Clinical trial NCT02826486
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: BioLineRx, Ltd.
Start date: 2016-09-01; Completion date: 2022-09-06
Enrollment: 80 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will assess the efficacy and safety of BL-8040 in combination with pembrolizumab (Keytruda®) and BL-8040/ Pembrolizumab in combination with liposomal irinotecan (Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) in subjects with metastatic pancreatic adenocarcinoma.

Detailed description:
This will be an open-label, two-cohort, phase IIa study in subjects with metastatic pancreatic adenocarcinoma.

The study will be comprised of 2 cohorts,. Each includes approximately 40 subjects with unresectable metastatic pancreatic adenocarcinoma. Cohorts will be conducted sequentially (one after the other).

Each cohort study consists of two periods:

* Monotherapy period: One week, with BL-8040 administered daily on days 1-5.
* Combination therapy:

Cohort 1: Three-week cycles of a combination of BL-8040 administered three times a week (TIW) and pembrolizumab administered once every three weeks.

Cohort 2: Onivyde®/5-FU/LV every 2 weeks, pembrolizumab once every 3 weeks and BL-8040 twice a week.

Cohort 1: Subjects with metastatic pancreatic adenocarcinoma will be enrolled and receive BL-8040 monotherapy for five days followed by a combination treatment of BL-8040 and pembrolizumab. During the monotherapy period, eligible subjects will receive daily subcutaneous (SC) injections of BL-8040 (1.25 mg/kg) on Days 1 - 5.

From Day 8, subjects will begin a combination period consisting of treatment with SC BL-8040 TIW and pembrolizumab once every three weeks. The combination therapy will continue for up to 35 cycles of pembrolizumab approximately two years), or until progression, clinical deterioration or Early Termination, whichever comes first.

Cohort 2: Subjects with metastatic pancreatic adenocarcinoma that have progressed following first-line treatment with gemcitabine-based chemotherapy will be enrolled and receive BL-8040 monotherapy for five days followed by a combination treatment of BL-8040, pembrolizumab and chemotherapy. During the monotherapy period, eligible subjects will receive daily SC injections of BL-8040 on Days 1 - 5.

From Day 8, subjects will begin a combination period consisting of:

* IV Onivyde® followed by IV leucovorin (LV), followed by IV fluorouracil (5-FU), every 2 weeks.
* Pembrolizumab every three weeks.
* BL-8040 twice a week

The combination therapy will continue for up to 35 treatments (approximately two years), or until progression, clinical deterioration or Early Termination, whichever comes first.

Arms: arm 1: BL-8040 monotherapy 1.25 mg/kg subcutaneous (SC) injections daily on Days 1-5 of Week 1 of treatment.

Combination therapy period begins following monotherapy treatment and consists of:

* Pembrolizumab 200 mg once every three weeks.
* Beginning on Day 10, BL-8040 three times a week arm 2: BL-8040 monotherapy 1.25 mg/kg subcutaneous (SC) injections daily on days 1-5 of week 1 of treatment.

Combination therapy period begins following monotherapy treatment and consists of:

* IV Onivyde® 70 mg/m2 over 90 minutes followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks.
* Pembrolizumab 200mg once every three weeks.
* Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing.
Interventions: intervention 1: BL-8040 intervention 2: Pembrolizumab intervention 3: Chemotherapy
Intervention descriptions: intervention 1: BL-8040 subcutaneous (SC) injections intervention 2: Pembrolizumab will be given as a 30-minute IV infusion intervention 3: • IV Onivyde® followed by IV leucovorin (LV), followed by IV fluorouracil (5-FU), every 2 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
BioLineRx.com 
Israel Headquarters 
Modi’in Technology Park 
2 HaMa’ayan Street 
Modi’in 7177871, Israel 
Phone: +972.8.642.9100  
 
 
 
NCT Number: 
NCT02826486 
Sponsor Study Number: 
BL-8040.PAC.201 
Official Study Title: 
A Phase IIa, Multicenter, Open-Label Study to Assess the 
Safety and Efficacy of the Combination of BL-8040 and 
Pembrolizumab in Subjects with Metastatic Pancreatic 
Cancer, the COMBAT Study 
Document Version and Date: 
Clinical Study Protocol, Version 4.1, 16 June 2019 
 


 
Investigational Products: 
BL-8040 and 
Pembrolizumab 
Abbreviated Title: A phase IIa, Multicenter, 
Open-label Study to Assess the Safety and 
Efficacy of the Combination of BL-8040 and 
Pembrolizumab in Subjects with Metastatic 
Pancreatic Cancer, the COMBAT study 
Protocol No.  
BL-8040.PAC.201 
Phase: IIa 
 
Version and Date: 
Version 4.1,  
June 16th 2019 
 
Protocol: BL-8040.PAC.201 
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CLINICAL STUDY PROTOCOL 
A PHASE IIA, MULTICENTER, OPEN-LABEL STUDY TO ASSESS 
THE SAFETY AND EFFICACY OF THE COMBINATION OF BL-8040 
AND PEMBROLIZUMAB IN SUBJECTS WITH METASTATIC 
PANCREATIC CANCER, THE COMBAT STUDY 
Sponsors: 
BioLineRx, Ltd. 
 
 
 
 
IND No. 
 
Investigational Medicinal 
Products: 
BL-8040 (previously BKT-140) 
Pembrolizumab 
Principal Investigator(s): 
 
Protocol Number: 
BL-8040.PAC.201 
Study Phase: 
IIa 
Sponsor Contact: 
 
Study Safety Officer:  
 
Protocol Version and Date: 
Version 4.1, June 16th, 2019 
 
 
 
 
Confidentiality Statement 
This protocol is a confidential communication document of BioLineRx, Ltd. The recipient of this document agrees not to 
disclose the information contained herein to others without prior written authorization of BioLineRx, Ltd. except that this 
document may be disclosed to appropriate Institutional Review Boards/Independent Ethics Committees or duly authorized 
representatives of regulatory authorities, under the condition that they maintain confidentiality. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Investigational Products: 
BL-8040 and 
Pembrolizumab 
Abbreviated Title: A phase IIa, Multicenter, 
Open-label Study to Assess the Safety and 
Efficacy of the Combination of BL-8040 and 
Pembrolizumab in Subjects with Metastatic 
Pancreatic Cancer, the COMBAT study 
Protocol No.  
BL-8040.PAC.201 
Phase: IIa 
 
Version and Date: 
Version 4.1,  
June 16th 2019 
 
Protocol: BL-8040.PAC.201 
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Principal Investigator 
By signing below, I, the Investigator, approve the protocol and agree to conduct the clinical 
trial according to all stipulations of the protocol as specified in both the clinical and 
administrative sections, Case Report Form (CRF) and any protocol-related documents (subject 
to any amendments agreed to in writing between the Sponsor and Principal Investigator). I 
agree to comply with the ICH-GCP, World Medical Association Declaration of Helsinki (and 
relevant updates) and applicable local regulations. I agree to ensure that the Confidential 
Information contained in this document will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
BioLineRx Ltd. I understand that the study may be terminated, or enrollment suspended at any 
time by Sponsor, or by me, at my center, if it becomes necessary in my opinion, to protect the 
best interests of the study subjects. 
 
 
 
Name 
Investigator Signature 
Date 
 
 
Center’s Name 
 
 City, Country 
 
 




 
 
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Table of Contents 
Page 
Protocol Signature Page ....................................................................................................................... 3 
Protocol Version History Page ............................................................................................................. 5 
List of Tables ....................................................................................................................................... 12 
Protocol Synopsis ................................................................................................................................ 13 
Glossary ............................................................................................................................................... 27 
1 
Introduction ............................................................................................................................... 30 
1.1 
BL-8040 ....................................................................................................................................... 30 
1.1.1 
Preclinical Studies .................................................................................................................. 31 
1.1.2 
Clinical Studies ....................................................................................................................... 31 
1.2 
Pembrolizumab .......................................................................................................................... 32 
1.2.1 
Pharmaceutical and Therapeutic Background ........................................................................ 32 
1.2.2 
Preclinical and Clinical Trials ................................................................................................ 33 
1.3 
Chemotherapy: Nanoliposomal irinotecan with fluorouracil and Leucovorin (Onivyde® 
with 5-FU/LV) ............................................................................................................................ 33 
1.4 
Therapeutic Indication .............................................................................................................. 33 
1.5 
Study rationale ........................................................................................................................... 34 
1.5.1 
Rationale for Addition of Chemotherapy (Protocol Version 3) ............................................. 36 
1.6 
Dose selection rationale ............................................................................................................. 37 
1.6.1 
Rationale for BL-8040 Dose and Regimen Selection............................................................. 37 
1.6.2 
Rationale for Pembrolizumab Dose Selection ........................................................................ 39 
1.6.3 
Rationale for Onivyde/5-FU/LV Combination Dose and Regimen Selection ....................... 40 
2 
Study Objectives and Endpoints ............................................................................................. 40 
2.1 
Objectives ................................................................................................................................... 40 
2.2 
Study endpoints .......................................................................................................................... 40 
2.2.1 
Primary Endpoint .................................................................................................................... 40 
2.2.2 
Secondary Endpoint ................................................................................................................ 40 
2.2.3 
Safety and Tolerability ........................................................................................................... 40 
2.2.4 
Exploratory ............................................................................................................................. 41 
3 
Study Design .............................................................................................................................. 41 
3.1 
Trial Diagram ............................................................................................................................ 42 
4 
Study Population ....................................................................................................................... 43 
4.1 
Inclusion Criteria ....................................................................................................................... 43 
4.2 
Exclusion Criteria ...................................................................................................................... 45 
4.3 
Subject Identification ................................................................................................................ 46 
4.4 
Screening Failures ..................................................................................................................... 47 
4.5 
Removal, Replacement, or Early Withdrawal of Subjects from Therapy or Assessment .. 47 
4.6 
Handling of Withdrawals .......................................................................................................... 48 
4.7 
Discontinuation of Study Therapy after CR ........................................................................... 48 


 
 
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4.8 
Sponsor's Termination of Study ............................................................................................... 48 
5 
Study Procedures and Assessments ......................................................................................... 48 
5.1 
Screening Period (Day -21 to Day 0) ........................................................................................ 48 
5.2 
Baseline visit (Day 1 before first dose of any of the study drugs) .......................................... 49 
5.3 
Treatment Period ....................................................................................................................... 50 
5.3.1 
Monotherapy........................................................................................................................... 50 
5.3.2 
Combination Treatment .......................................................................................................... 51 
5.4 
Termination or Early Discontinuation Study Visit ................................................................ 53 
5.5 
Safety follow-Up visit ................................................................................................................. 54 
5.6 
Long-Term Follow-Up of Survival ........................................................................................... 54 
5.7 
Unscheduled Visit ...................................................................................................................... 54 
5.8 
Safety Assessments..................................................................................................................... 54 
5.8.1 
Adverse Events (AEs) ............................................................................................................ 55 
5.8.2 
Concomitant Medications ....................................................................................................... 55 
5.8.3 
Vital Signs, Height and Weight .............................................................................................. 55 
5.8.4 
Electrocardiogram .................................................................................................................. 55 
5.8.5 
Physical Examination and Directed Physical Examination .................................................... 55 
5.8.6 
Laboratory Safety Assessments .............................................................................................. 56 
5.9 
ECOG Performance Status ....................................................................................................... 57 
5.10 Pharmacodynamic Evaluations ................................................................................................ 57 
5.11 Planned Genetic Analysis .......................................................................................................... 58 
5.12 Efficacy Assessments ................................................................................................................. 58 
5.12.1 
Imaging Assessment ............................................................................................................... 58 
5.12.2 
Planned Biopsy Analysis ........................................................................................................ 61 
5.13 Blood Sampling and Processing ............................................................................................... 62 
5.14 Time Windows for Safety and Efficacy Assessments ............................................................. 62 
6 
Investigational Product ............................................................................................................ 62 
6.1 
Identity of Investigational Product .......................................................................................... 62 
6.1.1 
BL-8040 .................................................................................................................................. 62 
6.1.2 
Pembrolizumab ....................................................................................................................... 62 
6.1.3 
Chemotherapy: Onivyde®/5-FU/LV ...................................................................................... 62 
6.2 
Study Drug Administration and Dosage .................................................................................. 62 
6.2.1 
BL-8040 .................................................................................................................................. 62 
6.2.2 
Pembrolizumab ....................................................................................................................... 63 
6.2.3 
Onivyde/5-FU/LV .................................................................................................................. 64 
6.3 
Study Medication Source and Instructions for Use ................................................................ 64 
6.3.1 
BL-8040 .................................................................................................................................. 64 
6.3.2 
Pembrolizumab ....................................................................................................................... 64 
6.3.3 
Chemotherapy......................................................................................................................... 64 
6.4 
Distribution and Shipment of Study Medication .................................................................... 65 
6.5 
Storage, Dispensing and Return of the Investigational Medicinal Product ......................... 65 
6.5.1 
BL-8040 .................................................................................................................................. 65 


 
 
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6.5.2 
Pembrolizumab ....................................................................................................................... 65 
6.5.3 
Chemotherapy......................................................................................................................... 66 
6.6 
Accountability and Compliance of Investigational Medicinal Product ................................ 66 
6.7 
Concomitant Therapy ............................................................................................................... 66 
6.7.1 
Contraception, use in Pregnancy and Nursing Women .......................................................... 67 
6.7.2 
Allowed Medications .............................................................................................................. 68 
6.7.3 
Prohibited Concomitant Medications ..................................................................................... 68 
6.7.4 
Dose Modifications ................................................................................................................ 69 
6.7.5 
Rescue Medications & Supportive Care ................................................................................. 77 
7 
Safety and Pharmacovigilance ................................................................................................. 80 
7.1 
Adverse Event (AE) ................................................................................................................... 80 
7.2 
Serious Adverse Events (SAE) .................................................................................................. 82 
7.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor ...... 83 
7.2.2 
Reporting Period of Serious Adverse Event ........................................................................... 84 
7.2.3 
Definition of an Unexpected Adverse Event .......................................................................... 84 
7.2.4 
Exceptions in the Reporting of SAE ....................................................................................... 84 
7.2.5 
Notification of Serious Adverse Event (SAE) ........................................................................ 85 
7.3 
Events of Clinical Interest ......................................................................................................... 86 
7.4 
Reporting of Pregnancy and Lactation to the Sponsor .......................................................... 86 
8 
Statistical Methodology ............................................................................................................ 87 
8.1 
Sample Size Consideration ........................................................................................................ 87 
8.2 
Data Analyses Sets ..................................................................................................................... 87 
8.2.1 
Intent-to-Treat (ITT) Analysis Set .......................................................................................... 87 
8.2.2 
Modified Intent-to-Treat (mITT) Analysis Set ....................................................................... 87 
8.3 
Efficacy Endpoints and Analyses ............................................................................................. 88 
8.3.1 
Significance Level .................................................................................................................. 88 
8.3.2 
Primary Efficacy Endpoint: Objective Response Rate According to RECIST1.1 (ORRRECIST1.1)
 ................................................................................................................................................ 88 
8.3.3 
Secondary Efficacy Endpoints................................................................................................ 88 
8.4 
Safety analyses ........................................................................................................................... 89 
8.4.1 
Treatment Emergent Adverse Events (TEAEs) ...................................................................... 89 
8.4.2 
Laboratory Data ...................................................................................................................... 90 
8.4.3 
Vital Signs .............................................................................................................................. 90 
8.4.4 
ECG ........................................................................................................................................ 91 
8.4.5 
Safety Assessment - Physical Examinations .......................................................................... 91 
8.5 
Tolerability Assessment............................................................................................................. 92 
8.6 
More Detailed Statistical Analysis Plan (SAP) ........................................................................ 92 
8.7 
Statistical Software .................................................................................................................... 92 
8.8 
Ongoing Safety Assessment and Dose-Limiting Toxicity (DLT) ........................................... 92 
9 
Ethics .......................................................................................................................................... 95 
9.1 
Institutional Review Board or Independent Ethics Committee ............................................ 95 
9.2 
Ethical Conduct of the study .................................................................................................... 95 
9.3 
Subject Information and Consent ............................................................................................ 95 


 
 
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9.4 
Subject Insurance ...................................................................................................................... 96 
9.5 
Informing the General Practitioner ......................................................................................... 96 
9.6 
Personal Data Protection .......................................................................................................... 96 
9.7 
data review Monitoring ............................................................................................................. 96 
9.8 
Protocol Exceptions and Deviations ......................................................................................... 97 
9.9 
Protocol Amendments ............................................................................................................... 97 
10 
Quality Control and Quality Assurance ................................................................................. 97 
10.1 Audits and Inspections .............................................................................................................. 97 
10.2 Study Monitoring ....................................................................................................................... 98 
10.3 Quality Laboratory Standards ................................................................................................. 98 
10.4 Study Documentation ................................................................................................................ 99 
10.4.1 
Source Document ................................................................................................................... 99 
10.4.2 
Recording of Data on Case Report Form (CRF) .................................................................... 99 
10.4.3 
Investigator Site File ............................................................................................................. 100 
10.5 Clinical Trial Supplies ............................................................................................................. 100 
10.6 Data Management .................................................................................................................... 100 
11 
Study Administration ............................................................................................................. 101 
11.1 Participating Centers............................................................................................................... 101 
11.2 Required Documents Prior to Study Initiation ..................................................................... 101 
11.3 Study Completion .................................................................................................................... 102 
11.4 Clinical Study Report .............................................................................................................. 102 
11.5 Retention of Study Records .................................................................................................... 102 
11.6 Confidentiality and Publication of Study Results ................................................................. 102 
11.6.1 
General ................................................................................................................................. 102 
11.6.2 
Published Data ...................................................................................................................... 103 
12 
REFERENCES ....................................................................................................................... 105 
13 
Appendices ............................................................................................................................... 109 
13.1 Appendix A- flow chart ........................................................................................................... 109 
13.1.1 
Cohort 1 ................................................................................................................................ 109 
13.1.2 
Cohort 2 ................................................................................................................................ 114 
13.2 Appendix B - Eastern Cooperative Oncology Group Performance Status ........................ 120 
 
 
 
 


 
 
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List of Tables 
Table 1: Laboratory Tests ........................................................................................................ 56 
Table 2: Pharmacodynamic Assessments ................................................................................ 57 
Table 3: Imaging and Treatment after 1st Radiologic Evidence of PD ................................... 60 
Table 4: Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab ............................................................................... 71 
Table 5: Recommended Dose Modifications for Onivyde® ................................................... 74 
Table 6: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines ... 78 
Table 7: Severity of Adverse Events According to CTCAE (Version 5.0) ............................. 80 
Table 8: Relationship of Adverse Event to Treatment ............................................................. 82 
 
 
 


 
 
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Protocol Synopsis 
Study Title 
A phase IIa, multicenter, Open-Label Study to Assess the Safety and Efficacy of the 
Combination of BL-8040 and Pembrolizumab in Patients with Metastatic 
Pancreatic Cancer, the COMBAT study 
Sponsor 
BioLineRx 
Protocol No. 
BL-8040.PAC.201 
Clinical Sites 
~22 sites, globally in Israel, US and Spain 
Study Phase 
II 
Planned Sample 
Size 
Cohort 1: approximately 40 subjects 
Cohort 2: approximately 40 subjects  
Therapeutic 
Indication 
Cohort 1: Patients with unresectable metastatic pancreatic adenocarcinoma. 
Cohort 2: Patients with unresectable metastatic pancreatic adenocarcinoma who 
have progressed following a first-line gemcitabine-based therapy prior to 
enrollment. 
Study Objectives 
The objectives of the study are to assess the efficacy and safety of BL-8040 in 
combination with pembrolizumab and BL8040/ Pembrolizumab in combination 
with liposomal irinotecan (Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) in 
subjects with metastatic pancreatic adenocarcinoma. The mechanism of action of 
BL-8040, alone and when given in combination, will be studied further using blood 
and tumor tissue samples. 
Study Design  
This will be an open-label, two-cohort, Phase IIa study in subjects with metastatic 
pancreatic adenocarcinoma. The study consists of two periods: 
• 
Monotherapy period: One week, with BL-8040 administered daily on 
Days 1-5. 
• 
Combination therapy: 
o Cohort 1: Three-week cycles of a combination of BL-8040 
administered three times a week (TIW) and pembrolizumab 
administered once every three weeks. 
o Cohort 2: Onivyde®/5-FU/LV every 2 weeks, pembrolizumab once 
every 3 weeks and BL-8040 twice a week. 
Cohort 1: Subjects with metastatic pancreatic adenocarcinoma will be enrolled and 
receive BL-8040 monotherapy for five days followed by a combination treatment 
of BL-8040 and pembrolizumab. During the monotherapy period, eligible subjects 
will receive daily subcutaneous (SC) injections of BL-8040 (1.25 mg/kg) on 
Days 1 - 5. 
From Day 8, subjects will begin a combination period consisting of treatment with 
SC BL-8040 (1.25 mg/kg) TIW and pembrolizumab (200mg) once every three 
weeks. The combination therapy will continue for up to 35 cycles of pembrolizumab 


 
 
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(approximately two years), or until progression, clinical deterioration or Early 
Termination, whichever comes first. 
Cohort 2: Subjects with metastatic pancreatic adenocarcinoma that has progressed 
following first-line treatment with gemcitabine-based chemotherapy will be 
enrolled and receive BL-8040 monotherapy for five days followed by a combination 
treatment of BL-8040, pembrolizumab and chemotherapy. During the monotherapy 
period, eligible subjects will receive daily SC injections of BL-8040 (1.25 mg/kg) 
on Days 1 - 5. 
From Day 8, subjects will begin a combination period consisting of: 
• 
IV Onivyde® 70 mg/m2 over 90 minutes followed by IV leucovorin (LV) 
400 mg/m2 over 30 minutes or according to local standard, followed by IV 
fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. 
• 
Pembrolizumab 200mg once every three weeks. 
• 
Beginning on Day 10, BL-8040 twice a week and following the 
chemotherapy dosing. 
The combination therapy will continue for up to 35 treatments (approximately two 
years), or until progression, clinical deterioration or Early Termination, whichever 
comes first. 
An independent data monitoring committee (DMC) will review the accumulated 
study data according to the DMC charter in order to ensure subject welfare. Serious 
AEs will be monitored continuously throughout the study. 
Safety review of the accumulated data of subjects enrolled to Cohort 2 (Cohort 1 
already enrolled 37 subjects) will be performed by the independent DMC when the 
first 6 subjects and potentially when staggered to 12 subjects (Safety DLT Cohort) 
have completed 28 days of treatment including monotherapy and combination 
treatment. DMC recommendations will thereafter be presented to the Sponsor. The 
guidelines to be used by the DMC for the review of the Safety DLT Cohort are 
presented below: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing Safety Assessment and Dose-Limiting Toxicity 
Adverse events (AEs) will be reported from the time of signing informed consent 


 
 
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through 90 days after the last dose of the last study druga. 
The period considered for DLT assessment is defined as the time from the first dose 
of BL-8040 and up to the end of the first cycle of combination therapy (i.e. Day 1 
of monotherapy through Cycle 1/Day 21). 
Sites will be required to contact the Sponsor within 24 hrs if a subject presents with 
a DLT during the evaluation period. 
Beyond the DLT assessment period, data will be assessed continuously on an 
ongoing basis. AEs reported beyond the DLT assessment period will be captured 
within the Case Report Form (CRF); however, they will not be considered for DLT 
evaluation. 
Study Procedures 
Visit Requirements 
Screening 
From the time of Informed Consent Form (ICF) signature until Day 1 before dosing 
(Baseline visit). A window of 21 days is allowed for the Screening period 
procedures, with the exception of all laboratory assessments, which should be 
completed within 10 days prior to treatment initiation. Potential subjects will be 
assessed for fulfillment of the entry requirements as detailed below in the Inclusion 
and Exclusion Criteria sections of the synopsis. 
Screening period procedures: 
• 
Collect demographics and medical history 
• 
Collect MSI/dMMR status if available 
• 
Review prior and concomitant medications 
• 
AE recording 
• 
12 lead electrocardiogram (ECG) 
• 
Full physical examination (PE) 
• 
Vital signs 
• 
Height 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
• 
Prothrombin Time (PT)/International Normalized Ratio (INR) and 
Activated Partial Thromboplastin Time (aPTT) 
• 
Complete Blood Count (CBC) with differential 
• 
Chemistry panel 
• 
Urinalysis 
• 
T3, free T4, and thyroid stimulating hormone (TSH) 
• 
HIV, HBV and HCV serology 
• 
Blood for carbohydrate antigen 19-9 (CA 19-9) and Carcinoembryonic 
antigen (CEA) 
• 
Blood for biomarker testing including immunophenotyping, CXCR4 and 
PD-1 expression. 
• 
Tumor tissues collection from metastasis for tumor and correlative studies 
assessments (including MSI/dMMR status if not previously tested) 
• 
Blood for cells, DNA and RNA for biomarker correlative studies 
                                                 
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• 
Serum for biomarker correlative studies 
• 
Tumor imaging 
Subjects who failed the Screening procedures may be rescreened after consultation 
with the Sponsor. Rescreening should include all screening procedures listed in the 
protocol flow chart, including re-consent signature. 
Baseline 
Baseline visit refers to Day 1 of treatment before administration of study drug. A 
window of three days is allowed for the procedures and assessments of this visit. 
For the purpose of assessing efficacy, imaging procedures after monotherapy and 
before Cycle1/Day 1 of combination are considered Baseline imaging assessments. 
Baseline procedures: 
• 
AE recording 
• 
Prior and concomitant medications 
• 
Vital signs 
• 
Weight 
• 
Pregnancy test – serum or urine 
Treatment Period 
The treatment period is comprised of two periods: 
Monotherapy: This period will begin immediately after Baseline, preferably on the 
day of the Baseline assessments and will last for one week. During this period, BL-
8040 will be administered daily on Days 1 to 5. The following activities will be 
performed during this week. Details on the specific days for each assessment are 
presented in the flow chart (Appendix A) 
• 
Review AEs 
• 
Prior and concomitant medications 
• 
Vital signs 
• 
12 lead ECG 
• 
Directed PE 
• 
CBC with differential 
• 
Cohort 1: Blood for anti-BL8040 antibodies and complement activation 
Cohort 2:  Blood for anti-BL8040 antibodies 
• 
Blood for immunophenotyping by FACS 
• 
Blood for CA 19-9 and CEA 
• 
Blood for CXCR4 and programmed death - 1 (PD-1) expression 
• 
Tumor tissues collection from metastasis (biopsy)a for tumor and 
correlative studies assessments for Cohort 1 only 
• 
Blood for cells, DNA and RNA for biomarker correlative studies 
• 
Serum for biomarker correlative studies 
• 
Tumor imaging 
                                                 
a Only for the first 15 patients enrolled 


 
 
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Combination: This period will begin after the monotherapy period, on Day 8, and 
will include treatment with the following: 
Cohort 1: IV pembrolizumab followed by SC BL-8040 1 hr ± 30 min later. 
Cohort 2: 
• 
IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV LV 400 mg/m2 
over 30 minutes or according to local standard, followed by IV 5-FU 2400 
mg/m2 over 46 hours, every 2 weeks. 
• 
IV Pembrolizumab 200mg once every three weeks 
• 
Beginning on Day 10, SC BL-8040 1.25mg/kg twice a week after 
chemotherapy dosing. 
Details on the specific days for each assessment are presented in the flow chart 
(Appendix A) 
The following procedures will be performed during this period: 
• 
Review prior and concomitant medications 
• 
Review AEs 
• 
Cohort 2 only: assess specific toxicities to decide on Onivyde® dose 
modifications 
• 
12 lead ECG 
• 
Directed PE 
• 
Vital signs 
• 
Weight 
• 
ECOG performance status 
• 
CBC with differential 
• 
Chemistry panel 
• 
T3, free T4, and TSH 
• 
Cohort 1: Blood for anti-BL8040 antibodies and complement activation  
Cohort 2:  Blood for anti-BL8040 antibodies 
• 
Blood for CA 19-9 and CEA 
• 
Blood for immunophenotyping by FACS 
• 
Blood for CXCR4 and PD-1 expression 
• 
Blood for cells, DNA and RNA for biomarker correlative studies 
• 
 Serum for biomarker correlative studies 
• 
Tumor tissue collection from metastasis (biopsy)a for tumor and correlative 
studies assessments- for Cohort 1 only 
• 
Tumor imaging 
• 
Pregnancy test 
• 
BL-8040 administration three times a week for Cohort 1 and twice a week 
for Cohort 2 
• 
Pembrolizumab administration every three weeks 
• 
Cohort 2 only: Onivyde® with 5-FU/LV administered every 2 weeks. 
• 
An optional newly-obtained core or excisional biopsy for Cohort 1 only. 
 


 
 
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Termination visit 
The length of study treatment will be up to two years. A Termination visit will be 
conducted after two years, or before, in case of subject’s Early Termination. The 
reason for Termination/Early Termination should be accordingly captured within 
the CRFb. 
Termination visit procedures: 
• 
Review prior and concomitant medications 
• 
Review AEs 
• 
12 lead ECG 
• 
Full PE 
• 
Vital signs 
• 
ECOG performance status 
• 
CBC with differential 
• 
Chemistry panel 
• 
T3, free T4, and TSH 
• 
Cohort 1: Blood for anti-BL-8040 antibodies and complement activation 
Cohort 2: Blood for anti-BL-8040 antibodies  
• 
Blood for cells, DNA and RNA for biomarker correlative studies 
• 
Serum for biomarker correlative studies 
• 
Tumor imaging 
Safety follow-up 
A safety follow-up visit will be performed 90 days after the last dose of the last 
study drug. Exceptions that need a longer reporting period are as follow: 
• 
120 days for pregnancy or 30 days following cessation of study treatment 
if a new anti-cancer therapy is initiated. 
Safety follow-up procedures: 
• 
Review prior and concomitant medications 
• 
Review AEs 
• 
CBC with differential 
• 
Chemistry panel 
• 
T3, free T4, and TSH 
• 
12 lead ECG 
• 
Post- study anti-cancer therapy received 
Long-term follow-up for survival 
Subjects will be contacted by phone every 12 weeks after Termination/Early 
Termination in order to follow the subjects’ survival status. Post-study cancer 
therapy will be captured within the CRF as well. 
                                                 
a 
 
 


 
 
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Study Duration 
Core Study 
Screening Period: 21 days 
Monotherapy period: 1 week 
Combination treatment period Cohort 1: repeated cycles every 3 weeks for up to 2 
years 
Combination treatment period Cohort 2: for up to 2 years 
Safety Follow-up period: 90 days from the last of any of the study drugs 
Long-term follow-up for survival every 12 weeks until death 
Inclusion Criteria 
1. 
18 years and older 
2. 
Patients must sign a written informed consent prior to entering the study. 
3. 
Histologically confirmed (either previously or newly biopsied) metastatic 
unresectable pancreatic adenocarcinoma, including intraductal papillary 
mucinous neoplasm. 
4. 
Have measurable disease (≥ 1 measurable lesion) based on Response 
Evaluation Criteria In Solid Tumors (RECIST) v1.1 as determined by the site 
study team. Tumor lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions. 
5. 
Previous treatment lines 
a. Cohort 1: Have documented objective radiographic progression after 
stopping treatment with first-line or further therapy, i.e. chemotherapy 
and or radiotherapy. Surgery not followed with neoadjuvant therapy will 
not be considered as first-line therapy. 
b. Cohort 2: Have documented objective radiographic progression after 
stopping treatment with first-line, gemcitabine-based chemotherapy. Only 
primary metastatic patients will be allowed to participate. Patients with 
previous surgery for their pancreatic cancer will not be allowed to 
participate. 
6. 
Willing to submit an evaluable tumor tissue sample, preferably from a liver 
metastasis, unless tumor is considered inaccessible or biopsy is otherwise 
considered not in the subject’s best interest 
7. 
Complete resolution of toxic effect(s) of the most recent prior chemotherapy 
to Grade 1 or less (except alopecia). If the subject received major surgery or 
radiation therapy of > 30 Gy, they must have recovered from the toxicity 
and/or complications from the intervention. 
8. 
ECOG status ≤1. 
9. 
Life expectancy of at least 3 months. 
10. Adequate organ function at Baseline as defined below. All laboratory 
assessments should be performed within 10 days of treatment initiation 
a. Hematological: 
• White blood cell (WBC) ≥ 2,500/mm^3 
• Absolute neutrophil count 
o Cohort 1: ≥ 1000 /mm^3 
o Cohort 2: ≥ 1500 /mm^3 
• Platelet count ≥ 100,000/mm^3 
• Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 
• Hematocrit ≥30% 


 
 
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b. Renal function: 
• Creatinine ≤1.5x Upper limit of normal (ULN) OR measured or 
calculateda creatinine clearance (glomerular filtration rate [GFR]) can 
also be used in place of creatinine or (CrCl) > 60 mL/min for subject with 
creatinine levels > 1.5x institutional ULN 
c. Hepatic function: 
• Total Bilirubin: within institutional normal ranges 
• Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase 
(AST/SGOT) and Alanine Transaminase/Serum Glutamic Pyruvic 
Transaminase (ALT/SGPT): ≤2.5xULN OR ≤5xULN for subjects with 
liver metastases 
d. Coagulation: 
• INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
• Activated Partial Thromboplastin Time (aPTT): ≤1.5xULN unless subject 
is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
11. Subjects must use effective contraception: 
a. Female subjects must be of non-childbearing potential or, if of 
childbearing potential, must have a negative urine or serum pregnancy 
test within 72 hours prior to taking study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. The serum pregnancy test must be negative for the subject to 
be eligible. Non-childbearing potential is defined as (by other than 
medical reasons): 
• ≥45 years of age and has not had menses for over 2 years 
• Amenorrhoeic for > 2 years without a hysterectomy and 
oophorectomy and a Follicle Stimulating Hormone (FSH) value in the 
postmenopausal range upon pretrial (Screening) evaluation 
• Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation at least 6 weeks prior to Screening. 
Documented hysterectomy or oophorectomy must be confirmed with 
medical records of the actual procedure or confirmed by ultrasound. 
Tubal ligation must be confirmed with medical records of the actual 
procedure otherwise the subject must be willing to use two adequate 
barrier methods throughout the study, starting with the Screening visit 
through 120 days after the last dose of study therapy. Information 
must be captured appropriately within the site's source documents 
b. Male subjects must agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the last 
dose of study therapy. 
                                                 
a Creatinine clearance should be calculated per institutional standard 
 


 
 
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Exclusion Criteria 
A subject must be excluded from participating in the trial if he/she: 
1. 
Has a 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. 
For Cohort 2 only: subjects with a bowel obstruction. 
3. 
Has an active infection requiring systemic therapy or has an uncontrolled 
infection. 
4. 
Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions are adequately treated basal cell or squamous cell 
carcinoma that has undergone potentially curative therapy or carcinoma in 
situ of the cervix. 
5. 
Has an underlying medical condition that would preclude study participation. 
6. 
Has a disease that is suitable for therapy administered with curative intent. 
7. 
Is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 4 weeks of the first dose of treatment. 
8. 
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. 
9. 
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 
AE due to agents administered more than 4 weeks earlier. 
10. Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ 
Grade 1 or at Baseline) from AE due to a previously administered agenta. 
11. An active autoimmune disease that has required systemic treatment in the 2 
years preceding the study (i.e., with the use of disease-modifying agents, 
corticosteroids or immunosuppressive drugs). Note: 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 and is allowed. 
12. Has received transfusions of blood products (including platelets or red blood 
cells) or administration of colony stimulating factors (including Granulocyte 
Colony Stimulating Factor [G-CSF], GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to study Day 1. 
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
14. Has a history of interstitial lung disease. 
15. O2 saturation < 92% (on room air). 
                                                 
 
 
 
 


 
 
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16. For both Cohorts: Has 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. For 
Cohort 2: has ventricular arrhythmias or uncontrolled blood pressure, or 
severe arterial thromboembolic events less than 6 months prior to study 
initiation. 
17. 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. 
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. 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. Women with a positive 
pregnancy test within 72 hours from Baseline. 
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent or if the subject has previously participated in Merck MK-3475 clinical 
trials. 
21. Has a positive HIV test at Screening or at any time prior to Screening. 
Patients without a prior positive HIV test result will undergo an HIV test at 
Screening, unless not permitted per local regulations. 
22. Has known active Hepatitis B (defined as having a positive Hepatitis B 
surface antigen (HBsAg) test at Screening) or Hepatitis C (defined as 
having a positive HCV antibody test or a positive HCV RNA test at 
Screening) 
23. Has known history of Chronic Hepatitis B or C 
24. Has received a live vaccine within 30 days of the planned start of study 
therapy. Seasonal flu vaccines that do not contain live virus are permitted. 
25. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Note: Subjects with previously treated brain 
metastases may participate provided they are stable (without evidence of 
progression by imaging using the identical imaging modality for each 
assessment, either MRI or computerized tomography (CT) scan, for at least 
four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to Baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 14 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which 
is excluded regardless of clinical stability. 
26. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients. 
27. Cohort 2: Has clinical ascites requiring treatment 


 
 
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Investigational 
Product Route and 
Dosage Form 
BL-8040 
BL-8040, a synthetic polypeptide highly selective antagonist of CXCR4.  
BL-8040, a white to off-white powder, is freely soluble in water. It is manufactured 
in accordance with Good Manufacturing Practice (cGMP) by 
 
. During the 
monotherapy period, BL-8040 (1.25 mg/kg) will be administrated by SC injections 
daily on Days 1 - 5. From Day 8 subjects will begin the combination period which 
consists of treatment with SC BL-8040 (1.25 mg/kg) TIW. For Cohort 2 SC BL-
8040 (1.25 mg/kg) will be provided twice a week beginning on Day 10. 
Pembrolizumab 
Pembrolizumab [Keytruda® (US)], is a humanized monoclonal antibody against the 
programmed death -1 (PD-1) receptor protein. Pembrolizumab will be administered 
at a dose of 200 mg every three weeks using a 30-minute IV infusion. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (i.e., the infusion time is 30 
minutes -5 min/+10 min). 
Chemotherapy: Onivyde® with 5-FU/LV 
Onivyde® is a liposomal irinotecan, an inhibitor of topoisomerase I that prevents 
re-ligation of the DNA and causes double-strand DNA breakage leading to cell 
death. 5-FU is a nucleoside metabolic inhibitor that interferes with the synthesis of 
DNA and to a lesser extent, inhibits the formation of RNA. LV is an active, 
chemically-reduced derivative of folic acid. It enhances the therapeutic and toxic 
effects of 5-FU, without changing its pharmacokinetics. The combination has been 
approved in the US and EU for treatment of pancreatic cancer patients who have 
progressed following treatment with gemcitabine-based chemotherapy. 
In this study, in Cohort 2 only, Onivyde® 70 mg/m2 will be administered as an IV 
infusion over 90 minutes followed by IV LV 400 mg/m2 over 30 minutes or 
according to the local standard, followed by IV 5-FU 2400 mg/m2 over 46 hours, 
every 2 weeks.  
Concomitant 
Medications 
Medications or vaccinations specifically prohibited in the Exclusion criteria are 
not allowed during the ongoing trial. If there is a clinical indication for any 
medication or vaccination specifically prohibited during the trial, discontinuation 
of trial therapy may be required. The Investigator should discuss any questions 
regarding this with the Sponsor’s Medical Monitor. The final decision on any 
supportive therapy or vaccination rests with the Investigator and/or the subject's 
primary physician. However, the decision to continue the subject’s trial therapy 
requires the mutual agreement of the Investigator, the Sponsor, and the subject. 
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 on the CRF including all prescription, over-the-counter (OTC), herbal 


 
 
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supplements, and IV medications and fluids. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date should also be 
included in the CRF. 
All concomitant medications received within 30 days prior to the first dose of study 
treatment and 90 days after the last dose of trial treatment should be recorded. 
Concomitant medications administered more than 90 days after the last dose of trial 
treatment should be recorded for SAEs and events of clinical interest (ECIs). 
Several cases of transient hypotension were witnessed following the initial 
treatment with BL-8040. Therefore, caution should be taken with the use of negative 
chronotropic drugs such as beta blockers. When appropriate, beta blocker should be 
replaced to non-chronotropic negative drugs. 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the screening 
period and Treatment Phase of this trial: 
• 
Antineoplastic systemic chemotherapy (other than the one administered as 
part of the study in Cohort 2) or biological therapy. 
• 
Immunotherapy or other therapy not specified in this protocol. 
• 
Chemotherapy not specified in this protocol. 
• 
Investigational agents other than BL-8040 and pembrolizumab. 
• 
Radiation therapy: Radiation therapy to a solitary symptomatic lesion or 
to the brain may be considered on an exceptional case by case basis after 
consultation with the Sponsor. The subject must have clear, measurable 
disease outside the radiated field. Administration of palliative radiation 
therapy will be considered clinical progression for the purposes of 
determining Progression-free survival (PFS). 
• 
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, chickenpox, 
yellow fever, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (e.g. Flu - Mist®) are live 
attenuated vaccines and are not allowed. 
• 
Systemic glucocorticoids.  Exceptions include the use of glucocorticoids 
for modulating symptoms from an event of clinical interest of suspected 
immunologic etiology, for systemic and local reactions secondary to BL-
8040 and/or pembrolizumab treatment, and for premedication prior to 
Onivyde treatment in accordance with NCCN guidelines. The use of 
physiologic doses of corticosteroids may be approved after consultation 
with the Sponsora. 
                                                 
a 
 
 
 


 
 
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o Note: Inhaled steroids are allowed for management of asthma, and 
dermatological formulations are allowed to reduce the intensity of 
injection site reactions. 
• 
Cohort 2 only: 
o Strong CYP3A4 inducers are to be avoided if possible. Substitute 
non-enzyme inducing therapies at least 2 weeks prior to initiation 
of Onivyde®. 
o Strong CYP3A4 or UGT1A1 Inhibitors are to be avoided, if 
possible; discontinue strong CYP3A4 inhibitors at least 1 week 
prior to starting Onivyde®. 
o 5-FU may cause elevated coagulation times when administered 
with warfarin, possibly through inhibition of CYP2C9. 
Subjects who, in the assessment of 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 as 
medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase.  
Study Endpoints 
Primary 
• 
Objective Response Rate (ORRRECIST1.1) determined according to RECIST 
1.1 criteriaa. 
Secondary 
• 
Objective Response Rate (ORRirRECIST) determined according to 
irRECIST criteria. 
• 
Overall Survival (OS) 
• 
PFS 
• 
Disease Control according to RECISIT 1.1 (DCRECIST1.1) is defined as 
the sum of PRs and CRs and SDs. 
Safety and Tolerability 
• 
Treatment Emergent Adverse Events (TEAEs) 
• 
Laboratory safety data 
• 
Vital signs 
• 
ECG 
• 
PE 
• 
Early study discontinuations, overall and due to AE 
                                                 
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Exploratory 
• 
 
 
 
 
 
 
 
 
Statistical Analysis 
 
As this is an open-label, phase IIa two-cohort study to evaluate the safety, 
tolerability and preliminary efficacy study of two potential treatment regimens, 
neither power assessment, nor between-cohort formal hypotheses testing are 
currently planned for study outcome measures. 
The planned sample size of a total of 40 subjects for each of the two study cohorts 
is considered clinically appropriate for further characterization of the safety, 
tolerability and preliminary efficacy of the proposed treatment regimens in subjects 
with metastatic pancreatic adenocarcinoma. 
Outcome results of all safety, tolerability and preliminary efficacy data will be 
compared between the two study cohorts descriptively. 
The primary efficacy endpoint is the Objective Response Rate according to 
RECIST1.1 (ORRRECIST1.1) defined as the sum of PRs and CRs determined 
according to best response RECIST1.1 criteria. 
Principal analysis for inference will use the modified intent to treat (mITT) Analysis 
Set. The ORRRECIST1.1 rate and its lower 95% one-sided confidence limit (
 
) will be displayed for each study cohort. 
Sensitivity analysis will be done for the ITT analysis set. 
A more detailed Statistical Analysis Plan (SAP), amending the plan written for 
Cohort 1, will be developed during the data collection period of the initial 6 
subjects of Cohort 2. 


 
 
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Glossary 
Subject and patient will be used interchangeably throughout this document. 
Abbreviation/Term 
Definition 
AE 
Adverse Event 
ALT/SGPT 
Alanine Transaminase/Serum Glutamic Pyruvic Transaminase 
AML 
Acute Myeloid Leukemia 
aPTT 
Activated Partial Thromboplastin Time 
Ara-C 
Arabinofuranosyl Cytidine / Cytarabine / Cytosine Arabinoside 
AST/SGOT 
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase 
BIW 
Twice Weekly 
BM 
Bone Marrow 
CA 19-9 
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCR4 
CXC Chemokine Receptor Type 4 
DCR 
Disease control rate 
DILI 
Drug Induce Liver Injury 
DLT 
Dose-Limiting Toxicity 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Endothelial Growth Factor Receptor 
EMA 
European Medicines Agency 
ET 
Early termination 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FNA 
Fine Needle Aspirate 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 


 
 
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G-CSF 
Granulocyte Colony Stimulating Factor  
GFR 
Glomerular Filtration Rate 
GLP 
Good-Laboratory Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICI 
Immune checkpoint inhibitor 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
INR 
International Normalized Ratio (for blood coagulation tests) 
IRB 
Institutional Review Board 
ITSM 
Immunoreceptor Tyrosine-based Switch Motif 
ITT 
Intention To Treat 
KIR 
Killer-immunoglobulin-like receptor 
LOV 
Last Observed Value 
MDSC 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for regulatory Activities 
mITT 
Modified Intention To Treat 
MM 
Multiple Myeloma 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute  
NCS 
Not Clinically Significant 
NK cells 
Natural Killer cells 
NOAEL  
No Observed Adverse Effect Level 
NSCLC 
Non-small cell lung carcinoma 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OTC 
Over-The-Counter 
PB 
Peripheral Blood 
PD-1 
programmed death receptor 1 
PDAC 
pancreatic adenocarcinoma  
PE 
Physical Examination 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial Response 


 
 
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PT 
Prothrombin Time  
RECIST 
Response Evaluation Criteria In Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
Stable disease 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
TIL 
Tumor Infiltrating Lymphocytes 
TIW 
Three times a week 
TLS 
Tumor Lysis Syndrome 
TMDD 
Target-mediated drug disposition 
TSH 
Thyroid stimulating hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


 
 
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1 
INTRODUCTION 
Cancer immunotherapy,  a novel and rapidly growing field of research, investigates the use of 
therapies that harness the body’s own immune system in the fight against cancer. Tumors 
utilize a variety of mechanisms to evade host immune detection. There is mounting evidence 
that tumor-infiltrating immune cells such as myeloid-derived suppressor cells (MDSCs), 
regulatory T cells (Tregs) and tumor-associated macrophages, actively modulate the tumor 
microenvironment to suppress the effector arms of this response. The aim of the cancer 
immunotherapy approach is to prevent the tumor’s ability to suppress its own detection and 
elimination by the host immune system. A number of biologic agents that target a range of 
immune signaling mechanisms, e.g., programmed-death receptor 1 (PD-1)/ programmed-death 
receptor ligand 1 (PD-L1), Lymphocyte-activation gene 3 (LAG-3), and killer-
immunoglobulin-like receptor (KIR), are in clinical development for the treatment of a variety 
of cancers. However, a fraction of subjects do not respond to these therapies as a result of local 
immunosuppression mediated by stromal cells (mostly fibroblasts). It was found that activated 
fibroblasts in the tumor stroma mediate immune suppression in several mouse models of 
cancer. One suggestion for the basis of the immune suppression involves the production of the 
chemokine, CXCL12, by the fibroblastic stromal cells. Binding of 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. 
Preclinical studies have demonstrated that this immune suppression is interrupted by 
administration of inhibitors of CXC chemokine receptor 4 (CXCR4), the receptor for CXCL12, 
which leads to the rapid accumulation of T cells among cancer cells, thereby uncovering the 
efficacy of immune checkpoints inhibitors. 
 
 
1.1 
BL-8040 
BL-8040 (previously named BKT140) is a highly selective CXCR4 antagonist developed by 
BioLineRx Ltd. as a novel therapy for the treatment of cancer. 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
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1.2 
PEMBROLIZUMAB 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety 
profile and is in clinical development as an IV immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. 
 
 
1.2.1 Pharmaceutical and Therapeutic Background 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1.2.2 Preclinical and Clinical Trials 
 
 
 
  
 
 
 
 
 
 
 
 
1.3 
CHEMOTHERAPY: NANOLIPOSOMAL IRINOTECAN WITH 
FLUOROURACIL AND LEUCOVORIN (ONIVYDE® WITH 5-FU/LV) 
Liposomal irinotecan is a liposome-encapsulated formulation of the topoisomerase-1 inhibitor 
irinotecan, developed to overcome the pharmacological and clinical limitations of non-
liposomal irinotecan[26,27]. 5-FU is a nucleoside metabolic inhibitor indicated for the 
treatment of patients with pancreatic adenocarcinoma[28]. LV is a chemically-reduced 
derivative of folic acid. It can enhance the therapeutic and toxic effects of 5-FU. Concurrent 
administration of LV does not appear to alter the plasma pharmacokinetics of 5-FU. 5-FU is 
metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate 
synthase (an enzyme important in DNA repair and replication). LV is readily converted to 
another reduced folate, 5,10- methylenetetrahydrofolate, which acts to stabilize the binding of 
fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this 
enzyme[29]. IV liposomal irinotecan injection (Onivyde®) is approved for use in combination 
with 5-FU and LV (5-FU/LV) in patients with metastatic pancreatic adenocarcinoma that has 
progressed following gemcitabine-based therapy. 
 
 
 
 
 
 
 
 
 
 
1.4 
THERAPEUTIC INDICATION 
Pancreatic cancer is a malignant neoplasm of the pancreas with a low early- diagnosis rate and 
poor prognosis. Its incidence rate has risen in recent years and it now comprises 1%-2% of 
common tumors. Each year about 185,000 individuals globally are diagnosed with this 
condition. As its symptoms are usually non-specific, pancreatic cancer is often not diagnosed 
until it reaches an advanced stage. The only potentially curative therapy for pancreatic cancer 
is surgical resection. Unfortunately, tumors in only 20% patients are resectable at the time of 
diagnosis. Even among those patients who undergo resection for pancreatic cancer and have 
tumor-free margins, the 5-year survival rate is only 10%-25%[30,31]. The overall 5-year 
survival rate among patients is less than 5%, which constitutes the highest mortality rates 
among solid malignancies. The overall median survival is less than 1 year from diagnosis, 
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The anatomical structure of the pancreas is very complicated. The high interstitial tension and 
inadequate blood perfusion of the pancreatic tumors give them extreme resistance to most 
chemotherapy drugs. Consequently, conventional systemic IV chemotherapy often fails to 
reach effective concentrations. High dosages may cause severe adverse reactions, thus 
impairing the immune system and reducing the potential therapeutic effect. The failure of 
clinical treatment in patients with pancreatic ductal adenocarcinoma is often attributed to the 
early metastatic growth, a high level of drug resistance to standard therapy options and high 
rates of local recurrence[32]. 
Despite recent advances in chemotherapeutics and in our understanding of the molecular 
biology of pancreatic cancer, there has been limited progress in therapeutic options for 
metastatic disease. Over the past four decades, studies of several combination therapies have 
demonstrated minimal or no survival benefit compared with gemcitabine alone. Gemcitabine 
monotherapy had been the standard of care for patients with metastatic pancreatic cancer for 
several years, until combination therapy with gemcitabine plus erlotinib was shown to increase 
median survival by 2 weeks. However, the modest survival benefit was tempered by a 
significant side effect profile and the high cost of treatment. Later, the multidrug combination 
of LV, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) showed an increased median survival 
of 4.3 months; however, given its side effect profile, it is available only to a select group of 
patients with advanced pancreatic cancer. Recently, the gemcitabine plus nab-paclitaxel 
combination was shown to increase median survival by 1.8 months, with increased OS at 1 and 
2 years; AEs were reasonable; they included cytopenias and peripheral neuropathy[33]. The 
current National Comprehensive Cancer Network recommendations suggest acceptable 
chemotherapy combinations for patients with good performance status (i.e., ECOG 
performance status of 0 or 1), good pain management, patent biliary stent, and adequate 
nutritional intake; these combinations include FOLFIRINOX, gemcitabine plus nab-paclitaxel, 
and gemcitabine plus erlotinib. The only recommended option for patients with poor 
performance status is gemcitabine monotherapy. In 2015, Onivyde® was the first 
chemotherapeutic agent approved in the US and in the EU in combination with 5-FU and LV, 
for the treatment of patients with metastatic adenocarcinoma of the pancreas in second line 
settings, after disease progression following gemcitabine-based therapy[26,34]. 
1.5 
STUDY 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 CTLA-4 and 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. 










 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
OBJECTIVES 
The objectives of the study are to assess the efficacy and safety of BL-8040 in combination 
with pembrolizumab and BL8040/ Pembrolizumab in combination with liposomal irinotecan 
(Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) in subjects with metastatic pancreatic 
adenocarcinoma. The mechanism of action of BL-8040, alone and when given in combination, 
will be studied further using blood and tumor tissue samples. 
2.2 
STUDY ENDPOINTS 
2.2.1 Primary Endpoint 
• Objective Response Rate (ORRRECIST1.1) determined according to Response 
Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria. 
2.2.2 Secondary Endpoint 
• Objective Response Rate (ORRirRECIST) determined according to irRECIST criteria. 
• OS. 
• PFS. 
• Disease Control according to RECISIT 1.1 (DCRECIST1.1) is defined as the sum of 
partial responses (PRs), CRs and SDs. 
2.2.3 
Safety and Tolerability 
• TEAEs 
• Laboratory safety data 
• Vital signs 
• ECG 
• Physical examination (PE) 
• Early study discontinuations, overall and due to AE 


 
 
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3 
STUDY DESIGN 
This will be an open-label, single arm, Phase IIa study in subjects with metastatic pancreatic 
adenocarcinoma. The study consists of two periods: 
• Monotherapy period: One week, with treatment using BL-8040 on Days 1-5 
• Combination therapy: 
o Cohort 1: Three-week cycles of a combination of BL-8040 TIW and 
pembrolizumab once every three weeks. 
o Cohort 2:  Onivyde®/5-FU/LV every 2 weeks, pembrolizumab once every 3 
weeks and BL-8040 twice a week. 
Cohort 1: Subjects with metastatic pancreatic adenocarcinoma will be enrolled and receive BL-
8040 monotherapy for five days followed by a combination treatment of BL-8040 and 
pembrolizumab. During the monotherapy period, eligible subjects will receive daily SC 
injections of BL-8040 (1.25 mg/kg) on Days 1 - 5. 
From Day 8, subjects will begin a combination period consisting of treatment with SC BL-
8040 (1.25 mg/kg) TIW and pembrolizumab (200 mg) once every three weeks. The 
combination therapy will continue for up to 35 cycles of pembrolizumab (approximately two 
years), or until progression, clinical deterioration or early Termination, whichever comes first. 
Cohort 2: Subjects with metastatic pancreatic adenocarcinoma that have progressed following 
first-line treatment with gemcitabine-based chemotherapy will be enrolled and receive BL-
8040 monotherapy for five days followed by a combination treatment of BL-8040, 
pembrolizumab and chemotherapy. During the monotherapy period, eligible subjects will 
receive daily SC injections of BL-8040 (1.25 mg/kg) on Days 1 - 5. 
From Day 8, subjects will begin a combination period consisting of: 
• IV Onivyde® 70 mg/m2 over 90 minutes followed by IV leucovorin (LV) 400 mg/m2 
over 30 minutes or according to the local standard, followed by IV fluorouracil (5-FU) 
2400 mg/m2 over 46 hours, every 2 weeks. 
• Pembrolizumab 200mg once every three weeks. 
• Beginning on Day 10, BL-8040 twice a week and after chemotherapy dosing. 
The combination therapy will continue for up to 35 treatments (approximately two years), or 
until progression, clinical deterioration or early Termination, whichever comes first. 
 
An independent data monitoring committee (DMC) will review the accumulated study data 
according to the DMC charter in order to ensure subject welfare. Serious AEs (SAEs) will be 
monitored continuously throughout the study. 
Safety review of the accumulated data of subjects enrolled to Cohort 2 (Cohort 1 already 
enrolled 37 subjects) will be performed by the independent DMC when the first 6 subjects and 
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completed 28 days of treatment including monotherapy and combination treatment. DMC 
recommendations will thereafter be presented to the Sponsor. The guidelines to be used by the 
DMC for the review of the Safety DLT Cohort are presented below: 
• If 0 out of 6 subjects experience a DLT during the first cycle of treatment, the 
combination treatment will be considered as eligible for further evaluation and 
recruitment will continue without a pause. 
• If 1 out of 6 subjects experiences a DLT, the Safety DLT Cohort will be expanded to 
12 subjects. 
• If ≥ 2 out of 6 subjects experience a DLT, the DMC will assess the risk/benefit ratio of 
the combination treatment and recommend one or more of the following: 1) the Safety 
DLT Cohort should be expanded to 12 subjects, 2) the protocol should be modified, 3) 
the treatment schedule should be changed or 4) the study should be discontinued. 
• If ≤ 2 out of 12 subjects experience a DLT in the expanded Safety DLT Cohort, 
recruitment can be continued to the full proposed study size. 
• If > 2 out of 12 subjects experience a DLT in the expanded Safety DLT Cohort, the 
DMC will determine whether recruitment will be stopped, or recruitment can be 
continued with or without a protocol modification. 
Efficacy data will be assessed throughout the study, without stopping recruitment. The 
assessment will include review all the available data, i.e. imaging, biopsies, safety assessment, 
etc. and will assess the clinical benefit of the investigated combination treatments. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Appendix A in Section 13.1. 
 
3.1 
TRIAL DIAGRAM 
 


 
 
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4 
STUDY POPULATION 
Male and female subjects 18 years old and older with metastatic unresectable PDAC will be 
enrolled in this trial. Inclusion/Exclusion criteria will be assessed during the Screening period 
unless otherwise specified within the specific criteria. 
Entry criteria are absolute. Any subject not meeting one or more inclusion criteria or meeting 
one or more Exclusion Criteria is not allowed to enter the trial. If a variable’s limit is presented 
in a criterion, then that limit may not be exceeded. 
4.1 
 INCLUSION CRITERIA 
In order to be eligible for participation in this trial, the subject must satisfy the following: 
1. 18 years and older 
2. Patients must sign a written informed consent prior to entering the study. 
3. Histologically confirmed (either previously or newly biopsied) metastatic unresectable 
pancreatic adenocarcinoma, including intraductal papillary mucinous neoplasm. 
4. Have measurable disease (≥ 1 measurable lesion) based on RECIST v1.1 as determined 
by the site study team. Tumor lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions. 
5. Previous treatment lines 
a. Cohort 1: Have documented objective radiographic progression after stopping 
treatment with first-line or further therapy, i.e. chemotherapy and or radiotherapy. 
Surgery not followed with neoadjuvant therapy will not be considered as first-line 
therapy. 
b. Cohort 2: Have documented objective radiographic progression after stopping 
treatment with first-line, gemcitabine-based chemotherapy. Only primary 
metastatic patients will be allowed to participate. Patients with previous surgery 
for their pancreatic cancer will not be allowed to participate. 
6. Willing to submit an evaluable tumor tissue sample, preferably from a liver metastasis, 
unless tumor is considered inaccessible or biopsy is otherwise considered not in the 
subject’s best interest 
7. Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except alopecia). If the subject received major surgery or radiation therapy of > 
30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
8. ECOG status ≤1. 
9. Life expectancy of at least 3 months. 
10. Adequate organ function at Baseline as defined below. All laboratory assessments should 
be performed within 10 days of treatment initiation 
a. Hematological: 
• White blood cell (WBC) ≥ 2,500/mm^3 
• Absolute neutrophil count 
o Cohort 1: ≥ 1000 /mm^3 
o Cohort 2: ≥ 1500 /mm^3 
• Platelet count ≥ 100,000/mm^3 
• Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 


 
 
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• Hematocrit ≥30% 
b. Renal function: 
• Creatinine ≤1.5x Upper limit of normal (ULN) OR measured or calculateda 
creatinine clearance (glomerular filtration rate [GFR]) can also be used in place 
of creatinine or (CrCl) > 60 mL/min for subject with creatinine levels > 1.5x 
institutional ULN 
c. Hepatic function: 
• Total Bilirubin: within institutional normal ranges 
• Aspartate aminotransferase/ serum glutamic oxaloacetic transaminase 
(AST/SGOT) and Alanine amino transferase/ serum glutamate-pyruvate 
transaminase (ALT/SGPT): ≤2.5xULN OR ≤5xULN for subjects with liver 
metastases 
d. Coagulation: 
• INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long 
as PT or PTT is within therapeutic range of intended use of anticoagulants 
• aPTT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as 
PT or PTT is within therapeutic range of intended use of anticoagulants 
11. Subjects must use effective contraception: 
a. Female subjects must be of non-childbearing potential or, if of childbearing potential, 
must have a negative urine or serum pregnancy test within 72 hours prior to taking 
study medication. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. The serum pregnancy test must be negative for 
the subject to be eligible. Non-childbearing potential is defined as (by other than 
medical reasons): 
• ≥45 years of age and has not had menses for over 2 years 
• Amenorrhoeic for > 2 years without a hysterectomy and oophorectomy and a 
Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon 
pretrial (Screening) evaluation 
• Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation at least 6 weeks prior to Screening. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of 
the actual procedure or confirmed by ultrasound. Tubal ligation must be 
confirmed with medical records of the actual procedure otherwise the subject 
must be willing to use two adequate barrier methods throughout the study, 
starting with the Screening visit through 120 days after the last dose of study 
therapy. Information must be captured appropriately within the site's source 
documents 
b. Male subjects must agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.  
 
Please see Section 6.7.1 - Contraception for a list of acceptable birth control methods. 
                                                 
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4.2 
EXCLUSION CRITERIA 
A subject must be excluded from participating in the trial if he/she: 
1. 
Has a 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. 
For Cohort 2 only: subjects with a bowel obstruction. 
3. 
Has an active infection requiring systemic therapy or has an uncontrolled infection. 
4. 
Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions are adequately treated basal cell or squamous cell carcinoma that has 
undergone potentially curative therapy or carcinoma in situ of the cervix. 
5. 
Has an underlying medical condition that would preclude study participation. 
6. 
Has a disease that is suitable for therapy administered with curative intent. 
7. 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
8. 
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. 
9. 
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 AE due to agents 
administered more than 4 weeks earlier. 
10. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at 
Baseline) from AE due to a previously administered agenta. 
11. 
An active autoimmune disease that has required systemic treatment in the 2 years 
preceding the study (i.e., with the use of disease-modifying agents, corticosteroids or 
immunosuppressive drugs). Note: 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 and is allowed. 
12. 
Has received transfusions of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including Granulocyte Colony 
Stimulating Factor [G-CSF], GM-CSF or recombinant erythropoietin) within 4 weeks 
prior to study Day 1. 
13. 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
14. 
Has a history of interstitial lung disease. 
15. 
O2 saturation < 92% (on room air). 
16. 
For both Cohorts: Has unstable angina, new onset angina within the last 3 months, 
myocardial infarction within the last 6 months, and current congestive heart failure New 
                                                 
a Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify 
for the study. If subject underwent major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. 


 
 
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York Heart Association Class III or higher. For Cohort 2: has ventricular arrhythmias 
or uncontrolled blood pressure, or severe arterial thromboembolic events less than 6 
months prior to study initiation. 
17. 
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. 
18. 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
19. 
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. Women with a positive pregnancy test within 72 hours 
from Baseline. 
20. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if 
the subject has previously participated in Merck MK-3475 clinical trials. 
21. 
Has a positive HIV test at Screening or at any time prior to Screening.  Patients 
without a prior positive HIV test result will undergo an HIV test at Screening, unless 
not permitted per local regulations. 
22. Has known active Hepatitis B (defined as having a positive Hepatitis B surface antigen 
(HBsAg) test at Screening) or Hepatitis C (defined as having a positive HCV antibody 
test or a positive HCV RNA test at Screening) 
23. 
Has known history of Chronic Hepatitis B or C 
24. 
Has received a live vaccine within 30 days of the planned start of study therapy. 
Seasonal flu vaccines that do not contain live virus are permitted. 
25. 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Note: Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging using the 
identical imaging modality for each assessment, either MRI or computerized 
tomography (CT) scan, for at least four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 14 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability. 
26. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
27. Cohort 2: Has clinical ascites requiring treatment 
 
4.3 
SUBJECT IDENTIFICATION 
Each consented subject will receive a unique subject number that will be used to identify the 
subject for all procedures that occur from Screening throughout the end of study or until the 
subject terminates from the study. Each subject will be assigned only one subject number. 


 
 
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Subject numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will retain the original subject number assigned 
at the initial Screening visit. A single subject may not be assigned more than one subject 
number. 
Specific details on the Screening visit requirements (Screening/rescreening) are provided in 
Section 5.1. 
4.4 
SCREENING FAILURES 
Subjects who fail to meet the entrance criteria at any stage during the Screening period are 
defined as screening failures. All screening failures will be documented on the appropriate 
log which will be kept in the Investigator's Site File. 
4.5 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS 
FROM THERAPY OR ASSESSMENT 
Subjects are free to discontinue the study drugs and/or their participation in the study at any 
time and without prejudice to further treatment. The Investigator must withdraw any subject 
from the study if that subject requests to be withdrawn, or if it is determined that continuing in 
the study would result in a significant safety risk to the subject. Patients can terminate the study 
treatment early (i.e. before two years) in the case of CR (see Section 4.7). Subjects that 
discontinue the study drug will continue to participate in the survival follow-up of the study 
for up to 5 years, unless they withdrew their consent to continue their participation in the study 
as well. 
Subjects withdrawn from the study prior to the Baseline visit or prior to first injection of any 
of the study drugs will be replaced by the Investigator to achieve the appropriate number of 
subjects, regardless of the reason for withdrawal. 
If a subject discontinues from the trial during the DLT evaluation period for any reason other 
than safety, a replacement subject may be enrolled if deemed appropriate by the Investigator 
and Sponsor in order to reach the target number for DLT assessment. Subjects who 
discontinued the trial during the DLT period because of progression will not be considered for 
DLT assessment; however, they will be counted as having progressed for the efficacy analysis. 
The replacement subject will be assigned a unique treatment/ number. The trial site should 
contact the Sponsor for the replacement subject’s treatment number. 
The subject's use of study drug may be discontinued for any of the following reasons: 
• Toxicity 
• Death 
• Request of regulatory agency 
• Sponsor request 
• Primary care physician or Investigator request: Investigator decides that withdrawal 
from the study is in the best interest of the subject 
• Withdrawal of consent by subject 
• Disease Progression 
• Female subject who becomes pregnant 
• Lost to follow-up 


 
 
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• Subject is non-compliant with study procedures / study protocol 
• Other 
• See Section 6.7.4 for dose-modification and treatment attenuation recommendation for 
each study drug. 
4.6 
HANDLING OF WITHDRAWALS 
If a subject is withdrawn from the study, every effort should be made to determine the reason. 
This information will be recorded on the subject’s Case Report Form (CRF). All subjects who 
withdraw from the study prematurely, regardless of cause, should undergo all Early 
Discontinuation Study Visit procedures (see Section 5.4), safety follow-up visit and continue 
the long-term follow-up for survival. 
If withdrawal is caused by an AE that the Investigator considers may be related to the study 
drug, the AE will be reported to the institutional review board/independent ethics committee 
(IRB/IEC) as per local guidelines if required. 
Any SAE must be reported to the Sponsor or Sponsor's designee by telephone or fax within 24 
hours of the Investigator’s becoming aware of the event and to the IRB/IEC according to local 
regulations (for SAE notification procedures, refer to Section 7.2.5). 
All AEs will be followed up with appropriate medical management until the outcome is 
determined or stabilized, according to the Investigator’s clinical judgment. All follow-up 
information will be recorded in the subject's CRF until resolution of the AE. 
4.7 
DISCONTINUATION OF STUDY THERAPY AFTER CR 
Discontinuation of study drugs may be considered for subjects who have attained a confirmed 
CR, that: 
• Have been treated for at least 24 weeks with the combination therapy and 
• 
Received at least two treatment cycles of combination therapy beyond the date when 
the initial CR was declared. 
4.8 
SPONSOR'S TERMINATION OF STUDY 
The Sponsor reserves the right to discontinue the study at any time at the participating centers 
for any reason. 
Regulatory Authorities also have the right to terminate the study for any reason. 
5 
STUDY PROCEDURES AND ASSESSMENTS 
The schedule of events for this study is shown in Section 13.1, Appendix A1. No protocol-
related procedures should be performed before the subject provides written informed consent. 
Study-related events and activities (including specific instructions, procedures, concomitant 
medications, dispensing of study medication, and descriptions of AEs) should be recorded in 
the appropriate source documents and CRF. 
5.1 
SCREENING PERIOD (DAY -21 TO DAY 0) 
From the time of Informed Consent Form (ICF) signature until Day 1 before dosing (Baseline 
visit). A window of 21 days is allowed for the Screening period procedures, with the exception 
of all laboratory assessments, which should be completed within 10 days of treatment 
initiation. At the Screening visit the purpose and procedures of the study will be fully 
explained to participants. Those wishing to enroll in the study will sign a written ICF prior to 


 
 
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initiating any evaluations or study-related procedures. After signing informed consent, male 
and female subjects aged ≥18 years will be assessed for fulfillment of the entry requirements 
as detailed below in the Inclusion and Exclusion Criteria sections 4.1 and 4.2. 
The following assessments should be done at Screening period-Visit 1 (exceptions are defined 
below): 
1. 
Collect demographics and medical history 
2. 
Collect MSI/dMMR status if available 
3. 
Review prior and concomitant medications 
4. 
AEs 
5. 
12 lead ECG 
6. 
Full PE 
7. 
Vital signs 
8. 
Height 
9. 
ECOG performance status 
10. 
Laboratory assessments should be performed within 10 days of treatment 
initiation. 
a.  PT/INR and aPTT 
b. Complete blood count (CBC) with differential 
c. Chemistry panel 
d. Urinalysis 
e. T3, free T4, and thyroid stimulating hormone (TSH)a 
11. 
HIV, HBV and HCV serology 
12. 
Blood for CA 19-9 (in Cohorts 1 and 2) and CEA (in Cohort 2 only) 
13. 
Tumor tissue collection from metastasis (biopsy) for tumor and correlative 
studies assessments (including MSI/dMMR status if not previously tested) 
14. 
Blood for cells, DNA and RNA for biomarker correlative studies. 
15. 
Serum for biomarker correlative studies.  
16. 
Tumor imaging assessment CT or MRI 
Subjects who failed the Screening procedures may be rescreened after consultation with the 
Sponsor. Rescreening should include all screening procedures listed in the protocol flow chart, 
including re-consent signature. 
5.2 
BASELINE VISIT (DAY 1 BEFORE FIRST DOSE OF ANY OF THE STUDY 
DRUGS) 
Baseline visit refers to Day 1 of treatment before administration of study drug. A window of 
                                                 
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three days is allowed for the procedures and assessments of this visit. 
For the purpose of assessing efficacy, imaging procedures after monotherapy and before 
Cycle1/Day 1 of combination are considered Baseline imaging assessments. 
Baseline procedures: 
1. 
AE recording 
2. 
Prior and concomitant medications 
3. 
Vital signs 
4. 
Weight 
5. 
Pregnancy test – serum or urine 
5.3 
TREATMENT PERIOD 
The treatment period is comprised of two periods: 
• Monotherapy period: One week, with BL-8040 administered daily on Days 1-5. 
• Combination therapy: 
o Cohort 1: Three-week cycles of a combination of BL-8040 administered three 
times a week (TIW) and pembrolizumab administered once every three weeks. 
o Cohort 2: Chemotherapy: Onivyde®/5-FU/LV every 2 weeks, pembrolizumab 
once every 3 weeks and BL-8040 twice a week. 
5.3.1 Monotherapy 
This period will begin immediately after Baseline, preferably on the day of the Baseline 
assessments and will last for one week. During this period, BL-8040 will be administered daily 
on Days 1 to 5. Pre-medication with systemic antihistamines is recommended in order to 
minimize the occurrence of BL-8040 related local injection site reactions and/or systemic 
reactions. Details on the specific days for each assessment are presented in the flow chart 
(Appendix A). 
5.3.1.1 Week 1 (Days 1-5) Procedures 
1. 
Review of AEs at each visit 
2. 
Prior and concomitant medications 
3. 
CBC with differential, daily on Days 1-5 pre-dose and 4 hr (± 2 hr) post-dose 
on Day 1 and 5 
4. 
a.   Cohort 1: Blood for anti-BL8040 antibodies and complement activation on 
Day 1, pre-dose and 4 hr (± 2hr) post-dose. . 
b.   Cohort 2: Blood for anti-BL8040 antibodies pre-dose on Day 1. 
5. 
Blood for immunophenotyping by FACS on Day 1 and 5 pre-dose and 4 hr 
(± 2 hr) post-dose. 
6. 
Directed PE on Day 5 (+ up to 3 days, but before the beginning of the 
combination period) 
7. 
Vital signs Day 5 pre-dose of BL-8040, post-dose assessment maybe collected 
upon Investigator decision 
8. 
12 lead ECG- Pre dose on Day 1 


 
 
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9. 
Blood for CA 19-9 (in Cohorts 1 and 2) and CEA (in Cohort 2 only) on Day 5 
(+ up to 3 days, but before the beginning of the combination period) 
10. 
Blood for CXCR4 and PD-1 expression on Day 1 and 5 pre-dose and 4 hr 
(± 2 hr) post-dose. 
11. 
Tumor tissue collection from metastasis (biopsy) for assessment according to 
Section 5.12.2, on Day 5 (+ up to 4 days, but before the beginning of the 
combination period). Biopsy during the monotherapy period will be performed 
only for the first 15 subjects enrolled in Cohort 1. 
12. 
Tumor imaging assessment on Day 5 (+ up to 4 days, but before the beginning 
of the combination period). 
13. 
Blood for cells, DNA and RNA for biomarker correlative studies on Day 5 (+ 
up to 3 days, but before the beginning of the combination period). 
14. 
Serum for biomarker correlative studies on Day 5 (+ up to 3 days, but before the 
beginning of the combination period). 
5.3.2 Combination Treatment 
Cycles are defined according to the pembrolizumab three-week-cycle schedule of 
treatment. 
From Day 8 (+ up to 4 days) subjects will begin a combination period consisting of treatment 
with: 
Cohort 1:  IV pembrolizumab every 3 weeks, followed by SC BL-8040 1.25mg/kg, 1 hr ± 30 
min later TIW. 
Cohort 2: 
• IV Onivyde® 70 mg/m2 over 90 minutes, followed by IV LV 400 mg/m2 over 30 
minutes or according to local standard, followed by IV 5-FU 2400 mg/m2 over 46 hours, 
every 2 weeks. 
• IV Pembrolizumab 200mg once every three weeks. 
• Beginning on Day 10, SC BL-8040 1.25mg/kg twice a week after chemotherapy dosing. 
The combination therapy will continue until progression, clinical deterioration or early 
Termination. 
Pre-medication with systemic antihistamines is recommended in order to minimize the 
occurrence of BL-8040 related local injection site reactions and/or systemic reactions. 
Premedication with dexamethasone is allowed prior to Onivyde dosing, and on days 2 and 3 
post-dosing, for acute and delayed emesis prevention in accordance with the National 
Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology  for 
Antiemesis, V.1 (Feb 2019), if deemed necessary by the study investigator. 
The following assessments should be done at each cycle (time window will be ± 3 days unless 
otherwise specified): 
1. 
Review prior and concomitant medications at all visits 
2. 
Review of AEs at all visits 
3. 
Directed PE on Day 1 pre-dose beginning in Cycle 2 


 
 
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4. 
Vital signs will be assessed on Day 1 of each cycle before study drug 
administration, post-dose vital sign assessment may be collected upon 
Investigator decision 
5. 
Weight will be assessed at the beginning of each week during the combination 
treatment period before the first injection of the week.  BL-8040 dose will be 
adjusted accordingly 
6. 
ECOG performance status on Day 1 of each cycle 
7. 
Chemistry panel on Day 1 of each cycle before study drug administration 
8. 
Treatment administration: 
a. Cohort 1: 
i. BL-8040 administration three times a week 
ii. Pembrolizumab administration on Day 1 of each cycle 
b. Cohort 2: 
i. BL-8040 administration two times a week 
ii. Pembrolizumab administration on Day 1 of each 3-week cycle 
iii. Onivyde®/5-FU/LV every 2 weeks 
9. 
An optional additional core or excisional biopsy (not Fine needle aspiration 
[FNA]) may be performed during the study provided the subject has agreed to 
it specifically. Only for Cohort 1. 
The following assessments should be done at specific cycles (time window will be ± 3 days 
unless otherwise specified): 
1. 
CBC with differential 
a. Cycle 1: 
• Before each BL-8040 dose for assessment of WBC (no window is 
allowed for CBC prior to BL-8040 injection). Further assessments will 
be performed as deemed necessary by the Investigator. 
• 4 hr (±2 hr) post-injection for the first three doses of BL-8040 for 
assessment of WBC. 
b. Cycle 2 and onward: 
• Before the first three doses of BL-8040 for assessment of WBC (no 
window is allowed for CBC prior to BL-8040 injection). Further 
assessments should be performed as deemed necessary by the 
Investigator. 
2. 
12 lead ECG on Day 1 of Cycle 1 pre-dose and 4 hr (± 2 hr) after the 
combination treatment 
3. 
T3 (total or free), free T4 and TSH on Day 1 of Cycle 1 and thereafter on Day 
1 of every two cycles beginning in Cycle 2 prior to dosing 
4. 
Pregnancy test – serum or urine every two cycles beginning in Cycle 2 
5. 
a.   Cohort 1: Blood for anti-BL8040 antibodies and complement activation: 
Day 1 before administration of any of the study drugs, every two cycles 
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b.   Cohort 2: Blood for anti-BL8040 antibodies on Day 1 before 
administration of any of the study drugs, every two cycles beginning Cycle 1. 
6. 
Blood for CA 19-9 (in Cohorts 1 and 2) and CEA (in Cohort 2 only) on Day 1 
of every two cycles beginning in Cycle 2. 
7. 
Blood for immunophenotyping by FACS: 
a. Cohort 1: on Day 21 of Cycle 2  
b. Cohort 2: on Day 15 of Cycle 1 and Day 21 of Cycle 2  
8. 
Blood for CXCR4 and PD-1 expression on Day 15 of Cycle 1 and Day 21 of 
Cycle 2  
9. 
Blood for DNA and RNA for biomarker correlative studies:  
a. Cohort 1: at the time of the biopsies 
b. Cohort 2: Blood for cells, DNA and RNA correlative studies will be 
collected on Cycle 1/Day 15 prior to the second cycle of chemotherapy and 
on Day 21 of every two cycles beginning in Cycle 3.  
10. 
Cohort 1: Tumor tissue collection from metastasis (biopsy): on Day 21 of 
Cycle 2 (± 4 days) during the combination period will be performed beginning 
with subject 16 and up to the last enrolled subject as detailed in Section 5.12.2. 
11. 
Tumor imaging assessment will be done at the end of Cycle 2, and then every 
3 cycles up to one year of treatment (Cycle 17) and then every 4 cycles until 
end of Cycle 34 /Termination visit (two years of treatment). 
12. 
Serum for biomarker correlative studies will be collected on Cycle 1/Day 15 
prior to the second cycle of chemotherapy and on Day 21 of every two cycles 
beginning in Cycle 3.  
5.4 
TERMINATION OR EARLY DISCONTINUATION STUDY VISIT 
A Termination visit will be performed after two years of treatment. 
An Early Discontinuation Study Visit will be performed for subjects who withdraw from the 
study for the reasons specified in Section 4.5 (time window will be ± 14 days). 
All reasons for treatment discontinuation will be documented in the source documents. Only 
one reason (the most severe) for early discontinuation should be recorded in the CRF. If one of 
the reasons for discontinuation is an AE, this should be chosen as the reason. Every effort 
should be made to follow-up these subjects until resolution or stabilization of the AE. 
At this visit the following activities will be performed. Exceptions for assessments may be 
provided in case these assessments were done 1-2 cycles prior to Termination visit 
1. 
Review prior and concomitant medications 
2. 
Review of AEs 
3. 
12 lead ECG 
4. 
Full PE 
5. 
Vital signs 
6. 
ECOG performance status 
7. 
CBC with differential 
8. 
Chemistry panel 


 
 
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9. 
T3 (total or free), free T4, and TSH 
10. 
a.   Cohort 1: Blood for anti-BL8040 antibodies and complement activation 
b.   Cohort 2: Blood for anti-BL8040 antibodies 
11. 
For Cohort 1: Blood for DNA and RNA for correlative studies 
12. 
Tumor imaging 
 
5.5 
SAFETY FOLLOW-UP VISIT 
After Termination/Early Termination visit, a safety follow-up visit will be performed 
approximately 90 days after the last dose of the last study drug (or within 7 days prior to 
initiation of a new anti-cancer treatment, whichever comes first). The subject will be monitored 
for AEs up to the safety follow-up visit or until resolution of toxicity to Grade 0-1 or AE 
stabilization, whichever occurs later. SAEs should be reported when occur within 90 days and 
pregnancies when occurred within 120 days of study termination, or, in both cases, 30 days 
following cessation if a new anti-cancer therapy is initiated (see Section 7.2.1). 
The following assessment will be performed during this visit. 
1. 
Review of AEs 
2. 
Review prior and concomitant medications 
3. 
Post- study anti-cancer therapy received 
4. 
CBC with differential 
5. 
Chemistry Panel 
6. 
T3 (total or free), freeT4, TSH 
7. 
12 lead ECG 
5.6 
LONG-TERM FOLLOW-UP OF SURVIVAL 
All subjects will be contacted by phone every 12 weeks (± 4 weeks) in order to assess their 
survival status regardless of the reason for discontinuation (i.e. early termination [ET] or after 
two years). This Follow-up will continue for up to 5 years unless they withdrew their consent 
to continue their participation in the study. During these phone calls, subjects will be asked to 
provide, among others, an update about disease status and post- study anti-cancer therapy 
received. All the data will be collected and entered within the CRF as well. 
5.7 
UNSCHEDULED VISIT 
An unscheduled visit may be performed at any time during the study at the subject's request or 
as deemed necessary by the Investigator. The date and reason for the unscheduled visit will be 
recorded. AE monitoring and concomitant medication recording will be performed by the 
Investigator. Other procedures and evaluations will be completed as deemed necessary by the 
Investigator and may include (but are not limited to) laboratory safety tests, vital signs and 
physical examination. 
5.8 
SAFETY ASSESSMENTS 
Safety assessments will be based on changes from Baseline of clinical signs and symptoms 
reported by the subject or observed by the Investigator, including AEs, concomitant medication 
use, treatment compliance, tolerability (e.g. dropouts due to AEs), vital signs, ECGs, physical 
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5.8.1 Adverse Events (AEs) 
Adverse Events (AEs) will be assessed at all study visits throughout the study. 
Any new AE that occurs between scheduled assessment visits should be brought to the attention 
of the Investigator and recorded in the subject’s medical file and on the appropriate CRF page. 
AEs will be reported and graded in accordance with the latest National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (currently version 
5.0) and coded by Data Management using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA; see Section 7.1 for more details). 
5.8.2 Concomitant Medications 
Concomitant medication use will be recorded from Baseline through all study visits. 
5.8.3 Vital Signs, Height and Weight 
Vital signs will be measured at Screening, at Baseline and pre-dose on Day 5 of the 
monotherapy treatment. Post-dose assessment may be performed as deemed necessary by the 
Investigator. During the combination period, vital signs will be assessed on Day 1 of each cycle 
before study drug administration. Further assessment may be performed upon Investigator 
decision. 
Vital signs will include blood pressure, pulse, oral temperature, O2 saturation and respiration 
rate following a minimum of 5 minutes of rest as per standard practice at the study site. 
Significant findings noticed after the start of study drug which meet the definition of an AE 
must be recorded on the AE CRF module. 
Height will be recorded only at Screening. 
Weight will be recorded at Baseline and on at the beginning of each week (combination period) 
before dosing in order to calculate the BL-8040 dose. 
5.8.4 Electrocardiogram 
An ECG will be performed at the Screening and Baseline (Day 1 pre-dose) visits. 
During the combination period, an ECG will be performed on Cycle 1/Day 1 pre-dose and 4 
hours (± 2 hours) after the last study drug administered. An ECG will be performed at the 
Termination visit and at any safety follow-up visit as well. 
Additional ECGs will be performed at the discretion of the Investigator or upon the Sponsor’s 
request. The subject should rest for at least 10 minutes before the measurement is taken. 
ECG printouts will be evaluated by the Investigator or designee, signed and dated and filed in 
the source documentation file. When potentially Clinically Significant findings are detected by 
the Investigator or designee; a cardiologist should be consulted for a definitive interpretation 
and appropriate treatment if required. All communications and diagnoses should be filed in the 
source documentation file. The Investigator/Investigator’s designee/local cardiologist is 
responsible for determining whether the ECG findings are of clinical significance. All 
abnormalities shall be closely monitored until stabilized or resolved. Clinically significant 
finding should be reported within the AEs CRF page. 
5.8.5 Physical Examination and Directed Physical Examination 
A full PE will be conducted at Screening and at the time of discontinuation. The PE will include 
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ophthalmologic, gastrointestinal, hepatic, endocrine/metabolic, musculoskeletal system, 
dermatological, lymph nodes, neurological system and, where appropriate, other body systems 
as indicated in the study schedule. 
A directed PE will be conducted on Day 5 of the monotherapy period (± 3 days but before the 
first dose of the combination) and on Day 1 of each cycle beginning at Cycle 2 (± 3 days but 
before the first dose of the combination of Cycle 2) (see Study Flow Chart–Appendix A). 
During a directed PE, particular attention should be focused on identifying possibly drug-
related AEs and managing these AEs effectively. 
Information about the PE must be present in the source documentation at the study site. 
Significant findings that are present prior to the start of study drug must be included in the 
Relevant Medical History/ Current Medical Conditions CRF. Significant findings made after 
the start of study drug which meet the definition of an AE must be recorded on the AE CRF 
module. 
5.8.6 Laboratory Safety Assessments 
 
 
 
 
 
 
 
 
Table 1: Laboratory Tests 
a For menopause confirmation 
b if abnormal results are noted 
c if total bilirubin is elevated above the upper limit of normal 






 
 
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• If radiologic imaging verifies initial progressive disease, tumor assessment should be 
repeated ≥4 weeks later in order to confirm progressive disease with the option of 
continuing treatment per below. 
• If repeat imaging shows less than a 20% increase in tumor burden compared to nadir, 
stable or improved previous new lesion (if identified as cause for initial progressive 
disease), and stable/improved non-target lesions (if identified as cause for initial 
progressive disease), treatment may be continued/resumed. 
• If repeat imaging confirms progressive disease due to any of the scenarios list below, 
subjects will be discontinued from study therapy (exception noted in Table 3). 
• In determining whether or not the tumor burden has increased or decreased, site study 
team should consider all target lesions as well as non-target lesions (please refer to the 
irRECIST TIP Sheet). 
Scenarios where progressive disease is confirmed at repeat imaging: 
• Tumor burden remains increased by ≥ 20% and at least 5 mm absolute increase 
compared to nadir 
• Non-target lesions resulting in initial progressive disease is worse (qualitative) 
• New lesion resulting in initial progressive disease is worse (qualitative) 
• Additional new lesion(s) since last evaluation 
In subjects who have initial evidence of radiological progressive disease, it is at the discretion 
of the treating physician whether to continue a subject on study treatment until repeat imaging 
is obtained. This clinical judgment decision should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Subjects may 
continue to receive treatment while waiting for confirmation of progressive disease if they are 
clinically stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease. 
If the site study team assessed disease progression and the subject is clinically stable (described 
above), it is at the discretion of the site Investigator to continue to treat and image the subject 
at least 4 weeks after the first tumor imaging indicating progressive disease. irRECIST would 
then be followed by the study site to determine if the follow-up tumor imaging confirms 
progressive disease. Subjects who have unconfirmed disease progression may continue on 
treatment and follow the regular imaging schedule intervals until progression is confirmed, 
provided they have met the conditions detailed above. 
 
 


 
 
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irRECIST Assessment of Disease 
As noted above, if tumor imaging shows initial disease progression, the study site may elect to 
continue treatment, repeat imaging ≥ 4 weeks later and assess tumor response or confirmed 
progression per irRECIST (see Table 3). 
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. 
Table 3: Imaging and Treatment after 1st Radiologic Evidence of PD 
In determining whether or not the tumor burden has increased or decreased, study site 
Investigators should consider all target lesions as well as non-target lesions (please refer to the 
irRECIST TIP Sheet). Subjects that are deemed clinically unstable are not required to have 
repeat tumor imaging for confirmation. 
For a clinically stable subject with first radiologic evidence of progressive disease by RECIST 
1.1 (i.e., unconfirmed progression of disease), it is at the discretion of the site Investigator to 
continue treating the subject with the assigned treatment per protocol until progression of 
disease is confirmed at least 28 days from the date of the scan first suggesting progressive 
disease. If radiologic progression is confirmed by subsequent scan, then the subject will be 
discontinued from trial treatment. If radiologic progression is not confirmed by irRECIST per 
the site, then the subjects may continue on treatment and follow the regular imaging schedule 
intervals until progression is confirmed at a later time point by the site. 
NOTE: If a subject has confirmed radiographic progression (i.e. two 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 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
1st radiologic 
evidence of 
progressive 
disease by 
RECIST 1.1 
Repeat tumor imaging 
≥4weeks at site to confirm 
progressive disease 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by irRECIST 
Repeat tumor 
imaging at ≥ 4 weeks 
to confirm 
progressive disease 
per physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging 
confirms 
progressive 
disease by 
irRECIST at 
the local site 
No additional tumor 
imaging Required 
 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor) 
No additional tumor 
imaging required 
N/A 
Repeat tumor 
imaging shows 
SD, PR or CR 
by irRECIST 
by the local 
site 
Continue regularly 
scheduled tumor 
imaging assessments 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue regularly 
scheduled tumor 
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 study 
schedule.  


 
 
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confirmatory tumor imaging, an exception to continue treatment may be considered following 
consultation with the Sponsor. In this case, if treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in Appendix 13.1 Study Flowchart 
Any subject deemed clinically unstable should be discontinued from trial treatment at the first 
radiologic evidence of progressive disease and is not required to have repeat imaging for 
progressive disease confirmation. 
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 2 cycles ± 7 days), until (1) the start of 
new anti-cancer treatment, (2) disease progression (3) death, or (4) the end of the study, 
whichever occurs first. 
irRECIST data will be collected in the CRF 
5.12.2 Planned Biopsy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
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5.13 BLOOD SAMPLING AND PROCESSING 
Samples will be collected for safety and efficacy analysis, anti-drug antibodies titer and 
determination of BL-8040 plasma concentrations at the time points indicated in Study Flow 
Chart (see Section 13.1) 
Instructions for the collection, processing, storage and shipment of samples are detailed in the 
Laboratory Manual provided by the Sponsor. 
5.14 TIME WINDOWS FOR SAFETY AND EFFICACY ASSESSMENTS 
Time windows are provided in Section 5 for each specific assessment and in Appendix A- Flow 
chart. 
6 
INVESTIGATIONAL PRODUCT 
6.1 
IDENTITY OF INVESTIGATIONAL PRODUCT 
6.1.1 BL-8040 
BL-8040 is a highly selective CXCR4 antagonist co-developed by 
. 
and BioLineRx Ltd. as a novel investigational therapy for the treatment of cancer. 
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 
 
 
 
 
. 
6.1.2 Pembrolizumab 
 
 
 
6.1.3 Chemotherapy: Onivyde®/5-FU/LV 
Onivyde is an injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, 
liposomal dispersion in a single-dose vial. 
Fluorouracil injection is supplied as a pharmacy bulk package as a vial containing 2.5 g/50 mL 
(50 mg/mL) fluorouracil. 
Leucovorin Calcium for injection is supplied as a sterile lyophilized powder. The 350 mg vial 
is preservative-free. The inactive ingredient is sodium chloride 140 mg/vial for the 350 mg 
vial. Sodium hydroxide and/or hydrochloric acid are used to adjust the pH to approximately 
8.1 during manufacture. 1 mg of leucovorin calcium contains 0.002 mmol of leucovorin and 
0.002 mmol of calcium. 
6.2 
STUDY DRUG ADMINISTRATION AND DOSAGE 
6.2.1 BL-8040 
Trial treatment with BL-8040 will be administrated by SC injection of 1.25 mg/kg daily as 
monotherapy for 1 week, beginning on Day 1 daily through Day 5. Subjects will receive once 
daily SC injections of BL-8040 in the morning.  Pre-medication with systemic antihistamines 
with or without analgesics is recommended in order to minimize the occurrence of BL-8040 
related local injection site reactions and/or systemic reactions. 




 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.3 Onivyde/5-FU/LV 
Onivyde should be administered prior to LV and 5-FU. Onivyde 70 mg/m2 as an IV infusion 
over 90 minutes, followed by LV 400 mg/m2 IV over 30 minutes or according to local standard, 
followed by 5-FU 2400 mg/m2 IV over 46 hours, every 2 weeks. Patients homozygous for the 
UGT1A1*28 allele will initiate Onivyde® at 50 mg/m2, and the dose can be increased if 
tolerated at later cycles.  Due to the moderate emetic risk of Onivyde, premedication with 12 
mg Dexamethasone PO/IV is allowed once prior to Onivyde dosing.  An additional 8 mg 
Dexamethasone PO/IV may be given on days 2 and 3 post-dosing in accordance with the 
NCCN guideline for antiemesis V.1 (Feb 2019), if deemed necessary by the study investigator. 
Specific instructions on the reconstitution and administration of chemotherapy during the study 
are included in the Pharmacy Manual. 
6.3 
STUDY MEDICATION SOURCE AND INSTRUCTIONS FOR USE 
6.3.1 BL-8040 
BL-8040 drug substance (4F-benzoyl-TN14003 peptide) is a white or off-white powder 
synthetic polypeptide, freely soluble in water and in 0.45% Sodium Chloride (half normal 
saline). It is manufactured in accordance with (cGMP) requirements by 
 
  
Reconstitution and administration instructions will be provided in a separate Pharmacy 
Manual. 
6.3.2  Pembrolizumab 
Pembrolizumab is a monoclonal antibody (mAb) and is provided as a solution for infusion 
administered via IV infusion. The drug product is a clear to opalescent liquid essentially free 
of visible particles. The product is manufactured according to good manufacturing practice by 
Merck & Co, Inc. Administration instructions will be provided in a separate Pharmacy Manual. 
6.3.3 Chemotherapy 
6.3.3.1 Onivyde® 
Dosage Form and Strength 
Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal 
dispersion in a single-dose vial. 
Preparation and Administration 
Onivyde® is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 
Preparation 
• Withdraw the calculated volume of Onivyde® from the vial. Dilute Onivyde in 500 mL 
5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted 
solution by gentle inversion. 


 
 
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• Protect diluted solution from light. 
• Administer diluted solution within 4 hours of preparation when stored at room 
temperature or within 24 hours of preparation when stored under refrigerated conditions 
[2ºC to 8ºC (36ºF to 46ºF)]. Allow diluted solution to come to room temperature prior 
to administration. 
•  Do NOT freeze. 
For more details please refer to the Onivyde® label:   
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207793lbl.pdf 
6.3.3.2 5-FU and LV 
5-FU and LV drugs will be provided according to institutional guidelines at each study site. 
6.4 
DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION 
The study drugs product will be packed and shipped in appropriate boxes. If, upon arrival at 
the clinical investigation site, study drug supplies appear to be damaged, the study monitor 
should be contacted immediately. 
Each shipment of study drug supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, product certificate of analysis, acknowledgment of 
receipt and other appropriate documentation. The shipment form will assist in maintaining 
current and accurate inventory records. The study staff will confirm the receipt of clinical 
supply to the study monitor. 
All study supplies should arrive at the pharmacy/Investigational site in sufficient quantity and 
in time to enable dosing as scheduled. The Sponsor or its representative must notify the site 
Investigator’s designee prior to dispatch of drug supplies, with the anticipated date of their 
arrival. 
6.5 
STORAGE, DISPENSING AND RETURN OF THE INVESTIGATIONAL 
MEDICINAL PRODUCT 
6.5.1 BL-8040 
Vials of BL-8040 for injection should be stored in the refrigerator (2-8°C) in its original 
packaging, protected from light. 
Records should also be kept by the Investigator or designee as to how much study drug was 
dispensed to each subject. The study monitors must periodically check the study drug supplied 
to ensure expiry date and sufficient amount of study drug, and be sure that drug accountability 
is being performed at each visit, and the drug accountability logs are maintained. 
All investigational products must be kept in a secure area with access to the study drug limited 
to designated study personnel. 
Only trained personnel under the supervision of either the Investigator or the local pharmacist 
are authorized to dispense and administer study drug to participating subjects. 
Further details and instructions will be provided in the Pharmacy Manual. 
6.5.2 Pembrolizumab 
Pembrolizumab (MK-3475) Solution for infusion, 100 mg/ 4 mL vial should be stored at 
refrigerated conditions (2 – 8 °C) and protected from light. 


 
 
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Records should also be kept by the Investigator or designee as to how much study drug was 
dispensed to each subject. The study monitors must periodically check the study drug supplied 
to ensure expiry date and sufficient amount of study drug and be sure that drug accountability 
is being performed at each visit, and the drug accountability logs are maintained. 
All investigational products must be kept in a secure area with access to the study drug limited 
to designated study personnel. 
Only trained personnel under the supervision of either the Investigator or the local pharmacist 
are authorized to dispense and administer study drug to participating subjects. 
Further details and instructions will be provided in the Pharmacy Manual. 
6.5.3 Chemotherapy 
Chemotherapy will be provided at each site according to the standard of care. 
6.6 
ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL 
MEDICINAL PRODUCT 
Each delivery must be acknowledged by the hospital pharmacist (or authorized study team 
member responsible for the investigational medicinal product) by filling in the receipt record 
form and returning it by fax/email to the Sponsor or designee. Accurate, complete and timely 
documentation of study drug distribution will be maintained by the pharmacy and the study 
staff of the investigational site which may include confirmation of receipts of clinical supply, 
drug accountability logs and other forms. 
The medical center pharmacist (or authorized study team member responsible for the 
investigational medicinal product) is responsible for ensuring the supervision of the storage 
and allocation of these supplies, which will be forwarded to the Investigator at the appropriate 
time before administration. The Investigator may dispense investigational drug only to subjects 
enrolled in the study. 
Drug accountability records must be maintained by the clinical investigation site at all times. 
At the last study visit, all used and unused investigational drug will be collected, and drug 
accountability performed by the study staff. The study monitor will check these regularly 
during monitoring visits. 
The subject number, the date, batch number/pack number and quantity of study drug used by 
the subject will be checked for correctness and recorded on the appropriate accountability 
forms. Unused drug supplies will be returned to the Sponsor. At the end of the study, all clinical 
supplies and the corresponding accountability forms must be returned to the Sponsor, the study 
monitor, or designee for reconciliation or destruction. A photocopy of these records must be 
kept at the clinical investigation site. 
The inventory will be made available to the study monitor who will verify accountability and 
verify dose during the course of the study. 
Study drug orders, records of study drug receipts, dispensing records and inventory forms 
located at the site will be examined and reconciled by the study monitor periodically during 
and at the end of the study 
6.7 
CONCOMITANT THERAPY 
At the Screening visit, relevant treatments currently received by the subject will be recorded in 
the subject’s CRF including treatment's name, indication, dose, total daily dose and start and 
stop dates. 


 
 
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Any medications (including prescription, over-the-counter (OTC), herbal supplements and 
other health store-type products) to be taken during the study must be approved by the 
Investigator. 
Concomitant medication use will be recorded from Screening through the safety follow visit. 
Treatment provided after study termination will be captured as part of the survival status 
assessment. The following information should be recorded: treatment's name (generic, if 
possible), indication, dose and start and stop dates. 
Medications or vaccinations specifically prohibited in the Exclusion Criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation of trial therapy may be required. The 
Investigator should discuss any questions regarding this with the Sponsor’s Medical Monitor. 
The final decision on any supportive therapy or vaccination rests with the Investigator and/or 
the subject's primary physician. However, the decision to continue the subject’s trial therapy 
requires the mutual agreement of the Investigator, the Sponsor, and the subject. 
6.7.1 Contraception, use in Pregnancy and Nursing Women 
6.7.1.1 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. BL-8040 effect on 
fetus in utero was not tested to date. 
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). 
Males and non-pregnant, non-breastfeeding females may only be enrolled if they are willing to 
use 2 methods of birth control or are considered highly unlikely to conceive. Highly unlikely 
to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 2 years will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study. The two birth 
control methods can be either two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Subjects should start using birth control from study visit 1 (or 21 days 
prior to the initiation of study medication for oral contraception) and throughout the study 
period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), or sponge, all of which are to be combined with a spermicide, or a copper 
intrauterine device as per local regulations or guidelines. Appropriate hormonal contraceptives 
will include any registered and marketed contraceptive agent that contains an estrogen and/or 
a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
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) for the duration of the study and during the follow-up period defined in 
Section 7.4 Reporting of Pregnancy and Lactation to the Sponsor. 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. 


 
 
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6.7.1.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with study drugs, 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 Sponsor without delay and within 24 hours if 
the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). The study Investigator 
will make every effort to obtain permission to follow the outcome of the pregnancy and report 
the condition of the fetus or newborn to the Sponsor. If a male subject impregnates his female 
partner, the study personnel at the site must be informed immediately and the pregnancy 
reported to the Sponsor and followed as described above and in Section 7.4- Reporting of 
Pregnancy and Lactation to the Sponsor. 
6.7.1.3 Use in Nursing Women 
It is unknown whether pembrolizumab or BL-8040 are 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 breastfeeding are not eligible for enrollment. 
6.7.2 Allowed 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 on the CRF including all 
prescription, OTC, herbal supplements, and IV medications and fluids. If changes occur during 
the trial period, documentation of drug dosage, frequency, route, and date may also be included 
in the CRF. 
All concomitant medications received within 30 days prior to the first dose of study treatment 
and 90 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered more than 90 days after the last dose of trial treatment should be recorded for 
SAEs and events of clinical interest (ECIs). 
 
 
 
6.7.3 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening period and 
Treatment Phase of this trial: 
• 
 
 
 
 
 
 
 
 
 
 
 




 
 
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6.7.4.1 BL-8040 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7.4.2 Dose-Modification and Toxicity Management for Immune-Related AEs 
Associated with Pembrolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 


 
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6.7.4.3 Onivyde® 
The recommended[26] dose modifications for Onivyde® are listed in. 
Table 5: Recommended Dose Modifications for Onivyde® 
Toxicity 
NCI-CTCAE v4.0 
Occurrence 
Onivyde® 
adjustment in 
patients receiving 70 
mg/m2 
Patients homozygous 
for UGT1A1*28 
without previous 
increase to 70 mg/m2 
Grade 3 or 4 
adverse 
reactions 
Withhold Onivyde®. 
Initiate loperamide for late onset diarrhea of any severity. 
Administer intravenous or subcutaneous atropine 0.25 to 1 mg 
(unless clinically contraindicated) for early onset diarrhea of any 
severity. 
Upon recovery to ≤ Grade 1, resume Onivyde® at: 
First 
50 mg/m2 
43 mg/m2 
Second 
43 mg/m2 
35 mg/m2 
Third 
Discontinue 
Onivyde 
Discontinue Onivyde 
Interstitial Lung 
Disease 
First 
Discontinue 
Onivyde 
Discontinue Onivyde 
Anaphylactic 
Reaction 
First 
Discontinue 
Onivyde 
Discontinue Onivyde 
6.7.4.4 Dose Modifications for 5-FU 
Withhold fluorouracil for any of the following[28]: 
• Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in 
patients with no history of coronary artery disease or myocardial dysfunction 
• 
Hyperammonemic encephalopathy 
• 
Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances 
• 
Grade 3 or 4 diarrhea 
• Grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) 
• Grade 3 or 4 mucositis 
• Grade 4 myelosuppression 
Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-
plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose. 


 
 
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There is no recommended dose for resumption of fluorouracil administration following 
development of any of the following adverse reactions: 
• Cardiac toxicity 
• Hyperammonemic encephalopathy 
• Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances 
6.7.4.5 Dose Modifications for Leucovorin 
No specific dose recommendations within the label[29]. 
6.7.4.6 Dose Modifications Guidelines for Managing Overlapping Toxicity 
Oncology patients with advanced disease often experience adverse events that may be a result 
of their underlying disease, the study medications, or a combination of these. Furthermore, 
different study drugs have the potential to cause overlapping toxicities, making it difficult to 
determine the causality of these reactions. In such cases, the treating physician should use his 
or her best judgement in evaluating which drug is most suspect (e.g. based on his knowledge 
and experience, the patients’ clinical condition and the temporal relation between the dosing 
and the reaction onset, etc.), and dose modifications should be implemented accordingly. The 
treating physician may consult with the study medical monitor when additional guidance is 
needed on a case by case basis.  Specific guidance for the management of diarrhea is provided 
below, in section 6.7.4.6.1. 
6.7.4.6.1 EVALUATION AND MANAGEMENT OF DIARRHEA DURING 
PEMBROLIZUMAB, 5-FU AND BL-8040 COMBINATION THERAPY 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
                                                 
a Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based 
management. Ther Adv Med Oncol 2010; 2(1):51-63. doi: 10.1177/1758834009355164. 


 
 
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6.7.5 Rescue Medications & Supportive Care 
6.7.5.1 Allowed Concomitant Medications  
• Pre-medication 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 (and not as pre-medication) of these reactions.  
Premedication with dexamethasone is allowed prior to Onivyde dosing, and on days 2 
and 3 post-dosing, for acute and delayed emesis prevention in accordance with the 
NCCN guideline V.1, if deemed necessary by the study 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. 
• 
 
Additional medications/therapies to manage treatment or disease emergent conditions will be 
allowed at the discretion of the Investigator in consultation with the Sponsor, in advance where 
possible. In case there is a change in therapy related to an AE, the Sponsor or Investigator may 
decide to withdraw the subject (refer to Section 4.6). 
6.7.5.2 Supportive Care Guidelines for BL-8040 
 
 
6.7.5.2.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7.5.3 Supportive Care Guidelines for Pembrolizumab 
 
 
 
 
 
 
 
 


 
 
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nformation, please refer to the Common Terminology Criteria for Adverse Events v5.0 
 
6.7.5.4 Supportive Care Guidelines for Chemotherapy 
 
 
 
 
 
[26,28,29]. 
 


 
 
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7 
SAFETY AND PHARMACOVIGILANCE 
7.1 
ADVERSE EVENT (AE) 
An AE is defined in the International Conference on Harmonization (ICH) E6 as “any untoward 
medical occurrence in a subject or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.” 
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it fulfills one or more of the following: 
• Results in subject's withdrawal by the Investigator 
• Is associated with an SAE 
• Is associated with clinical signs or symptoms 
• Is considered by the physician to be of clinical significance 
A new condition or the worsening of a pre-existing condition will be considered an AE. 
AEs do not include the following: 
• Medical/surgical procedures are not AEs (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if the procedure was 
not planned at Screening visit. 
• Overdose of concomitant medication without any signs or symptoms unless the subject 
is hospitalized for observation. 
• Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred). 
• Progression of the cancer under study, unless it is considered to be drug-related by the 
Investigator. 
All AEs, whether observed by the Investigator or designee or volunteered by or elicited from 
the subject, should be recorded individually on an AE CRF page with the following 
information: the specific event or condition, whether the event was present pre-Baseline or not, 
the dates and times (using the 24 hour clock, where midnight is 00:00 and noon is 12:00) of 
occurrence, duration, severity, relationship to study medication, action taken to study drug, 
outcome, and whether considered non-serious or serious, drug-related or not. 
Once the subject has signed the ICF, AEs will be recorded until the end of the Follow-up period. 
The severity of the AE will be assessed by the investigating physician in accordance with the 
definitions below. A SAE must fulfill the requirements listed in Section 7.2. 
AEs severity (Table 7) will be recorded and graded according to the latest version of the NCI-
CTCAE (currently version 5.0) and coded into the database according to the latest version of 
MedDRA (currently version 22.0). 
Table 7: Severity of Adverse Events According to CTCAE (Version 5.0) 
Grade Description 


 
 
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0 
No AE or within normal limits 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL) 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
A semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available 
The following definitions should be used for toxicities/AEs that are not defined in the CTCAE: 
• Mild (Grade 1): The AE is noticeable to the subject but does not interfere with routine 
activity, no medical intervention is required; 
• Moderate (Grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest; 
• Severe (Grade 3): The AE significantly limits the subject’s ability to perform routine 
activities despite symptomatic therapy; 
• Life-threatening (Grade 4): The subject is at immediate risk of death. 
The Investigator will document his opinion of the relationship of the AE to treatment with 
investigational product using the criteria outlined in Table 8. 
Outcome to Date are classified as follows: 
• Recovered: The subject has fully recovered from the AE with no residual effects 
observable 
• Recovered with sequelae: The subject has recovered from the AE with residual effects 
observable 
• Improved: the subject status improved but has not been fully recovered 
• Ongoing: AE is not recovered 
• Fatal 
• Unknown 
AEs will be coded by Data Management using the latest version of MedDRA (currently version 
22.0) AE dictionary. 
All AEs, serious and not serious, will be recorded on the AE Case Report Form, and if relevant, 
the Concomitant Medications Record in the CRF will be updated. Severity and relationship to 
study drug will be assessed by the Investigator as described in and treatment respectively.  
Particular attention should be made to ensure no discrepancies between the AE and the SAE 
form (i.e., outcome, severity, relationship must be consistent). TEAEs are defined as AEs 
observed after 1st dose of study drug. 


 
 
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The relationship of an AE to the study drug is characterized as follows: 
Table 8: Relationship of Adverse Event to Treatment 
Term 
Definition 
Clarification 
No 
reasonable 
possibility 
(not 
related) 
 
This category applies to AEs 
which, after careful 
consideration, are clearly due 
to extraneous causes 
(disease, environment, etc) 
or to AEs, which, after 
careful medical 
consideration at the time 
they are evaluated, are 
judged to be unrelated to the 
study drug. 
The relationship of an AE may be considered 
“no reasonable possibility” if it is clearly due 
to extraneous causes or if at least 2 of the 
following apply: 
• It does not follow a reasonable temporal 
sequence from the administration of the 
test drug. 
• It could readily have been produced by 
the patient’s clinical state, environmental 
or toxic factors, or other modes of 
therapy administered to the patient. 
• It does not follow a known pattern of 
response to the test drug. 
• It does not reappear or worsen when the 
drug is re-administered. 
Reasonable 
possibility 
(related) 
 
This category applies to AEs 
for which, after careful 
medical consideration at the 
time they are evaluated, a 
connection with the test drug 
administration cannot be 
ruled out with certainty nor 
felt with a high degree of 
certainty to be related to the 
study drug. 
The relationship of an AE may be considered 
“reasonable possibility” if at least 2 of the 
following apply: 
• It follows a reasonable temporal sequence 
from administration of the drug. 
• It cannot be reasonably explained by the 
known characteristics of the patient’s 
clinical state, environmental or toxic 
factors, or other modes of therapy 
administered to the patient. 
• It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an AE does not 
disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists. 
• It follows a known pattern of response to 
the test drug. 
7.2 
SERIOUS ADVERSE EVENTS (SAE) 
An SAE is any AE occurring at any dose that suggests a significant hazard or side effect, 
regardless of the Investigator or Sponsor's opinion concerning the relationship to the 
investigational medicinal product and that result in, but may not be limited to, any of the 
following outcomes: 
• Death (regardless of the cause) 
• A life-threatening experience 


 
 
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• Inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care 
facility) 
• A persistent or significant disability/incapacity 
• A congenital anomaly or birth defect in an offspring of a study subject. 
Significant medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or 
that they occurred as a consequence of the event. 
Hospitalization for elective treatment of a pre-study condition (pre-Baseline) that did not 
worsen while on study and optional hospitalizations not associated with a clinical AE (e.g. 
elective cosmetic surgery) are not considered SAEs. 
Significant medical events are those that may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious 
outcomes listed above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; such an AE will normally be considered serious by this criterion. 
Progression of the cancer under study is not considered an AE unless it is considered to be 
drug-related by the Investigator. 
In addition to the above criteria, AEs meeting any of the below criteria, although not serious 
per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs as significant 
medical events to meet certain local requirements. 
Therefore, these events are considered serious by the Sponsor for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose, refer to Section 7.3 events of clinical interest 
Methods for follow-up for these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
A life-threatening adverse drug experience is any AE that places the subject, in the view of 
the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
Any newly emergent SAE, after treatment is discontinued or the subject has completed the 
study, and that is considered to be related to the study drug or study participation, should be 
recorded and reported immediately to Sponsor or delegate. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor 
Pembrolizumab 
 
 


 
 
 
 
 
 
 
BL-8040 
 
 
 
 
 
 
 
 
 
7.2.2 Reporting Period of Serious Adverse Event 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment /allocation must be reported by the Investigator if the participant is 
receiving placebo run-in or other run-in treatment, if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure. 
All AEs or ECIs from the time of treatment/ allocation through 90 days following cessation of 
study treatment must be reported by the investigator. 
All AEs meeting serious criteria, from the time of treatment/ allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if the 
participant initiates new anti-cancer therapy, whichever is earlier must be reported by the 
investigator. 
All pregnancies and exposure during breastfeeding, from the time of treatment/ allocation 
through 120 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anti-cancer therapy must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an Investigator at any time outside of the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered to be drug-related. 
All subjects with SAEs must be followed up for outcome. 
7.2.3 Definition of an Unexpected Adverse Event 
An unexpected adverse drug event is any AE, the specificity or severity of which is not 
consistent with information in the current IB for an unapproved investigational product. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is a SAE assessed as unexpected 
by the Sponsor and that is judged by either the reporting Investigator or the Sponsor to have a 
reasonable causal relationship to the investigational medicinal product. 
7.2.4 Exceptions in the Reporting of SAE 
Elevations of blood cells are expected with BL-8040 treatment as a part of the mechanism of 
action. These elevations should not be reported as AEs or SAEs provided they are not 


 
 
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associated with clinical symptoms. In case of clinical symptoms, the final diagnosis should be 
reported accordingly as an AE or SAE depending of the severity. 
7.2.5 Notification of Serious Adverse Event (SAE) 
Initial Notification of SAEs 
An initial SAE report form must be completed and sent via email/fax to the sponsor within 24 
hours of the Investigator’s knowledge of the event. Any fatal or life-threatening event should 
be reported immediately by phone, fax or email. Reporting SAEs to regulatory authorities 
and/or IRBs must comply with local regulations. 
PhV representative: 
 
  
 
The initial SAE report will be followed within 24 hours by a completed SAE report including 
a sufficiently detailed narrative to allow for a medical assessment of the case, as well as copies 
of hospital case reports, results of applicable diagnostic tests, laboratory results, biopsy results, 
autopsy reports and other documents when requested and applicable. 
Minimum Criteria for a Valid Initial SAE Case: 
For regulatory purposes, initial SAE reports should be submitted to the Sponsor’s Medical 
Monitor or designee immediately and should include: 
1. 
A suspected study drug (whether or not it is suspected to be related to one or 
both study drugs) 
2. 
An identifiable subject (e.g. study subject code number) 
3. 
An AE with the Investigator’s assessment of seriousness 
4. 
An identifiable reporting source (Investigator contact details) 
Once sent, the SAE form and accompanying documentation should be placed in the SAE 
section of the Investigator’s site file. 
SAEs will be reported to the IRB/IEC and regulatory authorities as required by local 
regulations and ICH-GCP guidelines. 
Follow-up of SAEs: 
Follow-up of all SAEs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, an SAE may be defined as “ongoing without 
further follow-up” if mutually agreed by the Investigator and Sponsor. 
A Follow-up SAE report form must be completed by the site (marked as “Follow-up report”) 
and sent to the Medical Monitor within a reasonable timeframe (an SAE Follow-up report is 
required whether or not there is any additional information to the initial report). 
The contact information for Follow-up SAE reporting is the same as for initial SAE reports 
(see above section). 
As for the initial SAE report, once sent, the Follow-up SAE report and accompanying 
documentation should be placed in the SAE section of the Investigator’s site file. 


 
 
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7.3 
EVENTS OF CLINICAL INTEREST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 
REPORTING OF PREGNANCY AND LACTATION TO THE SPONSOR 
Although pregnancy and lactation are not considered AEs, 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 Baseline must 
be reported by the Investigator and the subject should be excluded from the trial. 
Pregnancies and lactations that occur from the time of Baseline through 120 days following 
cessation of study drugs, or 30 days following cessation of treatment if the subject initiates new 
anti-cancer 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 
(under Important Medical Event). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 


 
 
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8 
STATISTICAL METHODOLOGY 
As this is an open-label, Phase IIa two-cohort study to evaluate the safety, tolerability and 
preliminary efficacy study of two potential treatments regimens, neither power assessment, nor 
between cohorts formal hypotheses testing are currently planned for study outcome measures. 
The planned sample size of a total of 40 subjects for each of the two study cohorts is considered 
clinically appropriate for further characterization of the safety, tolerability and preliminary 
efficacy of the proposed treatment regimens in subjects with metastatic pancreatic 
adenocarcinoma. 
Outcome results of all safety, tolerability and preliminary efficacy data will be compared 
between the two study cohorts descriptively. 
The primary efficacy endpoint is the ORR according to RECIST1.1 (ORRRECIST1.1) defined as 
the sum of PRs and CRs determined according to best response RECIST1.1 criteria. 
Principal analysis for inference will use the mITT Analysis Set. The ORRRECIST1.1 rate and its 
lower 95% One-Sided Confidence Limit (
 
) will be 
displayed for each study cohort. Sensitivity analysis will be done for the ITT analysis set. 
A more detailed Statistical Analysis Plan (SAP), amending the plan written to Cohort 1, will 
be developed during the data collection period of the initial 6 subjects of Cohort 2. 
8.1 
SAMPLE SIZE CONSIDERATION 
The planned sample size of a total of 40 subjects for each of the two study cohorts is considered 
clinically appropriate for further characterization of the safety, tolerability and preliminary 
efficacy of the proposed treatment regimens in subjects with metastatic pancreatic 
adenocarcinoma. 
8.2 
DATA ANALYSES SETS 
The following data analysis sets are defined for this study: 
8.2.1 Intent-to-Treat (ITT) Analysis Set  
The Intent-to-Treat (ITT) analysis set will consist of all data collected for all subjects who have 
been enrolled into the study and treated for at least once with any of the study drugs. This 
analysis set will serve as the principal analysis set for safety inference and for OS and PFS 
inference. 
8.2.2 Modified Intent-to-Treat (mITT) Analysis Set 
The Modified Intent-to-Treat (mITT) analysis set is a subset of the ITT set. This set will consist 
of data from all subjects who met all of the below criteria: 
• 
Treated with and of study drugs at least once, and, 
• 
Underwent at least 1 post-Baseline CT scan. 
The mITT analysis set will serve as the principal analysis set for efficacy inference (except for 
the OS and PFS analyses). 
 


 
 
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8.3 
EFFICACY ENDPOINTS AND ANALYSES 
All efficacy endpoints will be evaluated for the mITT analysis set with the exception of the 
PFS and OS that will be evaluated for the ITT Analysis Set. The two study cohorts will be 
compared descriptively. 
8.3.1 Significance Level 
No between-cohort significance tests are planned for this study. 95% One-Sided Confidence 
Limits for each cohort response estimates will be provided when applicable. 
8.3.2 Primary Efficacy Endpoint: Objective Response Rate According to RECIST1.1 
(ORRRECIST1.1) 
The primary efficacy endpoint is the Objective Response Rate according to RECIST1.1 
(ORRRECIST1.1) defined as the sum of PRs and CRs determined according to best response 
RECIST1.1 criteria. Principal analysis for inference will use the mITT Analysis Set. The 
ORRRECIST1.1 rate and its lower 95% One-Sided Confidence Limit (
 
 
) will be displayed for each study cohort separately. Sensitivity analysis 
will be done for the ITT analysis set. 
8.3.3 Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed: 
8.3.3.1 ORRirRECIST 
The Objective Response Rate according to irRECIST (ORRirRECIST) is defined as the sum of 
PRs and CRs determined according to best response irRECIST criteria. 
Principal analysis for inference will use the mITT Analysis Set. The ORRirRECIST rate and its 
lower 95% One-Sided Confidence Limit (
 
) will be 
displayed for each study cohort separately. 
Sensitivity analysis will be done for the ITT analysis set. 
8.3.3.2 Overall Survival (OS) 
The analysis of OS will be performed for the ITT Analysis Set for each study cohort separately. 
The distribution of the time to event from first dose of either study drug will be presented using 
Kaplan-Meier Plot. Censoring, for event free subjects, will use the last day subject is alive. 
Median time to event as well as its lower 95% One-Sided Confidence Limit will be extracted 
from the 
 
 table. The 6-Months OS estimate and its 
lower 95% One-Sided Confidence Limit (extracted from SAS dataset generated while using 
the 
 
) will be presented as well. 
Number of deaths and death rate as well as its lower 95% One-Sided Confidence Limit (
 
) will also be displayed. 
8.3.3.3 Progression-Free Survival (PFS) 
The analysis of PFS will be performed for the ITT Analysis Set. 
The distribution of the time to event from first dose of either study drug will be presented using 
Kaplan-Meier Plot. Censoring, for event free subjects, will use the last day subject is alive. The 


 
 
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distribution of the time to event will be presented using Kaplan-Meier Plots. Censoring, for 
event free subjects, will use the last day subject is alive. 
Median time to event as well as its lower 95% One-Sided Confidence Limit will be extracted 
from the 
 table. The 6-Months PFS estimate and its 
lower 95% One-Sided Confidence Limit (extracted from SAS dataset generated while using 
the 
 
) will be presented as well. 
8.3.3.4 Disease Control (DC) 
DC is defined as the sum of PRs and CRs and SDs determined according to: 
• 
DCRECIST1.1 is defined as the best response according to RECIST1.1. 
• 
DCirRECIST is defined as the best response according to irRECIST. 
Number of events and event rates as well as lower 95% One-Sided Confidence Limit (
 
) will be provided. 
8.3.3.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
SAFETY ANALYSES 
All safety assessments will use the ITT analysis set and will consist of all data collected for all 
subjects who have been enrolled into the study and treated for at least once with either study 
drugs. This analysis set will serve as the principal analysis set for safety inference. 
8.4.1 Treatment Emergent Adverse Events (TEAEs) 
AEs are to be recorded from the time a subject has signed the ICF until the end of subject’s 
study participation in the study (including the safety follow-up period), regardless of study drug 
administration. 
The MedDRA dictionary Version 22 will be used to standardize the terms used by the 
investigator to describe the AEs. 
AE analyses will include only the TEAEs, namely, those events which started at the time of 
first study drug administration or afterwards. 
The following analyses are pre-planned for AEs: 
• 
The incidence (no. of patients) and frequency (no. of events) of most frequent TEAEs 
(>10% of subjects) by Preferred Term. 


 
 
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• 
The incidence (no. of patients) and frequency (no. of events) of most frequent TEAEs 
(>10% of subjects) by High Level Term (HLT). 
• 
The incidence (no. of patients) and frequency (no. of events) by System Organ Class 
(SOC). 
• 
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down by 
SOC, HLT and Preferred Term. 
• 
For each attribute of AEs (e.g. seriousness, severity) a summary table will be provided 
displaying the incidence (no. of patients) and frequency (no. of events) when broken 
down by event attribute classification, by SOC and Preferred Term. 
• 
The incidence (no. of patients) and frequency (no. of events) of serious TEAEs broken 
down by SOC, Preferred Term and by study drugs relationship. 
• 
The incidence (no. of patients) and frequency (no. of events) of injection site reactions 
will be provided when broken down by Preferred Term. 
• 
The incidence (no. of patients) and frequency (no. of events) of systemic reactions will 
be provided when broken down by Preferred Term as described below: 
8.4.2 Laboratory Data 
Analyses of safety laboratory data will be performed in the following manner: 
• 
The proportion (%) of patients who reach WBC > 60,000/μL will be presented by study 
visits and across all post-Baseline visits. 
• 
Laboratory measurements were categorized with reference to the local sites normal 
ranges as Low, Normal or High. The incidence (no. of subjects) of abnormal values at 
any time first study drug administration, calculated for subjects with normal values at 
Baseline will be provided. Analysis will include, per tested parameter, those subjects 
with normal baseline and at least one post-treatment measurement. Summary table will 
display the number and relative percentage of subjects with at least one abnormal value 
at any time post 1st study drug administration. 
• 
Abnormal laboratory measurements of potentially clinical significance were also been 
classified by the sites as Clinically Significant (CS) or Not Clinically Significant (NCS). 
Summary table will display the number and relative percentage of subjects with at least 
one CS assessment, for each laboratory parameter and across all laboratory parameters 
at any time post 1st study drug administration. 
• 
Quantitative laboratory parameters will be summarized by study visits according to the 
below: 
o Descriptive statistics of measured values and changes from Screening Visit (Note: 
Laboratory assessments were not collected at Baseline Visit). 
o Graphical display of measured values will be presented using Box-Plots and figures 
of mean values ±SE across study visits. 
8.4.3 Vital Signs 
Analyses of vital signs data will be performed in the following manner: 


 
 
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• 
Descriptive statistics of quantitative parameters measured at scheduled visits and at Last 
Observed Value (LOV) will be provided along with changes from Baseline. 
• 
Graphical presentation of mean values + 1 standard error of the mean as well as Box-
Plots of quantitative parameters measured at scheduled visits and at LOV will be 
provided as well. 
• 
Summary table of the number and percent (%) of subjects with at least one post 1st study 
drug CS assessment, along with data listing of all vital signs data of these subjects will 
be provided. The denominator for this analysis will be number of subjects with at least 
one post 1st study drug vital signs assessment. 
• 
The distribution of Investigator's assessment (Normal, Abnormal NCS and Abnormal 
CS) done for each parameter evaluated will be provided by study visit. 
8.4.4 ECG 
Analyses of ECG data will be performed in the following manner: 
• 
Descriptive statistics of quantitative parameters measured at scheduled visits and at LOV 
will be provided along with changes from baseline. 
• 
Graphical presentation of mean values + 1 standard error of the mean as well as Box-
Plots of quantitative parameters measured at scheduled visits and at LOV will be 
provided as well. 
• 
Summary table of the number and percent (%) of subjects with at least one post 1st study 
drug administration CS overall assessment, along with data listing of all ECG data of 
these subjects will be provided. The denominator for this analysis will be number of 
subjects with at least one post Monotherapy D1 ECG assessment. 
• 
QTcF prolongation is defined as QTcF>440(msec) for males and QTcF>460(msec) for 
females at any time post 1st study drug administration. Summary table of the number and 
percent (%) of subjects with at least one post Monotherapy D1 QTcF prolongation, along 
with data listing of all ECG data of these subjects will be provided. The denominator for 
this analysis will be number of subjects with at least one post 1st study drug 
administration. 
• 
The distribution of overall Investigator's assessment of ECG (Normal, Abnormal NCS 
and Abnormal CS) will be provided by study visit. 
8.4.5 Safety Assessment - Physical Examinations 
Physical examinations and directed physical examinations were to be performed as described 
in the study scheme. Accordingly: 
• 
Full PE will be conducted at Screening and at the time of discontinuation. These data 
will be summarized as outlined below: 
o 
Assessment results, for each body system, were classified as Normal, Abnormal NCS or 
Abnormal CS. The distribution of number of subjects by body system examined and 
result assessments made will be presented by scheduled visit. 
o 
Shift analysis from Screening to End of Treatment will be provided. 


 
 
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o 
The number and the proportion of subjects with abnormal assessments of clinical 
significance will be displayed. 
• 
Directed PE will be conducted on Day 5 of the monotherapy period (± 3 days but before 
the first dose of the combination) and on Day 1 of each cycle beginning at Cycle 2 (± 3 
days but before the first dose of the combination of cycle 2). 
These data will be summarized in a frequency table displaying the number and proportion 
(%) of subjects with any change in physical examination by visit and overall, across all 
post-Baseline visits. 
8.5 
TOLERABILITY ASSESSMENT 
Tolerability and drop-out assessments will be performed for the ITT Analysis Set for the below 
metrics: 
• 
Proportion of subjects (%) who prematurely discontinued from the study by reason of 
discontinuation. 
• 
Time of early study discontinuation for whatever reason. 
• 
Time of early study discontinuation due to AEs. 
The distribution of the time to event will be presented using Kaplan-Meier Plots. Median time 
to event will be extracted from the 
 table.  The 6-
Months early-Termination-frees-subjects estimate and its lower 95% One-Sided Confidence 
Limit (extracted from SAS dataset generated while using the 
 
 
) will be presented as well. 
8.6 
MORE DETAILED STATISTICAL ANALYSIS PLAN (SAP) 
A more detailed SAP, amending the plan written to Cohort 1, will be developed during the 
data collection period of the initial 6 subjects of Cohort 2. 
8.7 
STATISTICAL SOFTWARE 
All data listings, summary tables and statistical analyses will be generated using SAS® 
Version 9.4 or higher (SAS is a registered trademark of the SAS Institute Inc., Cary, NC, 
USA). 
8.8 
ONGOING SAFETY ASSESSMENT AND DOSE-LIMITING TOXICITY 
(DLT) 
AEs will be reported from the time of informed consent signature through 90 days of the last 
dose of the last study drug. 
An independent DMC will review the accumulated study data according the DMC charter in 
order to ensure subjects welfare. Serious AEs will be monitored continuously throughout the 
study. 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
a First cycle of combination, Day 1 to 21, for the first six to twelve patients that complete this period 


 
 
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o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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9 
ETHICS 
9.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS 
COMMITTEE 
Prior to initiation of the study, the Investigator will submit the study protocol and amendments, 
IB and amendments, ICF and any other documents that may be provided to the subject or any 
other documents requested by the IRB/IEC for review and approval. 
The names and affiliations of all members of the IRB/IEC must be provided to the PI and 
BioLineRx. In lieu of this, the IRB/IEC must certify that it has been officially 
authorized/recognized according to the national legislation. 
The IRB/IEC must provide written approval of the study to keep in the Investigator’s file. 
Records of approval of all documents pertaining to this study, including the local Regulatory 
Authority, should be filed as such. The Investigator will not begin the study until the protocol, 
ICF and any other document provided to the subject have been approved by the IRB/IEC. The 
Investigator must agree to make any required progress reports to the IRB/IEC, as well as reports 
of SAEs, life-threatening conditions or death. The IRB/IEC will also be notified of Part 1 
preliminary results. 
9.2 
ETHICAL CONDUCT OF THE STUDY 
All clinical work conducted under this protocol is subject to ICH-GCP (E6) guidelines. This 
includes an inspection by Sponsor or its designee, health authority or IRB/IEC representatives 
at any time. The Investigator must agree to the inspection of study-related records by health 
authority representatives and/or Sponsor or its designee. 
The study will be conducted in accordance with Sponsor and/or designee’s standards operating 
procedures and the following guidelines: 
• GCP: Consolidated Guideline (International Conference on Harmonization of 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, May 
1996). 
• Declaration of Helsinki: Brazil, 2013. 
• US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) and/or EU 
Directives; and/or local country regulations and guidelines. 
9.3 
SUBJECT INFORMATION AND CONSENT 
Prior to Screening for the study each subject will be informed in detail about the study drugs 
to be administered and the nature of the clinical investigation including the risks and 
discomforts to be expected. The basic elements of informed consent as specified by the US 
Government (21 CFR 50.25) and ICH-GCP will be followed. The subjects will also be 
instructed that they are free to withdraw their consent and discontinue their participation in the 
study at any time without prejudice. Written consent will be obtained from each subject to be 
involved in the clinical trial by using the IRB/IEC-approved ICF prior to the conduct of any 
study-related activity. A copy of the ICF will be submitted together with this protocol and must 
be approved by the IRB/IEC prior to study commencement. Each subject will be given a copy 
of the written ICF, and each subject’s chart will include the signed ICF for study participation. 
The original subject signed and dated ICFs will be maintained per ICH record retention 
requirements. Regulatory authorities may check the existence of the signed ICF in this central 
study folder if not having performed so during the study. 


 
 
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The initial ICF, any subsequent revised written ICF and any written information provided to 
the subject must receive the IRB/ERC’s approval/favorable opinion in advance of use. The 
subject or his/her legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial. The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures 
the subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature. 
9.4 
SUBJECT INSURANCE 
A product liability to cover against injury and damages arising from the use of investigational 
products in this project is provided by the Sponsor for the total duration of the study covering 
the subjects and Investigators in respect of the risks involved in conducting this study according 
to this protocol. The insurance policy will be filed in the Investigator’s site file or can be made 
available to the Investigator and to the IRB/IEC upon request. 
Subjects will be insured through contract between an insurance company and the Sponsor. 
9.5 
INFORMING THE GENERAL PRACTITIONER 
When required by location regulation, the Investigator will inform the subject's primary care 
physician of his/her participation in the study, by sending a letter to the physician. 
9.6 
PERSONAL DATA PROTECTION 
The Sponsor will comply with local regulations and with the principle of a subject’s right to 
protection against invasion of privacy. Throughout this trial, all subject data will be identified 
only by a subject identification number and subject initials and date of birth.  The subject must 
be informed and consent to authorized personnel of the Sponsor, such as study monitor, auditor, 
etc. and relevant health regulatory agencies having direct access to personal medical data to 
assure a high-quality standard of the study. At the subject's request, medical information may 
be given to his or her personal physician or other appropriate medical personnel responsible 
for his or her welfare. 
9.7 
DATA REVIEW MONITORING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.8 
PROTOCOL EXCEPTIONS AND DEVIATIONS 
Departures from the protocol should be avoided, unless required for the safety of the subject. 
Protocol deviations, and if possible the reason for occurrence, will be documented by the study 
monitor in visit reports and will be included in the final clinical study report. The Investigator 
must report any protocol deviations to the Sponsor or the Sponsor's designee, should they 
occur. If required, the Investigator should also report deviations to the IRB/IEC in accordance 
with local regulations and within a reasonable time. No prospective waivers will be allowed 
for subjects who do not fulfill the inclusion/Exclusion Criteria. 
9.9 
PROTOCOL AMENDMENTS 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/IEC in 
accordance with local requirements and, if required, to the Regulatory Authority, either as an 
amendment or a notification. Approval for amendments must be received before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be conducted according to GCP as outlined by ICH Topic E6 step 5 guidelines. 
The Sponsor's SOPs will be followed to ensure that clinical trials are conducted, and data are 
generated, documented and reported in compliance with the protocol, GCP and applicable 
regulatory requirements. 
10.1 AUDITS AND INSPECTIONS 
The study may be audited according to the Sponsor's or its designee's Quality Assurance 
inspection program. The purpose of the audit is to determine whether or not the study is being 
conducted and monitored in compliance with the study protocol and ICH-GCP guidelines. 
Audit visit(s) will be arranged in advance with site personnel at a mutually acceptable time. 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Sponsor or its designees or the 
Regulatory Authority inspectors after appropriate notification. The verification of the CRF data 
must be made by direct inspection of source documents. The auditor may ask to visit the 


 
 
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facilities where laboratory samples are collected, where the investigational product is stored 
and prepared and any other facility used during the study. These audits or inspections may take 
place at any time, during or after the study, and are based on the national regulations, as well 
as ICH guidelines. 
10.2 STUDY MONITORING 
Monitoring of the study, which is the responsibility of the Sponsor, may be delegated to a CRO. 
The study monitor will advise the Investigator regarding the practical conduct of the study and 
maintaining compliance with the protocol, GCP and all applicable regulatory requirements. 
Before study initiation, at the site initiation visit or at an Investigator’s meeting, a Sponsor or 
CRO representative will review the protocol and CRFs with the Investigator and staff. The 
Sponsor/CRO will also be responsible for training study personnel in the study-specific 
procedures. 
Throughout the course of the study, the study monitor will oversee the conduct and the progress 
of the study by frequent contacts with the Investigator and his staff. Contact will include 
telephone calls and on-site visits. During the on-site visits, the CRF will be reviewed for 
completeness and accuracy with corresponding source documents. As part of the data audit, 
source documents will be made available for review by the study monitor. The study monitor 
will also perform drug accountability checks and will periodically review the Investigator study 
file to ensure completeness of documentation in all respects of clinical study conduct. 
Periodically, some or all of the facilities used in the study (e.g., local laboratory, pharmacy) 
may be reviewed. Monitoring visits will be arranged in advance with site personnel at a 
mutually acceptable time. Sufficient time must be allowed by the site personnel for the monitor 
to review CRFs and relevant source documents. The Investigator should be available to answer 
questions or resolve data clarifications. The Investigator or appointed delegate will receive the 
study monitor during these on-site visits, cooperate in providing the documents for inspection 
and respond to enquiries. 
The Investigator will ensure that the study participants are aware of and consent to their 
personal information being scrutinized during the data verification process, as part of study-
related monitoring, inspection and/or auditing, by properly authorized persons associated with 
Sponsor or by domestic and/or foreign regulatory authorities. However, the subject’s 
participation and personal information will be treated as strictly confidential to the extent that 
the applicable law permits and will not be made publicly available. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period. 
10.3 QUALITY LABORATORY STANDARDS 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the central and local institution 
laboratories. 
Before the study begins, where applicable, the laboratories to be used in the study will provide 
a list of the reference ranges for all laboratory tests to be undertaken and details of the method 
used for quality control. These will be held in the Investigator Site File and the Trial Master 
File. The methods employed for each assay should be available on request. Any change in the 
laboratory, its procedures, references, values, etc. during the study must be notified promptly 
to the Sponsor. 


 
 
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When academic laboratories are used in this study, they may be exempt from some or all of the 
above requirements on a case by case basis. 
10.4 STUDY DOCUMENTATION 
Study documents will include the following: 
• Signed ICFs 
• Source documents (e.g. subject files, medical notes) 
• Investigator copies of the CRFs and SAE reports 
• Investigator site file and its content 
• Study manual (including imaging tip sheet) 
• Laboratory Manual 
• Study Pharmacy Manual (includes instructions for use) 
• Training materials 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period. 
10.4.1 Source Document 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents. 
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
records, care records or completed scales for each study participant. Source documents should 
be kept in a secure and limited access area. All source documents must be accurate, clear, 
unambiguous, permanent and capable of being audited. They should be made using a 
permanent form of recording (ink, typing, printing, optical disc etc). They should not be 
obscured by correcting fluid or have temporary attachments (such as removable self-stick 
notes). Source documents that are computer generated and stored electronically must be 
printed, signed and dated by the Investigator. 
Source data for subjects registered to the study should indicate the date the ICF was signed, 
participation in a clinical trial with the clinical protocol number and title, treatment number and 
evidence that inclusion/Exclusion Criteria have been met. 
10.4.2 Recording of Data on Case Report Form (CRF) 
The development of the CRF will be the responsibility of the Sponsor or its designee. 
All the pertinent data will be recorded on an electronic Case Report Form (eCRF). All eCRFs 
will be completed in English and will be reviewed by study monitors for accuracy and 
completeness. All data pertaining to the visit should be recorded in the eCRF no later than five 
days after the completion of the visit. The Investigator is responsible for verifying that all data 
entries in the eCRFs are accurate and correct. The PI must sign the completed CRF prior to its 
submission to the Sponsor. 
A representative of the Sponsor or designee will instruct the Investigator and his/her staff prior 
to the enrollment of the first subject and will train them on recording the findings into the EDC 
system. 


 
 
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EDC System on the Electronic CRFs (eCRFs): 
After the enrollment of the first subject, a study monitor will periodically monitor the progress 
of the study. The study monitor will also have the ability to review query statuses remotely 
which may warrant more frequent contact with the Investigator and his/her staff. The 
Investigator will make available to the study monitor the computer that accesses the eCRFs, 
source documents, signed consent forms and all other study-related documents. The 
Investigator will be responsible for reviewing eCRFs, providing resolution to data queries 
generated by the study monitor via the EDC system, providing missing or corrected data, and 
approving all changes performed on his/her data, and endorsing the subject data within the 
EDC system. This approval method will include applying an electronic signature, a uniquely 
assigned username and a password, that together would represent a traditional handwritten 
signature. 
The Investigator will agree to the inspection of study-related records by the Sponsor, external 
auditor and/or health authority representatives. 
10.4.3 Investigator Site File 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for monitoring 
and/or auditing by the Sponsor/or designee and regulatory agencies. 
10.5 CLINICAL TRIAL SUPPLIES 
The Sponsor or designee will be responsible for supplying clinical trial supplies to the sites. 
The PI will be responsible for the administration, inventory and accountability of all clinical 
trial supplies provided to the site, exercising accepted medical and pharmaceutical practices. 
An accurate and timely record of the disposition of all clinical supplies must be maintained. 
The supplies and inventory record must be made available for inspection upon request. Upon 
completion or Termination of the study, the Investigator will return the remaining clinical 
supplies along with a copy of the inventory record and a record of the clinical supplies returned. 
A copy of these records should be maintained in the site study files. Under no circumstances 
will the Investigator allow the study drugs to be used other than as directed by this 
protocol. 
Clinical trial supplies include, but are not limited to: CRFs, lab supplies, and study drugs. 
10.6 DATA MANAGEMENT 
Data Management services will be provided by the Sponsor or designee. The Data Management 
system will be specified in the Data Management Plan. 
After the data has been entered and verified, various edit checks will be performed to ensure 
the accuracy, integrity and validity of the database. These edit checks may include: 
• Missing value checks 
• Range checks 
• Consistency checks 
• Sequence checks 
• Protocol adherence checks 
Queries generated from these checks will be sent to the investigational site for resolution, and 
the database will be updated to reflect query resolutions as appropriate. 


 
 
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AEs will be coded using the latest version of MedDRA (currently version 22.0). Prior and 
concomitant medications will be coded according to the World Health Organization (WHO) 
Drug Dictionary. 
11 STUDY ADMINISTRATION 
11.1 PARTICIPATING CENTERS 
Five to ten sites 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION 
Prior to the start of this study, all pre-investigational requirements must be met by the 
Investigator and study site. These may include: 
• Appropriate local health authority documentation properly signed and dated by the 
required Investigator (i.e., documents required for submission to the local IRB/IECs or 
applicable regulatory authorities). 
• Signed copy (original) of the approved protocol. 
• Completed and signed statement of Investigator. 
• A signed Clinical Trial Agreement. 
• Curriculum vitae for the Investigator and sub-Investigator (may be collected at site 
initiation visit). 
• IRB/IEC name and address; and membership list (may be collected at site initiation 
visit). 
• Letter of approval from the IRB/IEC for both protocol (identified by protocol title and 
number) and ICF (identified by protocol title and number). 
• Copy of the IRB/IEC-approved written ICF to be used in the study (that has also been 
approved by the Sponsor). 
• Provisions for direct access to source/data documents, if necessary, for trial-related 
monitoring, audits, IRB/IEC review and regulatory inspection. 
• Name and location of the laboratory utilized for laboratory assays and other facilities 
conducting tests, as well as a copy of the laboratory certificate and list of normal 
laboratory values (can be collected at site initiation visit). 
In case a laboratory certification is not available, a written statement as to how the laboratory 
complies with quality assurance should be provided. 
Upon satisfactory receipt of all required regulatory documents, the Sponsor will arrange for 
study drugs to be delivered to the study site. Supply of all other study materials will be the 
responsibility of the Sponsor and/or designee. Subject entry should not begin until after the 
required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred. All personnel expected to be involved in the conduct 
of the study will undergo study initiation which will include review of study protocol, 
instructions for CRF completion, AE reporting and overall responsibilities including those for 
drug accountability and study file maintenance. 
The Investigator and/or designee (study monitor) will be provided with an Investigator's file. 
This file should be used for all trial-related documents. The Investigator will be responsible for 


 
 
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keeping the Investigator's file updated and ensuring that all required documents are filed. The 
file will be inspected during monitoring visits. 
11.3 STUDY COMPLETION 
This study is expected to end when all required subjects have been enrolled and the last subject 
has completed the study and all query resolutions have been completed. 
Data and materials that are required before the study can be considered complete and/or 
terminated include, but are not limited to: 
• Laboratory findings, clinical data and all special test results from Screening through the 
end of the follow-up period 
• CRF properly completed by appropriate study personnel and signed by the Investigator 
• Completed Drug Accountability Records 
• Statement of outcome for each SAE reported 
• Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable) 
• Retention of Study Documents Statement 
11.4 CLINICAL STUDY REPORT 
A clinical study report will be developed by the Sponsor on completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
11.5 RETENTION OF STUDY RECORDS 
The Investigator will retain copies of the approved protocol, completed CRF, signed ICFs, 
relevant source documents and all other supporting documentation related to the project as 
defined in ICH-E6 Section 8 related to the project per ICH-E6 record retention requirements 
for at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product in a secure and safe facility with limited access. If the Investigator is 
unable to retain the study documents for the required amount of time, the Sponsor or designee 
must be informed of the individual who will be assuming this responsibility. 
The Sponsor will notify, in writing, the Investigator when the clinical study data may be 
discarded. The Investigator will take measures to prevent accidental or premature destruction 
of these documents. 
These files must be made available for inspection upon reasonable request by authorized 
representatives of the Sponsor and/or the relevant regulatory agencies. 
11.6 CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS 
11.6.1 General 
All data and information supplied by or on behalf of the Sponsor or otherwise acquired or 
obtained by any Research Institution, the Principal Investigator and other Investigators 
(“Recipients”) in any manner, in connection with or in performance of this study, is considered 
“Confidential Information.” This Confidential Information includes, but is not limited to, the 
IB, this protocol and any information relating thereto, CRFs and other scientific data, 


 
 
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information relating to Sponsor’s Investigational Product and treatment methodology and 
information relating to Sponsor’s (or its affiliates’) commercial, technical and financial 
information, research technology, products, inventions, trade secrets and research and 
development. The results produced in performance of the study and any data, information or 
other material collected or generated in the course of performing the study shall be promptly 
disclosed to Sponsor in full, in writing, and are also considered Confidential Information. This 
Confidential Information shall be the sole property of the Sponsor. 
Except for Publishable Results (defined below) to the extent it may be published under 
Section 11.6.2, throughout the duration of the study and after its completion, Recipients shall 
 (i) not disclose Confidential Information to others without the written consent of the 
Sponsor, except to those of its employees who have a need to know the Confidential 
Information in order to enable Recipients’  to fulfill their obligations hereunder, and where 
such employees are bound by written contractual obligations covering Confidential 
Information that are no less restrictive or protective than those contained herein, provided that 
Recipients shall remain liable for any disclosure or use of Confidential Information by such 
employees; 
(ii) use the same degree of care to preserve confidentiality of Confidential Information 
as they use for their own information of like nature, which shall not be less than reasonable 
degree of care; and 
(iii) not use Confidential Information for any purpose except in the performance of this 
study. Promptly at Sponsor’s request, or upon completion of the study, Recipients will 
discontinue use and return to Sponsor or destroy, in accordance with Sponsor’s instructions, 
all copies or other manifestations of Confidential Information that may be in their possession 
or control, except to the extent expressly required hereunder and to comply with applicable 
laws (defined below). 
Should a recipient be required to disclose Confidential Information pursuant to law, regulation, 
judicial or administrative order or request by a governmental or other entity authorized by law 
to make such request, recipient shall (i) promptly notify Sponsor prior to such disclosure, (ii) 
cooperate with Sponsor and provide assistance in seeking a protective order or other suitable 
protection with respect to the Confidential Information, and (iii) only disclose such 
Confidential Information to the extent pursuant to said law, regulation, judicial or 
administrative order, or request by a governmental or other authorized entity. 
At the subject’s request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. The personal physician 
will be notified by site personnel of subject participation in the study. 
11.6.2 Published Data 
The original CRFs and the data generated from the CRFs or otherwise obtained during the 
study under this study protocol will become the property of the Sponsor. Publication of the 
results of this study (“Publishable Results”) in an appropriate peer-reviewed journal after the 
conclusion of the study ("Publication") made be made as provided herein. Publication must be 
undertaken in a responsible and ethical manner, taking into account relevant external standards 
regarding the manner and content of scientific, technical and medical publications and in 
subject to applicable laws, rules, regulations, policies and guidelines ("Applicable Laws"). 
Authorship will be determined by mutual agreement between Sponsor and Principal 
Investigator. Sponsor shall be mentioned in all Publications unless contrary instruction is given 
by Sponsor. Review and comment by Sponsor authorized personnel on draft abstracts and 


 
 
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manuscripts for Publication or presentation is required prior to publication or 
presentation.  Authors shall submit a copy of any abstracts, manuscripts or other material 
proposed for publication or presentation ("Draft Publications") to the Sponsor for its approval 
no fewer than sixty (60) days prior to the intended date of submission of such Draft Publications 
to any journal, publisher, and/or third party. The Sponsor has the right, at its discretion (a) to 
evaluate Draft Publications for accuracy and concurrence regarding data, evaluations, and 
conclusions, (b) to provide an opportunity for Sponsor to share with the Investigator(s) any 
new or unpublished information of which he or she may be unaware, (c) to ensure that no 
Confidential Information or other Sponsor proprietary information is being utilized and has 
been included, and (d) evaluate Draft Publications to determine if patent applications need to 
be filed on any information disclosed therein. If the Sponsor determines that such Draft 
Publication contains Confidential Information or could otherwise be detrimental to Sponsor's 
intellectual property interest or have other adverse effects on its business, and notifies Principal 
Investigator of its determination, the Principal Investigator, Research Institutions and other 
Investigators/authors shall remove such Confidential Information from the Draft Publication 
or at Sponsor's election, modify it to remove language that is detrimental to Sponsor's 
intellectual property or other interests, and refrain from submitting such Draft Publication to a 
journal, publisher and/or other third party for additional ninety (90) days from Sponsor's 
notification to allow for filing of patent applications or the taking of such other measures as 
Sponsor deems appropriate to establish, preserve and protect its intellectual property or other 
interests. Principal Investigator, other Investigators and Research Institutions further agree to 
redact or modify those sections of the Draft Publication which Sponsor in good faith determines 
falls within (a) to (d) above 


 
 
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[3] Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, et al. CXCR4 antagonist 
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[4] Beider K, Darash-Yahana M, Blaier O, Koren-Michowitz M, Abraham M, Wald H, et al. 
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and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
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[19] Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits 
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[20] Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer—
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[38] Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ 
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[39] Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, et al. Targeting 
CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-
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[40] Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor 
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[41] Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, et al. CXCR4 antagonist 
4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Exp 
Hematol 2011;39:282–92. 
[42] Beider K, Ribakovsky E, Abraham M, Wald H, Weiss L, Rosenberg E, et al. Targeting 
the CD20 and CXCR4 pathways in non-hodgkin lymphoma with rituximab and high-
affinity CXCR4 antagonist BKT140. Clin Cancer Res Off J Am Assoc Cancer Res 
2013;19:3495–507. doi:10.1158/1078-0432.CCR-12-3015. 
[43] Zhang Y, Patel S, Abdelouahab H, Wittner M, Willekens C, Shen S, et al. CXCR4 
inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells 
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[44] Fahham D, Weiss ID, Abraham M, Beider K, Hanna W, Shlomai Z, et al. In vitro and in 
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analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of 
breast cancer. FEBS Lett 2003;550:79–83. 
[46] Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased 
survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 
2013;369:1691–1703. 
[47] Hidalgo MM, Epelbaum R, Semenisty V, Geva R, Golan T, Borazanci EH, et al. 
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic 
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doi:10.1200/JCO.2018.36.5_suppl.88. 
[48] Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing 
potential synergies. Cancer Immunol Res 2015;3:436–43. doi:10.1158/2326-6066.CIR-
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[49] Khoja L, Kibiro M, Metser U, Gedye C, Hogg D, Butler MO, et al. Patterns of response 
to anti-PD-1 treatment: an exploratory comparison of four radiological response criteria 
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2016;115:1186–92. doi:10.1038/bjc.2016.308. 
[50] Wang-Gillam A, Li C-P, Bodoky G, Dean A, Shan Y-S, Jameson G, et al. Nanoliposomal 
irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous 
gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. 
Lancet Lond Engl 2016;387:545–57. doi:10.1016/S0140-6736(15)00986-1. 






 
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13.2 APPENDIX B - EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
Eastern Cooperative Oncology Group (Zubrod-ECOG)1,2 
Description 
Grade 
Fully active, able to carry on all  
pre-disease activities without restriction. 
0 
Restricted in physically strenuous  
activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50%  
of waking hours. 
2 
Capable of only limited self-care,  
confirmed to bed or chair more than 50% of waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
4 
1Zubrod, C.G., et al. Appraisal of Methods for the Study of Chemotherapy of Cancer in Man. Journal of Chronic Diseases, 11:7-33, 1960. 
2 Oken, M.M., et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol (CCT) 5: 649-655, 1982