After the end of treatment, each subject will be followed for 30 
days for AE monitoring.  Serious adverse events (SAEs) will be collected for 30 days after the end of 
treatment.   
This study will be conducted in conformance with Good Clinical Practices (GCP). 


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2.2 
Trial Diagram 
Figure 1. Trial Design:  
 
 
 
 
 
 
 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective:   To assess the overall response rate (complete response, partial response) after treatment 
with BL-8040 and Pembrolizumab. 
Hypothesis:  The increase in immune cell infiltration into pancreatic cancers will slow disease 
growth, and may result in regression of disease.   
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To determine the ability of BL-8040 by itself and in combination with pembrolizumab 
to increase T cell infiltration into the tumor. 
Hypothesis:  One of the anticipated effects of BL-8040 is the mobilization of immune cells from the 
bone marrow and peripheral blood.  Another anticipated effects are a reduction of stroma, an 
increased infiltration of immune cells into tumor and a decrease of the Myeloderived suppressor 
cells in the tumor microenvironment.  If so, we should be able to measure these changes both after 
single agent BL-8040 administration, as well as after combined treatment with BL-8040 and 
Pembrolizumab.    
1+ Prior Rx
ECOG 0-1
Liver met 
amenable 
for biopsy
Measurable 
Disease
CT within 2 
weeks
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Wk 6
Wk 7
Wk 8
BL d1-5
BL d8-12
Week off
BL d22, 25
BL d29, 32
BL d43, 46
Week off
BL d50, 53
Beginning of Pembro – Cycle #1 - d22
Cycle 1
Cycle 2
Cycle 3
Pembro – Cycle # 2 - d43
Biopsy
d15-0
Biopsy
d15-21
Biopsy
d53+
Correlative Studies Blood:
Weekly Monday; Weeks 1-9; and End of Treatment
Laboratory Assessments:
d1-5; 8-12; 22, 25, 29, 32, 43, 46, 50, 53
Tumor Imaging:
Pre-screening visit; Week 9, q9w, and End of treatment
Tumor Biopsy:
Pre-Screening visit; Week 3, and End of week 8 or week 9
Wk 9
Week off
Refer to page 27, “Blood Analysis” 


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(2) Objective:  To determine if BL-8040 treatment results in increases in circulating immune cells.   
Hypothesis:  A putative mechanism of BL-8040 is an increase in the release of immune cells from 
the bone marrow environment.  If so, this should be simple to demonstrate through serial blood 
sampling.      
(3) Objective: To estimate the safety and tolerability of intravenous administration of pembrolizumab in 
combination with sub-cutaneously injected BL-8040 in subjects with advanced pancreatic cancer.   
Hypothesis:  That pembrolizumab and BL-8040 are safe and effective in subjects with advanced 
pancreatic cancer.   
3.3 
Exploratory Objectives 
(1) Objective:  To evaluate Overall response rate (ORR) per irRECIST and duration of response 
(DOR), disease control rate (DCR), time to progression (TTP), progression free survivial (PFS), 
and Overall survivial (OS) per RECIST and irRECIST assessed by MD Anderson investigators. 
(2) Objective: To explore the association between PD-L1 expression by immunohistochemistry, 
shed PD-L1 level, somatic gene expression profiling and antitumor efficacy of pembrolizumab 
based on RECIST 1.1 imaging criteria as well as overall survival. 
  
(3) Objective: To explore the relationship between genomic variation and response to the treatment 
administered.  Variation across the human genome may be analyzed for association with clinical 
data collected in this study.   
(4) Objective: Tissue and blood immune monitoring will be conducted through our immune 
platform group as detailed per the biomarker section based on 3 biopsies done at the following 
time points: 1) pre-treatment, 2) during the third week of cycle 1, and 3) during the third week of 
cycle 3. 
  
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Immunotherapeutic agents such as anti-CTLA4 antibodies and anti-PD-L1 antibodies enhance the 
immune system’s response to cancer.  They are effective in a number of tumor types – for example, 
melanoma and non-small cell lung cancer.  However, these agents have been shown to be ineffective 
against pancreatic ductal adenocarcinoma (PDA).  In one early example, BMS-936559, an anti-PD-L1 
antibody, was administered to a group of patients with advanced cancer.  While responses were seen in 
patients with melanoma, non-small cell lung cancer, renal cell cancer, and ovarian cancer, none of the 14 
patients with pancreatic adenocarcinoma demonstrated a radiologic response2.  In a later study, 
investigators at Johns Hopkins treated PDA patients with either ipilimumab alone or in combination 
with the GVAX vaccine.3  Again, disappointingly, while some patients demonstrated transient stable 
disease, there were no objective responses to the combination.  One potential mechanism for an absence 
of efficacy in PDA patients is an ability of these cancers to exclude immune cells from the tumor 


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stroma.  Accordingly, this study will address whether BL-8040 can overcome this barrier to 
immunotherapy. 
4.1.1 Pharmaceutical and Therapeutic Background – BL-8040 
Please refer to the Investigator’s Brochure for updated BL-8040 information 
BL-8040 is a 14 residue synthetic peptide capped with an aromatic ring.  It binds and inhibits the 
CXCR4 chemokine receptor with high affinity.  BL-8040 was shown to be a specific antagonist of 
CXCR4 and to have a slow dissociation rate from the receptor, with receptor occupancy extending over 
24 hours. 
There are four potential mechanisms by which BL-8040 may improve the activity of immunotherapy in 
PDA.  First, BL-8040 has demonstrated accelerated mobilization of adult white blood cells (neutrophils, 
monocytes, lymphocytes) from the bone marrow to the peripheral blood4.  A single dose in adult healthy 
volunteers resulted in a substantial increase in T cells, B cells, NK cells, and dendritic cells into the 
peripheral blood.  These include both naïve and effector memory T lymphocyte subsets.  One hope is 
that cells mobilized by this agent may then be available to infiltrate 
into tumor. 
A second potential mechanism includes distraction of stromal 
barriers to immune cell entry into the tumor.  The tumor 
microenvironment of pancreatic ductal adenocarcinomas (PDA) 
actively suppresses infiltration of immune cells by secretion of SDF-
1/CXCL12, which restrains immune cells from penetrating into the 
interior of the tumor.  CXCR4 inhibition allows T-cell infiltration 
into the interior of the tumor, allowing for a potential synergistic 
effect with PD-L1 antibodies.5  Carcinoma Associated Fibroblasts 
(CAFs) secrete CXCL12/SDF-1, which in turn coats cancer cells in 
the tumor.  CXCL12 bound to tumor cells suppresses the ability of 
immune cells to enter the tumor and exert an immunological effect.  
The application of an exogenous CXCR4 antagonist (AMD3100) to tumor cells in vitro blocks CXCL12 
and allows for increased immune suppression.  In a mouse model, combination of this exogenous 
CXCR4 antagonist with PD-L1 antibody was synergistic in inducing T-cell infiltration into the tumor, 
resulting in tumor shrinkage.   FACS analysis confirmed increases in CD45, CD11c, GR1, and CD3, 
among other T cell markers. 
In addition to allowing effector T cells into the tumor, disruption of the CXCR4/CXCL12 interaction 
may also reduce T suppressor cells from entering the tumor.  Righi6 and others have demonstrated this 
effect in ovarian cancer model, noting a reduction of FoxP3 T suppressor cells.  As this appears to be 
distinct from the impact on effector cells, this may be considered a third mechanism of action of BL-
8040. 
A fourth potential mechanism of action of BL-8040 is through upregulation of CCL20, a 
chemoattractant for dendritic cells (DCs).  Prior work with colon cancer and melanoma cell lines has 
demonstrated that tumor associated DCs reside at the periphery of the tumor and may fail to effectively 


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stimulate local T cells from a naïve state to an effector state.7  Stimulation of dendritic cells may result 
in mature, primed cells that are more capable of inducing an immune response.8,9  CCL-20/macrophage 
inflammatory protein-3a (MIP-3a) is a chemoattractant for dendritic cells, and may increase the number 
of DCs in tumor.10  BL-8040 has been shown to increase CCL20 production by PDA tumor cells.  One 
goal of this study is to assess whether  such an increase may be found in PDA patients treated with this 
agent.      
4.1.2 Pharmaceutical and Therapeutic Background – Pembrolizunab 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
MK-3475 
Pembrolizumab (Keytruda, MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.   
Keytruda® (pembrolizumab) is a programmed death receptor-1 (PD-1)-blocking antibody indicated for 
the treatment of: 
 
1. Patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, 
if BRAF V600 mutation positive, a BRAF inhibitor. 
 
2. Patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved 
test and who have 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 KEYTRUDA 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades.  Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors 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 unwanted or excessive immune responses, including autoimmune 
reactions.  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).  The structure of murine PD-1 has been resolved.  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by which 


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PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  
Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as 
well as subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors .  Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment 
of patients with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
Therapeutic studies in mouse models have shown that the administration of antibodies blocking the PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor 
rejection, either as a monotherapy or in combination with other treatment modalities.  Anti-mouse PD-1 
or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a monotherapy in models of 
squamous cell carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma.  Blockade of the 
PD-1 pathway effectively promotes CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, 
granzyme B and perforin, indicating that the mechanism of action involves local infiltration and 
activation of effector T-cell function in vivo 11-16.  Experiments have confirmed the in vivo efficacy of 
PD-1 blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the Investigator’s Brochure [IB]). 
Clinical trials have demonstrated efficacy using pembrolizumab in subjects with advanced melanoma, 
non-small cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric adenocarcinoma.  In addition, recent data demonstrates emerging evidence of 
single-agent activity in additional tumor types such as mesothelioma, urothelial cancer, ovarian cancer, 
neuroendocrine carcinoma, and small cell lung cancer. 


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4.1.4 Ongoing Clinical Trials 
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, non- small cell 
lung cancer, and a number of other advanced solid tumor indications and hematologic malignancies.  
For study details refer to the IB. 
 
4.2 
Rationale 
Cancer immunotherapy is a novel and rapidly growing field of research investigating the use of 
therapies that harness the body’s own immune system in the fight against the tumor. Tumors utilize a 
variety of mechanisms to evade host immune detection. Cancer cells, as well as infiltrating monocytic 
cells, including dendritic cells and macrophages—express PD-L1, which suppresses the proliferative 
and effector responses of T cells by engaging the inhibitory PD-1 receptor on these cells. In addition, 
there is mounting evidence that some tumor-infiltrating immune cells such as MDSCs, T-regulatory 
cells (Tregs) and tumor-associated macrophages, actively modulate the tumor microenvironment to 
suppress the effector arms of this response. The aim of cancer immunotherapy  is to prevent the tumor’s 
ability to suppress its own detection and elimination by the host immune system. The therapeutic effect 
of blocking antibodies to the immune checkpoint regulators cytotoxic T-lymphocyte–associated protein 
4 (CTLA-4) and the programmed cell death protein 1 (PD-1)/PD-L1 receptor-ligand pair is considered a 
major breakthrough in the treatment of several solid tumors. Nevertheless, it has become apparent that 
even if these T cell checkpoint antagonists overcome some of the immune-suppressive effects of the 
tumor microenvironment, other, more fundamental inhibitory reactions in the tumor microenvironment 
may constitute the underlying reason for the fact that many subjects— especially those with 
microsatellite stable colorectal cancer, ovarian cancer, prostate cancer, and pancreatic ductal 
adenocarcinoma — rarely exhibit objective responses to these therapies. 
It was found that activated fibroblasts in the tumor stroma mediate immune suppression in several 
mouse models of cancer. The basis of the immune suppression involves the production of the 
chemokine, CXCL12, by cancer associated fibroblasts. Binding of this CXCL12 by T cells leads to their 
exclusion from the vicinity of the cancer cells. T cell exclusion causes antagonists of T cell checkpoints 
to be ineffective, despite the presence of cancer-specific CD8+ T cells. The exclusion of CD8+ T cells 
from the vicinity of cancer cells in CRC was shown to correlate with a poor long-term clinical 
outcome17,18. Exclusion of T cells from the vicinity of cancer cells was also found in ovarian cancer19,20 
and PDA5. Thus, the tumor microenvironment can limit the capacity of T cells to accumulate among 
cancer cells. This immune suppression is interrupted by administering inhibitors of CXCR4, the receptor 
for CXCL12, which leads to the rapid accumulation of T cells among cancer cells, thereby uncovering 
the efficacy of immune checkpoints inhibitors5,21. 
BL-8040 (BKT-140) is a 14-residue, cyclic, synthetic peptide capped with an aromatic ring. BL-8040 
was shown in vitro and in vivo to be a specific antagonist of CXCR4 with high affinity to the CXCR4 
receptor (0.54-5.4 nM) and long receptor occupancy (>48hrs). BL-8040 is considered the most active 
CXCR4 peptide antagonist among inhibitors of the same class. In vitro and in vivo preclinical studies 
have shown that in addition to its activity as a mobilizer of hematopoietic cells, BL-8040 exhibits a 
CXCR4-dependent preferential anti-tumor effect against malignant cells overexpressing CXCR422-24. 
The efficacy of BL-8040 and its analogues for blocking CXCR4 in vitro and in vivo has been 


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documented in numerous preclinical studies, including in vitro and in vivo models for small cell lung 
carcinoma, breast cancer, malignant melanoma, neuroblastoma and pancreatic cancer25,26 (and 
unpublished). As a CXCR4 antagonist, BL-8040 affects the trafficking of immune cells to the tumor 
microenvironment. It was found that administration of BL-8040 induces the mobilization of NK cells, T 
cells and B-cells from the BM and lymph nodes into the periphery. Using a syngeneic cancer model in 
mice it was demonstrated that BL-8040 may eliminate the immunological barrier and allow the 
accumulation of immune cells within the tumor microenvironment (further details are available in the 
BL-8040 IB). 
These findings raise the possibility that increasing the proportion of cancer-specific T cells may be more 
effective if immunotherapy is combined with a CXCR4 antagonist that alters the immune-suppressive 
tumor microenvironment. The aim of this study is to examine the effectiveness of combining BL-8040, a 
CXCR4 antagonist, with pembrolizumab, a PD-1 monoclonal antibody, in pancreatic ductal 
adenocarcinoma patients. 
Blood samples taken throughout the study (baseline, weekly through week 6, end of study) will be 
investigated specifically for carbohydrate antigen 19-9 (CA 19-9) expressed on the surface of cancer 
cells as a glycolipid and as an O-linked glycoprotein. CA 19-9 has been identified in the tissue and sera 
of subjects with gastrointestinal tumors including esophageal, gastric, biliary and pancreatic cancer. CA 
19-9 is the most extensively studied and validated serum biomarker for the diagnosis of pancreatic 
cancer in symptomatic subjects. The CA 19-9 serum level can provide important information with 
regards to prognosis, overall survival, and response to chemotherapy as well as predict post-operative 
recurrence. 
Blood samples will also be characterized by flow cytometric immunophenotyping to study the kinetics 
and identity of immune cells enriched in the blood of treated subjects following treatment with the study 
drugs (baseline, weekly for the first six weeks). Flow cytometric immunophenotyping will evaluate 
individual cells in suspension for the presence and absence of specific antigens (including but not 
limited to: CD45, CD3, CD4, CD8, CD56, CD11b, CD86, CD25 and Foxp3) to determine which 
immune cells are enriched in the blood circulation following the treatment. In addition, the expression 
and receptors' occupancy by the study drugs will be assessed by means of flow cytometry analysis using 
specific antibodies against the two targeted proteins, PD-1 and CXCR4.  
Biopsy samples from tumor tissue (liver metastasis) will be evaluated for immune cells infiltration by 
immunohistochemistry and/or immunofluorescence. Using specific markers against specific antigens 
(including but not limited to: CD45, CD3, CD4, CD8, CD56, CD11b, CD86, CD25 and Foxp3). This 
study will provide qualitative information with regards to the kinetics and identity of immune cells 
enriched in the tumor tissue following treatment with the study drugs. Biopsy samples will also be 
characterized for expression of specific proteins by immunohistochemistry and/or immunofluorescence 
(including but not limited to: PDL-1, FAP, CCL20, CXCL12 and apoptotic markers) to better 
understand the molecular signaling affected by treatment with the study drugs and its correlation with 
response to the treatment under evaluation. 


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4.2.1 Rationale for the Trial and Selected Subject Population 
As a pilot study, we are seeking both an objective response rate to the combination, as well as sufficient 
numbers of patients who will be amenable for serial biopsies which might inform us as to changes in 
tumor biology and immune infiltrates after both BL-8040 as a single agent and in combination with 
pembrolizumab. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
4.2.2.1 Pembrolizumab (MK-3475) 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose recently 
approved in the United States and several other countries for treatment of melanoma subjects is 2 mg/kg 
Q3W.  Information on the rationale for selecting 200 mg Q3W is summarized below. 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity 
of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 
3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All 
three dose levels were well tolerated and no dose-limiting toxicities were observed.  This first in human 
study of MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to 
date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from other clinical 
studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days).  This early PK and pharmacodynamic 
data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 
were found to be dependent on body weight. The relationship between clearance and body weight, with 
an allometric exponent of 0.59, is within the range observed for other antibodies and would support both 
body weight normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain 
well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W 
vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
 


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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 
mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for 
both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of 
tumor burden or indication on distribution behavior of pembrolizumab (as assessed by the population 
PK model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
4.2.2.2 BL-8040 
Dose Selection 
In the Phase I/IIa study BKTSC001 (NCT01010880), a dose escalation study to assess the safety of BL-
8040 for induction of mobilization of progenitor and stem cells from the BM to the PB in subjects with 
multiple myeloma, a total of 18 subjects were exposed to escalating doses according to the following 
scheme: 
Group dose BL-8040 mg/kg [free base] 
N 
1 
0.006 [0.0048] 
2 
2 
0.03 [0.024] 
4 
3 
0.1 [0.08] 
4 
4 
0.3 [0.24] 
4 
5 
0.9 [0.72] 
4 
 
In Phase I study, BL-8040.02 (NCT02073019), the safety, tolerability, pharmacodynamic and PK effect 
of ascending doses of BL-8040 were assessed in healthy subjects. The study had two phases, escalation 
and expansion. A total of 26 subjects were exposed to escalating doses of BL-8040 according to the 
following scheme: 
Group dose 
BL-8040 mg/kg (free 
base) 
N (escalation) 
N (expansion) 
1 
0.5 
8 (6 active) 
- 
2 
0.75 
8 (6 active) 
- 


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3 
1.0 
8 (6 active) 
8 
 
In addition, ascending doses of BL-8040 were assessed in the BL-8040.01 (NCT01838395) study, a 
phase IIa study to assess the safety and efficacy of BL-8040 in subjects with relapsed/refractory acute 
myeloid leukemia. A total of 25 subjects were exposed to seven days of BL-8040 according to the 
protocol’s escalation scheme and three additional subjects received compassionate use therapy 
according to the scheme below. All doses were found to be safe and well tolerated and the 1.5 mg/kg 
was selected for the currently ongoing expansion phase.  
Group dose 
BL-8040 mg/kg (free N (escalation) 
Compassionate use 
1 
0.5 
3 
- 
2 
0.75 
3 
- 
3 
1.0 
6 
- 
4 
1.25 
4 
2 
5 
1.5 
6 
1 
6 
2.0 
3 
- 
 
The maximum tolerated dose (MTD) in humans for BL-8040 has not been reached. A similar PK profile 
was observed across different clinical studies showing similar exposure between healthy volunteers, 
multiple myeloma subjects and AML subjects. Adequate receptor occupancy was confirmed from the 
1.0 mg/kg dose and higher. The rationale for the suggested combination relies on the ability of BL-8040 
as a CXCR4 antagonist to mobilize immune cells from the BM and the lymph nodes to the PB. Rapid 
and dose-dependent mobilization of WBCs was seen in both, preclinical studies (mice) and humans 
treated with BL-8040. BL-8040 induces rapid (2-4 hrs), dose-dependent and transient mobilization of 
WBCs, including monocytes, B-cells, T cells and NK cells. The mobilization effect of BL-8040 was 
observed at doses of 0.5-2.0mg/kg in all conducted clinical trials. In addition, immune suppression by 
the tumor microenvironment involves the production of the chemokine, CXCL12 the ligand of CXCR4, 
by the fibroblastic stromal cells. Binding of CXCL12 by T cells results in their exclusion from the 
vicinity of the cancer cells. T cell exclusion occurs in several types of human adenocarcinomas, causes 
antagonists of T cell checkpoints to be ineffective, despite the presence of cancer-specific CD8+ T cells. 
This immune suppression may be interrupted by administering BL-8040, an inhibitor of CXCR4, the 
receptor for CXCL12, which leads to the rapid accumulation of T cells among cancer cells, thereby 
uncovering the efficacy of the anti-PD-1 and eliminating cancer cells. The effect was seen in mice at a 
dose range of 10-20 mg/kg, equivalent to 0.83-1.66 mg/kg, respectively, in humans. 
Although the higher dose tested in the BL-8040.01 study (1.5 mg/kg) in combination with cytarabine 
was found to be safe and well tolerated and MTD was not achieved, our policy with new combinations 
is to leave safety margins and use a dose lower than the highest tested exposure in humans. In general, 
BL-8040 at the dose of 1.25 mg/kg was observed to be associated with a favorable safety profile with 


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the most common AEs being injection site irritation, flushing, and itching, and systemic reactions that 
were successfully managed with pre-medication. 
Based on the above safety, mobilization and preclinical effect on the tumor microenvironment the 1.25 
mg/kg dose was selected for the combination study. 
Regimen Selection 
The considerations for the proposed regimen (BL-8040 monotherapy at days 1-5 and 8-12 followed by 
BL-8040 two times a week [BIW] in combination with pembrolizumab 200 mg every three weeks 
[Q3W] fixed-dose regimen) are as follows: 
1. The aim of the BL-8040 monotherapy at days 1-5 and 8-12 is to enable the identification of a 
single agent effect of BL-8040 on increased T cell infiltration. 
2. For the combination cycles, the long receptor occupancy of BL-8040 (48-72 hrs) supports a BIW 
administration that will ensure continuous CXCR4 inhibition in order to facilitate T effector cell 
infiltration. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
4.2.3.1.1 Primary Efficacy Endpoints 
Objective response rate by RECIST will be the primary endpoint.  Immunotherapy has so far been 
disappointing in pancreatic cancer patients, with little response observed among patients treated with 
immune checkpoint inhibitors.  Observed responses would suggest a synergistic relationship between 
the two medications.  If the combination of pembrolizumab and BL-8040 does have clinical efficacy, we 
would hope to show this in at least a small number of patients enrolled in our study (see statistical 
design, section 8). 
4.2.3.1.2 Secondary efficacy endpoints 
Secondary efficacy endpoints will include among others, progression free survival and overall survival.  
Secondary endpoints are defined as follow: 
1) 
ORR (overall response rate) , defined as the proportion of subjects who have a CR or PR 
using irRECIST 1.1 and with confirmatory assessment as required per irRECIST at any 
time during the trial.  Observed responses would suggest a synergistic relationship between 
the two medications.  Subjects with unknown or missing response information will be 
treated as non-responders. 
 
2) 
DCR (disease control rate), defined as the proportion of subjects who have a CR, PR, or SD 
(stable disease) using RECIST 1.1 and with confirmatory assessment as required by 


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irRECIST at any time during the trial.  Subjects with unknown or missing response 
information will be as not meeting this definition. 
 
3) 
DOR (duration of response), defined in the subset of subjects with a CR or PR, based on 
RECIST 1.1 and with confirmatory assessment as required per irRECIST, as the time from 
first documented evidence of CR or PR until the first documented sign of disease 
progression or death due to any cause, whichever occurs first. Subjects who are alive, have 
not progressed, have not initiated new anti-cancer treatment, and have not been determined 
to be lost to follow-up are considered ongoing responders at the time of analysis. 
 
4) 
PFS (preogression free survivial), defined as the time from the 1st dose of study treatment 
to the first documented disease progression according to RECIST 1.1 and with 
confirmatory assessment as required per irRECIST, or death due to any cause, whichever 
occurs first. If a subject does not have a documented date of progression or death, PFS will 
be censored at the date of the last adequate assessment. 
 
5) 
OS (overall survivial), defined as the time from the date of the 1st dose of study to the date 
of death due to any cause. Censoring will be performed using the date of last known 
contact for those who are alive at the time of analysis. 
 
Toxicity endpoints will include treatment emergent adverse events. 
4.2.3.1.3 Exploratory Efficacy Endpoints 
Tissue and blood immune monitoring will be conducted through our immune platform group as detailed 
per the biomarker section based on 3 biopsies done at the following time points: 1) pre-treatment, 2) 
during the third week of cycle 1, and 3) during the third week of cycle 3. Exploratory efficacy objectives 
of this study are to explore the association between biomarkers including PD-L1 protein expression by 
IHC, CXCR4 expression, MSI status, mutation burden, cytokine profile, and gene expression profiling, 
and antitumor efficacy and survival outcome of pembrolizumab based on RECIST 1.1 as assessed by 
MD Anderson investigators in subjects with pancreatic cancer; and to evaluate ORR, DOR, TTP and 
PFS per irRECIST  assessed by MD Anderson investigators.  
4.2.3.2 Immune-related RECIST (irRECIST) measurements 
RECIST 1.1 will be the imaging criteria we will use for response assessment. In addition we will us a 
modified RECIST 1.1 criteria adapted to account for the unique tumor response characteristics seen with 
pembrolizumab treatment.  Immunotherapeutic agents such as pembrolizumab may produce anti-tumor 
effects by potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest a clinical response after an initial increase in tumor burden or even the appearance of 


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new lesions.  Standard RECIST 1.1 thus, may  not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab.  
Based on an analysis of patients with melanoma enrolled in Keynote 001, 7% of evaluable patients 
experienced delayed or early tumor pseudoprogression.  Of note, patients who had progressive disease 
by RECIST 1.1 but not by immune-related response criteria had longer OS than patients with 
progressive disease by both criteria.  Additionally, the data suggest that RECIST 1.1 may underestimate 
the benefit of pembrolizumab in approximately 15% of patients.  These findings support the need to 
apply a modification to RECIST 1.1 that takes into account the unique patterns of atypical response in 
immunotherapy and enable treatment beyond initial radiographic progression.  
irRECIST is RECIST 1.1 adapted to account for the unique tumor response seen with immuno-
therapeutics as described in Nishino et al.1.  The assessment of unidimensional target lesions and 
response categories per irRECIST are identical to RECIST 1.1.  However, Merck has implemented an 
adaptation related to new lesions, non-target and tumor burden assessment in order to confirm 
radiographic progression.  irRECIST will be used by the investigators to assess tumor response and 
progression, and make treatment decisions as well as by MD Anderson investigators in support of all 
secondary and exploratory response  endpoints.  Confirmation of PD for irRECIST endpoints will be 
taken from central imaging retrospectively, according to irRECIST definition.   
4.2.3.3 Safety Endpoints 
The safety objective of this trial is to characterize the safety and tolerability of pembrolizumab in 
combination with BL-8040 in subjects with previously systemically treated pancreatic cancer.  The 
primary safety analysis will be based on subjects who have toxicities as defined by CTCAE, v4.03. 
The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded on case report forms or electronically  using PDMS/CORe 
and DMI.  AEs will be analyzed including, but not limited to, all AEs, SAEs, fatal AEs, and laboratory 
changes.  Furthermore, specific events will be collected and designated as events of clinical interest 
(ECIs) as described in Section 7.2.3.2 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of 
trial treatment or before the initiation of a new anti-neoplastic treatment, whichever comes first.  All 
AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade 
>1 will be followed until the resolution or stabilization of the AE to Grade 0-1 or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 30 days following cessation 
of treatment should be followed and recorded. 
4.2.3.4 Biomarker Research 
Biomarker research to identify factors important for pembrolizumab therapy will be pursued.  Tumor 
and blood samples (including serum and plasma) from this study may undergo proteomic, genomic, 
metabolomic, and transcriptional analyses.  Additional research may evaluate factors important for 
predicting responsiveness or resistance to pembrolizumab therapy and other immunologic targets. 


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We will avail ourselves of the services of the M.D. Anderson Tissue Molecular Pathology laboratory – 
in particular, the immunoprofiling lab (TMPIL) directed by Ignacio Wistuba.  Some of the research may 
be conducted at Merck Researh Labs and affiliates.  Assays may include but are not be limited to: 
Tumor PD-L1 Expression 
In the pembrolizumab PN001 and PN012 studies, PD-L1 immunohistochemistry (IHC) has successfully 
been used as a biomarker in the NSCLC and head and neck cancer cohort, respectively, to enrich for a 
subpopulation with high response to pembrolizumab27.  Therefore, the relationship between PD-L1 
expression in pancreatic tumor tissue and response to treatment with pembrolizumab will be evaluated.  
PD-L1 expression in tumor cells and inflammatory cells within pre-treatment tumor tissue samples will 
be characterized by IHC and retrospectively tested for association with response to pembrolizumab.  The 
range of PD-L1 staining in a population of pancreatic tumors may also be used to identify a cut-off, 
above which a tissue is scored as biomarker positive. 
Multiplex Immunofluorescence Analysis (mIF) may be performed on tumor core samples.  Three panels 
will be utilized. Currently, there are two Vectra panels optimized: Panel #1, CD3, CD4, CD8, CD68, 
PD-L1, pan-cytokeratin and DAPI; Panel #2, PD-1, CD45RO, FOXP3, Granzyme B, CD57, pan-
cytokeratin and DAPI. We will optimize a modified Panel #1 and Panel #2 according to Merck request 
including TIM-3, PD-1 (provided by Merck) and LAG-3. A new Myeloid Panel will be developed and 
optimized for the study:  Myeloid Panel #3, includes CD68, CD163, CD11b, CD33, CD14, Cd66b, pan-
cytokeratin and DAPI. These three modified panels will be classified as Panels 6-8, respectively in the 
IHC lab.  For muliplex IF analysis, we will use the Opal chemistry and multispectral microscopy Vectra 
system (Perkin-Elmer) which includes the Nuance software; analysis will be performed using the 
InForm software. 
The appropriate cellular localization of the markers and the type of cells that express the markers will be 
taken into account when scoring them. For quantification of PD-1 and other immune markers (immune 
cells infiltrates, immune checkpoints and other proteins) whole tissue sections or five randomly selected 
one-mm square areas within the tumor region will be selected for analysis. In selected cases, peritumoral 
and intratumoral areas will be examined. The expression of markers in malignant cells will be evaluated 
using image analysis to determine the percentage of positive cells (0 to 100) and intensity (0 to 3+), with 
a total score ranging from 0 to 300 (H-score system). The intensity is classified as 0 (absent), 1 (weak 
apparently only on 100x magnification), 2 (moderate apparent on 50x magnification), and 3 (strong 
apparent on 16x magnification). This scoring system provides criteria that can be reproduced more 
consistently by pathologists.  
The expression of protein markers and inflammatory cells will be examined using an infiltrate density 
score established by the number of cells expressing a determined marker by tissue area. The data and 
digital images will be deposited in a central database for review by pathologists. Among other markers, 
we will study the expression of the following CD3, CD4, CD8, PD-L1, PD-1, FOXP3, CD45RO, CD57, 
CD68, and Granzyme B; additional markers will be selected according to the PI’s decision. 


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Immune-related Gene Expression Profile (GEP)  
Intratumoral expression levels of select genes will be analyzed using an analytically validated platform, 
such as the NanoString nCounter Analysis System.  Association between the immune-related GEP and 
response to pembrolizumab has been established using these genes in melanoma and in cancers from 
clinical studies KN012 (head and neck, bladder, and gastric cancers) and KN028 (ovarian, esophageal, 
and other cancers) 28-30.  Data from these cohorts has been used to derive a GEP which combines the 
expression levels of several key genes into a single scalar score.  The pattern of association in the 
esophageal cohort of KN028 using a prototype GEP suggested the ability to identify patients who may 
not respond to pembrolizumab by identifying tumors that have low values of the GEP.  The GEP 
includes genes from immune-regulatory pathways and a GEP score will be tested for association with 
response to pembrolizumab in retrospective fashion.  The relationship between GEP and the probability 
of response will be used to develop cut-offs that may have high clinical utility.  
The immune-gene related panels available range from 100 to 800 genes. Alternatively, if very limited 
tissue sections are available tumor tissue scraped from one or two histology sections will be placed in 
the RNA lysate and examined for gene expression using the HTG Edge-Seq™ platform and their 
immune-oncology panel (IOP) composed of 550 genes.  These Nanostring and HTG–Edge analyses will 
be performed using FFPE tissue from the CNB specimens in the TMPIL. 
Transcriptional Analyses 
In addition to examining an immune-related GEP described above, global messenger RNA profiling will 
also be pursued.  Expression of individual genes related to the immune system may also be evaluated 
such as immune signatures and critical cytokines (e.g., IL-10).  MicroRNA profiling may also be 
pursued in serum samples. 
Proteomic Analysis 
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released into the 
blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this expression with 
response to pembrolizumab (MK-3475) therapy, as well as levels of PD-L1 IHC or protein in the tumor.  
Blood would be a less invasive compartment compared to tumor from which to measure PD-L1 protein 
biomarker.  In addition to this specific protein biomarker, both tissue and blood derivatives can be 
subjected to proteomic profiling studies using a variety of platforms that could include but are not 
limited to immunoassay, or liquid chromatography/mass spectrometry.  This approach could identify 
novel protein biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy. 
Gene Analyses 
The application of new technologies, such as next generation sequencing, has provided scientists the 
opportunity to define certain tumor types at the genetic level as being ‘hypermutated’ or it can detect the 
presence of specific t-cell clones within the tumor microenvironment.  There is a potential that this 
hypermutated state and the detection of increased T-cell clonality may correlate with response to 
pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state or lack of T-cells clones may 
correlate with non-response.   


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Planned Genetic Analysis  
Understanding genetic determinants of drug response is an important endeavor during medical research.  
This research will evaluate whether genetic variation within a clinical trial population correlates with 
response to the treatment(s) under evaluation.  If genetic variation is found to predict efficacy or adverse 
events, the data might identify optimal use of therapies in the patient population.  This research 
contributes to understanding genetic determinants of efficacy and safety associated with the treatments 
in this study.  
Whole Exome Sequencing 
Flash freezing of biopsy cores in liquid nitrogen may allow for RNA-squencing and Whole Exome 
Sequencing of tumor.  This analysis will be performed using fresh frozen tissue specimens from both 
CNB and resected tumor tissues at MD Anderson Sequencing Facilities. 
Blood Analysis 
Patients will have peripheral blood collected at weeks 1, 4, 7, 16, at the time of a confirmed response, 
and on discontinuation of treatment. 
Flow cytometry: High order flow cytometry panels will be designed with input from the investigators at 
the time of analysis. The panels may include but not be limited to: 1) delineation of major immune cell 
types (T cells, B cells, NK cells, DCs, MDSCs), 2) determination of T cell differentiation status and 
limited functionality (IFNg, TNFa, GB) and 3) defining the expression level of costimulatory and 
coinhibitory molecules on T cells and myeloid cells. The proposed studies will be conducted on 
cryopreserved PBMCs. All time points belonging to a patient will be stained and acquired at the same 
time to avoid any technical variation (sample at time of progression will be omitted for responders if 
analysis needs to be completed when patient is still responding). Briefly, up to 40 cc of peripheral blood 
from pancreatic cancer patients prior to the initiation of treatment, and at up to7 time points throughout 
treatment will be processed fresh (within 24h of being drawn) for PBMC isolation. PBMCs will be 
cryopreserved and stored in Liquid Nitrogen until use. Plasma will be frozen at -80C until use. For flow 
cytometric analysis cells will be thawed and stained right away. Samples will be stained for surface 
and/or intracellular markers using standard procedures. Stained samples will be fixed and acquired on a 
flow cytometer (Fortessa) within one week. Single color controls will be used to adjust compensation 
and Fluorescence minus one (FMO) controls will be used to set positive gates for markers where the 
negative and positive population do not clearly separate. Fixable viability dye will be included in all 
panels to discriminate dead cells. 
Liquid Biopsy Analysis:  Using plasma specimens, genotyping analysis of circulating free DNA 
(cfDNA), circulating tumor cells (CTCs), and exosome (exo)-DNA will be perfomed to monitor tumor 
response and progression at the Molecular Testing Developmental Laboratory (MTDL; Ignacio Wistuba 
and Raja Luthra) housed in TMP. For cfDNA, both ultra-deep next-generation sequencing (NGS) 
mutation analysis of a panel of 50 genes (CMS50) (Ion Torrent PGM and Ion Proton), as well as uniplex 
or multiplex digital droplet PCR (ddPCR, BioRad and Raindance) are available (Raja Luthra, MTDL), 
using 40-50 ng of DNA extracted from 4-5 ml of plasma (blood, purple top). For CTC analysis, isolation 
of cells will be performed using the Cynvenio or CellSearch platforms using 10 ml of blood (1 tube 


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purple top), followed by NGS or ddPCR analysis of gene mutations (Beverly Handy, MTDL). For exo-
DNA analysis, at least 5 ml of plasma will be used for exosome isolation utilizing a ultracentrifugation-
based method followed by NGS (WES, targeted-sequencing, RNA-sequencing). Liquid biopsy has a 
total ~20 ml blood requirement, using 2 purple top tubes (EDTA). 
Serum Cytokine Analysis:  Serum cytokines to be measured include IFN-γ, granzyme B, perforin, IL-10, 
CCL20/MIP3α, CXCL12/SDF-1.  Standard pancreatic cancer markers will also be assessed (e.g. CA 19-
9, CEA).  Additional cytokines may be selected at the discretion of the investigators based on emerging 
literature. 
 
4.2.3.5 Future Biomedical Research   
As an optional procedure for willing patients, the M.D. Anderson and Merck will retain specimens for 
Future Biomedical Research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes. 
 
4.3 
Benefit/Risk 
Subjects in clinical trials may not  receive direct benefit from treatment during participation, as clinical 
trials are designed to provide information about the safety and effectiveness of an investigational 
medicine. Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
Selected patients will have a diagnosis of a pancreatic adenocarcinoma, and will have received at least 
one prior regimen of therapy for metasatic disease.  Patients may have had an unlimited number of 
treatments in the neoadjuvant or adjuvant setting prior to the appearance of metastatic disease. 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma based on 
pathology report 
2. Be willing and able to provide written informed consent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 


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4. Have measurable disease based on RECIST 1.1 Target lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.   
5. Have had prior treatment with first-line therapy  
Note: the same image acquisition and processing parameters should be used throughout the study 
for a given subject. 
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion 
from a metastatic site.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained samples 
cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived 
specimen only upon agreement from Merck .  The specimen must be from a biopsy site that 
would be accessible for at least one subsequent biopsy after initiation on the trial.  
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Have a predicted life expectancy of greater than 3 months. 
9. Demonstrate adequate organ function as defined in Table 1. All screening labs should be 
performed within 10 days of treatment initiation.   
 Table 1. Adequate Organ Function Laboratory Values: 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000/mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 14 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤  ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 1.5 X ULN  
Albumin 
>3.3 mg/dL in the absence of  dehydration 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 


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10. Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of 
study medication (Cycle 1, Day 1) (female subjects of childbearing potential).  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
11. Be willing to use an adequate method of contraception for the course of the study through 120 
days after the last dose of study medication (male and female subjects of childbearing potential. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception   for the 
subject. 
Acceptable methods of contraception are as follows: 
• Single method (one of the following is acceptable): 
o 
intrauterine device (IUD) 
 
o 
vasectomy of a female subject’s male partner 
 
o 
contraceptive rod implanted into the skin 
 
• Combination method (requires use of two of the following): 
 
o 
diaphragm   with   spermicide   (cannot   be   used   in   conjunction   
with   cervical cap/spermicide) 
 
o 
cervical cap with spermicide (nulliparous women only) 
 
o 
contraceptive sponge (nulliparous women only) 
 
o 
male condom or female condom (cannot be used together) 
 
o 
hormonal contraceptive: oral contraceptive pill (estrogen/ progestin pill 
or progestin- only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma, 
pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell 
carcinoma. Vater and periampullary duodenal or common bile duct malignancies. 
2. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy,  herbal/complementary oral or IV medicine, or 
used an investigation device within 4 weeks of the first dose of treatment.  
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 


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4. Had a solid organ or hematologic transplant. 
5. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use 
of disease-modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
6. Has a diagnosed additional malignancy within 1 year prior to first dose of study treatment with 
the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin and/or curatively resected in situ cervical and/or breast cancers. 
7. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous 
system (CNS) metastases and/or carcinomatous meningitis as assessed by the investigator and 
radiology review. 
8. Subjects excluded if there is a history of (non-infectious) pneumonitis that required steroids, 
evidence of interstitial lung disease, or active, non-infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator, including dialysis. 
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 120 days after the last dose of trial 
treatment. 
13. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 agents, or if 
the subject has previously participated in Merck pembrolizumab clinical trials. 
14. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
15. Has known Hepatitis B or Hepatitis C 
16. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1). 
a. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
17. Has a known history of active TB   (Bacillus Tuberculosis) 
 
18. Unable to tolerate a contrast enhanced CT or MRI for staging/restaging purposes 
 
19. Hypersensitivity to pembrolizumab or any of its excipients. 


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20. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to such agents 
administered more than 4 weeks earlier. 
21. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered small molecule agent. 
a. Note:  Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion 
and may qualify for the study. 
b. Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
22. Patients requiring beta blockade are disqualified from participating in this study. 
23. Patients who, in the estimation of the treating physician or primary investigator, have had a 
clinical deterioration of their ECOG performance within the month prior to enrollment. 
24. The use of natural or synthetic cannabinoids 
25. Patients with unstable angina, new onset angina within the last 3 months, myocardial infarction 
within the last 6 months, and current congestive heart failure New York Heart Association Class 
III or higher. 
5.2 
Trial Treatments  
The treatment to be used in this trial is outlined below in Table 2 
Table 2.  Trial Treatment: 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen / 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
BL-8040 
1.25 mg/kg 
See chart 
Subcutaneous 
See chart 
Experimental 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of trial treatments in 
accordance with the protocol and any applicable laws and regulations 
Treatment will be based on three week cycles.  In cycle 1, a daily dose of BL-8040 will be administered 
subcutaneously on days 1-5 and 8-12 (e.g. Mon-Fri for the first two weeks).  No pembrolizumab will be 
administered during cycle 1.   


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A pre-treatment biopsy is mandated prior to the start of cycle 1.  A second biopsy is mandated during the 
third week of cycle 1.  An optional biopsy will be requested during the third week of cycle 3. 
Cycles two and beyond will include pembrolizumab, administered on day 1 of each 21 day cycle, and 
BL-8040, administered BIW on days 1, 4, 8, and 11 of each 21 day cycle. 
5.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) and BL-8040 are provided in 
the Investigator’s Brochures. 
5.2.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology.  These adverse events may occur shortly after the first dose or several months 
after the last dose of treatment.  
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs as per 
Table 3 below. See Section 5.5.2 for supportive care guidelines, including use of corticosteroids. 
Table 3. Dose Modification Guidelines for Drug-Related Adverse Events: 
Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure 
Resume pembrolizumab when patients are clinically 
and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy with 
pembrolizumab can be continued while 
endocrine replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  


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Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Or recurrent gr 2 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b 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/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; Refer to Table 4 – Infusion 
Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Merck. The reason for interruption should be documented in the 
patient's study record. 
For BL-8040, in case of clinical evidence of leukostasis or WBC >60,000/µL, BL-8040 will be skipped. 
Treatment with BL-8040 may be resumed when WBC ≤60,000/µl and/ or there are no signs of 
leukostasis. BL-8040 injections can be skipped for any reason as per Investigator judgment; however 
they must be skipped in case of a significant increase in WBC >60,000/μL, measured prior to 
administration of the next BL-8040 injection and/or evidence of leukostasis. In this case daily WBC 
assessment should be done, and BL-8040 treatment can be resumed provided the WBC counts decrease 
to ≤ 60,000/μL. Pre-dosing WBC monitoring should continue as long as the WBC count is ≥40,000/μL. 
For values <40,000/μL daily WBC monitoring can be stopped and further analysis should be done based 
on the Investigator’s judgment. 
 
In case more than two consecutive doses are skipped during the monotherapy period and more than three 
consecutive doses (a week of treatment) during the combination period, the primary investigator will 
assess the risk-benefit and decide whether there is a need for treatment sequence modification or 
whether the subject should discontinue the study participation. 
 
During cycle 1, if fewer than 7 doses of BL-8040 can be administered during the first two weeks of 
therapy, it will be to the investigator’s discretion whether to complete the remaining doses during week 
3. 
 


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5.2.3 Timing of Dose Administration 
Cycle 2 Day 1 treatment with pembrolizumab should begin on schedule, but a delay of up to 3 days is 
permitted. 
Trial treatment should begin on Day 1 of each cycle after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 
3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.   
BL-8040 will be administered as a single subcutaneous dose in the Ambulatory Treatment Center or 
CTRC.  A delay of pembrolizumab does not necessarily require a delay of BL-8040 if the reason for 
delay is unlikely to be or unrelated to BL-8040. 
The Investigators’ Brochures contain specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution as well as the BL-80040 preparation and 
administration. 
BL-8040 dosing may be adjusted by ± 1 day for either patient convenience or at the discretion of the 
investigator, with a maximum of one dose per day.  The final dose of BL-8040 in each cycle may be 
deferred by up to three days.  Missed doses of BL-8040 will otherwise not be replaced with the 
exception of cycle 1.  During cycle 1, if fewer than 7 doses of BL-8040 can be administered during the 
first two weeks of therapy, it will be to the investigator’s discretion whether to complete the remaining 
doses during week 3 
Hydrocortisone 100 mg IV and diphenhydramine (25 mg PO or IV, each repeated once if necessary) 
may be given for systemic reactions to BL-8040 and may be used prophylactically for subsequent BL-
8040 dose administration). 
5.2.4 Trial Blinding/Masking 
This is an open-label trial.  All parties will know the treatment administered. 
5.3 
Treatment Assignment 
All enrolled subjects will treated in a non-randomised fashion. 
 
5.4 
Stratification 
No stratification based on age, sex or other characteristics will be used in this trial.  


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5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with the Merck Clinical team.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded in the DMI database including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date will also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. Allowed Concomitant Medications. 
 
• Premedication prior to BL-8040 injection with antihistamines in order to minimize the 
occurrence of BL-8040 related systemic reactions is recommended. Systemic steroids are 
allowed for the treatment of these reactions; they may be used as pre-medication for these 
reactions at the discretion of the investigator. 
• Clinically appropriate measures in case of BL-8040-related local injection site reactions e.g., 
local corticosteroids, systemic and local painkillers, antihistamines, local treatments etc. 
• Antiemetic drugs (e.g., Ondansetron) as required clinically based on local guidelines for subjects 
experiencing nausea. 
• Prophylactic antibiotics when appropriate. (e.g., quinolone or cephalosporin), anti-fungals (e.g., 
voriconazole) and antivirals (e.g., valacyclovir). 
•  Blood products, commonly required in oncology subjects. 
• Low-dose steroids are allowed as pre-medication for blood transfusion or with IV anti-fungals. 
 
Additional medications/therapies to manage treatment or disease emergent conditions will be allowed at 
the discretion of the Investigator in consultation with Merck and BiolineRx, in advance where possible. 
In case there is a change in therapy related to an AE, the Investigator may decide to withdraw the subject 


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5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
Note:  Prior CNS radiation is a contraindication to enrollment as noted in the exclusion 
criteria.  After enrollment, radiation therapy to a symptomatic solitary lesion or to the 
brain may be allowed at the investigator’s discretion.  Such a radiated lesion must not be a 
RECIST 1.1 target lesion and the subject must have clear measurable disease outside the 
irradiated field. 
 
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, BCG, and typhoid vaccine.  
• Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/COPD are permitted) for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology or treatment of systemnic and local injection 
reaction secondary to BL-8040 treatment.  The use of physiologic doses of corticosteroids may 
be approved after consultation with the primary investigator and Merck. 
• Chronic use of NSAIDs with a high risk of bleeding, for example, indomethacin, ibuprofen, 
naproxen, or similar agents. Chronic use of aspirin up to 325 mg/day is permitted. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
It is important for investigators to review each medication (prescription and non-prescription) the 
subject is taking before starting the study and at each study visit.  
• At each visit, subjects should be questioned about any new drug they are taking.  
• To minimize the risk of adverse drug interactions, every effort should be made to limit the 
number of concomitant drugs to those that are truly essential.  
• Drugs known to be hepatotoxic (i.e., drugs with a warning of hepatotoxicity in the package 
insert) should be avoided during the dosing period. Investigators are encouraged to review each 
medication for potential hepatotoxicity by searching the www.livertox.nih.gov website. 


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Listed below are specific restrictions for concomitant therapy during the course of the trial. 
The following medications/therapies are contraindicated during the dosing period and for 14 days 
thereafter: 
Known hepatotoxic drugs, including but not limited to:  
• Etifoxine 
• Isoniazid 
• Nitrofurantoin 
• Ketoconazole 
• Amiodarone 
• Phenytoin 
• Herbal supplements 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Rescue Medications 
No rescue medications are specified to be used in this trial. 
5.6.2 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms 
do not improve with administration of corticosteroids.   Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
Note: if after evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 


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o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add 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) and of bowel perforation (such 
as peritoneal signs and ileus).   
o 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.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis,  administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 


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 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy.  However, this will require discontinuation of study treatment. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
• Hepatic: 
Refer to Section 7.2.4.2. for specific hepatic events of clinical interest 
Treatment interruption and discontinuation:   
Elevated transaminases and alkaline phosphatase may be seen during treatment.  Treatment 
should be interrupted per dose modification table above.  Evaluation of subjects with elevated 
transaminases, direct bilirubin, and alkaline phosphatase should involve a work-up to assess for 
infection (spontaneous bacterial peritonitis or other), viral reactivation (if relevant), vascular 
thrombosis, biliary obstruction, possible hepatotoxic medications, tumor progression, alcohol 
toxicity, and effects of pembrolizumab.  In 1567 subjects with other cancers treated with 
pembrolizumab, rates of autoimmune hepatitis were 1%, so it is quite rare.  However, it needs to 
be considered in the differential of elevated liver function tests.  
• For Grade 4 total bilirubin or PT/INR, study treatment should be permanently discontinued. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.  
• 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.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4. Infusion Reaction Treatment Guidelines: 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but responds promptly 
to symptomatic treatment (e.g., antihistamines, 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for < =24 hrs 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will 
be held until symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., 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. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
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 readily available during the period of drug administration. 
 
 
Patients who develop a reaction to BL-8040 may be treated with hydrocortisone (100 mg IV) and 
diphenhydramine (25 mg IV or PO, repeated if necessary). 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  


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(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; 
in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to first dose of study treatment;  
screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last dose of 
study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 


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• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is 
consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local 
regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not 
qualify as an acceptable method of contraception for subjects participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study subjects 
of childbearing potential must adhere to the contraception requirement (described above) from the day 
of study medication initiation (or 14 days prior to the initiation of study medication for oral 
contraception) throughout the study period up to 120 days after the last dose of trial therapy.  If there is 
any question that a subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the primary investigator and Merck without delay and within 72 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 Merck.   If a male subject impregnates his 
female partner the study personnel at the site must be informed immediately and the pregnancy reported 
to Merck and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion 
of the investigator should any untoward effect occur.  In addition, a subject may be withdrawn by the 
investigator  if enrollment into the trial is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding discontinuation or withdrawal are provided in 
Section 7.1.5 – Other Procedures. 


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A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 4.2.3.2 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 4.2.3.2 
• Unacceptable adverse experiences  
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 12 months of uninterrupted treatment with pembrolizumab or 17 administrations of 
study medication, whichever is later. 
a. Note: 17 treatments (approx. 1 year) are calculated from the first dose.. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and 
Section 7.1.6 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring (serious adverse events will be collected for 30 days after the end of 
treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented disease 
progression each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that 
have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with 
pembrolizumab beyond the date when the initial CR was declared.   


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5.8.2 Treatment after Initial Radiologic Progression (irRECIST-based Management) 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns seen with such an approach 
may extend beyond the typical time course of responses seen with cytotoxic agents, and can manifest 
as a clinical response after an initial apparent increase in tumor burden (i.e., pseudoprogression) or 
even the appearance of new lesions. Standard RECIST-based assessment of disease progression 
may, thus, not provide an accurate assessment of response to immunotherapeutic agents such as 
pembrolizumab. For this reason, irRECIST has been developed to help guide treatment decisions 
during tumor immunotherapy. 
 
For subjects who have initial radiological evidence of radiological PD by RECIST 1.1, the 
investigator may elect to continue a subject on study treatment until repeat imaging is obtained.  
This clinical judgment decision by the investigator should only be made if the subject is clinically 
stable, based on clinical factors including performance status, clinical symptoms, and laboratory 
data. Such subjects may continue to receive study treatment and an imaging-based tumor 
assessment should be repeated ≥ 4 weeks later in order to reassess PD per investigator 
assessment. 
 
Clinical stability is defined by the following: 
 
• Absence of signs and  symptoms of clinically significant progression of disease, including 
worsening of laboratory values 
 
• No decline in ECOG performancestatus 
 
• Absence of rapid progression of disease (this is at the discretion of the investigator) 
 
• Absence of tumor progression at critical anatomical sites that requires urgent alternative 
medical intervention (e.g., CNS metastasis with potential for cord compression) 
 
NOTE: Any subject deemed clinically unstable should be discontinued from trial treatment at 
1st radiologically assessed evidence of PD and is not required to have repeat imaging for PD 
confirmation. 
 
In determining whether or not the tumor burden has increased or decreased per irRECIST, all 
target and non-target lesions as well as any incremental new lesion(s) should be considered. 
 
Upon repeat imaging, PD will be confirmed if ANY of the following occur by irRECIST: 
 
• Tumor burden remains increased by ≥ 20%, and at least 5 mm absolute increase compared to 
nadir 
• Non-target  disease  resulting  in  initial  diagnosis  of  PD  is  worse  (qualitative assessment) 
• New lesion resulting in initial diagnosis of PD is worse (qualitative assessment) 
• Additional new lesion(s) since last evaluation 


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• Additional new non-target lesion progression since last evaluation 
 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from trial therapy. 
 
Upon repeat imaging, PD will have failed to be confirmed if ALL of the following occur by 
irRECIST: 
• Tumor burden is increased by < 20 %, or < 5 mm absolute increase compared to nadir 
• Non-target  disease  resulting  in  initial  diagnosis  of  PD  is  stable  or  improved (qualitative 
assessment) 
• New lesion resulting in initial diagnosis of PD is stable or improved (qualitative assessment) 
• No incremental new lesion(s) since last evaluation  
• No incremental new non-target progression since last evaluation 
 
If repeat imaging fails to confirm PD by irRECIST and the subject continues to be clinically stable, 
treatment may continue and follow the regular imaging schedule. 
 
When feasible, subjects should not be discontinued until PD is confirmed by radiology 
assessment. This allowance to continue treatment despite initial radiologic PD takes into account 
the observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response. Subjects who are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flares include any of the following scenarios: 
 
• Worsening of existing target lesion(s) 
• Worsening of existing non-target lesion(s) 
• Development of new lesion(s) 
 
Additional details about RECIST 1.1 and irRECIST are referenced in the appendices.  
 
Table 5. Imaging and Treatment after First Radiologic Evidence of PD (irRECIST-based 
Management): 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of 
PD by RECIST 
1.1 
Repeat imaging 
at ≥4 weeks to  
confirm PD 
May continue study treatment 
at the investigator’s discretion 
while awaiting confirmatory 
tumor imaging by irRECIST. 
Repeat imaging at 
≥4    weeks    to 
confirm   PD   
per 
Physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging 
No additional 
Discontinue treatment 
(exception is possible upon 
No additional 
N/A 
Imaging required 
imaging required 


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confirms PD by 
irRECIST 
consultation with Merck) 
Repeat tumor 
imaging shows 
SD, PR or CR 
by irRECIST 
Continue regularly 
scheduled imaging 
assessments 
Continue study treatment at the 
investigator’s discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart study treatment if condition has 
improved 
and/or 
clinically 
stable 
per 
investigator’s discretion. Next tumor image 
should 
occur according to the regular 
imaging schedule outlined in the protocol 
 
5.9 
Subject Replacement Strategy 
Patients who do not receive study drug, and patients who receive BL only (cycle 1) and who withdraw 
for reasons unrelated to safety or efficacy may be replaced in the cohort at the discretion of the 
investigator. 
5.10 Beginning and End of the Trial 
The overall trial begins when the first subject signs the informed consent form.  The overall trial ends 
when the last subject completes the last study-related phone-call or visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator). 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies that indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of a pharmaceutical company decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made for patients. 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
 
 
 


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Table 6. Study Flow Chart: 
Trial Period 
Screen 
Treatment Week 
End 
of Rx 
Post Treatment 
Treatment Cycle: 
Screenng Visit 
1 
2 
3 
4 
 
Repeated Every 3 
Weeks,starting in Week 4 
At 
D/C 
Safety 
Follow 
Up 
Follow 
Up 
Visit  
Survival 
Follow 
Up  
5 
6 
7 
8 
9 
Scheduling Window (days) 
-28 to -1 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
@D/C 
30 d. 
Q10w 
±4¥ 
Q12 w 
±3.© 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and 
Medical 
History; Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-study anti-cancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures and Assessments 
Review Adverse Events 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Physical Examination incl. vital 
signs, weight and ECOG PS 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
Laboratory Procedures 
Pregnancy Test (within 72h of d1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential† 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
PT/PTT, Serum Chemistry, T3, 
FT4, TSH, UA 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Hep B, Hep C, EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements and Correlative Science 
Tumor Imaging 
X 
“Week 9, then every 9 weeks, ±7d,” 
X 
 
X 
 
Tissue Collection 
X 
 
 
X 
 
 
 
 
 
* 
 
 
 
 
Correlative Blood Collection 
 
Weeks 1, 4, 7, 16, with confirmed response, and on discontinuation of treatment. 
Treatment Administration 
Pembrolizumab 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
BL-8040 (doses/week)** 
 
5 
5 
 
2 
2 
 
2 
2 
 
 
 
 
 
† Prior to and within 24 hours of each dose of BL          *Optional Biopsy week third week of cycle 3        **See text for allowed schedule variations  © After 
disease progression or new anticancer treatment..  ¥ After discontinuation of treatment but before disease progression, new anticancer treatment, or 
death. 
 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and/or Merck 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive 
in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed 
consent be obtained from the subject.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are considered 
to be clinically significant by the Investigator.  Details regarding the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as medical history.  
If the subject has lost at least 15 lbs. (6.8 kg) over the 3 months prior to screening, “weight loss” should 
be entered as an active condition on the Medical History.  As well, any autoimmune disorders, 
regardless of onset date, should be recorded.   
Disease details regarding the subject’s pancreatic cancer will be recorded separately and not listed as 
medical history. 
7.1.1.2 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding the subject’s 
pancreatic cancer. 
7.1.1.3 Prior and Concomitant Medications Review 
7.1.1.3.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record in the DMI database prior medication taken by the subject within 28 
days before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.  


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7.1.1.3.2 Concomitant Medications 
The investigator or qualified designee will record medication in the DMI database, if any, taken by the 
subject during the trial from the time of signing the informed consent form until the Safety Follow-up 
Visit.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 
7.2. 
7.1.1.4 Disease Details and Treatments 
7.1.1.4.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status and 
will capture them within the CRF.  
7.1.1.4.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries and will capture them within the CRF.  
7.1.1.4.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the last dose 
of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up. Details 
on new anti-cancer therapy should be recorded within the CRF. 
7.1.1.5 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify the subject 
for all procedures that occur prior to treatment.  Each subject will be assigned only one screening 
number.  Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will retain the original screening number assigned at the 
initial screening visit. 
Specific details on the screening visit requirements (screening/rescreening) are provided in Section 
7.1.6.1.1   
7.1.1.6 Assignment of Randomization Number 
N/A; There will be no randomization.  
A single subject cannot be assigned more than 1 identification number 
7.1.1.7 Study Medication Administration 
Trial Treatment: 


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Monotherapy: SC BL-8040 on week 1: days 1-5, week 2: days 8-12 and week 3 off. 
 
Combination:  
• Pembrolizumab 200mg IV Q3W.  
• BL-8040 SC BIW on weeks 1 and 2 of each cycle (1.25mg/kg) 
• Week 3 of each cycle off 
 
In general, the window for each visit is ± 3 days unless otherwise noted. The first dose of the 
treatment is counted as Cycle 1 Day 1.  
 
7.1.1.8 Survival Status 
After the start of new anti-cancer treatment or documented disease progression, the subject should 
be contacted every 12 weeks to assess for survival status until death, withdrawal of consent, or the 
end of the trial, whichever occurs first. 
 
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, 
unless otherwise discussed with Merck and/or BiolineRx. The reason for interruption should be 
documented in the patient's study record. BL-8040 and pembrolizumab can be delayed provided when it 
is resumed will continue to be given with the same schedule as defined within the protocol. 
 
If pembrolizumab is held for reasons unrelated to BL-8040, the latter agent may be continued for up to 
three weeks as a single agent. 
The total volume of pembrolizumab infused will be compared to the total volume prepared to determine 
compliance with each dose of pembrolizumab administered.  The instructions for preparing and 
administering pembrolizumab are provided in the Investigator Brochures.   
The number of BL-8040 doses provided will be compared to the total number of doses planned 
according to the schedule of treatment in order to determined compliance. 
Administration of trial medication will be performed by MDA nursing staff; patients will be observed 
for 30 minutes after dosing.   
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse 


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experiences will be graded and recorded throughout the study and during the follow-up period according 
to NCI CTCAE Version 4.03 (see Section 11.2).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs). 
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 12-Lead Electrocardiogram 
As specified in the Study Flow Chart (section 6.0), a standard 12-lead ECG will be performed once 
during the screening phase and then as clinically indicated. Clinically significant abnormal findings at 
screening phase should be recorded as medical history.  After the first dose of trial treatment, new 
clinically significant abnormal findings should be recorded as AEs. 
 
7.1.2.3 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full physical 
exam should be performed during screening, After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.   
7.1.2.4 Weight and Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 
6.0).  Vital signs should include temperature, pulse, respiratory rate and blood pressure.  Weight should 
be assessed at the beginning of each cycle for BL-8040 dose calculation. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening and prior to each cycle of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Cross sectional imaging will be performed with either contrast enhanced CT or MRI.  RECIST 1.1 
criteria will be used to determine disease response31.   
See Section 4.2.3.1 and 7.1.4.1 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
See Section 4.2.3.4 


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A tumor tissue sample from a newly obtained core, incisional or excisional biopsy (preferably from 
a metastatic site) must be submitted for characterization of PD-L1 expression, GEP, and MSI. The 
submitted tumor tissue specimen must be of sufficient quality and quantity for assessment of all 
three of these primary biomarkers.  
Submission of an both a frozen specimen and FFPE tumor tissue block is preferred, but tumor 
tissue from a new biopsy in formalin is also acceptable. If unstained slides are submitted, the slides 
must be freshly cut and submitted to the testing laboratory within 14 days from the slide sectioning 
date.  All submitted slides must be cut from a single tumor tissue sample specimen. Tissue sample 
collection date and slide cut date will be are documented. Slides submitted more than 14 days 
after cutting or cut from more than one tissue specimen is not acceptable and a new specimen 
will be required. 
 
In cases in which an adequate amount of tumor tissue has not been provided to allow for 
evaluation of all three primary biomarkers, additional tumor tissue must be provided. If additional 
tumor tissue from the same specimen is available, tumor tissue from that specimen of sufficient 
quantity and quality for assessment of the remaining required biomarkers must be submitted. If a 
sufficient amount of additional tumor tissue from the same specimen is NOT available, a different 
newly obtained tumor tissue specimen of sufficient quantity and quality for assessment of all three 
primary biomarkers must be submitted. 
Future Biomedical Research 
  
The following specimens are to be obtained as part of Future Biomedical Research: 
 
• Remaining DNA for future use 
• Remaining tumor tissue 
• Remaining DNA and RNA from correlative samples 
• Remaining plasma and serum from biomarker samples 
 
CT-guided core biopsies will be performed prior to treatment, during the third week of cycle 1, and 
during the third week of cycle 3.  Whenever possible the biopsies will be taken from the same metastatic 
site.   
7.1.3 Laboratory Procedures/Assessments 
Routine labs at screening are to be drawn as shown in table 7, below. 
Refer to the Trial Flow Chart - Section 6.0 for the schedule of laboratory assessments. 
7.1.3.1   Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
 Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   
Table 7. Laboratory Tests: 
Hematology 
Chemistry 
Urinalysis 
Other 


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Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell 
Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil 
Count 
BUN 
results are noted 
Free tyroxine (T4) 
Absolute 
Lymphocyte Count 
Total Protein 
Urine pregnancy test 
† 
Thyroid stimulating hormone 
(TSH) 
 
Uric Acid 
 
Hepatitis B & C AB 
 
Calcium 
 
Blood for correlative studies 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is elevated 
above the upper limit of normal) 
 
 
 
Creatinine 
 
 
 
 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing, except 
for CBC that need to be done within 24 before the BL-8040 dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial treatment.  
7.1.3.1.1 Pregnancy Tests 
All women who are being considered for participation in the trial, and who are not surgically sterilized 
or postmenopausal, must be tested for pregnancy within 72 hours of cycle 1 of trial treatment. If a urine 
test is positive or not evaluable a serum test will be required.  Subjects must be excluded/discontinued 
from the study in the event of a positive or borderline-positive test result.   


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7.1.3.2 Central Laboratory Assessments 
Sample collection timing, storage and shipment instructions for the Central Laboratory assessments will 
be provided in the laboratory SOP (submitted as a separate document).   
7.1.3.3 Pharmacokinetic/Pharmacodynamic Evaluations 
There will be no PK evaluation in this trial 
7.1.3.3.1 Planned Genetic Analysis Sample Collection 
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples will be 
provided in the lab SOP submitted as an attached document.  This sample should be drawn for planned 
analysis of the association between genetic variants in DNA and drug response.  If there is either a 
documented law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection 
of the sample for these purposes, then this sample will not be collected at that site.  If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject agrees as to 
this as an optional procedure in the ICD.   
7.1.4 Efficacy Measurements 
7.1.4.1 Tumor Imaging and Assessment of Disease 
Tumor imaging should be acquired by computed tomography (CT, strongly preferred).  Magnetic 
resonance imaging (MRI) should be used when CT is contraindicated or for imaging in the brain.  The 
same imaging technique regarding modality and use of contrast should be used in a subject throughout 
the trial to optimize the visualization of existing and new tumor burden.   
Expedited confirmation of measurable disease based on RECIST 1.1 by MD Anderson radiology at 
screening will be used to determine subject eligibility.  Confirmation of measurable disease by MD 
Anderson radiology per RECIST 1.1 is required prior to subject enrollment.  Although RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, Merck allows a maximum of 10 target 
lesions in total and 5 per organ.   
All scheduled images will be assessed by MD Anderson radiology for all study. In addition, additional 
imaging (including other modalities) that are obtained at an unscheduled time point to determine disease 
progression, as well as imaging obtained for other reasons but captures radiologic progression, should 
likewise be assessed.  
7.1.4.1.1 Initial Tumor Imaging 
Initial tumor imaging at screening must be performed within 28 days prior to the date of enrollment.  
The site study team must review screening images to confirm the subject has measurable disease per 
RECIST 1.1.  Prior to enrollment, the screening images that have been done during during rutine 
management, must be submitted to MD Anderson radiology for confirmation of measurable disease per 
RECIST 1.1.   


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Scans performed as part of routine clinical management are acceptable for use as screening tumor 
imaging if they are of diagnostic quality, were performed within 28 days prior to the first date of 
treatment, and can be assessed by MD Anderson radiology.  
Subjects with previously treated brain metastases may participate provided they have stable brain 
metastases, i.e. without evidence of progression by imaging (confirmed by magnetic resonance imaging 
[MRI] if MRI was used at prior imaging, or confirmed by computed tomography [CT] imaging if CT 
used at prior imaging) for at least 4 weeks prior to the first dose of trial treatment (Day 1).  Any 
neurologic symptoms must have returned to baseline, there must be no evidence of new or enlarging 
brain metastases, and they must not have used steroids for brain metastases for at least 30 days prior to 
first dose as per local site assessment.  This exception does not include carcinomatous meningitis, as 
subjects with carcinomatous meningitis are excluded regardless of clinical stability.   
7.1.4.1.2 Tumor Imaging During the Trial 
The first on-study imaging assessment should be performed at 9 weeks (63±7 days) from the date of 
enrollment.  Subsequent tumor imaging should be performed Q9W (63±7 days) or more frequently if 
clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts.  Imaging should continue to be performed until disease progression (unless site PI elects 
to continue treatment and follow irRECIST), the start of new anti-cancer treatment, withdrawal of 
consent, death, or notification by Merck, whichever occurs first.  All supplemental imaging, done 
outside from MD Anderson, must be submitted to MD Anderson radiology for retrospective review.   
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor imaging assessment ≥4 weeks from 
the date the response was first documented.  The tumor imaging for confirmation of response may be 
performed ≥4 weeks after the first indication of response, or at the next scheduled scan (i.e., 9 weeks 
later), whichever is clinically indicated.  Subjects will then return to regular scheduled imaging every 9 
weeks (63±7 days) within the year of the study..  Subjects who obtain a local confirmation scan do not 
need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at 
the subsequent scheduled imaging time point. 
Per irRECIST, disease progression should be confirmed by the site at least 4 weeks after site-assessed 1st 
radiologic evidence of PD in clinically stable subjects.  Subjects who have unconfirmed disease 
progression may continue on treatment at the discretion of the investigator until progression is 
confirmed on a subsequent study.  Subjects who obtain a confirmation scan do not need to undergo the 
next scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point if clinically stable. Subjects who have confirmed disease progression as 
assessed by the site will discontinue the treatment.   
7.1.4.1.3 End of Treatment and Follow-up Tumor Imaging 
In subjects who discontinue trial treatment, tumor imaging should be performed at the time of treatment 
discontinuation (±4 week window).  If a previous scan was obtained within 4 weeks prior to the date of 
discontinuation, then a scan at treatment discontinuation is not mandatory.  In subjects who discontinue 
trial treatment due to documented disease progression, this is the final required tumor imaging.   


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In subjects who discontinue trial treatment without documented disease progression, every effort should 
be made to continue monitoring their disease status by tumor imaging at an interval of every 10 ± 4 
weeks until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of 
the study, whichever occurs first.   
7.1.4.1.4 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be applied by MD Anderson investigators as the primary measure for assessment of 
tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease 
status (e.g., discontinuation of study therapy).  Confirmation of PR and CR for RECIST 1.1 will be 
taken from central imaging retrospectively.   
7.1.4.1.5 irRECIST Assessment of Disease 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response seen 
with immunotherapeutic drugs.  irRECIST will be used by the investigator to assess tumor response and 
progression, and make treatment decisions.  This data will be collected in the clinical database.  
Treatment efficacy based on irRECIST as assessed by MD Anderson radiology review will be evaluated 
retrospectively.   
When feasible, subjects should not be discontinued until progression is confirmed by the investigator.  
This allowance to continue treatment despite initial radiologic progressive disease (PD) takes into 
account the observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat tumor imaging for confirmation of PD.  Tumor flare 
includes any of the following scenarios: 
• Worsening of existing target lesion(s) 
• Worsening of existing non-target lesion(s) 
• Development of new lesion(s) 
In subjects who have initial evidence of radiological PD by RECIST 1.1 as determined by the site, it is 
at the discretion of the PI whether to continue a subject on study treatment until repeat imaging is 
obtained.  This clinical judgment decision by the investigator should be based on the subject’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data.  Subjects may 
receive study treatment and tumor assessment should be repeated ≥4 weeks later to confirm PD by 
irRECIST per site assessment.  Clinical stability is defined as the following:  
1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values, 
2) No decline in ECOG performance status, 
3) Absence of rapid progression of disease, and 


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4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention.    
Any subject deemed clinically unstable should be discontinued from trial treatment at site-assessed 1st 
radiologic evidence of PD and is not required to have repeat imaging for PD confirmation. 
In determining whether or not the tumor burden has increased or decreased per irRECIST, the 
investigator should consider all target and non-target lesions as well as any incremental new lesion(s). 
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by irRECIST:  
• Target lesion sum of diameters increased <20% or <5 mm absolute increase compared to nadir, 
• Non-target disease resulting in initial PD is qualitatively stable or improved, 
• New lesion resulting in initial PD is qualitatively stable or improved, 
• No incremental new lesion(s) since last evaluation, and 
• No incremental new non-target lesion progression since last evaluation.   
If repeat imaging does not confirm PD by irRECIST as assessed by the investigator and the subject 
continues to be clinically stable, treatment may continue and follow the regular imaging schedule.   
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by irRECIST: 
• Target lesion sum of diameters remains increased by ≥20% and at least 5 mm absolute increase 
compared to nadir, 
• Non-target disease resulting in initial PD is qualitatively worse, 
• New lesion resulting in initial PD is qualitatively worse, 
• Additional new lesion(s) since last evaluation, or 
• Additional new non-target lesion progression since last evaluation.   
If repeat imaging confirms PD by irRECIST as assessed by the investigator and the subject continues to 
be clinically stable, treatment may continue and follow the regular imaging schedule.   
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the subject is achieving a clinically meaningful 
benefit and there is no further increase in the tumor burden at the confirmatory tumor imaging, an 
exception to continue treatment may be considered following consultation with Merck.  In this case, if 
treatment is continued, tumor imaging should continue to be performed following the intervals as 
outlined in Trial Flow Chart.   
Table 8. Imaging and Treatment after First Radiologic Evidence of PD: 
 
Clinically Stable 
Clinically Unstable 


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CR = complete response; irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; N/A = not applicable; PD = 
progressive disease; PR= partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.   
Figure 2. Imaging and Treatment for Clinically Stable Subjects after First Radiologic Evidence of 
Progressive DiseaseImaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease. 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD by 
RECIST 1.1  
Repeat imaging at >4 
weeks at site to 
confirm PD 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
irRECIST. 
Repeat imaging at 
>4 weeks to confirm 
PD per physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging confirms PD 
by irRECIST 
No additional 
imaging required 
Discontinue treatment 
(exception is possible 
upon consultation with 
Merck) 
No additional imaging 
required 
N/A 
Repeat tumor 
imaging shows SD, 
PR or CR by 
irRECIST 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the 
Investigator’s discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study treatment if 
condition has improved and/or 
clinically stable per 
Investigator’s discretion. Next 
tumor image should occur 
according to the regular 
imaging schedule outlined in 
the protocol 


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CIV = central imaging vendor; irRECIST = immune-related Response Evaluation Criteria In Solid Tumors; PD = progressive 
disease; PI = principal investigator; Q9W = every 9 weeks; RECIST = Response Evaluation Criteria In Solid Tumors; SFU = 
survival follow-up. 
 
7.1.5 Other Procedures 
7.1.5.1 Withdrawal/Discontinuation 
Subjects who discontinue/withdraw from treatment prior to completion of the treatment regimen should 
be encouraged to continue to be followed for all remaining study visits. 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the end of study visit should be performed at the time of discontinuation.  Any adverse events which are 
present at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.   
7.1.5.1.1 Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their specimens and all 
derivatives destroyed.   Subjects may withdraw consent at any time by contacting the principal 
investigator for the main trial.  If medical specimens from the trial are still available, the investigator 
will contact Merck using the designated mailbox (clinical.specimen.management@merck.com), and a 
form will be provided by Merck to obtain appropriate information to complete specimen withdrawal.  
Subsequently, the subject's specimens will be removed from the biorepository and be destroyed.  A letter 
will be sent from Merck to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress at the time of 
request for destruction or already performed prior to the request being received by Merck will continue 
to be used as part of the overall research trial data and results.   No new analyses would be generated 
after the request is received. 
In the event that the medical records for the main trial are no longer available (e.g., if the investigator is 
no longer required by regulatory authorities to retain the main trial records) or the specimens have been 
completely anonymized, there will no longer be a link between the subject’s personal information and 
their specimens.  In this situation, the request for specimen destruction cannot be processed. 
7.1.6 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 


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7.1.6.1 Screening 
7.1.6.1.1 Screening Period 
Approximately 28 days prior to treatment initiation, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1.  Screening procedures may be 
repeated.  
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of repeat screening test 
if performed within the specified time frame and the inclusion/exclusion criteria is met.  Subjects who 
are rescreened will retain their original screening number.  Results of a test performed prior to the 
subject signing consent as part of routine clinical management are acceptable in lieu of a screening test 
if performed within the specified time frame.   
Screening procedures are to be completed within 28 days prior to the first dose of trial treatment except 
for the following:   
• The informed consent form must be signed prior to completing any protocol-specified 
procedure. 
 
• To meet the requirement for the submission of tumor tissue from a newly obtained 
specimen, the tissue sample must have been collected since the completion of the most 
recent cancer therapy. 
 
• The investigator or qualified designee will perform a full physical exam within 28 days prior 
to Cycle 1 Day 1. 
 
• Laboratory tests and evaluation of ECOG status are to be performed within 28 days prior to 
the first dose of trial treatment. 
 
• For women of reproductive potential, a urine pregnancy test will be performed within 3 days 
prior to the first dose of trial treatment. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required (performed by the MDA laboratory). 
 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results 
from assessments performed during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the inclusion/exclusion criteria 
is met. 
 
7.1.6.2 Treatment Period 
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-related details 
are provided above in the Trial Procedures (Section 7.1 Trial Procedures). 


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Patients are eligible for up to 17 cycles (approximately 1 year) of treatment on Pembrolizumab.  
Treatment will follow the paradigm outlined in section 2.2.  Cycle 1 will consist of single agent BL-
8040.  Cycle 2 will consist of BL-8040 plus pembrolizumab, given on day 1.  The third week of each 
cycle will be without therapy.  
7.1.6.3 Post-Treatment Visits 
 
7.1.6.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of 
trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-
neoplastic therapy, whichever occurs first.  SAEs that occur within 30 days of the end of treatment or 
before initiation of a new anti-cancer treatment should also be followed and recorded.   
 
7.1.6.3.2 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 9 weeks (± 3 weeks) by radiologic imaging to monitor 
disease status.  Every effort should be made to collect information regarding disease status until the start 
of new anti-neoplastic therapy, disease progression, death, or end of the study.  Information regarding 
post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
    
7.1.6.3.3 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first.  
7.2 
Investigator Communication with Merck and BiolineRx for Overdose, Pregnancy, 
Lactation, Serious Adverse Events, Events of Clinical Interest (ECI), and non-serious Events 
of Clinical Interest.   
 
 
All events described within this section (7.2.X) must be reported to Merck and BiolineRx within two 
working days.  All Such events must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide 
Product 
Safety; 
FAX 
215 
993-1220) 
and 
BioLineRx 
(BioLineRx 
Safety: 
safety8040@biolinerx.com, Fax: +972 8 6429137) 
 


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All life-threatening or fatal events, that are unexpected, and related to the study drug, must also have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
All such events will be recorded using the PDMS/CORe and DMI systems. 
 
7.2.1 Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether or 
not considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Merck’s and/or BioLineRx products, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events.  Examples of this may include, 
but are not limited to, teething, typical crying in infants and children and onset of menses or menopause 
occurring at a physiologically appropriate time. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment begins must be 
reported by the investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure. 
From the start of treatment through 30 days following cessation of treatment, all adverse events must be 
reported by the investigator. Such events will be recorded at each examination.  The investigator will 
make every attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified procedure or 
intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to guidelines for standard AE 
reporting.  
 
7.2.2 Definition of an Overdose  
Pembrolizumab 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment of overdose 


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of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.” 
BL-8040 
For this trial, an overdose will be defined as ≥3.75 mg/kg (3 times the dose) of BL-8040. In case of 
overdose the subject should be observed closely for any signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated. In case of abnormal low blood counts due to BL-
8040 overdose, subjects should be followed until blood counts recover.  
 
7.2.3 Reporting of Pregnancy and Lactation to Merck and BioLineRx 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported 
to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before the start of treatment 
must be reported by the investigator if they cause the subject to be excluded from the trial, or are the 
result of a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.   
Pregnancies and lactations that occur from the start of treatment through 120 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
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 Merck.   If a male subject impregnates his 
female partner the study personnel at the site must be informed immediately and the pregnancy reported 
to Merck and BiolineRx and followed as described above.  
 
 


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7.2.4 Serious Adverse Events and Events of Clinical Interest 
7.2.4.1 Serious Adverse Events 
Refer to Table 9 for additional details regarding each of the above criteria. 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have caused 
death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject 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 (21 CFR 
312.32). 
 
• 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have 
a written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last dose of drug, unless the participant withdraws consent. Serious adverse events 
must be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are related to 


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the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
 
Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
7.2.4.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be reported within 2 working days to Merck Global Safety and the MDA IND office.  
For the time period beginning when the consent form is signed until the start of treatment, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 2 working days to Merck Global 
Safety and BioLineRx safety 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, or a procedure. 
For the time period beginning at the start of treatment through 30 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 related to Merck and/or BioLineRx product, 
must be reported within 2 working days to Merck Global Safety and BioLineRx safety. 
Additional Events of clinical interest for this trial include: 
1.  An overdose of Merck and/or BioLineRx product, as defined in Section 7.2.2, 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.  
3.  In addition to overdose, Hepatic Events of Clinical Interest (ECIs) will include any of the following 
events.  All of these events will require holding pembrolizumab, notification of Merck and BiolineRx 
within 24 hours (as an adverse event), and, if appropriate, hepatology consultation. All cases of 
permanent discontinuation must also be reported within 7 days. For dose interval modification and 
treatment guidelines for these events, refer to Section 5.8.  
4. Summary of Hepatic Events of Clinical Interest 


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a. ALT*: 
i. Among subjects with Day 1 ALT <2x ULN, ALT ≥5x ULN 
ii. Among subjects with Day 1 ALT ≥2x ULN, ALT >3x the Day 1 level 
iii. ALT >500 U/mL regardless of baseline level 
(Subjects with ALT >5x ULN at Day 1 are not eligible for enrollment) 
b. AST: 
i. Among subjects with Day 1 AST <2x ULN, AST ≥5x ULN 
ii. Among subjects with Day 1 AST ≥2x ULN, AST >3x the Day 1 level 
iii. AST >500 U/mL regardless of baseline level 
(Subjects with ALT >5x ULN at Day 1 are not eligible for enrollment) 
c. Total Bilirubin: 
i. Among subjects with Day 1 levels <1.5 mg/dL, a value of >2.0 mg/dL 
ii. Among subjects with Day 1 levels that are ≥1.5 mg/dL, a value ≥2x the D1 level  
iii. Total bilirubin >3.0 mg/dL regardless of baseline level 
(Subjects with Total Bilirubin >2.0 mg/dL at Day 1 are not eligible for enrollment)  
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including: 
i. New onset ascites 
ii. GI bleeding suggestive of portal hypertension (eg esophageal or gastric varices) 
iii. Encephalopathy 
(Subjects with clinically apparent ascites or encephalopathy, or untreated varices 
are not eligible for enrollment) 
 
7.2.4.3 Required Reporting Procedures 
1. Immediate assessment 
All subjects 
• All subjects should be evaluated according to directions below within 72 hours of alert 
for non-overdose ECI  
• Procedures: 
o Obtain consult with hepatologist if appropriate 
o Obtain workup for hepatitis if no underlying hepatitis, including Hepatitis A, B,C, D, 
E, EBV, CMV 
o Assess for ingestion of drugs/supplements with hepatotoxic potential (see List of 
Prohibited medicine, section 5.5.2 of the protocol, for a list) 
o Assess for alcohol ingestion 
o Assess for potential bacterial infection, biliary obstruction, or occult GI bleeding 


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o Repeat ALT, AST, T. bili, D. bili, alk phos, GGT, INR, CBC with differential  
o Other laboratories or imaging studies as clinically indicated 
o Consider liver biopsy if indicated by hepatologist 
 
2. Permanent Discontinuation Criteria for Subjects With Non-overdose Hepatic ECI 
Therapy should also be permanently discontinued for:  
• ALT >20x ULN 
• CP score of ≥9 points; 
• GI bleeding suggestive of portal hypertension (e.g., esophageal or gastric varices); 
• New onset ascites; 
• Encephalopathy; or 
• Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities 
listed in #1 that are presumed immune-related. 
3. Diagnosis and Management of Non-Overdose Hepatic ECIs 
a. Other Hepatic Events of Clinical Interest 
• Infection needs to be ruled out with cultures of blood, urine, and ascites (if possible), as 
well as CXR and abdominal imaging if relevant. If infection is found, antibiotics should 
be started.   
• If T. bili is elevated above baseline, MRCP or ultrasound with doppler should be obtained 
to rule out vascular compromise, biliary obstruction and/or tumor progression.  If biliary 
obstruction is present, consultation with gastroenterology and/or interventional radiology 
should be obtained to see if obstruction may be relieved.  
• A careful review of drugs, including herbal and alternative medications, should be 
obtained, and alcohol use should be ruled out. Please see section 5.5.2 or drugs which 
may interfere with hepatic function.  
• For all of these cases, subjects may resume pembrolizumab if they are clinically stable 
after appropriate therapy, or discontinuation of offending agent, as long as  laboratory 
values have returned to grade 1 or baseline (if normal or grade 1 at start), or baseline 
grade within 3 weeks.  
• 
Subjects must be permanently discontinued if they are off pembrolizumab therapy for 
infection, obstruction, or drug/alcohol related toxicity more than 3 weeks, or if they have 
an esophageal bleed.  
 


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7.2.4.4 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck.  
Specifically, the suspected/actual events covered in this exception include any event that is disease 
progression of the cancer under study. 
The investigator will monitor unblinded aggregated efficacy endpoint events and safety data to ensure 
the safety of the subjects in the trial.  An efficacy/safety summary to the IND Office Medical Monitor 
will be submitted after the first five patients have completed study therapy, or administration is 
discontinued, whichever comes first, and every five evaluable patients thereafter, until 15 patients have 
completed study therapy.   
Any suspected SAE which upon review is not progression of the cancer under study will be forwarded 
to Merck Global Safety and BioLineRx safety as a SAE within 2 working days of determination that the 
event is not progression of the cancer under study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a SAE. 
 
 
7.2.5 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse event which changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets.  We will use the DMI database.  The PI or designee will be 
responsible for assigning attributions of adverse events to the study agent. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Table 9. Evaluating Adverse Events: 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); 


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or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless 
of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse event.  A pre-existing 
condition is a clinical condition that is diagnosed prior to the use of a Merck or BioLineRx product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to Merck  and 
BioLineRx within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck or BioLineRx product to be discontinued? 
Relationship to 
Merck Product  
Did Merck or BioLineRx product cause the adverse event? The determination of the likelihood that Merck or BioLineRx  
product caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between Merck and BioLineRx product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely 
Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck and/or BioLineRx product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the product; or (3) the trial is a single-dose drug trial); or 
(4) Merck or Bioline’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck and/or BioLineRx  product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or 
(2) the trial is a single-dose drug trial); or (3) product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY MERCK AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency with 
Trial Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck 
product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to 
his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
Merck product relationship). 
Yes, there is a reasonable possibility 
of Merck and/or BiolineRx product 
relationship. 
There is evidence of exposure to Merck and/or BioLineRx product.  The temporal sequence of the AE 
onset relative to the administration of Merck product is reasonable.  The AE is more likely explained by 
Merck or BioLineRx  product than by another cause. 
No, there is not a reasonable 
possibility of Merck or BioLineRx 
product relationship 
Subject did not receive the Merck or BioLineRx  product OR temporal sequence of the AE onset 
relative to administration of Merck or BioLineRx product is not reasonable OR the AE is more likely 
explained by another cause than the Merck or BioLineRx product.  (Also entered for a subject with 
overdose without an associated AE.) 
 
 
8.0 STATISTICAL ANALYSIS PLAN 
 
8.1 
Statistical Analysis Plan Summary 
Simon’s 2-stage design will be used.  The null hypothesis that the true response rate is 10% will be 
tested against a one-sided alternative.  In this treatment arm, 15 patients will be accrued.  If there is </= 
1 response in these 15 patients, research into this combination will be halted.  If we see >/= 2 responses, 


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we will plan to study (in a subsequent protocol) an additional 26 patients, for a total of 41.  The null 
hypothesis will be rejected if 8 or more responses are observed in 41 patients.  This design yields a type 
I error rate of 5% and power of 80% when the true response rate is 25%. 
 
The 15 patients needed for this analysis will be enrolled as one cohort.  Patients who do not receive 
study drug, and patients who receive BL only (cycle 1) and who withdraw from the study for reasons 
unrelated to safety or efficacy may be replaced in the cohort at the discretion of the investigator. 
Key elements of the statistical analysis plan are summarized below. The comprehensive plan is provided 
in Sections 8.1 to 8.12.   
Table 10. Key Elements of the Statistical Analysis Plan: 
Study 
Design 
Overview 
A Phase IIb Pilot study to assess the efficacy, safety and pharmacodynamics
effects of Pembrolizumab and BL-8040 in Patients with Metastatic Pancreatic 
Cancer. 
Treatment 
Assignment 
This is a single arm open-label study.  
Analysis Populations Efficacy: All Subjects as Treated (ASaT) 
Safety: All Subjects as Treated (ASaT) 
Primary Endpoints 
Overall Response rate. 
Statistical 
Methods
for 
Key 
Efficacy
Analyses 
Objective Response Rate (ORR) based on RECIST 1.1 assessed by the MDACC
imaging staff. The estimate of the ORR, along with its 95% confidence interval 
(CI) based on the Clopper-Pearson method 32, will be provided.  
Statistical 
Methods
for 
Key 
Safety
Analyses 
Counts and percentages of subjects with AEs will be provided.  
Interim Analysis 
No planned interim analysis for this pilot study.  
Multiplicity 
No multiplicity adjustment is planned in this Phase II study. 
Sample 
Size 
and 
Power  
The planned sample size is 15 subjects.   


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8.2 
Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the Clinical 
Biostatistics department of the Merck. 
This trial is being conducted as a non-randomized, open-label study, i.e., subjects, investigators, 
BiolineRx and Merck personnel will be aware of subject treatment assignments after each subject is 
enrolled. 
8.3 
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3. 
8.4 
Analysis Endpoints 
Efficacy and safety endpoints that will be evaluated are listed below. 
8.4.1 Efficacy Endpoints 
8.4.1.1 Primary Efficacy Endpoint 
Overall Response Rate 
8.4.1.2 Secondary Efficacy Endpoints 
To estimate the safety and tolerability of the combination treatment. 
To determine the impact of the two study agents on T cell infiltration into tumor 
To determine the impact of BL-8040 on circulating immune cells. 
 
8.4.1.3 Exploratory Efficacy Endpoints 
To evaluate Overall response rate (ORR) per irRECIST and duration of response (DOR), disease control 
rate (DCR), time to progression (TTP), progression free survivial (PFS), and Overall survivial (OS) per 
RECIST and irRECIST assessed by MD Anderson investigators. 
To explore the association between PD-L1 expression by immunohistochemistry, shed PD-L1 level, 
somatic gene expression profiling and antitumor efficacy of pembrolizumab based on RECIST 1.1 
imaging criteria as well as overall survival. 
To explore the relationship between genomic variation and response to the treatment administered.  
Variation across the human genome may be analyzed for association with clinical data collected in this 
study.   


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Tissue and blood immune monitoring will be conducted through our immune platform group as detailed 
per the biomarker section based on 3 biopsies done at the following time points: 1) pre-treatment, 2) 
during the third week of cycle 1, and 3) during the third week of cycle 3. 
8.4.2 Safety Endpoints 
To determine the rate of adverse events associated with study treatment. 
8.5 
Analysis Populations 
Eligible subjects enter the study when the patient number is assigned.  
8.5.1 Efficacy Analysis Populations 
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, PFS, and 
OS.  The ASaT population consists of all allocated subjects who received at least one dose of study 
treatment. 
The analysis population for DOR consists of responders (PR and CR). 
Details on the approach to handling missing data are provided in Table 13.   
8.5.2 Safety Analysis Populations 
The ASaT population will be used for the analysis of safety data in this study.  The ASaT population 
consists of all allocated subjects who received at least one dose of study treatment.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter.  To assess change from 
baseline, a baseline measurement is also required. 
8.6 
Statistical Methods 
8.6.1 Statistical Methods for Efficacy Analyses 
This section describes the statistical methods that address the primary and secondary objectives.  
This is an open-label pilot study. Fifteen patients will be treated. Descriptive statistics including with 
90% confidence interval will be computed. Observed response profile and PFS along with relevant 
confidence interval will be used to guide future development decisions.   
Table 11. Analysis Strategy for Efficacy Variables: 
Total evaluable patients Number of responders Response rate Lower 90% CI* Upper 90% CI* 
15 
1 
7% 
<1% 
27% 
15 
2 
13% 
2% 
36% 


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15 
3 
20% 
6% 
44% 
15 
4 
27% 
10% 
51% 
15 
5 
33% 
14% 
58% 
15 
6 
40% 
19% 
64% 
15 
7 
47% 
24% 
70% 
15 
8 
53% 
30% 
76% 
15 
9 
60% 
36% 
81% 
15 
10 
67% 
43% 
86% 
* Exact confidence interval computed by the method of Clopper and Pearson (Biometrika 26:404-413, 
1934) 
 
 
 
 
Table 12. Statistical Methods Per Endpoint Anaylsis: 
Endpoint/Variable 
(Description, 
Time 
Point) 
 
Statistical Method 
Analysis 
Population 
Missing Data Approach 
Primary Endpoint  
ORR – RECIST 1.1 by 
MD Anderson radiology  
exact method based on 
binomial distribution 
(Clopper-Pearson 
method) 
ASaT 
Subjects with missing data are 
considered non-responders 
Key Secondary Endpoints 


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Endpoint/Variable 
(Description, 
Time 
Point) 
 
Statistical Method 
Analysis 
Population 
Missing Data Approach 
DOR – RECIST 1.1 by 
MD Anderson radiology  
Summary statistics using 
Kaplan-Meier method, if 
sample size permits 
All 
responders 
Non-responders are excluded from 
analysis. Responders are censored 
according to the censoring rules 
listed in Table 13. 
DCR – RECIST 1.1 by 
MD Anderson radiology  
Exact method based on 
binomial distribution 
(Clopper-Pearson 
method) 
ASaT 
Subjects with missing data are 
considered as subjects with disease 
not under control 
TTP – RECIST 1.1 by 
MD Anderson radiology  
Summary statistics using 
Kaplan-Meier method 
ASaT 
Censored at last assessment 
PFS – RECIST 1.1 by 
MD Anderson radiology  
Summary statistics using 
Kaplan-Meier method 
ASaT 
Censored at last assessment 
OS 
Summary statistics using 
Kaplan-Meier method 
ASaT 
Censored at last known alive date 
 
 
 
 
 
Table 13. Censoring Rules for DOR: 
Situation 
Date of Progression or Censoring 
Outcome 
No progression nor death, no new anti-
cancer therapy initiated 
Last adequate disease assessment 
Censor 
(non-event) 
No progression nor death, new anti-
cancer therapy initiated 
Last adequate disease assessment before new 
anti-cancer therapy initiated 
Censor 
(non-event) 


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Situation 
Date of Progression or Censoring 
Outcome 
Death or progression after ≥2 
consecutive missed adequate disease 
assessments 
Last adequate disease assessment prior to the 
after ≥2 consecutive missed adequate disease 
assessments 
Censor 
(non-event) 
Death or progression after ≤1 missed 
adequate disease assessments 
PD or death 
End of 
response 
(Event) 
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not 
started a new anti-cancer therapy and have not been determined to be lost to follow-up.  
 
8.6.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse 
experiences (AEs), laboratory tests, and vital signs. 
Counts and percentages of subjects with AEs will be provided. 
8.6.3 Demographic and Baseline Characteristics 
The number and percentage of subjects screened, allocated, the primary reasons for screening failure, 
and the primary reasons for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies 
will be summarized either by descriptive statistics or categorical tables for all enrolled subjects.  
 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck and BioLineRx as summarized in Table 14. 
Table 14.  Product Descriptions: 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 


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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
BL-8040 73mg per vial 
Lyophilized Powder for Injection 
 
BL-8040, a white to off-white powder synthetic polypeptide, is freely soluble in water and in 0.45% 
Sodium Chloride (half normal saline). It is manufactured in accordance with current good manufacturing 
practice (cGMP) by MSD/N.V. (Organon, Kloosterstraat 6, 5349 AB, Oss, Netherlands). 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
All supplies will be provided open label.  Pembrolizumab will be provided as non-kitted single vials. 
BL-8040 will be provided in kit of 8 or 12 vials  
9.3 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.4 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
and BioLineRx or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 


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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality    
10.1.1 Confidentiality of Data 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is M e r c k 's 
responsibility to determine, based on these regulations, whether a request for Financial 
Disclosure information is required. It is the investigator's/subinvestigator's responsibility to comply 
with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by Merck in accordance with 21 CFR Part 54, 
to provide his/her financial interests in and/or arrangements with the Merck to allow for the 
submission 
of 
complete 
and 
accurate 
certification 
and 
disclosure 
statements. 
The 
investigator/subinvestigator(s) further agree to provide this information on a Certification/Disclosure 
Form, commonly known as a financial disclosure form, provided by Merck or through a secure 
password-protected electronic portal provided by Merck. The investigator/subinvestigator(s) also 
consent to the transmission of this information to Merck in the United States for these purposes. 
This may involve the transmission of information to countries that do not have laws protecting 
personal data. 
 
10.1.2 Confidentiality of Subject Records 
Merck, BiolineRx, IRB/ERC, or regulatory authority representatives may consult and/ or copy trial 
documents in order to verify source documents/ case report form data. By signing the consent form, 
the subject agrees to this process. If trial documents will be photocopied during the process of 
verifying source documents/ case report form information, the subject will be identified by unique 
code only; protected health information, such as full names and medical records number, will be 
masked prior to transmission to Merck or BiolineRx. 
 
All subject data used and disclosed in connection with this trial must be treated in accordance with all 
applicable privacy laws, rules and regulations. 
 
10.1.3 Confidentiality of Investigator Information 
Certain personal identifying information with respect to the investigator, and all sub-investigators 
and trial site personnel, may be used and disclosed for trial management purposes, as part of a 
regulatory submissions, and as required by law. This information may include: 
 
1. name, address, telephone number and e-mail address; 
 
2. hospital or clinic address and telephone number; 
 


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3. curriculum vitae or other summary of qualifications and credentials; and 
 
4. other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to Merck, 
BiolineRx, and subsidiaries and affiliates, in your country and other countries, including 
countries that do not have laws protecting such information. Additionally, the investigator’s 
name and business contact information may be included when reporting certain serious adverse 
events to regulatory authorities or to other investigators. By signing this protocol, the investigator 
expressly consents to these uses and disclosures. 
 
10.1.4 Confidentiality of IRB/IEC Information 
The investigator is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The investigator is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies. 
 
 
 
11.0 APPENDICES 
11.1 Merck Code of Conduct for Clinical Trials 
 
Merck* 
Code of Conduct for Clinical Trials 
I. Introduction 
A. Purpose 
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our products. As such, 
we are committed to designing, implementing, conducting, analyzing and reporting these trials in compliance with the highest ethical 
and scientific standards. Protection of subject safety is the overriding concern in the design of clinical trials. In all cases, Merck 
clinical trials will be conducted in compliance with local and/or national regulations and in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki.  
B. Scope 
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative research efforts). This Code is not intended to apply 
to trials which are observational in nature, or which are retrospective. Further, this Code does not apply to investigator-initiated trials 
which are not under the control of Merck. 
II. Scientific Issues 


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A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or 
pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may conduct outcomes 
research trials, trials to assess or validate various endpoint measures, or trials to determine subject preferences, etc.   
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of the trial.  
Research subjects must meet protocol entry criteria to be enrolled in the trial.  
2. Site Selection 
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities and staff, 
previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites are evaluated by Merck 
personnel to assess the ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity 
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical Practice.  Merck 
reviews clinical data for accuracy, completeness and consistency. Data are verified versus source documentation according to 
standard operating procedures.  Per Merck policies and procedures, if fraud, misconduct or serious GCP-non-Compliance are 
suspected, the issues are promptly investigated. When necessary, the clinical site will be closed, the responsible regulatory 
authorities and ethics review committees notified and data disclosed accordingly.  
B. Publication and Authorship 
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of results may not be appropriate 
since the trial may be underpowered and the analyses complicated by statistical issues of multiplicity. 
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. In summary, 
authorship should reflect significant contribution to the design and conduct of the trial, performance or interpretation of the analysis, 
and/or writing of the manuscript.  All named authors must be able to defend the trial results and conclusions.  Merck funding of a 
trial will be acknowledged in publications.  


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III. Subject Protection 
A. IRB/ERC review 
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  Significant changes 
or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that changes required urgently to 
protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. For each site, the IRB/ERC and Merck 
will approve the subject informed consent form.  
B. Safety 
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential subjects will be 
informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial designs will take into account 
the local standard of care.  Subjects are never denied access to appropriate medical care based on participation in a Merck clinical 
trial.  
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for participation.  
Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or receipt of, medical care that may 
otherwise be available to them. 
C. Confidentiality 
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, only the 
investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical records that might 
identify the research subject by name.   
D. Genomic Research 
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by an Ethics 
Committee. 
IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring institution) in a fair 
manner for the work performed in support of Merck trials.   Merck does not pay incentives to enroll subjects in its trials.  However, 
when enrollment is particularly challenging, additional payments may be made to compensate for the time spent in extra recruiting 
efforts. 
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on chart review to 
identify potentially eligible subjects. 
B. Clinical Research Funding  
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring institution is being 
paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter the wording of the disclosure 
statement to be consistent with financial practices at that institution.  As noted above, publications resulting from Merck trials will 
indicate Merck as a source of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be consistent with 
local guidelines and practices including, in the U.S., those established by the American Medical Association (AMA).  
V. Investigator Commitment 


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Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing the protocol, 
agree to support these ethical and scientific standards. 
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a subsidiary of 
Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by context, Merck also 
includes affiliates and subsidiaries of Merck & Co., Inc." 
 
11.2 Common Terminology Criteria for Adverse Events 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events 
(CTCAE) 
version 
4.03 will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
11.3 List of Abbreviations      
Table 15. List of Abbreviations: 
Abbreviation/Term Definition 
2L 
Second Line 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
APaT 
All Patients as Treated 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CR 
Complete Response 
CrCl 
Calculated Creatinine Clearance 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DCR 
Disease Control Rate 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
DR 
Drug Related 
ECI 
Events of Clinical Interest 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EGJ 
Esophagogastric Junction 
eDMC 
external Data Monitoring Committee 
EOC 
Executive Oversight Committee 


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Abbreviation/Term Definition 
EORTC 
European Organisation for Research and Treatment of Cancer 
ERC 
Ethics Review Committee 
ESMO 
European Society for Medical Oncology 
FBR 
Future Biomedical Research 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FDAMA 
Food and Drug Administration Modernization Act 
FNA 
Fine Needle Aspirate 
GCP 
Good Clinical Practice 
GEP 
Gene Expression Profile 
GI 
Gastrointestinal 
GFR 
Glomerular Filtration Rate 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HEA 
Health Economic Assessment 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
irRECIST 
Immune related RECIST (Modification of RECIST 1.1) 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Integrated Web Response System 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 
MRI 
Magnetic Resonance Imaging 
MSD 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 
Inc. 
MSI-H 
Microsatellite Instability High 
NA or N/A 
Not Applicable 
NCI 
National Cancer Institute 
NSAID 
Non-Steroidal Anti-inflammatory Drug 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OTC 
Over-the-counter 
PD 
Progressive Disease 
PFS 
Progression Free Survival 


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11.4 ECOG Performance Status 
 Table 16.  ECOG Performance: 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
Abbreviation/Term Definition 
PIN 
Personal Identification Number 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PO 
Oral Administration 
PR 
Partial Response 
PT 
Prothrombin Time 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RR 
Response Rate 
Q3W 
Every 3 Weeks 
Q9W 
Every 9 Weeks 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SFU 
Survival Follow-Up 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SIM 
Site Imaging Manual 
SOP 
Standard Operating Procedures 
TIL 
Tumor Infiltrating Lymphocytes 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 


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care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
11.5 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.133 will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. In 
addition, volumetric analysis will be explored by central review for response assessment. 
11.6 Tip sheet for Resist 1.1 and irRESIST 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response seen 
with immunotherapeutic drugs.  irRECIST will be used by site investigator/local radiology review to 
assess tumor response and progression, and make treatment decisions.  This data will be collected in the 
clinical database.  Treatment efficacy based on irRECIST as assessed by the central imaging vendor 
review will be evaluated retrospectively.   
When feasible, subjects should not be discontinued until progression is confirmed by the local site 
investigator/radiology assessment.  This allowance to continue treatment despite initial radiologic 
progressive disease (PD) takes into account the observation that some subjects can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience subsequent 
disease response.  Subjects that are deemed clinically unstable are not required to have repeat tumor 
imaging for confirmation of PD. Tumor flare includes any of the following scenarios: 
• 
Worsening of existing target lesion(s) 
• 
Worsening of existing non-target lesion(s) 
• 
Development of new lesion(s) 
In subjects who have initial evidence of radiological PD by RECIST 1.1 as determined by the site, it is 
at the discretion of the PI whether to continue a subject on trial  treatment until repeat imaging is 
obtained (using irRECIST for subject management, see Table 6 and Figure 2).  This clinical judgment 
decision by the site investigator should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Subjects may receive trial  treatment and 
tumor assessment should be repeated ≥4 weeks later to confirm PD by irRECIST per site 
assessment.  Clinical stability is defined as the following:  
1)    Absence of symptoms and signs indicating clinically significant progression of disease, including 
worsening of laboratory values, 


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2)    No decline in ECOG performance status, 
3)    Absence of rapid progression of disease, and 
4)    Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention.    
Any subject deemed clinically unstable should be discontinued from trial treatment at site-assessed first 
radiologic evidence of PD and is not required to have repeat imaging for PD confirmation. 
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 PD is not confirmed at repeat imaging if ALL of the following occur by irRECIST:  
·         Target lesion sum of diameters is <20% or <5 mm absolute increase compared to nadir, 
·         Non-target disease resulting in initial PD is qualitatively stable or improved, 
·         New lesion resulting in initial PD is qualitatively stable or improved, 
·         No incremental new lesion(s) since last evaluation, and 
·         No incremental new non-target lesion progression since last evaluation.   
If repeat imaging does not confirm PD by irRECIST as assessed by the local site investigator and the 
subject continues to be clinically stable, treatment may continue and follow the regular imaging 
schedule.   
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by irRECIST: 
·         Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase compared to 
nadir, 
·         Non-target disease resulting in initial PD is qualitatively worse, 
·         New lesion resulting in initial PD is qualitatively worse, 
·         Additional new lesion(s) since last evaluation, or 
Additional new non-target lesion progression since last evaluation. If repeat imaging confirms PD due to 
any of the scenarios listed above, subjects will be discontinued from study therapy. 
.   
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the subject is achieving a clinically meaningful 
benefit and there is no further increase in the tumor burden at the confirmatory tumor imaging, an 


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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 Section 6.0 Trial Flow Chart and be submitted to the central imaging vendor.   
 
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Naderi E, Mostafaei M, Pourshams A, Mohamadkhani A. Network of microRNAs-mRNAs 
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Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-
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Vermi W, Bonecchi R, Facchetti F, et al. Recruitment of immature plasmacytoid dendritic cells 
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Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition 
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9. 
Fong L, Engleman EG. Dendritic cells in cancer immunotherapy. Annual review of immunology 
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10. 
Furumoto K, Soares L, Engleman EG, Merad M. Induction of potent antitumor immunity by in 
situ targeting of intratumoral DCs. The Journal of clinical investigation 2004;113:774-83. 
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Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-
myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annual review of immunology 
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Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ T 
cells against NY-ESO-1. The New England journal of medicine 2008;358:2698-703. 
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Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to 
phosphotyrosine. Proceedings of the National Academy of Sciences of the United States of America 
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15. 
Polcher M, Braun M, Friedrichs N, et al. Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) 
cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59:909-19. 
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Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma VM. Prognostic value of tumour-
infiltrating lymphocytes (TILs) in colorectal cancer. The Journal of pathology 1997;182:318-24. 
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Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic 
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Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within 
human colorectal tumors predict clinical outcome. Science 2006;313:1960-4. 
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Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in 
epithelial ovarian cancer. The New England journal of medicine 2003;348:203-13. 
20. 
Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high 
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