Conditions: Pancreatic Adenocarcinoma
Keywords: pancreatic cancer asparaginase gemcitabine Abraxane asparagine depletion onivyde nab-paclitaxel folinic acid fluorouracil irinotecan leucovorin amino acid RECIST 1.1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 512
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter, randomized, Phase 3 study in patients with ductal adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease.

Detailed description:
Patients who meet all inclusion and exclusion criteria will be randomized in a 1:1 ratio to one of the following treatment arms (see figure below):

* Arm A (investigational arm): eryaspase in combination with either gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI \[FOLinic acid-Fluorouracil-IRInotecan regimen\] or Onivyde®/5 fluorouracil/leucovorin), or
* Arm B (control arm): gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI or Onivyde/5-FU/leucovorin)

The chemotherapy will be investigator's choice and based on what patient has received in first line treatment. Treatment will continue until disease progression, unacceptable toxicity, or the patient's withdrawal of consent.

An End of Treatment visit should occur within approximately 30 days from last dose of eryaspase or chemotherapy regimen.

A survival follow-up period will include the collection of survival, progression of disease if applicable, treatment updates, and quality of life assessments every 8 weeks.

Arms:
arm 1: eryaspase 100 U/kg dosed every 2 weeks in combination with

Gemcitabine plus abraxane (albumin-bound paclitaxel) administered on Days 1, 8, and 15 of each 4 week cycle as follows:

* Abraxane (125 mg/m2) IV
* Gemcitabine (1000 mg/m2) IV

Or

Irinotecan plus 5-FU plus leucovorin administered on Days 1 and 15 of each 4 week cycle as follows:

* Onivyde 70 mg/m2 (irinotecan freebase) IV (recommended dose in patients homozygous for UGT1A1\*28 is 50 mg/m2)
* Leucovorin 400 mg/m2 IV
* 5 FU 2400 mg/m2

Or

* FOLFIRI: Irinotecan 180 mg/m2 IV
* Leucovorin 400 mg/m² IV
* 5 FU 400 mg/m² IV bolus
* 5 FU 2400 mg/m² IV continuous infusion over 46 hours immediately following bolus 5 FU arm 2: Standard treatment: Gemcitabine plus abraxane (albumin-bound paclitaxel) administered on Days 1, 8, and 15 of each 4 week cycle Or Irinotecan plus 5-FU plus leucovorin administered on Days 1 and 15 of each 4 week cycle

Interventions: intervention 1: eryaspase intervention 2: Gemcitabine plus Abraxane intervention 3: Irinotecan plus 5-FU plus leucovorin
Intervention descriptions: intervention 1: L-asparaginase encapsulated in erythrocytes (red blood cells) intervention 2: gemcitabine, Abraxane intervention 3: irinotecan, 5-FU, leucovorin

Protocol document:
Prot_000.pdf: 
This document contains information that is confidential and proprietary to ERYTECH Pharma. This information is being 
provided to you solely for the purpose of evaluating and/or conducting a clinical trial for ERYTECH Pharma. You may disclose 
the contents of this protocol only to study personnel under your supervision, your Independent Ethics Committee/Institutional 
Review Board, or duly authorized representatives of regulatory agencies. The foregoing shall not apply to disclosure required by 
any regulations; however, you will give prompt notice to ERYTECH Pharma of any such disclosure. 
 
Eryaspase 
Protocol GRASPANC 2018-01 
A Randomized, Phase 3 Study of Eryaspase in Combination with 
Chemotherapy versus Chemotherapy Alone as Second-Line 
Treatment in Patients with Pancreatic Adenocarcinoma 
TRYbeCA-1 – TRial of erYaspase in pancreatic CAncer 
Protocol Number: 
GRASPANC 2018-01 
EudraCT Number: 
2018-000572-15 
IND Number: 
018886 
Coordinating Investigators: 
Pascal Hammel, MD, PhD 
Hôpital Beaujon – Clichy, Paris, France 
E-mail: pascal.hammel@aphp.fr 
Phone: +33 (0)1 40 87 56 14 
Manuel Hidalgo, MD, PhD 
Weill Cornell Medicine – New York, NY, USA 
Email: mah4006@med.cornell.edu 
Phone: +1 646-962-2084 
Sponsor: 
ERYTECH Pharma 
60 avenue Rockefeller, 69008 Lyon, France 
Phone: +33 4 78 74 44 38 
Version Number: 
2.0 (Amended protocol), 14 December 2020 
Sponsor Contacts: 
Linda Grummer 
Study Team Leader 
Email: linda.grummer@erytech.com 
Phone: +1405-921-1605 
Sophie Salesse 
Study Team Leader 
Email: sophie.salesse@erytech.com 
Phone: +33 4 27 18 26 89 
Sponsor Medical Officer: 
Iman El Hariry 
Chief Medical Officer 
Email: iman.elhariry@erytech.com 
Phone: +33 6 79 74 67 80 
 


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Amended Protocol GRASPANC 2018-01 
Investigational Product: Eryaspase 
Version 2.0 (14th December 2020) 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 2 
LIST OF TABLES ......................................................................................................................... 8 
LIST OF FIGURES ....................................................................................................................... 9 
SPONSOR SIGNATURES .......................................................................................................... 10 
COORDINATING INVESTIGATOR SIGNATURES ............................................................... 11 
INVESTIGATOR’S AGREEMENT ........................................................................................... 12 
SYNOPSIS ................................................................................................................................... 13 
SCHEDULE OF EVENTS .......................................................................................................... 24 
ABBREVIATIONS ..................................................................................................................... 29 
1 
INTRODUCTION ........................................................................................................... 33 
1.1 
Background ................................................................................................................... 33 
1.1.1 
Pancreatic Cancer ....................................................................................................... 33 
1.1.2 
Tumor Cell Metabolism ............................................................................................. 33 
1.1.3 
Asparaginase .............................................................................................................. 34 
1.2 
Clinical Experience with Eryaspase .............................................................................. 35 
1.3 
Eryaspase in the Treatment of Pancreatic Cancer ......................................................... 35 
1.4 
Study Rationale ............................................................................................................. 41 
1.5 
Risk/Benefit Assessment .............................................................................................. 41 
1.5.1 
Known Potential Risks ............................................................................................... 41 
1.5.2 
Known Potential Benefits .......................................................................................... 42 
1.5.3 
Assessment of Potential Risks and Benefits .............................................................. 43 
2 
OBJECTIVES AND ENDPOINTS ................................................................................. 44 
2.1 
Primary Objective ......................................................................................................... 44 
2.2 
Secondary Objectives .................................................................................................... 44 
2.3 
Endpoints: ..................................................................................................................... 44 
3 
STUDY DESIGN............................................................................................................. 46 
3.1 
Overall Design .............................................................................................................. 46 
3.2 
Number of Patients ....................................................................................................... 49 
3.3 
Scientific Rationale for Study Design ........................................................................... 49 
3.3.1 
Choice of Chemotherapy (Control) ........................................................................... 49 
3.4 
Justification for Dose .................................................................................................... 49 


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3.5 
End of Study Definition ................................................................................................ 50 
4 
STUDY POPULATION .................................................................................................. 51 
4.1 
Inclusion Criteria .......................................................................................................... 51 
4.2 
Exclusion Criteria ......................................................................................................... 53 
4.3 
Screen Failures .............................................................................................................. 54 
5 
STUDY TREATMENTS ................................................................................................. 56 
5.1 
Description of Study Drugs .......................................................................................... 56 
5.1.1 
Eryaspase ................................................................................................................... 56 
5.1.2 
Gemcitabine and Abraxane ........................................................................................ 56 
5.1.3 
Irinotecan and 5-FU/Leucovorin ................................................................................ 56 
5.2 
Dosage and Administration........................................................................................... 57 
5.2.1 
Eryaspase ................................................................................................................... 57 
5.2.2 
Gemcitabine and Abraxane ........................................................................................ 57 
5.2.3 
Irinotecan and 5-FU/Leucovorin ................................................................................ 58 
5.2.4 
Guidelines for Treatment Discontinuation and Dose Modification ........................... 58 
5.2.4.1 
Dose Modification for Eryaspase............................................................................ 59 
5.2.4.2 
Dose Modifications for Chemotherapy (with or without Eryaspase) ..................... 59 
5.2.5 
Management of Events of special Interest ................................................................. 69 
5.2.5.1 
Management of Hypersensitivity Reactions with Eryaspase or Other Agents ....... 69 
5.2.5.2 
Management of Infusion/Transfusion Reactions .................................................... 70 
5.2.5.3 
Management of Diarrhea ........................................................................................ 72 
5.3 
Eryaspase Preparation/Handling/Storage/Accountability ............................................. 73 
5.3.1 
Acquisition and Accountability ................................................................................. 73 
5.3.1.1 
Acquisition .............................................................................................................. 73 
5.3.1.2 
Accountability ......................................................................................................... 74 
5.3.2 
Formulation, Appearance, Packaging, and Labeling ................................................. 74 
5.3.3 
Preparation ................................................................................................................. 74 
5.4 
Measures to Minimize Bias: Randomization and Blinding .......................................... 75 
5.4.1 
Blinding...................................................................................................................... 75 
5.4.2 
Randomization ........................................................................................................... 75 
5.5 
Compliance with Study Treatment ............................................................................... 75 
5.6 
Concomitant Therapy.................................................................................................... 75 


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5.6.1 
Prior Medications ....................................................................................................... 75 
5.6.2 
Permitted Medications ............................................................................................... 75 
5.6.3 
Prohibited Medications .............................................................................................. 76 
6 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL FROM THE STUDY .......................................................................... 77 
6.1 
Discontinuation of Study Treatment ............................................................................. 77 
6.2 
Participant Withdrawal from the Study ........................................................................ 77 
6.3 
Lost to Follow-Up ......................................................................................................... 78 
6.4 
Study Termination ........................................................................................................ 78 
7 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 80 
7.1 
Screening Assessments and Procedures........................................................................ 80 
7.2 
Randomization .............................................................................................................. 83 
7.3 
Treatment Phase Assessments and Procedures ............................................................. 83 
7.3.1 
Assessments prior to Initiation of Treatment on Cycle 1 Day 1 ................................ 83 
7.3.2 
Efficacy Assessments During the Treatment Phase ................................................... 84 
7.3.2.1 
Radiological Disease Assessments ......................................................................... 84 
7.3.2.2 
Health Outcomes ..................................................................................................... 84 
7.3.2.3 
Pharmacokinetic and Pharmacodynamic Assessments ........................................... 84 
7.3.2.4 
Immunogenicity ...................................................................................................... 84 
7.3.2.5 
Biomarker Assessments .......................................................................................... 85 
7.3.3 
Safety Assessments during the Treatment Phase ....................................................... 85 
7.4 
End of Treatment Visit.................................................................................................. 85 
7.5 
Follow-Up Phase Assessments and Procedures ............................................................ 86 
7.5.1 
Post-Study Subsequent Cancer Therapy .................................................................... 86 
7.5.2 
Survival Follow-Up ................................................................................................... 86 
7.6 
Efficacy Assessments .................................................................................................... 86 
7.6.1 
Radiological Disease Assessment and Evaluation of Response ................................ 86 
7.6.1.1 
Key Definitions ....................................................................................................... 87 
7.6.1.2 
Other Considerations .............................................................................................. 89 
7.6.1.3 
Measurement of Small Lesions on Follow-Up Scans ............................................. 89 
7.6.1.4 
Response Criteria .................................................................................................... 89 
7.6.1.5 
Determination of Radiological Best Overall Response .......................................... 90 


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7.6.2 
Health Outcomes ........................................................................................................ 90 
7.6.3 
Pharmacokinetic and Pharmacodynamic Assessments .............................................. 91 
7.6.4 
Immunogenicity ......................................................................................................... 92 
7.6.5 
Biomarker Assessments ............................................................................................. 92 
7.6.5.1 
Analysis of Tumor Tissues ..................................................................................... 92 
7.6.5.2 
Analysis of Plasma Samples ................................................................................... 92 
7.6.5.3 
Pharmacogenetic Analysis ...................................................................................... 93 
7.6.5.4 
Sample Collection, Storage, and Shipping ............................................................. 93 
7.6.5.5 
Bioanalysis .............................................................................................................. 93 
7.6.5.6 
Storage of Biological Samples for Potential Future Analysis ................................ 93 
7.7 
Adverse Events and Serious Adverse Events ............................................................... 94 
7.7.1 
Definition of Adverse Events ..................................................................................... 94 
7.7.2 
Definition of Serious Adverse Events ........................................................................ 94 
7.7.3 
Classification of Adverse Events ............................................................................... 94 
7.7.3.1 
Severity Grading ..................................................................................................... 94 
7.7.3.2 
Causality Assessment.............................................................................................. 95 
7.7.3.3 
Expectedness ........................................................................................................... 96 
7.7.4 
Time Period and Frequency for Adverse Event Assessment and Follow-Up ........... 96 
7.7.5 
Recording Adverse Events and Serious Adverse Events ........................................... 96 
7.7.6 
Serious Adverse Event Reporting .............................................................................. 97 
7.7.6.1 
Investigator Reporting Responsibilities for Serious Adverse Events ..................... 97 
7.7.6.2 
Expedited Reporting and Investigator Safety Reports ............................................ 97 
7.7.7 
Events of Special Interest........................................................................................... 97 
7.7.8 
Reporting of Pregnancy ............................................................................................. 98 
7.8 
CHANGES IN PROTOCOL DUE TO COVID-19 ...................................................... 98 
7.8.1 
Background ................................................................................................................ 98 
7.8.2 
Modified Protocol Required Procedures .................................................................... 99 
7.8.3 
Minimum Safety Assessments ................................................................................... 99 
7.8.4 
On-site Visit Schedules ............................................................................................ 100 
7.8.5 
Pharmacodynamic samples ...................................................................................... 101 
7.8.6 
Protocol Deviations .................................................................................................. 101 
7.8.7 
Clinical Monitoring .................................................................................................. 101 


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8 
STATISTICAL CONSIDERATIONS........................................................................... 102 
8.1 
Statistical Hypotheses ................................................................................................. 102 
8.2 
Sample Size Determination ......................................................................................... 102 
8.3 
Analysis populations ................................................................................................... 103 
8.4 
Statistical Analyses ..................................................................................................... 103 
8.4.1 
Analysis of the Primary Efficacy Endpoint ............................................................. 103 
8.4.2 
Analysis of the Secondary Endpoints ...................................................................... 103 
8.4.3 
Other Aspects of the Efficacy Analyses .................................................................. 104 
8.4.4 
Planned Interim Analyses ........................................................................................ 104 
8.4.5 
Subgroup Analyses .................................................................................................. 104 
8.4.6 
Independent Data Monitoring Committee (IDMC) ................................................. 104 
9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 106 
9.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................... 106 
9.1.1 
Informed Consent Process ....................................................................................... 106 
9.1.2 
Independent Ethics Committees and Regulatory Authorities .................................. 106 
9.1.3 
Study Completion or Discontinuation and Closure ................................................. 107 
9.1.4 
Protocol Adherence .................................................................................................. 107 
9.1.5 
Definition of Source Data ........................................................................................ 108 
9.1.6 
Access to Source Data ............................................................................................. 108 
9.1.7 
Confidentiality and Privacy ..................................................................................... 108 
9.1.8 
Data Quality Control ................................................................................................ 108 
9.1.9 
eCRF Completion using Electronic Data Capture ................................................... 109 
9.1.10 
Key Roles and Study Governance ........................................................................... 109 
9.1.11 
Safety Oversight....................................................................................................... 110 
9.1.12 
Clinical Monitoring .................................................................................................. 110 
9.1.13 
Site Audits and Inspections ...................................................................................... 110 
9.1.14 
Data Handling and Record Keeping ........................................................................ 111 
9.1.14.1 
Data Collection and Management Responsibilities .............................................. 111 
9.1.14.2 
Study Record Retention ........................................................................................ 111 
9.1.15 
Publication and Data Sharing Policy ....................................................................... 112 
9.2 
Protocol Amendment History ..................................................................................... 112 
10 
REFERENCES .............................................................................................................. 113 


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11 
APPENDICES ............................................................................................................... 117 
 


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LIST OF TABLES 
Table 1 ............ Schedule of Events ............................................................................................... 24 
Table 2 ............ Key Efficacy Outcomes in the ITT Population and ASNS Subpopulations in 
GRASPANC 2013-03 .......................................................................................... 36 
Table 3 ............ Incidence of Treatment-Related Treatment-Emergent Adverse Events Reported in 
at Least 10% of Patients by MedDRA Preferred Term - Safety Population ....... 40 
Table 4 ............ Treatment-Emergent Serious Adverse Events Reported in at Least 5% of Patients 
by MedDRA Preferred Term – Safety Population ............................................... 40 
Table 5 ............ Overview of AEs Affecting >10% of Patients in the Pooled Safety Population . 41 
Table 6 ............ Pre-Specified Dose Reductions for Adverse Events Related to Eryaspase ......... 59 
Table 7 ............ Dose Modifications for Gemcitabine, Abraxane, and Eryaspase ........................ 60 
Table 8 ............ Dose Modifications for Irinotecan, Onivyde, and Eryaspase .............................. 64 
Table 9 ............ General Guidelines for Managing Transfusion Reactions ................................... 70 
Table 10 .......... List of Laboratory Assessments ........................................................................... 81 
Table 11 .......... EORTC QLQ-30 Scales and Items [43] .............................................................. 91 
Table 12 .......... Minimum Safety Assessments ............................................................................. 99 
 


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LIST OF FIGURES 
Figure 1 ........... GRASPANC 2013-03: OS Kaplan-Meier Curves – Full ITT Population ........... 38 
Figure 2 ........... GRASPANC 2013-03: Best Response – Waterfall Plot (Percent Change from 
Baseline) (Eryaspase + Chemotherapy) ............................................................... 39 
Figure 3 ........... GRASPANC 2013 03: Best Response – Waterfall Plot (Percent Change from 
Baseline) (Chemotherapy Alone) ........................................................................ 39 
Figure 4 ........... Study Schema....................................................................................................... 46 
 
 


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SPONSOR SIGNATURES 
 
Protocol ID: 
GRASPANC 2018-01 
Protocol Title: 
A Randomized, Phase 3 Study of Eryaspase in Combination 
with Chemotherapy versus Chemotherapy Alone as 
Second-Line Treatment in Patients with Pancreatic 
Adenocarcinoma 
Protocol Version and Date: 
Version 2.0 (Amended protocol), 14th December 2020 
 
This amended clinical study protocol has been reviewed and approved by the study Sponsor. 
 
 
 
 
 
Signature 
Iman El Hariry, MD, PhD 
Chief Medical Officer 
 
Date 
 


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COORDINATING INVESTIGATOR SIGNATURES 
 
Protocol ID: 
GRASPANC 2018-01 
Protocol Title: 
A Randomized, Phase 3 Study of Eryaspase in Combination 
with Chemotherapy versus Chemotherapy Alone as 
Second-Line Treatment in Patients with Pancreatic 
Adenocarcinoma 
Protocol Version and Date: 
Version 2.0 (Amended protocol), 14th December 2020 
 
This amended clinical study protocol has been reviewed and approved by: 
 
 
 
 
 
Signature 
Pascal Hammel, MD, PhD 
Coordinating Investigator 
 
Date 
 
 
 
 
 
 
Signature 
Manuel Hidalgo, MD, PhD 
Coordinating Investigator 
 
Date 
 


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INVESTIGATOR’S AGREEMENT 
 
Protocol ID: 
GRASPANC 2018-01 
Protocol Title: 
A Randomized, Phase 3 Study of Eryaspase in Combination 
with Chemotherapy versus Chemotherapy Alone as 
Second-Line Treatment in Patients with Pancreatic 
Adenocarcinoma 
Protocol Version and Date: Version 2.0 (Amended protocol), 14th December 2020 
I have read the Protocol GRASPANC 2018-01, Version 2.0 (Amended protocol), 14th 
December 2020. I agree to abide by all provisions set forth herein. I will conduct the study as 
outlined herein, in accordance with Good Clinical Practice (GCP) and the Declaration of 
Helsinki, and will comply with the obligations and requirements of clinical investigators and all 
other requirements listed in the International Council for Harmonization (ICH) guideline for 
GCP. 
I agree to comply with all regulations regarding clinical research that apply in the country where 
I am based. I agree to comply with all legislation regarding protection of privacy that applies in 
the country where I am based. I understand that all information concerning eryaspase and this 
protocol is confidential, and I agree to not use this information for any purpose other than the 
evaluation and conduct of the clinical investigation without the prior written consent of 
ERYTECH Pharma. 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
 
 
 
 
Signature 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
Institution: 
 
 
 
 


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SYNOPSIS 
Study No.: GRASPANC 2018-01 
Title of Study: A Randomized, Phase 3 Study of Eryaspase in Combination with 
Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in Patients with 
Pancreatic Adenocarcinoma 
Number of Study Centers: approximately 100 study centers 
Phase of Development: 3 
Objectives: 
Primary Objective: 
To determine whether the addition of eryaspase to chemotherapy improves overall survival 
(OS) in second-line treatment of pancreatic adenocarcinoma compared to chemotherapy alone. 
Secondary Objectives: 
• To compare progression-free survival (PFS) between the two treatment arms. 
• To compare the objective response rate (ORR) and duration of response (DoR) 
between the two treatment arms. 
• To compare the disease control rate (DCR) between the two treatment arms. 
• To evaluate the safety and tolerability of eryaspase in combination with chemotherapy 
versus chemotherapy alone.  
• To assess the effect of eryaspase on quality of life using the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC 
QLQ-C30). 
• To determine the pharmacokinetics of eryaspase. 
• To assess the immunogenicity of eryaspase in terms of the induction of anti-
asparaginase (ASNase) antibodies and neutralizing antibodies. 
• To evaluate the relationship of clinical outcome with relevant biomarkers and genetic 
changes present in tumor tissues and blood and/or serum samples. 
• To investigate the predictive relationship between the patient’s deoxyribonucleic acid 
(DNA) sequence variation, e.g. exploratory single nucleotide polymorphism [SNP] 
genotyping in select candidate genes, and their response to combination treatment in 
terms of safety and tolerability (pharmacogenetics [PGx]). 
Endpoints: 
Primary Endpoint: 
Overall Survival (OS) in the ITT population. 
Secondary Endpoints: 
• Progression-free Survival (PFS),  
• Objective Response Rate (ORR)  


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• Duration of Response (DoR) 
• Disease Control Rate (DCR) 
• Pharmacokinetics and Pharmacodynamics 
• Anti- ASNase antibodies 
• Adverse events AEs 
• Quality of life (QoL) 
• Biomarkers  
Trial Design/Methodology: 
This is an open-label, multicenter, randomized, Phase 3 study in patients with adenocarcinoma 
of the pancreas who have failed only one prior line of systemic anti-cancer therapy for 
advanced pancreatic cancer and have measurable disease as defined by the modified Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. After provision of informed 
consent and conduct of screening assessments, patients who meet all inclusion and no 
exclusion criteria will be randomized in a 1:1 ratio to one of the following treatment arms (see 
figure below): 
• Arm A (investigational arm): eryaspase in combination with either 
gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-
Fluorouracil-IRInotecan regimen] or Onivyde®/5-fluorouracil/leucovorin), 
• Arm B (control arm): gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI or 
Onivyde/5-fluorouracil/leucovorin). 
 
 
The study will be divided into the following phases: 
• Screening Phase: Screening assessments should occur within 3 weeks of 
randomization for assessment of the patient’s overall eligibility. 
• Randomization Phase: Randomization will occur after the patient has been 
determined to be eligible. 


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• Treatment Phase: The first dose of chemotherapy will be administered within 3 days 
after randomization. Treatment will continue until objective disease progression, 
unacceptable toxicity, or the patient’s withdrawal of consent. Unacceptable toxicity is 
determined at investigator’s discretion, but as a guidance, unacceptable toxicity could 
consist of prolonged Grade 3 or 4 toxicity lasting more than 2 weeks. 
• In the investigational treatment arm (Arm A), eryaspase will be administered on Day 1 
and Day 15 of each 4-week cycle in combination with chemotherapy. Eryaspase will 
be administered by intravenous (IV) infusion over approximately 60 minutes, followed 
by one hour of rest and then followed by chemotherapy infusion. 
• Chemotherapy will be one of the following two treatment regimens: 
− Gemcitabine and Abraxane combination chemotherapy or 
− Irinotecan-based therapy: FOLFIRI (FOLinic acid-Fluorouracil-IRInotecan 
regimen) or Onivyde/5-fluorouracil (5-FU)/leucovorin (LV). 
• The choice of the chemotherapy regimen for a particular patient will be determined by 
the prior treatment received in the first-line setting. Thus: 
− If a patient received prior gemcitabine/Abraxane in the first-line setting, then on 
disease progression, the patient will be assigned to FOLFIRI (or 
Onivyde/5-FU/LV) in the current study. 
− If a patient received prior irinotecan-based therapy (FOLinic acid-Fluorouracil-
IRInotecan-Oxaliplatin; FOLFIRINOX), then on disease progression, the patient 
will be assigned to gemcitabine/Abraxane in the current study. 
• Follow-up Phase: Patients will be monitored for survival at 8-week intervals. Patients 
who discontinue treatment for reasons other than disease progression will continue to 
be assessed radiologically every 8 weeks until disease progression, or until withdrawal 
from the study, or death. 
Randomization will occur through an interactive web response system (IWRS). Patients will 
be randomized in a 1:1 ratio to chemotherapy with or without eryaspase. Randomization will 
be stratified according to the following factors: 
• Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1), 
• Chemotherapy regimen in this study (gemcitabine/Abraxane or irinotecan-based 
treatment [FOLFIRI or its equivalent Onivyde/5-FU/LV]), and 
• Time interval since initial diagnosis of advanced disease to date of randomization in 
the study (<6 months or ≥6 months). 
An Independent Data Monitoring Committee (IDMC) will be established to review safety and 
efficacy data at regular intervals, including the interim and final analyses. 
In addition, the safety of eryaspase in combination with irinotecan-based therapy or 
gemcitabine/Abraxane regimen will be reviewed by the IDMC after at least 10 patients are 
enrolled per regimen and have received at least one cycle of study therapy. The specific 
responsibilities and composition of the IDMC will be outlined in a separate document, the 
IDMC Charter. 


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Safety and Efficacy Evaluations 
Assessments and timing of data collection are detailed in the Schedule of Events (Table 1). 
Safety Evaluations 
Clinical and laboratory parameters and adverse events will be assessed in all patients to 
evaluate disease status and toxicity. Patients will have safety assessments (laboratory tests, 
physical exams, vital signs including temperature, heart rate, and blood pressure, 
electrocardiograms [ECGs; to be performed during screening and then as clinically indicated], 
and performance status score) performed on Day 1 and Day 15 of each cycle and at the end of 
treatment. 
Adverse event reporting will begin at the time of informed consent signature. Adverse events 
and concomitant medications will be collected until 90 days after the last dose of study 
treatment, or until start of a new anti-cancer treatment whichever is sooner. 
Efficacy Evaluations 
Tumor assessments utilizing thoraco-abdominal computed tomography (CT)/magnetic 
resonance imaging (MRI) scans will be repeated every 8 weeks, calculated from the date of 
randomization, until disease progression, or until withdrawal from the study, or death. Every 
effort should be made to adhere to the assessment schedule. The same imaging technique must 
be used throughout the study. For patients who discontinue treatment for reasons other than 
objective disease progression, and patients who start new anti-cancer treatment without 
evidence for objective disease progression, disease status evaluation will continue to be 
repeated every 8 weeks, calculated from the date of randomization, until disease progression. 
All radiological images must be collected in a de-identified manner, quality controlled, stored, 
and available for future review, including independent radiological review as necessary. 
Survival information will be collected by phone, follow-up visit, or medical records review 
every 8 weeks from the date of the EOT visit until the patient’s death, until the patient is lost 
to follow-up, or until study closure. Survival follow-up information will include collection of 
any subsequent anticancer therapy received after discontinuation from study medication. 
Quality of life (QoL) assessment (EORTC QLQ-C30) will be performed, at Day 1 of each 
cycle prior to dosing, at the end of treatment visit and every 8 weeks during survival follow 
up. 
Pharmacokinetics, Pharmacodynamics, and Translational Research 
Where possible, blood and plasma samples will be collected in the eryaspase arm for 
pharmacokinetic (PK) (ASNase activity) and pharmacodynamic determination, and for 
immunogenicity evaluation. 
Blood/plasma samples for PK and pharmacodynamic assessments will be collected at the 
following time points of Cycles 1 and 3 of study treatment: Day 1 prior to eryaspase 
administration, at 5-10 minutes post-eryaspase-infusion, at 5-8 days post-infusion (at the 
Investigator’s discretion), and at Day 15 pre-dose. Samples will be analyzed for whole blood 


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and plasma concentrations of ASNase and amino acids. The sparse PK data will be combined 
with previous data as part of a Population PK (POP PK) analysis. 
Samples for assessment of anti-L-ASNase antibodies and neutralizing antibodies will be 
collected pre-dose at Cycle 1 Day 1 and Day 15, at Day 1 of every second cycle thereafter, 
upon determination of disease progression and at the End of Treatment (EOT) visit, as 
specified in the Schedule of Events (Table 1). 
Exploratory biomarker analyses will examine potential predictive biomarkers correlating with 
eryaspase activity. Tissue samples will be collected at study start. In addition, blood/plasma 
samples for biomarker analysis will be collected from all patients at Cycle 1 Day 1 and 
Day 15, at Day 1 of every second cycle thereafter, upon determination of disease progression, 
and at the EOT visit. 
A blood sample for pharmacogenetic (PGx) analysis will be obtained once during the study, 
preferably during the screening phase, for patients who consent to this optional procedure. 
Number of Patients: The target sample size is 482 patients.  
Criteria for Inclusion: 
A patient will be eligible for the study if all the following criteria are met: 
1. Must be 18 years of age or older. 
2. Must have histologically confirmed pancreatic adenocarcinoma. 
3. Must have Stage III or IV disease (see APPENDIX 1). 
4. Must have received one line of systemic chemotherapy in the advanced setting with or 
without targeted agents, immunotherapy, or radiotherapy for treatment of advanced 
pancreatic adenocarcinoma. NOTE: patients whose disease progresses on, or within 3 
months of neo(adjuvant) chemotherapy may be considered eligible 
5. Must have radiological evidence of disease progression following most recent prior 
treatment, defined as appearance of any new lesion or increase of >20% of one or more 
existing lesions. 
6. Must have measurable lesion(s) per RECIST version 1.1 by CT scan with contrast (or 
MRI, if the patient is allergic to CT contrast media). 
• Measurable disease may be in the field of prior irradiation; however, at least 
4 weeks must have elapsed between the completion of radiation therapy and the 
baseline scan documenting disease status. 
• Bone disease is considered radiologically measurable only if there is at least a 50% 
lytic component. 
NOTE: Bone disease consisting of blastic lesion only is not measurable. 
7. Archival or fresh tumor tissue must be available for evaluating relevant biomarkers. 
Formalin-fixed paraffin-embedded [FFPE] block preferred, or a minimum of 
10 unstained FFPE slides of one archived block is required.  NOTE: if archival tissue 
is unavailable and an elective biopsy can’t be scheduled due to COVID, this will be 
waived. 


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NOTE: Cytology samples from fine needle aspirates or brushing biopsies are not 
sufficient. 
8. Must have adequate performance status (see APPENDIX 2 and APPENDIX 3): 
a. ECOG Performance Status (PS) score of 0, or 
b. ECOG PS score one and score ≥80 on Karnofsky Performance Status (KPS) scale. 
NOTE: Must have body mass index (BMI) ≥18.5 kg/m2 (obtained <14 days prior to 
randomization. 
9. Must have life expectancy of >12 weeks according to the investigator’s clinical 
judgment. 
10. Females of childbearing potential must have a negative pregnancy test at screening and 
additional negative pregnancy test prior to first dose. Males and females of 
childbearing potential must agree to use a highly effective method of contraception 
during treatment and for at least 6 months after the last dose of study treatment. These 
include, but not limited to: 
a. combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
i. intravaginal 
ii. transdermal 
b. progestogen-only hormonal contraception associated with inhibition of ovulation: 
i. injectable 
ii. implantable  
c. intrauterine device (IUD)  
d. bilateral tubal occlusion  
e. vasectomised partner  
f. sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) is intended. The true 
abstinence is when this is in line with the preferred and usual lifestyle of the 
patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception] 
g. males with partners of childbearing potential must agree to use condoms  
NOTE: Since an indirect interaction between components of the oral contraceptives 
and ASNase cannot be ruled out, oral contraceptives are not considered acceptable as 
contraceptive methods in the current clinical trial. A method other than oral 
contraception should be used in women of childbearing potential. 
NOTE: All chemotherapeutic agents may be teratogenic and excreted in breast milk. 
Patients who are breast feeding should consider alternative methods. 
11. Must have adequate laboratory parameters at baseline (obtained <14 days prior to 
randomization). Laboratory parameters outside of these ranges that are deemed 
clinically insignificant should be discussed with the medical monitor: 
a. Absolute neutrophil count ≥1.5 x 109/L. 


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b. Hemoglobin ≥9 g/dL. Patients with a baseline Hemoglobin ≥13 g/dL should be 
discussed with the medical monitor. 
c. Platelet count ≥100,000/mm3 (100 x 109/L). 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases). 
e. Total bilirubin ≤ 1.5 x institutional ULN. 
f. Serum creatinine within normal limits or calculated clearance >60 mL/min/1.73 m2 
for patients with serum creatinine levels above or below the institutional normal 
range.  
g. Acceptable coagulation parameters: plasma antithrombin III >70% and fibrinogen 
≥1.5 g/L. 
h. Serum albumin ≥3.0 g/dL. 
12. Patients requiring biliary stent placement must have the biliary stent placed >7 days 
prior to screening and must have normalization of bilirubin level after stenting. 
13. Must not be receiving therapy in a concurrent clinical study and must agree not to 
participate in any other interventional clinical studies during their participation in this 
trial while on study treatment. Patients taking part in surveys or observational studies 
are eligible to participate in this study. 
14. Must be able to understand and comply with the conditions of the protocol and must 
have read and understood the consent form and provided written informed consent. 
Criteria for Exclusion: 
A patient is not eligible to participate in the study if any of the following criteria are met: 
1. Resectable or borderline resectable pancreatic adenocarcinoma at the time of signing 
the informed consent. 
2. Histology other than pancreatic adenocarcinoma (for example, but not inclusive: 
neuroendocrine, adenosquamous, etc.). 
3. More than one line of prior treatment in advanced or metastatic setting. 
4. Patient has experienced medically significant acute decline in clinical status including 
a. Decline in ECOG PS to >1 (or KPS <70) between baseline visit and within 
72 hours prior to randomization. 
b. Weight loss of ≥10% during screening. 
5. Presence of active or symptomatic untreated central nervous system (CNS) metastases. 
NOTE: Patients with asymptomatic or stable CNS metastases are eligible, provided 
that the CNS metastases are radiologically and clinically stable, and the patient is off 
high-dose steroid treatment for at least one month prior to randomization. 
6. Prior radiotherapy to the only area of measurable disease. 
NOTE: Patients must have completed treatment and recovered from all acute 
treatment-related toxicities prior to administration of the first dose of eryaspase or 
chemotherapy. 
7. Bone as the only site of metastatic disease from pancreatic cancer (bone-only disease). 


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8. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 
3 months of randomization. 
NOTE: The revised Atlanta classification [1] requires that two or more of the 
following criteria be met for the diagnosis of acute pancreatitis: (a) abdominal pain 
suggestive of pancreatitis, (b) serum amylase or lipase level ≥3 x ULN, or (c) 
characteristic imaging findings using CT or MRI. 
9. Neurosensory neuropathy > Grade 2 at baseline. 
10. Pregnancy or breastfeeding. 
11. History of infection with human immunodeficiency virus (HIV) and/or active infection 
with hepatitis B or hepatitis C. 
NOTE: Patients with unknown status of hepatitis B or C must be tested and declared 
negative before randomization. 
12. Hypersensitivity to any of the components of the chemotherapy or ASNase. 
NOTE: Patients known to be homozygous for UGT1A1*28 who are assigned to an 
irinotecan-containing regimen must have the initial irinotecan dose reduced unless they 
have previously tolerated full doses of irinotecan. Subjects whose UGT1A1 status is 
not known but are being considered for irinotecan-based chemotherapy must be 
screened for UGT1A1*28 allele unless they have previously tolerated full doses of 
irinotecan before enrollment into the trial and must have the initial irinotecan dose 
reduced if demonstrated to be homozygous for the UGT1A1*28 allele. 
NOTE: Patients assigned to the irinotecan/5-FU arms in the study should not have 
dihydropyridine dehydrogenase deficiency (DPD). Patients whose DPD status is 
unknown at time of screening should be tested before enrollment in the 
irinotecan/5-FU arm unless they have previously tolerated full doses of 5-FU. 
13. Patients who have received live or live attenuated vaccines within 3 weeks of 
randomization. 
14. History of other malignancies 
NOTE: Adequately treated non-melanoma skin cancer or curatively treated in-situ 
cancer of the cervix may be eligible. 
NOTE: Patients successfully treated for other malignancies and are disease-free for at 
least 5 years may be eligible. 
15. Any other severe acute or chronic condition/treatments that may increase the risk of 
study participation including: 
a. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-
abdominal abscess within 6 months prior to randomization. 
b. Current or history within 6 months prior to randomization of medically significant 
cardiovascular disease including symptomatic congestive heart failure >New York 
Heart Association (NYHA) Class II, unstable angina pectoris, clinically significant 
cardiac arrhythmia. 
c. Patients with pre-existing coagulopathy (e.g. hemophilia). 


ERYTECH Pharma 
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d. Psychiatric illness/social situations or any other serious uncontrolled medical 
disorders in the opinion of the Investigator that would limit compliance with study 
requirements. 
Investigational Product, Dosage and Mode of Administration: 
Eryaspase is a dispersion for infusion of homologous (allogeneic) erythrocytes encapsulating 
recombinant E. coli L--ASNase, in a saline preservative solution. 
The dose of eryaspase is 100 U/Kg administered every two weeks (Day 1 and Day 15) until 
disease progression, unacceptable toxicity, or the patient’s withdrawal of consent. 
Eryaspase will be administered intravenously over approximately 60 minutes, followed by 
one hour of rest and then followed by chemotherapy infusions. 
Standard Chemotherapy dose and mode of administration: 
Gemcitabine plus Abraxane (albumin-bound paclitaxel) administered on Days 1, 8, and 15 
of each 4-week cycle as follows: 
• Abraxane (125 mg/m2) IV over 30-40 minutes followed by 
• Gemcitabine (1000 mg/m2) IV over 30 minutes. 
Onivyde (irinotecan nanoliposomal) + 5-FU/leucovorin administered on Days 1 and 15 of 
each 4-week cycle as follows: 
• Onivyde 70 mg/m2 IV over 90 minutes (recommended starting dose of Onivyde in 
patients homozygous for UGT1A1*28 is 50 mg/m2), 
NOTE: The approved dose of Onivyde is based on the NAPOLI-1[36] trial, in which 
Onivyde was given at a dose of 80 mg/m2 (i.e. equivalent of 70 mg/m2 of irinotecan 
free base). 
• Leucovorin 400 mg/m2 IV over 30 minutes, and 
NOTE: Modifications to the leucovorin dose per sites standard administration protocol 
may be allowed in the study following approval from the medical monitor. 
• 5-FU 2400 mg/m2 over 46 hours. 
FOLFIRI (irinotecan, 5-FU, and leucovorin) administered on Days 1 and 15 of each 4-week 
cycle as follows: 
• Irinotecan 180 mg/m2 IV infusion over 90 minutes (recommended starting dose of 
irinotecan in patients homozygous for UGT1A1*28 is 150 mg/m2), 
• Leucovorin 400 mg/m² IV infusion over two hours, 
NOTE: Modifications to the leucovorin dose per sites standard administration protocol 
may be allowed in the study following approval from the medical monitor. 
• 5-FU 400 mg/m² IV bolus injection over 2-4 minutes, immediately following 
leucovorin infusion, and 
• 5-FU 2400 mg/m² IV continuous infusion over 46 hours immediately following bolus 
5-FU (Days 1 and 2, and Days 15 and 16). 


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Rationale for Sample Size Estimation: 
With a power of 88.4% and an overall one-sided type I error of 2.5%, and including one 
interim analysis for efficacy with an O’Brien-Fleming-type stopping rule, a total of 390 deaths 
are required to detect a treatment effect hazard ratio of 0.725 for eryaspase plus chemotherapy 
versus chemotherapy alone. The interim analysis for efficacy will take place once 261 (67%) 
events have been observed.  
Assuming a recruitment period of 26 months, a median overall survival in the control group of 
6.0 months, a 10% probability of dropping out during the course of the study, and a minimum 
follow-up of 9 months, the study size will be based on the recruitment of 482 patients. 
 
Analysis Populations: 
Intent to Treat (ITT) population: All patients randomized, irrespective of whether they 
receive study medication. 
Safety population (SP): All randomized patients who receive at least one dose of study 
medication (eryaspase or chemotherapy). 
Per-Protocol (PP) population: The PP population is a subset of the ITT population, and 
consists of all randomized patients who meet the major inclusion criteria and none of the 
major exclusion criteria and who receive at least one cycle of treatment. 
Interim and Final Analyses: 
This study will have one interim analysis for superiority after 67% of the initial targeted 
numbers of events are observed.  
Primary Analysis: 
The primary analysis will be the comparison of OS between the two treatment arms in the ITT 
population using the one-sided stratified log-rank test, stratified for ECOG status, 
chemotherapy regimen, and time from diagnosis of advanced disease. 
Key Secondary Analyses: 
Progression-free survival (PFS) will be compared between the two treatment arms using the 
same method of analysis as for OS. 
The following efficacy analyses will also be performed in the ITT population: 
• ORR, defined as the proportion of patients who achieve objective tumor response 
(complete response [CR] or partial response [PR]) per RECIST 1.1. Each patient’s best 
overall response (BOR) will be summarized (CR, PR, stable disease [SD], progressive 
disease [PD], or unknown). 
• DCR (disease control rate), defined as the proportion of patients who achieve CR, PR 
and SD. 


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• DoR will be evaluated in patients who achieve CR/PR. It will be measured from the 
time CR/PR (whichever is first recorded) is first met to until the first date that 
recurrence or PD is objectively documented. 
Extensive evaluation of the consistency of treatment effect for OS and PFS across the 
population as a whole will be undertaken by providing analyses in subgroups, with displays in 
forest plots and p-values for interaction. 
All efficacy analyses will be repeated in the PP population. 
Confirmatory testing for the primary and secondary efficacy endpoints will be performed 
hierarchically (OS followed by PFS followed by DCR followed by ORR) in order to account 
for multiplicity. Any statistically significant findings occurring below a non-significant result 
in the hierarchy will be considered as exploratory findings. 
Safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy 
alone will be assessed by analyzing AEs (incidence, intensity, seriousness, and causal 
relationship of AEs to the study drug, action taken following AE), drug exposure (duration of 
treatment), dosing information/compliance, concomitant medications, clinical laboratory 
results, ECG findings, vital signs, physical examination, body weight, ECOG PS, and 
treatment and study termination status data. 
 


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SCHEDULE OF EVENTS 
Table 1 
Schedule of Events 
Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
(+3 
days)1  
 
 
D8 
 
 
 
 
D15 
(+ 3 
days)1  
 
 
 
D21 
 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
X 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Pancreatic cancer disease history (including 
previous anti-cancer therapies) 
X 
 
 
 
 
 
 
 
 
Physical exam (including height [screening 
only] and weight)  
X 
 
X 
 
X 
 
X 
X 
 
Vital signs (temperature, BP, and heart rate) 
X 
 
X 
 
X 
 
X 
X 
 
Performance status2 
X 
 
X 
 
X 
 
X 
X 
 
12-Lead ECG3 
X 
 
X 
 
 
Radiological assessments (CT or MRI)4 
X 
 
X (every 8 weeks [±3 days] from time of randomization until disease 
progression, or death) 
Randomization5 
 
X 
 
 
 
 
 
 
 
QoL assessment (EORTC QLQ-C30) 
 
 
X 
 
 
 
 
X 
X6 
AEs/SAEs 
X (collected from time of informed consent until 90 days after the last study treatment or start of new anti-
cancer treatment, whichever is sooner) 


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Table 1 
Schedule of Events 
Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
(+3 
days)1  
 
 
D8 
 
 
 
 
D15 
(+ 3 
days)1  
 
 
 
D21 
 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Concomitant medications 
X (record all medications taken 14 days prior to randomization to 90 days after the last study treatment or 
start of new anti-cancer treatment, whichever is sooner) 
Study Drug 
Blood phenotype7 
X7 
 
 
 
 
 
 
 
 
Prescription with current weight 
 
 
X8 
 
X8 
 
 
 
 
Irregular antibody screening test (IAST) 
X7 
 
X9 
 
X9 
 
 
 
 
IAST historical result if available 
X 
 
 
 
 
 
 
 
 
Pre-eryaspase dose complete compatibility 
test 
 
 
X10 
 
X10 
 
 
 
 
Eryaspase administration 
 
 
X 
 
X 
 
 
 
 
Chemotherapy 
 
 
Per standard of care 
 
 
Gemcitabine/abraxane 
 
 
X 
X 
X 
 
 
 
 
Irinotecan-based regimen 
 
 
X 
 
X 
 
 
 
 
Biological Exams 
Hematology, biochemistry, and coagulation 
panels; CA19-911 
X11,12 
 
X 
X17 
X 
X17 
X 
X 
 
Pregnancy test, for patients of childbearing 
potential13 
X 
 
X 
 
 
 
 
X 
 
Tumor tissue (for biomarker analysis, 
mandatory) 
X 
 
 
 
 
 
 
 
 


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Table 1 
Schedule of Events 
Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
(+3 
days)1  
 
 
D8 
 
 
 
 
D15 
(+ 3 
days)1  
 
 
 
D21 
 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Pharmacogenetic (PGx) sample (optional) 
X (once during the study, preferably during the screening phase) 
 
 
Plasma biomarkers such as ctDNA, 
proteomics, and transcriptomics (central labs)  
 
 
X18 
 
X14 
 
 
X 
 
Pharmacokinetic (ASNase activity) and 
pharmacodynamic (amino acid) sample 
(eryaspase arm only) 
 
 
X15 
 
X15 
 
 
 
 
Immunogenicity sample for anti-ASNase 
antibodies and neutralizing antibodies 
(eryaspase arm only) 
 
 
X18 
 
X14 
 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
X16 
Subsequent anti-cancer treatments 
 
 
 
 
 
 
 
 
X 
Abbreviations: D=Day; Rand=Randomization; BP=blood pressure; ECG=electrocardiogram; CT=computed tomography; MRI=magnetic resonance imaging; 
QoL=quality of life; EORTC QLQ-C30= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; AE=adverse 
event; SAE=serious adverse event; IAST=irregular antibody screening test; CA19-9=cancer antigen 19-9; ctDNA=circulating tumor deoxyribonucleic acid; 
ASNase=asparaginase. 
1. There must be a minimum of 10 days between 2 eryaspase injections. 
2. Per Eastern Cooperative Oncology Group (ECOG) /Karnofsky scales (KPS (if required per ECOG score) only during screening and at Cycle 1 Day 1) 
(See APPENDIX 2 and APPENDIX 3). 
3. Performed during screening, and then as clinically indicated. 
4. Radiological assessment to be completed within 3 weeks of randomization and then every 8 weeks (±3 days) from time of randomization until disease 
progression, start of subsequent anti-cancer therapy  or until withdrawal from the study, or death, using the same method throughout. Tumor 
assessments will continue in patients, who start new cancer treatment without evidence of disease progression Every effort should be made to adhere to 


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the evaluation schedule, irrespective of any treatment delays or modifications. Bone and/or brain scans are to be repeated every 12 weeks if clinically 
indicated. 
5. Randomization performed via interactive web response system (IWRS) within 3 days of 1st chemotherapy dose. 
6. During follow-up, questionnaire is to be completed every 8 weeks. 
7. A complete RBC phenotype (including D, C, E, c, e,  K and other antigens tested as per site practice), ABO blood group status, and Rhesus factor, all 
assessed on two separate samples (can be collected on the same day), to be done as soon as possible but preferably at least 5 working days before the 
first eryaspase infusion. Exact instructions are provided in the Investigational Medicinal Product (IMP) Manual.  Historical results of IAST can be used 
at screening if known and available. 
8. Prescription form indicating the patient’s identifiers as well as his/her most recently collected weight, the Investigator recipient of the product, and the 
place and time of the delivery must be sent as soon as possible once the eryaspase infusion is scheduled, and at the latest 5 working days prior to Cycle 1 
Day 1 and then 5 working days prior to each subsequent eryaspase infusion. Exact instructions are provided in the IMP Manual. 
9. IAST must be completed within 72 hours prior to each eryaspase administration. The results (of the previous infusion) will be provided to the Sponsor 
along with the prescription form prior to subsequent eryaspase infusion. 
10. In case of incompatibility, collection of an additional blood sample will be required for further investigation. 
11. Laboratory tests to be performed at local laboratory as follows: 
Hematology: Complete blood count with differential (hemoglobin, hematocrit, RBC count, white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and platelet count). 
Biochemistry: Sodium, potassium, bicarbonate, calcium, chloride, creatinine, albumin, ammonia, total bilirubin, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase, glucose, urea, triglycerides, total cholesterol, amylase, 
lipase and uric acid; Coagulation parameters – fibrinogen, antithrombin III. 
Tumor marker: CA19-9 
12. Baseline labs to be collected within 14 days of randomization. 
13. For patients of childbearing potential, serum pregnancy test to be performed during screening period and at End of Treatment and urine pregnancy test 
to be performed prior to dosing of any chemotherapy agent Day 1 of each cycle. Additional pregnancy testing should be performed in case of delayed 
menstrual period and is recommended to be performed monthly and until the end of treatment exposure extended by 30 days, in case of sexual activity. 
14. Pre-dose Day 15 sample to be collected only during Cycle 1. 
15. Where possible, samples to be collected Cycles 1 and 3 of study treatment on Day 1 prior to eryaspase administration, 5-10 minutes post-eryaspase 
infusion, 5 to 8 days post-infusion, and on Day 15 pre-dose. 
16. Survival follow to be conducted 8 weeks after the patient’s End of Treatment visit by phone, visit, or medical records review every 8 weeks (±3 days) 
from the date of the EOT visit (or date of last dose of study medication if patient is unable to come in due to declining health) until patient’s death, lost 
to follow up, or study closure. Subsequent therapy should be collected during this follow-up.  
17. For patients under eryaspase arm, in addition to regular evaluation of liver function tests before treatment administration, patients will be monitored on 
weekly basis in the event of occurrence of ≥Grade 2 elevation of liver enzymes and bilirubin levels. 
18. Performed pre-dose Cycle 1 Day 1 and then pre-dose Day 1 of every second cycle thereafter i.e., Cycle 3 Day 1, Cycle 5 Day 1, upon determination of 
disease progression, or EOT, whichever is sooner.as clinically indicated. 
** 
Additional lab tests may be required (e.g., weekly monitoring per standard practice or label requirements should be followed) and should be reported in 
the electronic Case Report Form (eCRF) if clinically significant. 


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ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ANSM 
Agence nationale de sécurité du médicament et des 
produits de santé 
ASCO 
American Society for Cooperative Oncology 
ASN 
Asparagine 
ASNase 
Asparaginase 
ASNS 
Asparagine synthetase 
ASNS 0/1+ 
Subgroup of patients with patients with low or no 
ASNS expression 
ASNS 2+/3+ 
Subgroup of patients with high ASNS expression 
AST 
Aspartate aminotransferase 
AT III 
Antithrombin III 
BP 
Blood pressure 
BMI 
Body Mass Index 
BOR 
Best overall response 
CA19-9 
Cancer antigen 19-9 
CD 
Compact disc 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
Complete response 
CSR 
Clinical Study Report 
DNA 
Deoxyribonucleic acid 
ctDNA 
Circulating tumor DNA 
DCR 
Disease control rate 


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Abbreviation or Specialist Term 
Explanation 
DCR8 
Disease control rates when stable disease is required to 
last for at least 8 weeks 
DCR12 
Disease control rates when stable disease is required to 
last for at least 12 weeks 
DCR16 
Disease control rates when stable disease is required to 
last for at least 16 weeks 
DoR 
Duration of response 
DPD 
Dihydropyrimidine dehydrogenase deficiency 
ECG 
Electrocardiogram 
ECOG 
European Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EORTC QLQ-C30 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded FFPE 
FOLFIRI 
FOLinic acid-Fluorouracil-IRInotecan regimen 
FOLFIRINOX 
FOLinic acid-Fluorouracil-IRInotecan-Oxaliplatin 
regimen 
mFOLFOX6 
Modified FOLinic acid-Fluorouracil-Oxaliplatin-6 
regimen 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
GGT 
Gamma-glutamyl transferase 
HCL 
Hydrochloride 
HHS 
Health and Human Services 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IAST 
Irregular antibody screening test 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ID 
Identification 
IDMC 
Independent Data Monitoring Committee 


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Abbreviation or Specialist Term 
Explanation 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
Kg 
Kilogram 
KPS 
Karnofsky Performance Status 
KRAS 
Kirsten rat sarcoma viral oncogene 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LV 
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ND 
No disease 
NE 
Non-evaluable 
NYHA 
New York Heart Association (classification) 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PAC 
Pancreatic adenocarcinoma 
PFS 
Progression-free survival 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetic 
POP PK 
Population pharmacokinetic 
PP 
Per Protocol 
PR 
Partial response 


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Abbreviation or Specialist Term 
Explanation 
PS 
Performance status 
PVC 
Polyvinyl chloride 
QA 
Quality assurance 
QC 
Quality control 
QoL 
Quality of life 
RBCs 
Red blood cells (erythrocytes) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SA 
Short axis 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SNP 
Single-nucleotide polymorphism 
SOE 
Schedule of Events 
SP 
Safety population 
SUSAR 
Suspected unexpected serious adverse reaction 
TRALI 
Transfusion-related acute lung injury 
TRYbeCA 
TRial of erYaspase in pancreatic CAncer 
U 
Units 
UGT 
Uridine 5'-diphosphate glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
5-FU 
5-fluorouracil 
 


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1 
INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 
Pancreatic Cancer 
Pancreatic adenocarcinoma (PAC) is one of the most aggressive and fatal malignancies, and is 
ranked as the seventh leading cause of cancer death.[2] The overall prognosis for PAC is poor, 
with a 5-year survival rate of 7%.[3] This is attributable to the difficulty of diagnosing pancreatic 
cancer in the early stages, poor tumor resectability, and poor response to chemotherapy.[4] 
Indeed, most patients with pancreatic cancer progress to either metastatic or locally advanced 
disease in the asymptomatic phase.[5] 
Current treatment strategies for non-resectable, metastatic disease focus on conventional 
cytotoxic therapies. Established first-line treatment options include gemcitabine-based 
chemotherapy, either alone or in combination with nab-paclitaxel, or the FOLFIRINOX regimen 
(a combination of leucovorin [LV], 5-fluorouracil [5-FU], irinotecan, and oxaliplatin).[5] 
Gemcitabine treatment results in only modest improvements in overall survival (OS) and quality 
of life (QoL).[6] While the FOLFIRINOX regimen has demonstrated a robust clinical benefit 
compared with gemcitabine,[7] this regimen should only be considered for patients with good 
performance status (Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 or 
1) due to considerable toxicity.[5 8] 
In the second-line setting, there remains a lack of consensus regarding the standard of care. 
Treatment options are dependent on the risk-benefit balance for the patient and the treatment 
received in the first line.[5] In 2017, treatment guidelines were updated to recommend that the 
combination of nanoliposomal irinotecan (Onivyde®) with fluoropyrimidine regimens (i.e., 
5-FU with LV) can be considered an active and tolerable treatment option in fit patients (ECOG 
PS ≥2) previously treated with gemcitabine-based therapy.[8 9] This combination extended 
survival by 1.9 months compared with patients treated with 5-FU in combination with LV.[10] 
No formal recommendations are available for patients who have progressed on first-line 
FOLFIRINOX; although gemcitabine is widely used in this setting, disease control is only 
achieved in one in 5 patients.[11] The limited efficacy provided by cytotoxic therapies is driving 
the need to identify novel targets for which to develop more effective therapeutic strategies.[4] 
1.1.2 
Tumor Cell Metabolism 
Targeting tumor cell metabolism is one of the prospective therapeutic approaches.[12] PAC is 
characterized by extensive reprogramming of cellular metabolism, which enables tumor cells to 
proliferate in a nutrient-poor, hypoxic microenvironment. The acquisition of activating mutations 
in the oncogenic KRAS (Kirsten rat sarcoma virus) gene, which are observed in more than 90% 
of PACs, is central to this process.[13] Mutations in KRAS mediate the reprogramming of 
metabolic pathways that allow continued cellular proliferation in the absence of nutrients 
required by normal cells.[14 15] However, such reprogramming leads to dependence on 
metabolites that are utilized through non-canonical metabolic pathways, distinguishing these 
cells from normal cells. One such dependency is on the amino acid glutamine, which fuels 
anabolic metabolism and maintains redox balance with PAC cells.[16 17] Glutamine deprivation 


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or inhibition of enzymes downstream of KRAS in this aberrant metabolic pathway results in 
suppression of PAC growth.[16] 
KRAS also regulates expression of amino acid transporters, which provide most of the biomass 
for growing cells.[18] This is despite the increased levels of glucose and glutamine consumption, 
which indicates that KRAS-mediated regulation of amino acid transporters is vital for tumor 
growth. In pancreatic cancer, KRAS has been shown to regulate macropinocytosis of proteins, 
yielding amino acids including glutamine and asparagine that may then enter the tricarboxylic 
acid cycle.[19] 
Although glutamine is important for many cellular processes, including anaplerosis and 
lipid/nucleotide synthesis through its catabolism to glutamate, asparagine is the only amino acid 
that requires glutamine for de novo synthesis. A non-essential amino acid, asparagine is 
synthesized from glutamine and aspartic acid by the enzyme asparagine synthetase (ASNS).[20] 
Enhanced ASNS expression is a mechanism through which PAC cells adapt to hypoxia and 
glucose deprivation.[21] ASNS protects PAC cells from apoptosis induced by glucose 
deprivation through suppression of JNK/SAPK activation.[21] 
Furthermore, it has also been demonstrated that KRAS, through ATF4 regulation, adapts amino 
acid uptake and asparagine biosynthesis.[22] As KRAS activation increases dependency on 
glutamine, knock-down of KRAS in low glutamine conditions results in poor clinical 
outcome.[22] Expression of ASNS – a target of ATF4 – has been identified as a key regulator of 
cancer cell proliferation, and contributes to apoptotic suppression, protein biosynthesis, and 
mTOR pathway activation.[22] Together, the modulation of glutamine and of asparagine levels 
leads to a critical vulnerability of PAC cells, which may be exploited in cancer therapeutics. 
1.1.3 
Asparaginase 
Asparaginase is a key component of multi-agent chemotherapy used in the treatment of 
childhood acute lymphoblastic leukemia (ALL). In ALL, as leukemic cells lack ASNS, ASNase 
exerts its anti-tumor effect through depletion of serum asparagine by catalyzing the deamination 
of asparagine to aspartic acid.[20] This starves susceptible cells of asparagine required for 
protein synthesis, which results in cell cycle arrest and, ultimately, apoptosis.[20 23] As 
glutamine also acts as a substrate for the enzyme,[24] ASNase treatment also depletes serum 
glutamine levels, contributing further to cell growth inhibition.[20] 
Several in vitro studies have demonstrated that reductions in both asparagine and glutamine 
levels are associated with inhibition of the mTOR pathway, which results in suppression of 
ribosomal protein synthesis.[25] Early experiments utilizing pancreatic cell lines demonstrated 
that inhibition of protein synthesis by ASNase could be reversed by supplementation with 
glutamine but not asparagine.[26] More recently, in cell lines expressing high levels of ASNS, 
glutamine was demonstrated to maintain the viability of cells in asparagine-deprived 
medium.[27] This suggests that glutaminase activity is an important component of the anti-tumor 
effect of ASNase, especially against tumors with high ASNS expression.[27] 
Despite this in vitro sensitivity, clinical studies in solid tumors have been limited due to the 
challenge of a narrow therapeutic index for ASNase. Excessive toxicity of native and pegylated 
ASNase (peg-ASNase) formulations has been observed in clinical studies of solid tumors 
(pancreatic, ovarian) and multiple myeloma.[28-30] Indeed, a recent phase 1 study evaluating 


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peg-ASNase in combination with gemcitabine in patients with metastatic solid tumors and 
lymphoma was terminated early due to toxicity.[31] 
1.2 
CLINICAL EXPERIENCE WITH ERYASPASE 
Encapsulation of ASNase within RBCs through a proprietary process is a novel approach to the 
delivery of ASNase at biologically effective doses with reduced propensity for toxic effects. The 
encapsulated ASNase remains biologically active, with a half-life of approximately two 
weeks.[32] It has been demonstrated that encapsulation has no effect on the permeability of 
RBCs to asparagine.[33] Thus, asparagine is actively transported across a concentration gradient 
into the RBC where it is de-aminated into aspartic acid and ammonia, depleting the serum of 
asparagine. It is postulated that the same process occurs with glutamine. 
Encapsulation prevents the rapid degradation of ASNase in the blood, thus prolonging activity, 
and limits exposure to the immune system, thus impeding its intrinsic immunogenicity, and in 
particular hypersensitivity reactions.[32] 
To date, five clinical trials have been conducted with eryaspase in pediatric and adult patients 
with ALL and acute myeloid leukemia (AML), and two clinical trials have been conducted in 
pancreatic cancer. The total number of patients treated thus far in the eryaspase clinical trial 
program is 307, as of a cut-off date of 28 Feb 2017. In the two studies in PAC, the total number 
of patients treated is 104. 
1.3 
ERYASPASE IN THE TREATMENT OF PANCREATIC CANCER 
The potential of eryaspase in advanced PAC is being evaluated. GRASPANC 2008-02, a Phase 1 
dose-escalation study, investigated eryaspase as a single agent in patients with metastatic PAC 
with at least two prior lines of therapy. Twelve patients received a single administration of 
eryaspase as monotherapy (25, 50, 100, or 150 U/Kg). No dose-limiting toxicity was reported. 
The recommended Phase two dose was determined to be 100 U/Kg every two weeks.[34] [35] 
GRASPANC 2013-03, a phase 2 trial in advanced PAC, was completed in 2017. This was a 
multicenter, open-label study investigating eryaspase in combination with gemcitabine or 
mFOLFOX6 (modified FOLinic acid-Fluorouracil-Oxaliplatin-6 regimen) as second-line 
treatment in patients with metastatic PAC. Patients were randomized in a 2:1 ratio to either 
eryaspase plus chemotherapy or chemotherapy alone, and were stratified according to 
chemotherapy regimen. The co-primary endpoints were progression-free survival (PFS) and 
overall survival (OS) in patients with low or no ASNS expression (ASNS 0/1+). Secondary 
endpoints included PFS and OS in the Intent to Treat (ITT) and high-ASNS expression 
(ASNS 2+/3+) populations, objective response, and toxicity. It should be noted that the study 
was not powered for the co-primary endpoints of PFS and OS. The conclusions regarding the 
efficacy of eryaspase when used in combination with gemcitabine or mFOLFOX6 chemotherapy 
in relation to these endpoints was to be based on observed hazard ratio (HR), with the study 
being considered positive if the HR for OS or for PFS was <0.85. 
A total of 141 patients were randomized, 95 to eryaspase plus chemotherapy and 46 to 
chemotherapy alone. The majority of patients (~90%) received gemcitabine during the study. 
Baseline demographics and disease characteristics were generally well-balanced between 


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treatment arms. Median age (range) was 63 years (37–84) in the eryaspase arm compared with 
63 years (43–80) with chemotherapy alone. 
Both co-primary endpoints were met in the ASNS 0/1+ subgroup (eryaspase, n = 66; control, 
n = 32), with HRs of 0.67 for PFS and 0.63 for OS, Table 2. 
Table 2 
Key Efficacy Outcomes in the ITT Population and ASNS Subpopulations 
in GRASPANC 2013-03 
 
Overall Survival (OS) 
 
ITT 
ASNS 0/1+ 
ASNS 2+/3+ 
 
Eryaspase 
+ Chemo-
therapy 
(95) 
Chemo-
therapy 
Alone 
(46) 
Eryaspase 
+ Chemo-
therapy 
(66) 
Chemo-
therapy 
Alone 
(32) 
Eryaspase + 
Chemo-
therapy 
(29) 
Chemo-
therapy 
Alone 
(14) 
Event rate, N (%)  
82 (86.3) 
42 (91.3) 
55 (83.3) 
28 (87.5) 
27 (93.1) 
14 (100.0) 
OS (weeks), 
Median (95% CI)  
26.1 
(21.0, 28.9) 
19.0 
(13.0, 21.7) 
27.0 
(22.3, 31.1) 
21.3 
(13.0, 31.0) 
21.0 
(14.9, 29.4) 
11.9 
(6.9, 19.7) 
HR (95% CI) 
0.60 (0.41, 0.87) 
0.63 (0.39, 1.01) 
0.52 (0.26, 1.04) 
Log-Rank p-value 
0.008 
0.056 
0.063 
OS rate at 
24 weeks 
56.2% 
35.8% 
59.8% 
46.0% 
48.1% 
14.3% 
 
 
Progression-Free Survival (PFS) 
 
ITT 
ASNS 0/1+ 
ASNS 2+/3+ 
 
Eryaspase 
+ Chemo-
therapy 
(95) 
Chemo-
therapy 
Alone 
(46) 
Eryaspase 
+ Chemo-
therapy 
(66) 
Chemo-
therapy 
Alone 
(32) 
Eryaspase + 
Chemo-
therapy 
(29) 
Chemo-
therapy 
Alone 
(14) 
Event rate, N (%)  
70 (73.7) 
36 (78.3) 
50 (75.8) 
23 (71.9) 
20 (69.0) 
13 (92.9) 
PFS (weeks), 
Median (95% CI) 
8.6 
(7.6, 14.6) 
6.9 
(6.0, 7.6) 
8.6 
(7.6, 14.6) 
7.6 
(6.1, 16.3) 
8.0 
(7.0, 14.9) 
6.0 
(4.4, 6.9) 
HR (95% CI) 
0.56 (0.37, 0.84) 
0.67 (0.40, 1.12) 
0.38 (0.18, 0.83) 
p-value 
0.005 
0.127 
0.015 
PFS rate at 
24 weeks 
18.7% 
5.8% 
20.4% 
9.0% 
14.3 
0% 
 
 
Objective Response Rate (ORR) 
 
ITT 
ASNS 0/1+ 
ASNS 2+/3+ 
 
Eryaspase 
+ Chemo-
therapy 
(95) 
Chemo-
therapy 
Alone 
(46) 
Eryaspase 
+ Chemo-
therapy 
(66) 
Chemo-
therapy 
Alone 
(32) 
Eryaspase + 
Chemo-
therapy 
(29) 
Chemo-
therapy 
Alone 
(14) 
Response rate, % 
(95% CI) 
12 (12.6) 
(6.7, 21.0) 
3 (6.5) 
(1.4, 17.9) 
10 (15.2) 
(7.5, 26.1) 
3 (9.4) 
(2.0, 25.0) 
2 (6.9) 
(0.8, 22.8) 
0 
(0.0, 23.2) 


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Table 2 
Key Efficacy Outcomes in the ITT Population and ASNS Subpopulations 
in GRASPANC 2013-03 
SD 
34 (35.8) 
8 (17.4) 
21 (31.8) 
7 (21.9) 
13 (44.8) 
1 (7.1) 
PD 
42 (44.2) 
31 (67.4) 
32 (48.5) 
18 (56.3) 
10 (34.5) 
13 (92.9) 
NE 
7 (7.4) 
4 (8.7) 
3 (4.5) 
4 (12.5) 
4 (13.8) 
0 
 
 
Disease Control Rate (DCR) 
 
ITT 
ASNS 0/1+ 
ASNS 2+/3+ 
 
Eryaspase 
+ Chemo-
therapy 
(95) 
Chemo-
therapy 
Alone 
(46) 
Eryaspase 
+ Chemo-
therapy 
(66) 
Chemo-
therapy 
Alone 
(32) 
Eryaspase + 
Chemo-
therapy 
(29) 
Chemo-
therapy 
Alone 
(14) 
DCR 
(CR+PR+SD), % 
(95% CI) 
46 (48.4) 
(38.0, 58.9) 
11 (23.9) 
(12.6, 38.8) 
31 (47.0) 
(34.6, 59.7) 
10 (31.3) 
(16.1, 50.0) 
15 (51.7) 
(32.5, 70.6) 
1 (7.1) 
(0.2, 33.9) 
OS: overall survival; ITT: Intent to Treat; ASNS: asparagine synthetase; CI: confidence interval; HR: hazard 
ratio; PFS: progression-free survival; ORR: objective tumor response rate; SD: stable disease; PD: progressive 
disease; NE: Non-evaluable (no follow-up scans [4 consent withdrawal; 4 randomized but not treated; 1 fatal 
event; 1 target lesions unassessed; 1 treated but discontinued treatment before follow-up scans]; NE was similar 
between Investigator and independent review); DCR: disease control rate; CR: complete response; PR: partial 
response. 
Response was determined per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria, based on 
independent radiological review. 
In the ITT population, OS was statistically significantly longer in the eryaspase arm compared to 
the chemotherapy arm alone. Median OS improved from 19.0 weeks in the control arm to 
26.1 weeks in the eryaspase arm, with an HR of 0.60 (95% CI: 0.41, 0.87; stratified log rank 
p = 0.008), Table 2 and Figure 1. 


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Figure 1 
GRASPANC 2013-03: OS Kaplan-Meier Curves – Full ITT Population 
The objective response rate was also higher in the eryaspase arm (12.6%) compared to the 
control arm (6.5%), as assessed by independent radiological review. Notably, there was one 
patient who achieved complete response in the eryaspase arm, Figure 2 and Figure 3. Similarly, 
the disease control rate (DCR) was also higher in the eryaspase arm (48.4% compared with 
23.9% in the control arm). 


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Figure 2 
GRASPANC 2013-03: Best Response – Waterfall Plot (Percent Change from 
Baseline) (Eryaspase + Chemotherapy) 
 
Figure 3 
GRASPANC 2013 03: Best Response – Waterfall Plot (Percent Change from 
Baseline) (Chemotherapy Alone) 


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Adverse events (AEs, Table 3) and serious adverse events (SAEs, Table 4) were slightly more 
frequent in the eryaspase arm; however, AEs resulting in treatment discontinuation and fatal 
outcomes were less frequent in the eryaspase arm. The safety profile of eryaspase added to 
chemotherapy revealed no unexpected findings, and eryaspase did not appear to add to the 
toxicity of chemotherapy. 
Table 3 
Incidence of Treatment-Related Treatment-Emergent Adverse Events 
Reported in at Least 10% of Patients by MedDRA Preferred Term - Safety 
Population 
Preferred Term 
Eryaspase +Chemotherapy 
(N = 93) 
Chemotherapy Alone 
(N = 44) 
Patients with at least one 
Adverse Event, n (%) 
86 (92.5) 
42 (95.5) 
Asthenia 
44 (47.3) 
24 (54.5) 
Nausea 
40 (43.0) 
20 (45.5) 
Thrombocytopenia 
40 (43.0) 
16 (36.4) 
Anemia 
30 (32.3) 
16 (36.4) 
Vomiting 
30 (32.3) 
10 (22.7) 
Diarrhea 
20 (21.5) 
11 (25.0) 
Neutropenia  
23 (24.7) 
7 (15.9) 
Decreased appetite 
11 (11.8) 
13 (29.5) 
Pyrexia 
15 (16.1) 
9 (20.5) 
Fatigue  
10 (10.8) 
5 (11.4) 
Stomatitis  
12 (12.9) 
3 (6.8) 
Positive IAST 
14 (15.1) 
0 
MedDRA: Medical Dictionary for Regulatory Activities; IAST: Irregular antibody screening test. 
The Safety population includes all randomized patients who received at least 1 dose of study drug. 
 
Table 4 
Treatment-Emergent Serious Adverse Events Reported in at Least 5% of 
Patients by MedDRA Preferred Term – Safety Population 
Preferred Term 
Eryaspase + Chemotherapy 
(N = 93) 
Chemotherapy Alone 
(N = 44) 
Patients with at least one SAE, 
n (%) 
42 (45.2) 
22 (50.0) 
General physical health 
deterioration 
7 (7.5) 
4 (9.1) 
Abdominal pain 
4 (4.3) 
1 (2.3) 
Gastrointestinal hemorrhage 
2 (1.1) 
3 (6.8) 


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Jaundice 
3 (3.2) 
1 (2.3) 
MedDRA: Medical Dictionary for Regulatory Activities: SAE: Serious adverse event.  
The Safety population includes all randomized patients who received at least one dose of study drug. 
1.4 
STUDY RATIONALE 
PAC is characterized by aberrant metabolic pathways, such as constitutive activation of KRAS 
signaling, that utilize asparagine and glutamine to circumvent the hypoxic and nutrient-poor 
tumor microenvironment. Perturbation of these pathways through deprivation of glutamine and 
asparagine results in loss of cell viability. 
The potential benefit of ASNase therapy in PAC has been explored previously; however, these 
studies were stopped early due to the excessive toxicity of the ASNase.[28] 
In the Phase 2 GRASPANC 2013-03 study, eryaspase demonstrated clinical benefits in terms of 
OS, PFS, and objective response rate (ORR) in the second-line treatment of metastatic PAC. The 
study met its primary endpoints, and the benefits of eryaspase (in terms of OS and PFS) reached 
statistical significance in the ITT population. 
Given the results of this Phase 2, proof-of-concept study, eryaspase has the potential to add to the 
limited treatment options available for second-line PAC. 
1.5 
RISK/BENEFIT ASSESSMENT 
1.5.1 
Known Potential Risks 
Eryaspase is a combination of two recognized products, RBCs and ASNase, whose safety 
profiles are well documented. Thus, the potential toxicity of eryaspase may arise from 3 main 
mechanisms: ASNase, RBCs, or a combination of the two components. 
Please refer to the investigator’s Brochure (IB) for additional details. 
To date, there have been 8 clinical studies which have evaluated eryaspase in 307 patients. 
Specifically, two studies have been conducted in PAC, with eryaspase administered to 
104 patients. Table 5 shows the adverse events reported in >10% of patients in the combined 
eryaspase-treated populations (ALL, AML, PAC), regardless of severity or attribution to 
treatment. 
In the Phase 2 GRASPANC 2013-03 study, the safety profile of eryaspase added to 
chemotherapy revealed no unexpected findings, and eryaspase did not appear to add to the 
toxicity of chemotherapy. 
Table 5 
Overview of AEs Affecting >10% of Patients in the Pooled Safety 
Population 
Preferred Term 
All Patients 
N = 307 
Patients with at least one AE, n (%)  
303 (98.7) 
Thrombocytopenia 
168 (54.7) 


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Table 5 
Overview of AEs Affecting >10% of Patients in the Pooled Safety 
Population 
Preferred Term 
All Patients 
N = 307 
Anemia 
131 (42.7) 
Neutropenia 
119 (38.8) 
Asthenia 
116 (37.8) 
Leukopenia 
100 (32.6) 
Pyrexia 
92 (30.0) 
Stomatitis 
90 (29.3) 
Nausea 
89 (29.0) 
Transaminases increased 
84 (27.4) 
Lymphopenia 
72 (23.5) 
Diarrhea 
71 (23.1) 
Hypokalemia 
68 (22.1) 
Febrile bone marrow aplasia 
67 (21.8) 
Abdominal pain 
66 (21.5) 
Vomiting 
63 (20.5) 
Antithrombin III decreased 
62 (20.2) 
Gamma-glutamyl transferase (GGT) increased 
62 (20.2) 
Hypoalbuminemia 
62 (20.2) 
Musculoskeletal pain 
61 (19.9) 
Hyperbilirubinemia 
54 (17.6) 
Hyperglycemia 
52 (16.9) 
Constipation 
48 (15.6) 
Lipase increased 
45 (14.7) 
Hyponatremia 
41 (13.4) 
Decreased appetite 
40 (13.0) 
Drug hypersensitivity 
39 (12.7) 
Edema 
35 (11.4) 
General physical health deterioration 
34 (11.1) 
Febrile neutropenia 
32 (10.4) 
Headache 
30 (9.8) 
Peripheral neuropathy 
30 (9.8) 
 
1.5.2 
Known Potential Benefits 


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The potential benefit for patients can be measured in terms of improvements in quality of life 
(QoL), OS, and PFS, factors associated with improved tumor control. The GRASPANC 2013-03 
study evaluated eryaspase in combination with chemotherapy in the second-line treatment of 
PAC. This study demonstrated improved OS and PFS in the ITT population, with an acceptable 
tolerability profile. 
1.5.3 
Assessment of Potential Risks and Benefits 
The potential benefit of ASNase therapy in PAC has been explored previously; however, these 
studies were stopped early due to the excessive toxicity of the ASNase.[28] 
In the Phase 2 GRASPANC 2013-03 study, eryaspase demonstrated clinical benefits in terms of 
OS, PFS, and ORR in the second-line treatment of metastatic PAC. 
The addition of eryaspase to chemotherapy did not lead to unexpected safety findings and did not 
appear to enhance the toxicity of chemotherapy. 
Overall, the potential benefits of eryaspase outweigh the expected risks of participation in the 
study. 


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2 
OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to determine whether the addition of eryaspase to 
chemotherapy improves overall survival (OS) in second-line treatment of pancreatic 
adenocarcinoma compared to chemotherapy alone. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• To compare progression-free survival (PFS) between the two treatment arms. 
• To compare the objective response rate (ORR) and duration of response (DoR) between 
the two treatment arms. 
• To compare the disease control rate (DCR) between the two treatment arms. 
• To evaluate the safety and tolerability of eryaspase in combination with chemotherapy 
versus chemotherapy alone  
• To assess the effect of eryaspase on quality of life using the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC 
QLQ-C30). 
• To determine the pharmacokinetics of eryaspase. 
• To assess the immunogenicity of eryaspase in terms of the induction of anti-ASNase 
antibodies and neutralizing antibodies. 
• To evaluate the relationship of clinical outcome with relevant biomarkers and genetic 
changes present in tumor tissues and blood and/or serum samples. 
• To investigate the predictive relationship between the patient’s DNA sequence variation, 
e.g. exploratory SNP genotyping and their response to combination treatment in terms of 
safety and tolerability (pharmacogenetics [PGx]). 
 
2.3 
ENDPOINTS: 
Primary Endpoint: 
Overall Survival (OS) in the ITT population. 
 
Secondary Endpoints: 
• Progression-free Survival (PFS), 
• Objective Response Rate (ORR) 
• Duration of Response (DoR) 
• Disease Control rate (DCR) 
• Pharmacokinetics and pharmacodynamics 
• Anti- ASNase antibodies 


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• Adverse events AEs 
• Quality of life (QoL) 
• Biomarkers 
 


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3 
STUDY DESIGN 
3.1 
OVERALL DESIGN 
This is an open-label, multicenter, randomized Phase 3 study in patients with adenocarcinoma of 
the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced 
disease and have measurable disease as defined by the Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) criteria. After provision of informed consent and conduct of screening 
assessments, patients who meet all inclusion and no exclusion criteria will be randomized in a 
1:1 ratio to one of the following treatment arms, Table 4: 
• Arm A (investigational arm): eryaspase in combination with either gemcitabine/Abraxane 
or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] 
or Onivyde/5-fluorouracil/leucovorin), 
• Arm B (control arm): gemcitabine/Abraxane, or irinotecan-based therapy (FOLFIRI or 
Onivyde/5-fluorouracil/leucovorin). 
 
 
Figure 4 
Study Schema  
The study will be divided into the following phases: 
Screening Phase: Screening assessments should occur within 3 weeks of randomization for 
assessment of the patient’s overall eligibility. 
Randomization Phase: Randomization will occur after the patient has been determined to be 
eligible. 
Treatment Phase: The first dose of chemotherapy will be administered within 3 days after 
randomization. Treatment will continue until objective disease progression, unacceptable 
toxicity, or the patient’s withdrawal of consent. Unacceptable toxicity is determined at 
investigator’s discretion, but as a guidance, unacceptable toxicity could consist of prolonged 
Grade 3 or 4 toxicity lasting more than two weeks. 


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In the investigational treatment arm (Arm A), eryaspase will be administered on Day 1 and 
Day 15 of 4-week cycle in combination with chemotherapy. Eryaspase will be administered by 
intravenous (IV) infusion over approximately 60 minutes, followed by one hour of rest and then 
followed by chemotherapy infusion. 
Chemotherapy will consist of one of the following two treatment regimens: 
− Gemcitabine and Abraxane combination chemotherapy 
− Irinotecan-based therapy: FOLFIRI (FOLinic acid-Fluorouracil-IRInotecan regimen) 
or Onivyde/5-fluorouracil (5-FU)/leucovorin (LV) 
The choice of the chemotherapy regimen for a particular patient will be determined by the prior 
treatment received in the first-line setting. Thus: 
− If a patient received prior gemcitabine/Abraxane in the first-line setting, then on 
disease progression, the patient will be assigned to FOLFIRI (or Onivyde/5-FU/LV) 
in the current study. 
− If a patient received prior irinotecan-based therapy (FOLFIRINOX), then on disease 
progression, the patient will be assigned to gemcitabine/Abraxane in the current 
study. 
Follow-up Phase: Patients will be monitored for survival at 8-week intervals. Patients who 
discontinue treatment for reasons other than disease progression will continue to be assessed 
radiologically every 8 weeks until disease progression, or until withdrawal from the study, or 
death. 
Randomization will occur through an interactive web response system (IWRS). Patients will be 
randomized in a 1:1 ratio to chemotherapy with or without eryaspase. Randomization will be 
stratified according to the following factors: 
• ECOG Performance Status(PS) score (0 or 1), 
• Chemotherapy regimen in this study (gemcitabine/Abraxane or irinotecan-based 
treatment [FOLFIRI or its equivalent Onivyde/5-FU/LV]), and 
• Time interval since initial diagnosis of advanced disease to randomization date 
(<6 months or ≥6 months). 
An Independent Data Monitoring Committee (IDMC) will be established to review safety and 
efficacy data at regular intervals, including the interim and final analyses. 
In addition, the safety of eryaspase in combination with irinotecan-based therapy or 
gemcitabine/Abraxane regimen will be reviewed by the IDMC after at least 10 patients are 
enrolled per regimen and have received at least one cycle of study therapy. The specific 
responsibilities and composition of the IDMC will be outlined in a separate document, the IDMC 
Charter. 
Safety and Efficacy Evaluations 
Assessments and timing of data collection are detailed in the Schedule of Events in Table 1. 
Safety Evaluations 
Clinical and laboratory parameters and adverse events will be assessed in all patients to evaluate 
disease status and toxicity. Patients will have safety assessments (laboratory tests, physical 


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exams, vital signs including temperature, heart rate, and blood pressure, electrocardiograms 
[ECGs performed during screening and then as clinically indicated], and performance status 
score performed on Day 1 and Day 15 of each cycle and at the End of Treatment visit. 
Adverse event reporting will begin at the time of informed consent signature. Adverse events and 
concomitant medications will be collected until 90 days after the last dose of study treatment or 
until start of new anti-cancer treatment, whichever is sooner. 
Efficacy Evaluations 
Tumor assessments utilizing computed tomography (CT)/magnetic resonance imaging (MRI) 
scans will be repeated every 8 weeks, calculated from the date of randomization, until disease 
progression, or until withdrawal from the study, or death. Every effort should be made to adhere 
to the assessment schedule. The same imaging technique must be used throughout the study. 
Patients who discontinue treatment for reasons other than disease progression will continue to be 
assessed radiologically every 8 weeks until disease progression, or until withdrawal from the 
study, or death. For patients who discontinue treatment for reasons other than objective disease 
progression, and patients who start new anti-cancer treatment without evidence for objective 
disease progression, disease status evaluation will continue to be repeated every 8 weeks, 
calculated from the date of randomization, ,until disease progression. All radiological images 
must be collected in a de-identified manner, quality controlled, stored, and available for future 
review, including independent radiological review as necessary. 
Survival information will be collected by phone, follow-up visit, or medical records review every 
8 weeks from the date of the EOT visit  until the patient’s death, until the patient is lost to 
follow-up, or until study closure. Survival follow-up information will include collection of any 
subsequent anticancer therapy received after discontinuation from study medication. 
QoL (EORTC QLQ-C30) assessment will be performed, at Day 1 of each cycle prior to dosing, 
at the End of Treatment visit, and every 8 weeks during survival follow up. 
Blood and plasma samples will be collected in the eryaspase arm for pharmacokinetic (PK) and 
pharmacodynamic determination and for immunogenicity evaluation. 
Pharmacokinetics, Pharmacodynamics, and Translational Research 
Where possible, blood/plasma samples for PK and pharmacodynamic assessments will be 
collected at the following time points of Cycles 1 and 3 of study treatment: Day 1 prior to 
eryaspase administration, at 5-10 minutes post-eryaspsase infusion, at 5-8 days post-infusion (at 
the Investigator’s discretion), and at Day 15 pre-dose. Samples will be analyzed for whole blood 
and plasma concentrations of ASNase and amino acids. The sparse PK data will be combined 
with previous data as part of a Population PK (POP PK) analysis. 
Samples for assessment of anti-ASNase antibodies and neutralizing antibodies will be collected 
pre-dose at Cycle 1 Day 1 and Day 15, at Day 1 of every second cycle thereafter, upon 
determination of disease progression, and at the End of Treatment (EOT) visit, as specified in the 
Schedule of Events (Table 1). 
Exploratory biomarker analyses will examine potential predictive biomarkers correlating with 
eryaspase activity. Tissue samples will be collected at study start. In addition, blood/plasma 
samples for biomarker analysis will be collected from all patients at Cycle 1 Day 1 and Day 15, 


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at Day 1 of every second cycle thereafter, upon determination of disease progression, and at the 
End of Treatment (EOT) visit, as specified in the Schedule of Events (Table 1). 
A blood sample for pharmacogenetic (PGx) analysis will be obtained once during the study, 
preferably during the screening phase, for patients who consent to this optional procedure. 
An effective contraception must be used by all patients during eryaspase treatment and for at 
least 6 months after discontinuation from eryaspase treatment. Since an indirect interaction 
between components of the oral contraception and free ASNase cannot be ruled out (potential 
increase in the risk of a change in coagulation parameters and thrombosis), oral contraceptives 
are not considered sufficiently reliable when co-administered with ASNase products. A method 
other than oral contraception should be used in women of childbearing potential. 
3.2 
NUMBER OF PATIENTS 
The target sample size is 482 patients. 
3.3 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
3.3.1 
Choice of Chemotherapy (Control) 
There is currently no standard of care for locally advanced or metastatic pancreatic cancer that 
has progressed following either FOLFIRINOX or a gemcitabine-based regimen. While there are 
potential options, there is no proven benefit for any regimen, and treatment choice is generally an 
extrapolation from front-line studies. Based on systematic reviews and National Comprehensive 
Cancer Network (NCCN) guidelines, gemcitabine-based therapy can be given to those 
previously treated with fluoropyrimidine-based chemotherapy. Fluoropyrimidine-based 
chemotherapy regimens are acceptable second-line options for patients who received prior 
gemcitabine-based therapy. Based the recent Phase 3 NAPOLI-1 trial [36], Onivyde was 
approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
in combination with 5-FU/leucovorin for use following gemcitabine-based therapy. Therefore, 
the choices of chemotherapy as the backbone of treatment in both treatment arms are justified. 
3.4 
JUSTIFICATION FOR DOSE 
The choice of dose and schedule for eryaspase (100 U/Kg given on Days 1 and 15 of each 4-
week cycle) is based on safety and tolerability data from the phase 1 monotherapy study in PAC 
patients [37]. This dose and schedule were evaluated in Study GRASPANC 2013-03, and have 
demonstrated encouraging signs of clinical benefit in terms of OS, PFS, and DCR in patients 
treated with eryaspase combined with chemotherapy compared to chemotherapy alone. 
The dosing schedule of chemotherapy agents will follow the label and standard practice for each 
respective agent. 


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3.5 
END OF STUDY DEFINITION 
A patient is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Events, 
Table 1. 
The end of the study is defined as completion of the last patient’s last visit. 


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4 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
Investigator’s team before patients are enrolled. 
4.1 
INCLUSION CRITERIA 
A patient will be eligible for the study if all the following criteria are met: 
1. Must be 18 years of age or older. 
2. Must have histologically confirmed pancreatic adenocarcinoma. 
3. Must have Stage III or IV disease (see APPENDIX 1). 
4. Must have received one line of systemic chemotherapy in advanced setting with or 
without targeted agents, immunotherapy, or radiotherapy for treatment of advanced 
pancreatic adenocarcinoma.   
NOTE: patients whose disease progresses on, or within 3 months of neo(adjuvant) 
chemotherapy may be considered eligible 
5. Must have radiological evidence of disease progression following most recent prior 
treatment, defined as appearance of any new lesion or increase of >20% of one or more 
existing lesions. 
6. Must have measurable lesion(s) per RECIST version 1.1 by CT scan with contrast (or 
MRI, if the patient is allergic to CT contrast media). 
• Measurable disease may be in the field of prior irradiation; however, at least 4 weeks 
must have elapsed between the completion of radiation therapy and the baseline scan 
documenting disease status. 
• Bone disease is considered radiologically measurable only if there is at least a 50% 
lytic component. 
NOTE: Bone disease consisting of blastic lesion only is not measurable. 
7. Archival or fresh tumor tissue must be available for evaluating relevant biomarkers. 
Formalin-fixed paraffin-embedded [FFPE] block preferred, or a minimum of 
10 unstained FFPE slides of one archived block is required.   
NOTE: if archival tissue is unavailable and an elective biopsy can’t be scheduled due to 
COVID, this will be waived. 
NOTE: Cytology samples from fine needle aspirates or brushing biopsies are not 
sufficient. 
8. Must have adequate performance status (see APPENDIX 2 and APPENDIX 3): 
a. ECOG Performance Status (PS) score of 0, or 
b. ECOG PS score one and score ≥80 on Karnofsky Performance Status (KPS) scale. 
NOTE: Must have body mass index (BMI) ≥18.5 kg/m2 (obtained <14 days prior to 
randomization.  
9. Must have life expectancy of >12 weeks according to the investigator’s clinical 
judgment. 


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10. Females of childbearing potential must have a negative pregnancy test at screening and 
additional negative pregnancy test prior to first dose. Males and females of childbearing 
potential must agree to use a highly effective method of contraception during treatment 
and for at least 6 months after the last dose of study treatment. These include, but not 
limited to: 
a. combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
i. intravaginal 
ii. transdermal 
b. progestogen-only hormonal contraception associated with inhibition of ovulation: 
i. injectable 
ii. implantable  
c. intrauterine device (IUD)  
d. bilateral tubal occlusion  
e. vasectomised partner  
f. sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) is intended. The true 
abstinence is when this is in line with the preferred and usual lifestyle of the patient. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception] 
g. males with partners of childbearing potential must agree to use condoms  
NOTE: Since an indirect interaction between components of the oral contraceptives and 
ASNase cannot be ruled out, oral contraceptives are not considered acceptable as 
contraceptive methods in the current clinical trial. A method other than oral contraception 
should be used in women of childbearing potential. 
NOTE: All chemotherapeutic agents may be teratogenic and excreted in breast milk. 
Patients who are breast feeding should consider alternative methods. 
11. Must have adequate laboratory parameters at baseline (obtained <14 days prior to 
randomization). Laboratory parameters outside of these ranges that are deemed clinically 
insignificant should be discussed with the medical monitor: 
a. Absolute neutrophil count ≥1.5 x 109/L. 
b. Hemoglobin ≥9 g/dL. Patients with a baseline Hemoglobin ≥13 g/dL should be 
discussed with the medical monitor 
c. Platelet count ≥100,000/mm3 (100 x 109/L). 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper 
limit of normal (ULN) (≤5 x ULN in presence of liver metastases). 
e. Total bilirubin ≤ 1.5 x institutional ULN. 
f. Serum creatinine within normal limits or calculated clearance >60 mL/min/1.73 m2 
for patients with serum creatinine levels above or below the institutional normal 
range.  
g. Acceptable coagulation parameters: plasma antithrombin III >70% and fibrinogen 
≥1.5 g/L. 
h. Serum albumin ≥3.0 g/dL. 


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12. Patients requiring biliary stent placement must have the biliary stent placed >7 days prior 
to screening and must have normalization of bilirubin level after stenting. 
13. Must not be receiving therapy in a concurrent clinical study and must agree not to 
participate in any other interventional clinical studies during their participation in this 
trial while on study treatment. Patients taking part in surveys or observational studies are 
eligible to participate in this study. 
14. Must be able to understand and comply with the conditions of the protocol and must have 
read and understood the consent form and provided written informed consent. 
4.2 
EXCLUSION CRITERIA 
A patient is not eligible to participate in the study if any of the following criteria are met: 
1. Resectable or borderline resectable pancreatic adenocarcinoma at the time of signing the 
informed consent. 
2. Histology other than pancreatic adenocarcinoma (for example, but not inclusive: 
neuroendocrine, adenosquamous, etc.). 
3. More than one line of prior treatment in advanced or metastatic setting. 
4. Patient has experienced medically significant acute decline in clinical status including 
a. Decline in ECOG PS to >1 (or KPS <70) between baseline visit and within 72 hours 
prior to randomization. 
b. Weight loss of ≥10% during screening. 
5. Presence of active or symptomatic untreated central nervous system (CNS) metastases. 
NOTE: Patients with asymptomatic or stable CNS metastases are eligible, provided that 
the CNS metastases are radiologically and clinically stable, and the patient is off high-
dose steroid treatment for at least one month prior to randomization. 
6. Prior radiotherapy to the only area of measurable disease. 
NOTE: Patients must have completed treatment and recovered from all acute treatment-
related toxicities prior to administration of the first dose of eryaspase or chemotherapy. 
7. Bone as the only site of metastatic disease from pancreatic cancer (bone-only disease). 
8. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 
3 months of randomization. 
NOTE: The revised Atlanta classification [1] requires that two or more of the following 
criteria be met for the diagnosis of acute pancreatitis: (a) abdominal pain suggestive of 
pancreatitis, (b) serum amylase or lipase level ≥3 x ULN, or (c) characteristic imaging 
findings using CT or MRI. 
9. Neurosensory neuropathy > Grade 2 at baseline. 
10. Pregnancy or breastfeeding. 
11. History of infection with human immunodeficiency virus (HIV) and/or active infection 
with hepatitis B or hepatitis C. 
NOTE: Patients with unknown status of hepatitis B or C must be tested and declared 
negative before randomization. 


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12. Hypersensitivity to any of the components of the chemotherapy or ASNase. 
NOTE: Patients known to be homozygous for UGT1A1*28 who are assigned to an 
irinotecan-containing regimen must have the initial irinotecan dose reduced unless they 
have previously tolerated full doses of irinotecan. Subjects whose UGT1A1 status is not 
known but are being considered for irinotecan-based chemotherapy must be screened for 
UGT1A1*28 allele unless they have previously tolerated full doses of irinotecan before 
enrollment into the trial and must have the initial irinotecan dose reduced if demonstrated 
to be homozygous for the UGT1A1*28 allele. 
NOTE: Patients assigned to the irinotecan/5-FU arms in the study should not have 
dihydropyridine dehydrogenase deficiency (DPD). Patients whose DPD status is 
unknown at time of screening should be tested before enrollment in the irinotecan/5-FU 
arm unless they have previously tolerated full doses of 5-FU. 
13. Patients who have received live or live attenuated vaccines within 3 weeks of 
randomization. 
14. History of other malignancies  
NOTE: Adequately treated non-melanoma skin cancer or curatively treated in-situ cancer 
of the cervix may be eligible. 
NOTE: Patients successfully treated for other malignancies and are disease-free for at 
least 5 years may be eligible. 
15. Any other severe acute or chronic condition/treatments that may increase the risk of study 
participation including: 
a. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-
abdominal abscess within 6 months prior to randomization. 
b. Current or history within 6 months prior to randomization of medically significant 
cardiovascular disease including symptomatic congestive heart failure >New York 
Heart Association (NYHA) Class II, unstable angina pectoris, clinically significant 
cardiac arrhythmia. 
c. Patients with pre-existing coagulopathy (e.g. hemophilia). 
d. Psychiatric illness/social situations or any other serious uncontrolled medical 
disorders in the opinion of the Investigator that would limit compliance with study 
requirements. 
4.3 
SCREEN FAILURES 
Screen failures are defined as patients who consent to participate in the study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, in order to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publication requirements and to respond to queries from 
regulatory authorities. 
This minimal information includes demography and reason for screen failure. 


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Patients who do not meet the criteria for participation in this study because of abnormal 
laboratory findings at screening may be rescreened. Rescreened patients should be assigned the 
same patient number as for the initial screening. 


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5 
STUDY TREATMENTS 
5.1 
DESCRIPTION OF STUDY DRUGS 
The study drugs include all chemotherapy agents used in both treatment arms, as well as the 
investigational drug which is eryaspase (Investigational Medicinal Product). 
The chemotherapy agents used in this study (gemcitabine, Abraxane, irinotecan, and 
5-FU/leucovorin) are commercially available and are being used in accordance with approved 
labeling. 
5.1.1 
Eryaspase 
Eryaspase is a dispersion for infusion of allogeneic RBCs encapsulating recombinant E. coli 
L-ASNase, in a saline preservative solution. 
Eryaspase is an off-shelf investigational agent. Eryaspase is produced for each individual patient 
taking into account blood group and phenotype and dose of ASNase appropriate for body weight. 
Please refer to the IB for information regarding properties of the drug substance and drug 
product. 
5.1.2 
Gemcitabine and Abraxane 
Gemcitabine is an antineoplastic agent. It is commercially available as a lyophilized powder for 
solution for IV use. Gemcitabine will be reconstituted/used as per the manufacturer’s suggestions 
and will be administered as per institutional procedure. 
Abraxane (protein-bound paclitaxel) is a microtubule inhibitor. It is commercially available as a 
lyophilized powder in a single-use vial for reconstitution for IV use. Abraxane will be 
reconstituted/used as per the manufacturer’s suggestions and will be administered as per 
institutional procedure. 
Gemcitabine and Abraxane will be sourced locally. Investigators are responsible for ensuring 
that patients receive supplies of gemcitabine and Abraxane for the entire duration of the study 
treatment, except in countries where regulatory authorities mandate that the Sponsor must supply 
all medications required for study participation. 
5.1.3 
Irinotecan and 5-FU/Leucovorin 
Irinotecan is an antineoplastic agent of the topoisomerase I inhibitor class. It is commercially 
available as an aqueous solution intended for dilution prior to IV infusion. Irinotecan will be 
reconstituted/used as per the manufacturer’s suggestions and will be administered as per 
institutional procedure. 
Onivyde (liposomal irinotecan) is a topoisomerase I inhibitor. It is commercially available as an 
opaque liposomal dispersion in a single-dose vial for IV infusion. Onivyde will be 
reconstituted/used as per the manufacturer’s suggestions and will be administered as per 
institutional procedure. 


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5-FU is an antineoplastic antimetabolite agent. It is commercially available as an injectable 
solution for IV use. 5-FU will be administered as per institutional procedure. 
Leucovorin is folinic acid (the active metabolite of folic acid). It is an essential coenzyme for 
nucleic acid synthesis and is used to enhance the cytotoxicity of 5-FU. It is commercially 
available as a powder for reconstitution for IV use. Leucovorin will be administered as per 
institutional procedure. 
Irinotecan or Onivyde and 5-FU/leucovorin will be sourced locally. investigators are responsible 
for ensuring that patients receive supplies for the entire duration of the study treatment, except in 
countries where regulatory authorities mandate that the Sponsor must supply all medications 
required for study participation. 
5.2 
DOSAGE AND ADMINISTRATION 
5.2.1 
Eryaspase 
At the treatment initiation, eryaspase will be prepared and dispatched after all screening 
assessments have been completed and the results reviewed and after it has been confirmed that 
the patient meets all eligibility criteria. 
The dose of eryaspase is 100 U/Kg, to be administered at Days 1 and 15 of each 4-week cycle 
until disease progression, unacceptable toxicity, or withdrawal of consent. 
Eryaspase is administered over approximately 60 minutes per bag, depending on the volume of 
the bag(s). The entire content of each bag is to be administered, unless otherwise specified. 
Eryaspase administration must be completed before the expiry time clearly stated on the label of 
the eryaspase bag. 
Date of administration, exact start and end times of infusion, and volume administered will be 
recorded on the Shipment and Administration Form (SAF) as described in the Investigational 
Medicinal Product (IMP) Manual and noted in the patient’s electronic Case Report Form 
(eCRF). 
Detailed instructions related to eryaspase administration and contact information in case of any 
issues are provided in the IMP Manual. 
5.2.2 
Gemcitabine and Abraxane 
Gemcitabine and Abraxane are to be administered on Days 1, 8, and 15 of each 4-week cycle as 
follows: 
− Abraxane: 125 mg/m2 IV over 30-40 minutes, followed by 
− Gemcitabine: 1000 mg/m2 IV over 30 minutes. 


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5.2.3 
Irinotecan and 5-FU/Leucovorin 
Onivyde (irinotecan nanoliposomal) + 5-FU/leucovorin are to be administered on Days 1 and 
15 of each 4-week cycle as follows: 
• Onivyde 70 mg/m2 IV over 90 minutes (recommended starting dose of Onivyde in 
patients homozygous for UGT1A1*28 is 50 mg/m2), 
NOTE: The approved dose of Onivyde is based on the NAPOLI-1[36] trial, in which 
Onivyde was given at a dose of 80 mg/m2 (i.e. equivalent of 70 mg/m2 of irinotecan free 
base). 
• Leucovorin 400 mg/m2 IV over 30 minutes, and 
NOTE: Modifications to the leucovorin dose per sites standard administration protocol 
may be allowed in the study following approval from the medical monitor. 
• 5-FU 2400 mg/m2 over 46 hours. 
 
FOLFIRI (irinotecan, 5-FU, and leucovorin) is to be administered every 2 weeks on Day 1 
and Day 15 of each 4-week cycle as follows: 
• Irinotecan 180 mg/m2 IV infusion over 90 minutes (recommended starting dose of 
irinotecan in patients homozygous for UGT1A1*28 is 150 mg/m2) 
• Leucovorin 400 mg/m² IV infusion over 2 hours  
NOTE: Modifications to the leucovorin dose per sites standard administration protocol 
may be allowed in the study following approval from the medical monitor. 
• 5-FU 400 mg/m² IV bolus injection over 2-4 minutes, immediately following leucovorin 
infusion, and 
• 5-FU 2400 mg/m² IV continuous infusion over 46 hours, immediately following bolus 
5-FU. 
5.2.4 
Guidelines for Treatment Discontinuation and Dose Modification 
Patients will be treated until disease progression, unacceptable toxicity as determined by the 
Investigator, or withdrawal of consent. Each patient will be evaluated for drug-related toxicity. If 
a patient experiences unacceptable toxicity for more than two weeks, then such patients should 
be withdrawn from study treatment. Unacceptable toxicity will be determined at the 
investigator’s discretion; however, as a guidance, unacceptable toxicity could consist of 
prolonged Grade 3 or 4 toxicity not resolving within two weeks. The medical monitor must be 
consulted if any patient requires further treatment delays or dose modifications. 
Throughout the study, the following toxicity criteria will be used to guide treatment 
modifications and treatment delays. However, standard practice at sites may also be referred to, 
particularly for any of the chemotherapy components.  
Appropriate supportive care will be provided for the management of drug-related toxicities.  
In the instance of adverse events that require course changes, then the general guidance is 
delaying dose as opposed to skipping a dose. This could mean that a cycle could be longer than 
4 weeks. 


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5.2.4.1 
DOSE MODIFICATION FOR ERYASPASE 
One 25% dose reduction of eryaspase is permitted at the first occurrence of an eryaspase-related 
toxicity. Additional dose reduction to 50% is allowed on second instance. If further dose 
reductions are necessary, then eryaspase should be discontinued. 
Table 6 presents guidelines for carrying out eryaspase dose reductions when deemed appropriate. 
Dose reduction approach will depend on whether the drug is at site and ready for infusion 
(during a cycle) or is planned for a subsequent cycle. Dose reduction during a cycle will follow 
an empirical estimation of the volume in the eryaspase bag. Dose reduction in subsequent cycles 
will be reflected in the prescription form and will therefore be carried out by reducing the dose 
level per unit of body weight to be used in manufacturing the drug for the next cycle(s). 
Table 6 
Pre-Specified Dose Reductions for Adverse Events Related to Eryaspase 
Dose level 
After manufacturing (during cycle) 
Before manufacturing (subsequent 
cycle) 
0 
100 U/Kg (full bag) 
100 U/Kg 
-1 
75% of the bag volume 
75 U/Kg 
-2 
50% of the bag volume 
50 U/Kg 
 
After a dose reduction, the dose of eryaspase may be re-escalated to the previous higher dose 
level, provided that toxicity resolves to at Grade 1 (or 2 where specified). 
Treatment with eryaspase may be delayed for up to 2 weeks at the first instance of an eryaspase-
related toxicity to allow for resolution of toxicity, defined as a return to ≤Grade 2, where 
indicated. The sponsor’s Medical Monitor must be consulted if any patient requires further 
treatment delays or dose modifications. If eryaspase-related adverse events do not resolve after a 
period of 2 weeks, the patient should discontinue eryaspase and should then complete the EOT 
visit and Follow-up visits per the Schedule of Events (Table 1). 
5.2.4.2 
DOSE MODIFICATIONS FOR CHEMOTHERAPY (WITH OR 
WITHOUT ERYASPASE) 
The product labeling information and local institutional practice should be referred to regarding 
hematological and non-hematological AEs attributable to the individual chemotherapy agents 
used in this study. In addition, it is recommended that patients receive pre-medication according 
to respective product labeling information. In case of Abraxane and Onivyde, pre-medication 
standard doses of dexamethasone (or an equivalent corticosteroid) together with a 5-
hydroxytryptamine 3 (5-HT3) antagonist (or other antiemetic) at least 30 minutes prior to start of 
chemotherapy infusion. 
5.2.4.2.1 
DOSE MODIFICATIONS FOR GEMCITABINE AND ABRAXANE 
Table 7 presents a summary of dose modifications for gemcitabine, Abraxane, and eryaspase. 
Patients who experience adverse events will be re-evaluated weekly, or more often according to 
the Investigator’s discretion. Dose delays or reduction for gemcitabine or Abraxane follow the 
respective prescribing information, and are provided in the table below for ensuring consistency 


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across sites. If toxicities do not resolve within two weeks, then the patient will discontinue the 
study treatment, but will continue to be followed for 90 days or until start of new anti-cancer 
treatment, whichever is first, for adverse events and serious adverse events. Thereafter, the 
patient will be followed for radiological disease assessment and survival until withdrawal from 
study or death. 
Table 7 
Dose Modifications for Gemcitabine, Abraxane, and Eryaspase 
 
Abraxane  
Gemcitabine  
Eryaspase 
Hypersensitivity Reactions: 
Grade 1: transient 
flushing/rash, 
intervention not 
indicated 
Maintain original dose 
level 
 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: intervention/ 
infusion interruption 
indicated; responds 
promptly to 
symptomatic treatment 
Maintain original dose 
level 
Maintain original dose 
level 
During cycle 
interrupt for transient 
period and then 
resume(1) 
Subsequent cycles  
Maintain dose level 
Grade 3: Prolonged 
recurrence of 
symptoms ± clinical 
sequelae, or 
anaphylaxis 
(symptomatic 
bronchospasm, 
edema/angioedema, 
hypotension, parenteral 
intervention required) 
infusion interruption 
indicated; responds 
promptly to 
symptomatic treatment 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Grade 4: Systemic 
allergic reaction or 
anaphylaxis 
Discontinue  
Discontinue  
Discontinue  
Pancreatitis: 
Grade 2: enzyme 
(lipase/amylase) 
elevation >3.0 ULN, or 
Radiological findings 
only 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 3: Symptomatic 
pancreatitis [Severe 
pain, vomiting; Lipase 
/amylase elevation 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  Delay 
until resolved to 
≤Grade 2, then ↓ to 
75% of dose 


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Table 7 
Dose Modifications for Gemcitabine, Abraxane, and Eryaspase 
 
Abraxane  
Gemcitabine  
Eryaspase 
>3.0 ULN for >3 days; 
Medical intervention 
needed 
Subsequent cycles  
75 U/Kg 
Grade 4: Symptomatic 
pancreatitis, 
life-threatening 
Discontinue  
Discontinue  
Discontinue  
Hepatic toxicity: 
No Hepatic metastasis 
Grade 1: ALT/AST 
>3.0 x ULN, and total 
bilirubin ≤1.5 x ULN 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: ALT/AST 
≤5.0 x ULN and total 
bilirubin ≤1.5 x ULN 
Maintain original dose 
level 
Maintain original dose 
level 
During cycle  ↓ to 
75% of dose 
Subsequent cycles   
100 U/Kg 
Grade 3: ALT/AST 
>5.0 x ULN, and total 
bilirubin >2 x ULN 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
100 mg/m2 
Subsequent cycles  
100 mg/m2  
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
During cycle  Delay 
until resolved to 
≤Grade 2, then ↓ to 
75% of dose 
Subsequent cycles  
75 U/Kg  
Grade 4: ALT/AST 
>20.0 x ULN, or total 
bilirubin >2 x ULN 
Discontinue 
Discontinue  
Discontinue 
Hepatic metastasis 
ALT/AST >5.0 x ULN 
- ≤10.0 x ULN 
and total bilirubin 
≤1.5 x ULN 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
ALT/AST >10.0 - 
20.0 x ULN, and total 
bilirubin ≤1.5 x ULN 
During cycle  delay 
until resolved to ≤10.0, 
then ↓ to 100 mg/m2 
Subsequent cycles  
100 mg/m2 
During cycle  delay 
dose until resolved to 
ALT/AST 
<10.0 x ULN, then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
During cycle  delay 
until resolved to ≤10.0, 
then ↓ to 50% of dose 
Subsequent cycles  
50 U/Kg  
ALT/AST 
>20.0 x ULN and total 
bilirubin ≤1.5 x ULN 
Discontinue  
Discontinue  
Discontinue 
Total bilirubin 
>2.0 x ULN 
Discontinue  
Discontinue  
Discontinue 


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Table 7 
Dose Modifications for Gemcitabine, Abraxane, and Eryaspase 
 
Abraxane  
Gemcitabine  
Eryaspase 
Motor or Sensory Neuropathy  
Grade 1 or Grade 2 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 3 or Grade 4 
 
During cycle  delay 
until resolved to 
≤Grade 2, then ↓ to 
100 mg/m2 
Subsequent cycles  
100 mg/m2 
During cycle  delay 
until resolved to 
≤Grade 2, then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
Maintain original dose 
level 
Hematological Toxicity – Neutropenia (Absolute Neutrophil Count [ANC]): 
Grade 1: <lower limit 
of normal (LLN) to 
1.5 x 109/L 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: <1.5 x 109/L 
- ≥1 x 109/L 
During cycle   delay 
until resolved to ≤Grade 1 
then ↓ to 100 mg/m2 
Subsequent cycles  
100 mg/m2 
During cycle   delay 
until resolved to ≤Grade 1 
then  then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
Maintain original dose 
level 
Grade 3: <1.0 x 109/L 
- ≥0.5 x 109/L 
Day 1  delay until 
resolved 
Day 8  ↓ to 
100 mg/m2 
Day 15  ↓ to 
75 mg/m2 
Day 1  delay until 
resolved 
Day 8  ↓ to 
800 mg/m2 
Day 15  ↓ to 
600 mg/m2 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Grade 4: <0.5 x 109/L 
or 
Febrile neutropenia 
Day 1  delay until 
resolved 
Day 8  delay dose 
Day 15  delay dose 
Day 1  delay until 
resolved 
Day 8  delay dose 
Day 15  delay dose 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Other hematological toxicities (anemia and thrombocytopenia) follow same guidelines as 
recommended for neutropenia 
Other laboratory investigations 
Any Grade 1 or 
Grade 2  
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Any Grade 3 or 
Grade 4 – not 
clinically significant 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
dose 
During cycle  Delay 
until resolved to 
≤Grade 2, then full 
dose 


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Table 7 
Dose Modifications for Gemcitabine, Abraxane, and Eryaspase 
 
Abraxane  
Gemcitabine  
Eryaspase 
Subsequent cycles  
Maintain original dose 
level 
Subsequent cycles  
Maintain original dose 
level 
Subsequent cycles  
Maintain original dose 
level 
Any Grade 3 or 
Grade 4 – clinically 
significant 
During cycle  delay 
until resolved to 
≤Grade 2, then ↓ to 
100 mg/m2 
Subsequent cycles  
100 mg/m2 
During cycle  delay 
until resolved to 
≤Grade 2, then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
During cycle  Delay 
until resolved to 
≤Grade 2, then ↓ to 
75% of dose 
Subsequent cycles 
75 U/Kg 
Other non-Hematological Adverse Event: 
Any Grade 1 toxicity 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Any other Grade 2 
toxicity 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Any other Grade 3 
toxicity 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
During cycle  delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Upper gastro-intestinal 
(GI) peptic ulcer 
Grades 2 or 3 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
During cycle  delay 
until resolved to 
≤Grade 1, then use next 
lower dose level  
Subsequent cycles  
next lower dose level  
Any other Grade 4 
toxicity 
During cycle delay 
until resolved to 
≤Grade 2, then ↓ to 
100 mg/m2 
Subsequent cycles  
100 mg/m2 
During cycle delay 
until resolved to 
≤Grade 2, then ↓ to 
800 mg/m2 
Subsequent cycles  
800 mg/m2 
During cycle delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Upper gastro-intestinal 
(GI) peptic ulcer 
Grade 4, and/or life-
threatening GI 
bleeding 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
full original dose 
Withdraw  
IMP Incompatibility: 


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Table 7 
Dose Modifications for Gemcitabine, Abraxane, and Eryaspase 
 
Abraxane  
Gemcitabine  
Eryaspase 
Positive serologic 
cross-match test result 
No actions for the chemotherapy. Repeat eryaspase manufacturing. 
If persists, discontinue.  
(1) Infusion may be resumed at a lower infusion rate, provided that it is within shelf-life and the infusion is 
completed within the 6-hour window of bringing eryaspase to room temperature. 
5.2.4.2.2 
DOSE MODIFICATIONS FOR IRINOTECAN AND 
5-FU/LEUCOVORIN 
Table 8 presents a summary of dose modifications for irinotecan, Onivyde, and eryaspase. 
Patients who experience adverse events will be re-evaluated weekly, or more often according to 
the Investigator’s discretion. Dose delays or reductions for irinotecan or Onivyde follow the 
respective prescribing information, and are provided in the table below for consistency across 
sites. If toxicities do not resolve to ≤Grade 2 within two weeks, then the patient will discontinue 
the study treatment, but will continue to be followed for 90 days or until start of new anti-cancer 
treatment, whichever is first, for adverse events and serious adverse events. The patient will be 
followed for radiological disease assessment and must complete an EOT visit and Follow-up 
visits per the Schedule of Events (Table 1). 
Following 5-FU treatment, mucositis, stomatitis, hand-foot syndrome, and diarrhea occur most 
commonly. Leukopenia is the usual dose-limiting toxicity after IV bolus administration. Patients 
with dihydropyrimidine dehydrogenase deficiency (DPD) are at risk of severe life-threatening 
toxicity with 5-FU. While severe deficiency is rare, 3-4% of the population has some degree of 
DPD deficiency. Patients with DPD deficiency cannot be enrolled in the 5-FU arm unless they 
have tolerated full doses of 5-FU previously. In general, dose modifications and delays follow a 
similar approach to that used with irinotecan. However, in case of mucositis or stomatitis, only 
5-FU (and not irinotecan or eryaspase) should be withheld during the cycle, and resumed at full 
dose in subsequent cycles. 
Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Hypersensitivity Reactions: 
Grade 1: transient 
flushing/rash, 
intervention not 
indicated 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: intervention/ 
infusion interruption 
indicated; responds 
promptly to 
symptomatic treatment 
Maintain original dose 
level 
Maintain original dose 
level 
During cycle  
interrupt for transient 
period and then 
resume(4) 
Subsequent cycles  
Maintain original dose 
level 


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Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Grade 3: Prolonged 
recurrence of 
symptoms ± clinical 
sequelae, or 
anaphylaxis 
(symptomatic 
bronchospasm, 
edema/angioedema, 
hypotension, parenteral 
intervention required) 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
150 mg/m2 
Subsequent cycles  
180 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
During cycle  delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Grade 4: Systemic 
allergic reaction or 
anaphylaxis 
Discontinue  
Discontinue  
Discontinue  
Pancreatitis: 
Grade 2: enzyme 
(lipase/amylase) 
elevation >3.0 x ULN, 
or Radiological 
findings only 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 3: Symptomatic 
pancreatitis [Severe 
pain, vomiting; Lipase 
or amylase elevation 
>3.0 x ULN for 
>3 days; and Medical 
intervention needed 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
150 mg/m2 
Subsequent cycles  
150 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
During cycle  Delay 
until resolved to 
≤Grade 2, then ↓ to 
75% of dose 
Subsequent cycles  
75 U/Kg 
Grade 4: Symptomatic 
pancreatitis, 
life-threatening 
Discontinue  
Discontinue  
Discontinue  
Hepatic toxicity: 
No Hepatic metastasis 
Grade 1: ALT/AST 
>3.0 x ULN, and total 
bilirubin ≤1.5 x ULN 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: ALT/AST 
≤5.0 x ULN and total 
bilirubin ≤1.5 x ULN 
During cycle  ↓ to 
150 mg/m2 
Subsequent cycles  
Maintain original dose 
level 
Maintain original dose 
level 
During cycle  ↓ to 
75% of dose 
Subsequent cycles  
Maintain original dose 
level 
Grade 3: ALT/AST 
>5.0 x ULN, and total 
bilirubin >2 x ULN 
Discontinue  
Discontinue  
During cycle  Delay 
until resolved to 
≤Grade 2, then ↓ to 
75% of dose 


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Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Subsequent cycles  
75 U/Kg 
Grade 4: ALT/AST 
>20.0 x ULN, or total 
bilirubin >2 x ULN 
Discontinue 
Discontinue  
 Discontinue 
Hepatic metastasis 
ALT/AST >5.0 x ULN 
- ≤10.0 x ULN 
and total bilirubin 
≤1.5 x ULN 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
ALT/AST >10.0 - 
20.0 x ULN, and total 
bilirubin ≤1.5 x ULN 
During cycle  delay 
dose until resolved to 
ALT/AST <5.0 x ULN, 
then ↓ to 120 mg/m2 
Subsequent cycles  
120 mg/m2 
During cycle  delay 
dose until resolved to 
ALT/AST <5.0 x ULN, 
then ↓ to 50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved to ≤10.0, 
then ↓ to 50% of dose 
Subsequent cycles  
50 U/Kg 
ALT/AST 
>20.0 x ULN and total 
bilirubin ≤1.5 x ULN 
Discontinue  
Discontinue  
Discontinue 
Total bilirubin 
>2.0 x ULN 
Discontinue  
Discontinue  
Discontinue 
Diarrhea  
Grade 1: 
(2-3 stools/day 
>pretreatment 
During cycle  delay 
until resolved, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
During cycle  delay 
until resolved, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: 
(4-6 stools/day 
>pretreatment) 
During cycle  delay 
dose until resolved, 
then ↓ to 150 mg/m2 
Subsequent cycles  
180 mg/m2 
During cycle  delay 
dose until resolved, 
then full dose 
Subsequent cycles  
70 mg/m2 
Maintain original dose 
level 
Grade 3: 
(7-9 stools/day 
>pretreatment) 
During cycle  delay 
dose until resolved, 
then ↓ to 150 mg/m2 
Subsequent cycles  
150 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Subsequent cycles  
43 mg/m2 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 


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Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Grade 4: 
(≥10 stools/day 
>pretreatment) 
During cycle  delay 
dose until resolved, 
then ↓ to 120 mg/m2 
Subsequent cycles  
120 mg/m2 
During cycledelay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Hematological Toxicity – Neutropenia (Absolute Neutrophil Count [ANC]): 
Grade 1: <LLN to 
1.5 x 109/L 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Grade 2: <1.5 x 109/L 
- ≥1 x 109/L 
During cycle  ↓ to 
150 mg/m2 
Subsequent cycles  
Maintain original dose 
level 
During cycle  delay 
dose until resolved, 
then full dose 
Subsequent cycles  
70 mg/m2 
Maintain original dose 
level 
Grade 3: <1.0 x 109/L 
- ≥0.5 x 109/L 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ 
150 mg/m2 
Subsequent cycles 
150 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Grade 4: <0.5 x 109/L 
or 
Febrile neutropenia 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ 
120 mg/m2 
Subsequent cycles  
120 mg/m2 
During cycle delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved to 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Other hematological toxicities (anemia and thrombocytopenia): follow same guidelines as 
recommended for neutropenia 
Other laboratory investigations 
Any Grade 1 or 
Grade 2  
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Any Grade 3 or 
Grade 4 – not 
clinically significant 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ 
150 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then full 
original dose 
During cycle  Delay 
until resolved to 
≤Grade 2, then full 
original dose 


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Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Subsequent cycles  
150 mg/m2 
Subsequent cycles  
50 mg/m2 
 
Subsequent cycles  
Maintain dose level 
Any Grade 3 or 
Grade 4 – clinically 
significant 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ 
120 mg/m2 
Subsequent cycles  
120 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  Delay 
until resolved to 
≤Grade 2, then then ↓ 
to 75% dose 
Subsequent cycles  
75 U/Kg 
Other non-Hematological Adverse Event: 
Any Grade 1 toxicity 
Maintain original dose 
level 
Maintain original dose 
level 
Maintain original dose 
level 
Any other Grade 2 
toxicity 
During cycle  delay 
dose until resolved to 
≤Grade 1, then ↓ to 
150 mg/m2 
Subsequent cycles  
180 mg/m2 
Maintain original dose 
level 
Maintain original dose 
level 
Any other Grade 3 
toxicity 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
150 mg/m2 
Subsequent cycles  
150 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Any other Grade 4 
toxicity(5) 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
120 mg/m2 
Subsequent cycles  
120 mg/m2 
During cycle  delay 
dose until resolved to 
≤Grade 2, then ↓ to 
50 mg/m2 
Second occurrence  
43 mg/m2 
Third occurrence  
Discontinue 
During cycle  delay 
until resolved 
≤Grade 2, then full 
dose 
Subsequent cycles  
Maintain original dose 
level 
Upper gastro-intestinal 
(GI) peptic ulcer 
Grades 2 or 3 
During cycle  delay 
until resolved to 
≤Grade 1, then use next 
lower dose level.  
Subsequent cycles  
next lower dose level 
During cycle  delay 
until resolved to 
≤Grade 1, then use next 
lower dose level  
Subsequent cycles  
next lower dose level 
During cycle  delay 
until resolved to 
≤Grade 1, then use next 
lower dose level  
Subsequent cycles  
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5.2.5 
Management of Events of special Interest 
Hypersensitivity reactions have been reported with Abraxane, irinotecan, Onivyde, and 
eryaspase. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 
antagonists as per institutional protocols. 
Eryaspase is an ASNase encapsulated into RBCs; therefore, the risk of allergic reactions is 
potentially attributed to one or more of the following causes: a) antibody-mediated clinical 
hypersensitivity reactions; b) non-antibody-mediated infusion reactions attributed to ASNase; 
and/or c) the RBC component in eryaspase. 
5.2.5.1 
MANAGEMENT OF HYPERSENSITIVITY REACTIONS WITH 
ERYASPASE OR OTHER AGENTS 
Generally, eryaspase does not require premedication for hypersensitivity reactions. However, 
eryaspase contains E. coli-derived ASNase, which has been associated with hypersensitivity 
reactions. These reactions range from local rash or flushing to severe systemic reactions with 
features such as urticaria, bronchospasm, angioedema, and severe anaphylactic shock. In the 
eryaspase program, there had been 15 (4.8%) Grade 3 or 4 allergic reactions as of 28 Feb 2017. 
The following is guidance for the treatment of hypersensitivity reactions. Treatment should be 
based on clinical presentation and is at the Investigator’s discretion. Institution-specific pre-
medication and/or treatment plans may also be followed if appropriate. 
Grade 2 Symptoms: 
• Stop administration. 
Table 8 
Dose Modifications for Irinotecan, Onivyde, and Eryaspase 
 
Irinotecan(1) 
Onivyde(2,3) 
Eryaspase 
Upper gastro-intestinal 
(GI) peptic ulcer Grade 
4, and/or life-
threatening GI bleeding 
Withdraw 
Withdraw  
Withdraw  
IMP Incompatibility: 
Positive serologic 
cross-match test result 
No actions for the chemotherapy. Repeat eryaspase manufacturing. 
If persists, discontinue.  
(1) For patients starting irinotecan at a reduced dose of 150 mg/m2 due to the presence of UGT1A1*28 
homozygous allele, dose should be reduced to 120 mg/m2 at first occurrence and an additional decrease of 
about 20% at the second occurrence of toxicity. 
(2) Onivyde dose reductions are presented based on a starting dose of 70 mg/m2 irinotecan free base (equivalent 
to 80 mg/m2 of Onivyde).  
(3) For patients starting Onivyde at a reduced dose of 50 mg/m2 irinotecan free base due to the presence of 
UGT1A1*28 homozygous allele, dose should be reduced to 43 mg/m2 at first occurrence and to 35 mg/m2 at 
the second occurrence. 
(4) Treatment with eryaspase can be resumed, provided that it is within shelf-life and the infusion is completed 
within the 6-hour window of bringing eryaspase to room temperature. 
(5) For mucositis or stomatitis, decrease only 5-FU, not irinotecan and not eryaspase. 


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• Administer IV dexamethasone 10 mg and diphenhydramine hydrochloride (HCL) 25 to 
50 mg. 
• After recovery of symptoms, treatment may be resumed once the patient is stable, if the 
product is not expired and the bag has been out of the cold box for less than 6 hours. 
• Use premedication for subsequent infusions of eryaspase. 
Grade 3 and 4 Symptoms (such as hypotension, angioedema, or respiratory distress): 
• Stop administration. 
• Administer IV dexamethasone 10 mg and diphenhydramine HCL 25 to 50 mg. 
• Add adrenaline or bronchodilators as indicated. 
• For Grade 4 toxicity, the treatment should be discontinued. 
Example of Infusion Premedication Regimen: 
• Dexamethasone 12 mg PO and diphenhydramine HCL 25-50 mg PO approximately 6 to 
12 hours prior to the next dose of eryaspase. 
5.2.5.2 
MANAGEMENT OF INFUSION/TRANSFUSION REACTIONS 
Allogeneic blood transfusions are associated with immune-related effects in the form of 
alloimmunization due to the exposure to alloantigens, cytokines, or other cellular components. 
Transfusion reactions are typically classified into the following entities [38]: i) transfusion-
related lung injury (TRALI); ii) volume overload in susceptible patients with cardiovascular 
problems ; iii) bacterial contamination; iv) acute hemolytic reactions, either immune-related with 
ABO incompatibility or non-immune related (for example, concomitant medications causing 
RBC hemolysis, incorrect storage of RBCs, or non-validated administration systems); 
v) non-hemolytic febrile reactions due to cytokines and other allo-proteins; and vi) allergic 
reactions, mostly related to unidentified allergens in the donor blood. 
Overall, eryaspase-related transfusion/infusion events have been reported in 25 (8.1%) patients 
enrolled in the combined clinical development program. None of these events were Grade 4 or 
fatal. Eryaspase utilizes leuko-depleted packed RBCs; its manufacturing process additionally 
helps to wash away any remaining leukocytes. Alloimmunization (switch from negative to 
positive anti-erythrocyte irregular antibodies) has been observed in 14.6% of patients (45 out of 
307) as of 28 Feb 2017. 
Management of transfusion/infusion reactions follows well-known published guidelines, as 
summarized in these publications [39-41]. It is recommended that Investigators follow 
institutional and local practice guidelines. Table 9 provides a summary of patient management 
for transfusion reactions. 
Table 9 
General Guidelines for Managing Transfusion Reactions 
Reaction 
Symptoms 
Interventions 
Increase in Temperature 
Increase in Temperature 


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Table 9 
General Guidelines for Managing Transfusion Reactions 
Reaction 
Symptoms 
Interventions 
Possible febrile non-
hemolytic reaction 
Incremental increase <1°C 
above baseline and no other 
new symptoms 
• Close observation, frequent vital signs 
measurement. 
• If stable and no other new symptoms, 
then continue with eryaspase. 
Possible bacterial 
contamination 
Incremental increase ≥1°C 
above baseline, or 
incremental increase <1°C 
with any other new 
symptoms (chills or rigors, 
hypotension, nausea, or 
vomiting) 
• 
Stop eryaspase; keep IV line open, 
assess patient, check patient ID 
and unit ID and compatibility. 
• 
Administer antipyretic drug. 
Strongly consider culturing blood 
product if ≥2°C increase in 
temperature or if high clinical 
suspicion of sepsis. 
Possible hemolysis 
For consistently febrile patient due to underlying disease or treatment 
with chemotherapy agents, when possible: 
Delay eryaspase if patient’s temperature is increasing. 
Treat fever with antipyretic drug before starting transfusion. 
Respiratory Symptoms 
Possible anaphylaxis, 
transfusion-associated 
circulatory overload, septic 
transfusion reaction, or 
transfusion-related acute 
lung injury 
Bronchospasm, dyspnea, 
tachypnea and hypoxemia, 
copious frothy pink-tinged 
fluid (from endotracheal 
tube) 
• 
Stop eryaspase; keep IV line open, 
assess patient, check patient ID 
and unit ID and patient 
compatibility. 
• 
Treat symptoms as indicated 
(adrenaline, antihistamines, 
steroids; oxygen and respiratory 
support, diuretics; fluid, blood 
pressure, and renal support). 
• 
Chest radiograph for presence of 
bilateral interstitial infiltrate, if 
suggestive of transfusion-related 
acute lung injury (TRALI). 
• 
Blood cultures (patient and 
product) if high clinical suspicion 
of sepsis. 
• 
Do not resume eryaspase. 
• 
Notify blood transfusion 
laboratory; return unit with 
administration set, plus post-
transfusion patient sample. 
Associated products can be 
quarantined. 
All Other Symptoms 


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Table 9 
General Guidelines for Managing Transfusion Reactions 
Reaction 
Symptoms 
Interventions 
Possible anaphylaxis, 
hemolytic transfusion 
reaction, fluid overload, or 
transfusion-related acute 
lung injury 
Chills, rigors, hypotension, 
nausea or vomiting, feeling of 
impending doom, back or 
chest pain, intravenous site 
pain, cough, dyspnea, 
hypoxia 
• 
Stop eryaspase; keep IV line open, 
assess unit, check patient ID and 
unit ID and patient compatibility. 
• 
Treat symptoms as indicated 
(adrenaline, antihistamines, 
steroids; oxygen and respiratory 
support; diuretics; fluid, blood 
pressure, and renal support). 
• 
Blood cultures (patient and 
product) if high clinical suspicion 
of sepsis. 
• 
Do not resume transfusion. 
• 
Notify blood transfusion 
laboratory; return unit with 
administration set, plus post-
transfusion patient sample. 
Associated products can be 
quarantined. 
IV: intravenous; ID: identification; TRALI: transfusion-related acute lung injury. 
5.2.5.3 
MANAGEMENT OF DIARRHEA 
Diarrhea is commonly reported with irinotecan and Onivyde, which typically has an onset in 
≤24 hours after starting Onivyde (early onset). A late onset (>24 hours) diarrhea has also been 
reported. When appropriately managed with anti-diarrheal treatment, diarrhea is generally mild 
to moderate. 
These broad general management principles are provided as a guideline to proactively avoid 
serious complications of diarrhea syndrome. These guidelines do not replace sound clinical 
judgment. 
In the event of diarrhea, patients should take loperamide at initial 4 mg dose, followed by 2 mg 
doses every 4 hours until 12 hours have lapsed without symptoms. Patients should be advised to 
increase fluid intake (water, sports drinks, clear juices, decaffeinated tea), and modify diet 
(banana, rice, apples and toast). 
• If mild to moderate diarrhea persists for more than 12 hours, loperamide should be taken 
at a dose of 2 mg every 2 hours 
• If mild to moderate diarrhea persist after 24 hours despite treatment with loperamide, a 
cocktail of atropine-diphenoxylate (Lomotil) and loperamide may be considered. 
Loperamide 2 mg may be alternated with one tablet of Lomotil every 3 hours. 
Loperamide should not be used for more than 48 consecutive hours due to risk of 
paralytic ileus. Oral antibiotic support (e.g. fluoroquinolone for 7 days) should be also 
considered. If diarrhea persists for more than 48 hours, loperamide should be stopped, 
and fluid replacement should be considered. 


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For Grade 3 or 4 diarrhea or complicated Grade 1 or 2 (severe cramping, severe 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, frank 
bleeding, dehydration), IV fluids should be used as appropriate, as well as prophylactic 
antibiotics. 
5.3 
ERYASPASE PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
5.3.1 
Acquisition and Accountability 
5.3.1.1 
ACQUISITION 
Eryaspase will be dispatched to the site only after receipt of the required information in 
accordance with ERYTECH procedures. 
• Information to be provided at study start: RBCs phenotype (including D, C, E, c, e, K 
and other antigens tested as per site practice), ABO blood group status, and Rhesus 
factor, all assessed on two separate samples, which can be collected on the same day. In 
addition, provide  historical results of an irregular antibody screening test (IAST), if 
available. This information is required at least 5 working days before the first infusion. 
• Prior to Cycle 1 Day 1 and each eryaspase dose: A prescription form indicating patient 
identifiers and body weight should be provided at the latest 5 working days prior to Cycle 
1 Day 1 (for all patients) and each eryaspase infusion (patients in eryaspase arm). 
• Information to be provided during the treatment phase: Results of IAST performed 
for previous eryaspase dose to be provided at the latest 5 working days prior to 
subsequent eryaspase infusion.  
• The following information is required before eryaspase can be shipped to the site: 
− The name and contact details of the recipient, who should be the investigator or 
designee. 
− The location for delivery (local pharmacy or blood bank). 
Detailed instructions for completing and providing the phenotype, blood group, and Rhesus 
factor information, the IAST results (from the previous infusion), and the prescription form are 
provided in the IMP manual. 
Eryaspase will be shipped to the Investigator in a qualified container by a specialized carrier, 
who will ensure that the cold chain is maintained between +2-8°C (35-46°F). 
If a temperature excursion outside the range of +2°C to +8°C (35-46°F) occurs, the product 
should be quarantined and ERYTECH Pharma should be contacted to determine the usability of 
the product. 
If it is not used immediately after receipt, it is mandatory that eryaspase be stored at temperatures 
between +2 and +8°C (35-46°F). 
Eryaspase may be stored at room temperature for up to 6 hours prior to administration, including 
infusion time; it must not be stored at room temperature for more than 6 hours. 


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5.3.1.2 
ACCOUNTABILITY 
The Investigator or designee is responsible for IMP accountability, reconciliation, and record 
maintenance (i.e., records of receipt, reconciliation, and final disposition). 
Further guidance and information concerning the final disposition of unused IMP are provided in 
the IMP Manual. 
5.3.2 
Formulation, Appearance, Packaging, and Labeling 
Please refer to the IB for details of eryaspase formulation and appearance. 
Eryaspase is packed in medical-grade polyvinyl chloride (PVC) blood bags according to GMP 
requirements and place in a photoprotective pocket. The final volume of the eryaspase bag 
depends on the patient’s weight and the dose prescribed. The volume of the bag ranges from 
50 mL to 300 mL depending on the individual patient’s dose (multiple bags may be required to 
achieve the full dose). 
Three (3) removable segment-tubes are attached to the bag for use in blood compatibility testing 
before administration. 
Label statements are specific to the clinical trial and comply with legal requirements for IMPs. 
The date and time of eryaspase expiration will be noted on the label. In addition, the label 
displays specific information necessary for traceability of source cell material and medicinal 
product (blood bank identifier for original RBCs, phenotype, patient identification number, etc.) 
to allow verification of the patient’s identity and blood group before administration. 
5.3.3 
Preparation 
Prior to eryaspase administration, an IAST and a complete compatibility test (cross-match test) 
between the patient’s blood and eryaspase, using the removable segment tubes, must be 
performed to confirm compatibility. In case a patient receives multiple bags of eryaspase to 
achieve the intended prescribed dose, separate cross-match tests must be performed with each 
eryaspase bag to confirm compatibility. 
Eryaspase should not be transferred to another container before infusion. Eryaspase should not 
be mixed or administered simultaneously with any other products, solutions, or medicinal 
products. 
After eryaspase administration, partially administered and empty bags may be destroyed locally 
under the biomedical waste disposal process as approved by the specific institution. However, in 
case of a product defect or quality issue, ERYTECH must be contacted for further instruction. 
Additional details will be described in the IMP Manual. 
Detailed instructions related to eryaspase administration and contact information in case of any 
issues are provided in the IMP Manual. 


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5.4 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
5.4.1 
Blinding 
 The study is an open-label pivotal trial. Investigators and patients will be unblinded to the 
treatment due to the nature of the investigational therapy. 
5.4.2 
Randomization 
Patients will be randomized to receive either chemotherapy in combination with eryaspase or 
chemotherapy alone in a 1:1 ratio, using an IWRS. At screening, the IWRS system will assign a 
unique patient number that will remain constant over the duration of the study. If a patient is 
rescreened after initial screen failure, the IWRS will allocate the same number. Treatment arm 
will be automatically determined by the IWRS system. Detailed instructions will be provided in 
the IWRS manual. 
Randomization will be stratified by these factors: 
• ECOG PS score (0 or 1), 
• Chemotherapy regimen (gemcitabine plus Abraxane or irinotecan-based therapy 
[FOLFIRI or Onivyde, 5-FU, and leucovorin]), and 
• Time interval since diagnosis of advanced disease to date of randomization in the study 
(<6 months or ≥6 months). 
5.5 
COMPLIANCE WITH STUDY TREATMENT 
Eryaspase will be administered by IV infusion under the supervision of study personnel. 
Compliance with the treatment dose and schedule will be documented in the source documents 
and recorded in the eCRF. 
5.6 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. All prescription medications, over-the-counter 
medications, and supplements used concomitantly or within 14 days prior to Cycle 1 Day 1 must 
be reported in the eCRF. 
5.6.1 
Prior Medications 
All treatments received within 14 days prior to Cycle 1 Day 1 will be recorded in the eCRF, 
including the name of the drug, route, indication, start date, and stop date (if applicable). In 
addition, any and all prior therapies for the treatment of pancreatic cancer (or cancer-related 
events such as bone pain) will also be recorded in the eCRF. 
5.6.2 
Permitted Medications 
Patients may receive supportive care for disease-related symptoms and for toxicity associated 
with study treatment. The date of supportive medication administration as well as the name and 
dosage regimen of each medication must be recorded in the eCRF. 


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The following treatments are permitted during the study: 
• Transfusion of blood products. 
Transfusion of fresh frozen plasma should be minimized, as it provides an exogenous 
source of asparagine. It is preferable to administer antithrombin III (AT III) concentrates 
in case of a decrease in AT III following eryaspase administration. Hemoglobin must be 
≥9 g/dL at Cycle 1 Day 1 and must be ≥8 g/dL before all subsequent doses. If 
hemoglobin is <8 g/dL, then appropriate measures must be taken according to standard 
clinical practice prior to further administration of chemotherapy. 
• Systemic and inhaled steroid treatment. 
A standard 3- to 5-day course of dexamethasone following the institutional standard of 
care is permitted for the prevention of treatment-induced nausea and vomiting. In 
addition, oral glucocorticoids at a daily dose of 1.5 mg dexamethasone (or equivalent) are 
permitted. 
• Palliative radiotherapy (e.g., for painful bone metastases). 
• Prophylactic granulocyte colony-stimulating factor (GCSF) in case of neutropenia. 
Details and indications for use of GCSF should follow American Society for Cooperative 
Oncology (ASCO) guidelines [42]. 
5.6.3 
Prohibited Medications 
During the treatment phase, the following treatments are prohibited: 
• Concomitant vaccination with live vaccines, due to increased risk of serious infection. 
Immunization with live or live-attenuated vaccines should take place no earlier than 
3 months after completion of eryaspase treatment. 
• Other L-ASNase products. 
• Highly hemolytic agents that may lead to RBC hemolysis: acetanilide, antipyrine 
(phenazone), and chloroquine and derivatives. 
• Prophylactic phenytoin. 


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6 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL FROM THE STUDY 
6.1 
DISCONTINUATION OF STUDY TREATMENT 
Discontinuation from eryaspase and/or chemotherapy treatment does not imply discontinuation 
from the study, and remaining study procedures should be completed as indicated by the study 
protocol. 
If a clinically significant finding is identified after enrollment, the investigator or qualified 
designee will determine whether any change in patient management is needed. Any new 
clinically relevant finding will be reported as an adverse event (AE). 
A patient may be withdrawn from treatment for any of the following reasons: 
• Unacceptable toxicity. 
• Objective disease progression following radiological assessment as determined by the 
investigator (per modified RECIST 1.1 criteria). 
• Patient’s withdrawal of consent for treatment. 
• Pregnancy 
• Investigator’s decision for other reasons, with documentation of reason(s) if not 
included in any of the above categories. 
NOTE: Clinical progression must be confirmed radiologically before treatment 
discontinuation and patient withdrawal. 
• Sponsor’s decision, including discontinuation of the study, with documentation of 
reason(s) in the eCRF. 
The reason for withdrawal will be recorded in the eCRF. 
The EOT visit must be performed and documented within 30 days after the last dose of eryaspase 
or chemotherapy. AEs/SAEs and concomitant medications must be collected up to 90 days after 
the last dose of study treatment or until start of new anti-cancer treatment, whichever is first. For 
details of the assessments to be performed, refer to the Schedule of Events (SOE), Table 1. 
6.2 
PARTICIPANT WITHDRAWAL FROM THE STUDY 
A patient may be withdrawn from the study for the following reasons: 
• Patient’s withdrawal of consent for the study. 
• Loss to follow-up. 
• Death. 
• Sponsor’s decision, including discontinuation of the study. 
The reason for withdrawal will be recorded in the eCRF. 
If a patient withdraws from the study during treatment, it is recommended that the EOT visit be 
performed and documented within 30 days if possible. For details of the assessments to be 
performed, refer to the SOE, Table 1. 


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If a patient withdraws from the study, the Investigator must make every effort to follow 
safety events to resolution, until the events stabilize, or until the patient’s death. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples that have 
been taken but not yet tested, and the Investigator must document this request in the site’s study 
records and inform the Sponsor within 5 working days. 
 
6.3 
LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he or she fails to return for scheduled visits and 
cannot be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the patient and reschedule the missed visit within 
one week, will counsel the patient on the importance of maintaining the assigned visit 
schedule, and will ascertain whether the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter [or local equivalent] to the patient’s last known mailing 
address). These contact attempts should be documented in the patient’s medical record or 
study file. 
• Should the patient continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of loss to follow-up. 
 
6.4 
STUDY TERMINATION 
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason. If the study is terminated, the Sponsor will notify the Investigators in writing. If 
the study is prematurely terminated or suspended, the Investigator will promptly inform study 
participants and the relevant IEC/IRB, and the Sponsor will provide the reason(s) for the 
termination or suspension to competent regulatory authorities. Study participants will be 
contacted as appropriate and will be informed of any changes to the study visit schedule. 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of an investigational site by the sponsor may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the sponsor’s procedures, or 
Good Clinical Practice (GCP) guidelines. 


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• Inadequate recruitment of patients by the Investigator. 
• Discontinuation of further drug development. 
The Investigator will be responsible for completing all study close-out procedures as required by 
the Sponsor and/or local regulatory authorities if a site is closed or the study is terminated early. 


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7 
STUDY ASSESSMENTS AND PROCEDURES 
Screening and study procedures and their timings are summarized in the Schedule of Events 
(SOE) in Table 1. 
Adherence to the study requirements, including those specified in the SOE, is essential and 
required for study conduct. Protocol waivers or exemptions are not allowed (with the exception 
of those in response to immediate safety concerns). 
All screening evaluations must be completed within 3 weeks prior to randomization, with 
confirmation that the patient continues to meet eligibility criteria prior to dosing on Cycle 1 
Day 1. The Investigator will maintain a screening and enrollment log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.  
The COVID-19 pandemic has impacted the conduct of this study, including travel restrictions 
and confinements of the trial participants and trial staff to perform study assessments. Several 
measures have been implemented by ERYTECH, and are reflected on trial assessments as 
described further below in the respective sections. 
7.1 
SCREENING ASSESSMENTS AND PROCEDURES 
All patients must sign and date an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved Informed Consent Form (ICF) prior to any screening assessments. 
However, an evaluation conducted as part of the patient’s routine clinical management (e.g., 
blood counts, disease evaluation) that is performed before signature of the ICF may be utilized 
for screening or baseline purposes provided that the procedure met the protocol-specified criteria 
and was performed within the time frame defined in the SOE (Table 1). Separate informed 
consent for the optional PGx assessment will be requested at the same time. 
For further information on the informed consent process, please refer to Section 9.1.1. 
Eligibility criteria are to be evaluated within 3 weeks prior to randomization, with confirmation 
that the patient continues to meet eligibility pre-dose on Cycle 1 Day 1. 
NOTE: Screening period longer than 3 weeks may be allowed due to COVID-19 related 
restrictions  
Screening Assessments to Be Completed within 3 Weeks prior to Randomization 
• Demography, including gender and date of birth. 
• Medical history, including cancer history and prior anticancer therapies. 
• Complete physical exam, including height and weight (height to be collected at screening 
only). 
• Vital signs: temperature, heart rate, and blood pressure. 
• ECOG PS, and KPS if ECOG PS is 1 (see APPENDIX 2 and APPENDIX 3). 
• Laboratory assessments (to be completed within 14 days of randomization): hematology, 
clinical chemistry, and coagulation panels will be completed at the local laboratory for 
the parameters defined in Table 10 below. All laboratory results must be documented in 
the eCRF. Additionally, reference ranges must be provided to the sponsor or its designee. 


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NOTE:  Please see Table 12 in Section 7.8.3 for Minimum Safety Labs required during 
COVID-19. 
• Serum pregnancy test (for patients of childbearing potential): a negative human chorionic 
gonadotropin test is required before the patient may receive any chemotherapy agent or 
eryaspase. 
• NOTE: A woman is considered of childbearing potential unless post-menopausal or 
permanently sterile by one of following methods: hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. A woman is considered postmenopausal in she has not had 
menses for 12 months without an alternative medical cause. 
• Collection of a paraffin-embedded tumor tissue block, or a minimum of 10 unstained 
slides, obtained from an archived or newly obtained tumor tissue sample for biomarker 
analysis. 
• Whole blood sample for PGx assessment (optional) 
• 12-lead ECG. 
• Baseline disease assessments: 
− Radiological imaging studies: 
o Chest CT scans. 
o Abdomen CT scans. 
o Brain MRI is indicated in patients with known/suspected brain metastasis at study 
entry. Brain scans will be repeated during the study at 12-week intervals if 
clinically indicated. 
o Bone scan is indicated in patients with known/suspected bone metastasis at study 
entry. Bone scans will be repeated during the study at 12-week intervals if 
clinically indicated. 
• Additional imaging as clinically indicated. 
− In general, CT scans are the preferred method of radiological assessment of the chest 
and abdomen; however, other techniques may be used (i.e., MRI). 
o The same imaging technique must be used for a given patient throughout the 
study. 
o Radiological images must be collected in a de-identified manner, quality 
controlled, stored, and available for future review and reading as necessary. 
• Prior and concomitant medications: record all medications the patient has received from 
14 days prior to randomization, as well as any and all prior therapies for the treatment of 
pancreatic cancer (or cancer-related events such as bone pain), and any currently ongoing 
medications. 
• Collection of AEs and SAEs from the date of informed consent. 
Table 10 
List of Laboratory Assessments 
Category 
Parameter 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 


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Table 10 
List of Laboratory Assessments 
Category 
Parameter 
RBC count 
White blood cell (WBC) count with differential 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
Coagulation: 
Fibrinogen 
Antithrombin III (AT III) 
 
Serum Chemistry and Tumor Markers: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Ammonia 
Amylase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH) 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total cholesterol 
Triglycerides 
Urea 
Uric acid 
CA19-9 
Other Laboratory Tests: 
Blood phenotype, Rh factor, and ABO blood 
group, all done on two separate samples 
Irregular antibody screening test (IAST) 
 
Pregnancy test for women of childbearing 
potential (serum at screening and at End of 


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Table 10 
List of Laboratory Assessments 
Category 
Parameter 
Treatment; urine on Cycle 1 Day 1 before 
treatment and as indicated during treatment for 
females of child-bearing potential) 
 
7.2 
RANDOMIZATION 
Patients who are found to be eligible for the study will be randomized to study treatment within 
3 days prior to Cycle 1 Day 1. Randomization will be done through the IWRS as described in 
Section 5.4.2. 
The following assessment will be performed at least 5 days prior to Cycle 1 Day 1: 
− RBC phenotype (including D, C, E, c, e, K and other antigens as per site practice), 
ABO blood group status, and Rhesus factor, all assessed on 2 separate samples, which 
can be collected on the same day. This information is required at least 5 working days 
before the first eryaspase infusion. 
A prescription form indicating patient identifiers and body weight, the recipient of the product 
(Investigator or designee), and the place and time of the delivery must be sent as soon as possible 
once the first infusion is scheduled (at the latest 5 working days before planned administration ). 
7.3 
TREATMENT PHASE ASSESSMENTS AND PROCEDURES 
7.3.1 
Assessments prior to Initiation of Treatment on Cycle 1 Day 1 
The following assessments will be performed on Cycle 1 Day 1 prior to initiation of study 
treatment. Screening laboratory tests and procedures may be substituted for those on Cycle 1 
Day 1 if performed within 5 days prior to Cycle 1 Day 1. 
• Symptom-directed physical examination, including body weight. 
• Vital signs: temperature, heart rate, and blood pressure. 
• ECOG PS, and KPS if ECOG PS is 1 (see APPENDIX 2 and APPENDIX 3). 
• EORTC QLQ-C30. 
• Hematology, clinical chemistry, and coagulation panels and CA19-9, Table 10. 
• Urine pregnancy test for patients of childbearing potential. A negative test is required 
before administration of any chemotherapy agent or eryaspase. 
• Baseline blood and plasma samples for pharmacokinetic and pharmacodynamic analysis 
(for patients in the eryaspase arm). 
• Baseline blood samples for immunogenicity (for patients in the eryaspase arm). 
• Baseline blood and plasma samples for biomarker analysis (both arms), such as ctDNA, 
proteomics, and transcriptomics. 
Prior to administration of the first infusion of eryaspase, (and each subsequent infusion during 
the treatment period), an IAST and complete compatibility (cross-match) test between the 


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patient’s blood and eryaspase should be performed using the removable segment tubes to 
confirm compatibility. In case a patient receives multiple bags of eryaspase to achieve the 
intended prescribed dose, a separate cross-match test must be performed with each eryaspase bag 
to confirm compatibility. In case of incompatibility, an additional blood sample may be required 
for further investigations. Details of collection and shipment are provided in the IMP Manual. 
7.3.2 
Efficacy Assessments During the Treatment Phase 
7.3.2.1 
RADIOLOGICAL DISEASE ASSESSMENTS 
CT/MRI of the chest and abdomen will be performed every 8 weeks (±3 days) calculated from 
the date of randomization until disease progression, patient’s withdrawal from study, or death. 
Every effort should be made to adhere to the assessment schedule, irrespective of any 
treatment delays or modifications. The same imaging technique must be utilized for a given 
patient throughout the study. 
Bone and/or brain scans are to be repeated every 12 weeks if clinically indicated. 
7.3.2.2 
HEALTH OUTCOMES 
Patient-reported outcomes will be measured using a standardized instrument, the EORTC 
QLQ-C30. The self-administered questionnaires will be completed every 4 weeks during the 
treatment phase. 
7.3.2.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
For patients in the eryaspase arm, blood/plasma samples for pharmacokinetic and 
pharmacodynamic assessment will be collected, where possible, at the following time points of 
Cycles 1 and 3: 
• Day 1 prior to eryaspase administration, 
• Day 1 at 5-10 minutes post- eryaspase infusion, 
• At 5-8 days post-infusion (at the Investigator’s discretion), and 
• At Day 15 pre-dose. 
Samples will be analyzed for whole blood and plasma concentrations of ASNase and amino 
acids. The sparse PK data will be combined with previous data as part of a Population PK 
(POP PK) analysis. To this effect, sample collection for PK and pharmacodynamics may be 
stopped based on the outcome of the evaluation of sample results during the course of the trial. 
The date and clock time for collection of each blood sample and for sample processing (e.g., 
time placed on ice, time of centrifugation, etc.) will be documented. Further details will be 
provided in the lab manual. 
7.3.2.4 
IMMUNOGENICITY 
For patients in the eryaspase arm, samples for assessment of anti-ASNase antibodies and 
neutralizing antibodies will be collected pre-dose at Cycle 1 Day 1, and Day 15 and at Day 1 of 
every second cycle thereafter (i.e., at Cycle 3 Day 1, Cycle 5 Day 1, and so on), and upon 
determination of disease progression, and EOT, whichever is sooner. 


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7.3.2.5 
BIOMARKER ASSESSMENTS 
Plasma Samples 
Plasma samples for biomarker analysis will be collected pre-dose on Cycle 1 Day 1 and Day 15 
and at Day 1 of every second cycle thereafter (i.e., at Cycle 3 Day 1, Cycle 5 Day 1, and so on), 
upon determination of disease progression, and EOT, whichever is sooner. 
Pharmacogenetic Sample 
An optional blood sample for pharmacogenetic (PGx) analysis will be obtained once during the 
study, preferably during the screening phase. A separate informed consent must be signed before 
the sample is obtained. 
7.3.3 
Safety Assessments during the Treatment Phase 
The following safety assessments will be performed pre-dose for all patients on Day 1, and 
Day 15, unless otherwise specified. 
• Hematology, clinical chemistry, and coagulation panels and CA19-9. 
• For patients under eryaspase arm, in addition to regular evaluation of liver function tests 
before treatment administration, patients will be monitored on weekly basis in the event 
of occurrence of ≥Grade 2 elevation of liver enzymes and bilirubin levels. 
• For women of childbearing potential, additional pregnancy testing should be performed 
in case of delayed menstrual period and is recommended to be performed monthly and 
until the end of treatment exposure extended by 30 days, in case of sexual activity.  
• Vital signs: temperature, heart rate, and blood pressure. 
• Symptom-directed physical examination, including body weight. 
• ECOG PS (see APPENDIX 2). 
• 12-lead ECG: as clinically indicated. 
• Collection of AEs: from time of informed consent until 90 days after the last study 
treatment or start of new anti-cancer treatment, whichever is sooner. 
• Review/recording of all concomitant medications added and/or changed from 14 days 
prior to randomization until 90 days after the last study treatment or start of new 
anti-cancer treatment, whichever is sooner. 
7.4 
END OF TREATMENT VISIT 
The End of Treatment (EOT) visit should be conducted as soon as possible (but no later than 
30 days) after the patient’s discontinuation of the study drug, and will include the following 
assessments: 
• Hematology, clinical chemistry, and coagulation panels and CA19-9. 
• Serum pregnancy test for patients of childbearing potential. 
• Vital signs: temperature, heart rate, and BP. 
• Symptom-directed physical exam, including body weight. 
• ECOG PS (see APPENDIX 2). 
• EORTC QLQ-C30. 
• Review of AEs and concomitant medications. 


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• Samples for immunogenicity (for patients in the eryaspase arm) and biomarker analysis 
(both arms). 
7.5 
FOLLOW-UP PHASE ASSESSMENTS AND PROCEDURES 
During the follow-up phase, the extent of efficacy evaluation will depend on the disease status: 
• In the absence of disease progression or starting new anti-cancer therapy 
− Radiological imaging of Tumor lesions to be carried out every 8 weeks until disease 
progression, 
− And then OS follow up every 8 weeks until death, lost for follow up or withdrawal 
from study 
• In the presence of objective disease progression or start of anticancer therapy 
−  OS follow up every 8 weeks until death, lost for follow up or withdrawal from study. 
 
Collection and follow-up of AEs and SAEs will occur until 90 days after discontinuation of the 
study drug, beginning of a new cancer treatment, or death, whichever occurs first. SAEs will be 
followed until resolution. 
For all patients who discontinue study treatment, the EORTC QLQ-C30 questionnaire will be 
completed every 8 weeks during the follow-up phase until withdrawal from the study or death. 
7.5.1 
Post-Study Subsequent Cancer Therapy 
Information will be collected about any subsequent cancer therapy given after discontinuation of 
study drug (s), including both medications and procedures. 
7.5.2 
Survival Follow-Up 
Survival information will be collected by phone, follow-up visit, or from medical records 
approximately every 8 weeks from the date of the EOT visit until the patient’s death, until the 
patient is lost to follow-up, or until study closure. Survival follow-up will include collection of 
information about any subsequent anticancer therapy received after discontinuation of study 
drug. 
If a patient fails to return for scheduled visits or is unreachable for survival follow-up, the 
following efforts should be made to contact him/her: 3 phone attempts, including the date and 
time, should be documented in the patient’s chart. If there is no response to the phone calls, a 
certified letter or local equivalent should be sent. After these efforts have been exhausted with no 
response, a patient should be considered as lost to follow-up. 
7.6 
EFFICACY ASSESSMENTS 
7.6.1 
Radiological Disease Assessment and Evaluation of Response 
CT/MRI scans of the chest and abdomen will be performed every 8 weeks, calculated from the 
date of randomization, until disease progression, or until withdrawal from the study, or death. 


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Every effort should be made to adhere to the assessment schedule. The same imaging 
technique must be utilized for a given patient throughout the study. 
Tumor response and disease progression will be evaluated in this study using a modified version 
of the criteria proposed by the RECIST Committee, version 1.1 (RECIST 1.1). The 
modifications to RECIST 1.1 will be used to more accurately and consistently assess responses 
in specific cases that are not addressed in RECIST 1.1. These modifications are indicated 
below in italics. 
7.6.1.1 
KEY DEFINITIONS 
7.6.1.1.1 
MEASURABLE DISEASE 
• Measurable non-nodal lesions: those that can be accurately measured in at least 1 
dimension, longest diameter (LD) to be recorded as ≥10 mm by CT scan (CT slice 
thickness no greater than 5 mm). 
• Malignant lymph nodes: to be considered pathologically enlarged and measurable, a 
lymph node must measure ≥15 mm in the short axis (SA) when assessed by CT scan (CT 
slice thickness recommended to be no greater than 5 mm). 
• It is recommended that slice gaps not be utilized for the image acquisition procedures. 
• All radiographic measurements should be taken and recorded in millimeters utilizing an 
electronic measurement method based on lesion boundary definition. 
• Lesions on chest X-ray will not be considered measurable. 
7.6.1.1.2 
NON-MEASURABLE DISEASE 
• All other lesions (or sites of disease), including small lesions (LD <10 mm or 
pathological lymph nodes ≥10 mm to <15 mm in the SA) as well as truly non-measurable 
lesions, are considered non-measurable disease. Lesions considered truly non-measurable 
include leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory 
breast disease, lymphangitic involvement of skin or lung, and masses or abdominal 
organomegaly identified by physical exam that are not measurable by reproducible 
imaging techniques. 
7.6.1.1.3 
TARGET LESIONS 
• Target lesions must be measurable lesions. 
• All lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, will be identified as target lesions, recorded and 
measured at baseline, and followed consistently throughout the study. 
• Target lesions should be selected on the basis of their size (based on LD for non-nodal 
lesions or SA for lymph nodes), their suitability for accurate repeated measurements, and 
on their being most representative of the patient’s tumor burden. 
• A sum of the diameters for all target lesions will be calculated and reported for each time 
point. The baseline sum of diameters will be used as a reference according to which the 
objective tumor response will be characterized. 


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7.6.1.1.4 
NON-TARGET LESIONS 
• All other lesions (or sites of disease, including any measurable lesions that were not 
selected as target lesions) will be identified as non-target lesions and indicated as present 
at baseline. 
• It is possible to record multiple non-target lesions involving the same organ as a single 
item (e.g., multiple enlarged pelvic lymph nodes or multiple liver metastases). 
• Measurements of these non-target lesions will not be performed, but the presence, 
absence, or unequivocal progression of these lesions should be noted for subsequent 
assessments. 
7.6.1.1.5 
NEW LESIONS 
• A separate assessment category of “new lesions” is defined as part of the independent 
reading. 
• The finding of a new lesion should be unequivocal (i.e., not attributable to differences in 
scanning technique, change in imaging modality, etc.). 
• If a new lesion is equivocal (i.e., because of its small size), and follow-up imaging 
confirms that it is definitely a new lesion, then the lesion will be considered to have 
appeared on the date of the initial scan, indicating disease progression as of that date.  
• A lesion identified on a follow-up scan in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
• A lesion that reappears at follow-up after a response of PR or stable disease is not 
considered new. The lesion’s LD (or SA for lymph nodes) is added back into the sum of 
diameters. 
• A lesion that reappears at follow-up after a CR is automatically considered PD. 
7.6.1.1.6 
LYMPH NODES 
• At baseline, lymph nodes with tumor burden will be considered target lesions if the SA is 
≥15 mm. 
• At baseline, lymph nodes will be considered non-target lesions if the SA is ≥10 mm and 
<15 mm. 
• At baseline, lymph nodes will be considered normal if the SA is <10 mm. 
• At subsequent assessments, a lymph node must measure ≥10 mm along the SA to be 
considered a new lesion. 
• A lymph node that was identified as a target lesion at baseline that falls below the 
measurable threshold at subsequent assessment and then gets larger is not considered 
new if it follows a PR or SD. The lymph node SA measurement is added back into the 
sum of diameters. 
• A lymph node that was identified as a target lesion at baseline that falls below the 
measurable threshold at subsequent assessment and then gets larger following a CR is 
automatically considered PD. 


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7.6.1.2 
OTHER CONSIDERATIONS 
7.6.1.2.1 
IRRADIATED LESIONS 
Previously irradiated lesions cannot be selected as target lesions. These lesions can be monitored 
to assess progression as non-target lesions. 
7.6.1.2.2 
HANDLING OF LESIONS THAT SPLIT 
When non-nodal and nodal lesions split or fragment, the individual diameters of the fragmented 
portions should be added together to calculate the target lesion sum. 
7.6.1.2.3 
HANDLING OF LESIONS THAT MERGE 
As lesions merge, a boundary between the lesions should be drawn so the LD or SA of each 
individual lesion can continue to be measured. If the lesions have merged in such a way that they 
can no longer be separated by this boundary, the LD or SA of the merged lesion should be 
measured. 
7.6.1.3 
MEASUREMENT OF SMALL LESIONS ON FOLLOW-UP SCANS 
7.6.1.3.1 
NON-NODAL LESIONS 
A non-nodal target lesion that is present but too small to measure accurately at evaluations after 
baseline (<5 mm but greater than 0 mm in unilateral dimension) will be classified as Too small 
to measure and will be assigned a value of 5 mm for the purposes of determining the sum of 
diameters. All other lesions (i.e., ≥5 mm) will have actual size recorded. 
7.6.1.3.2 
LYMPH NODES 
A target lymph node should always have the actual SA measurement recorded, even if the lymph 
node regresses to <10 mm on study. This means that when lymph nodes are included as target 
lesions, the sum of diameters may not be zero even if CR criteria are met, since a normal lymph 
node is defined as having an SA of <10 mm. 
7.6.1.4 
RESPONSE CRITERIA 
7.6.1.4.1 
TARGET LESION RESPONSE CRITERIA 
• Complete response (CR): Disappearance (or normalization) of all target lesions. 
− Any pathological lymph nodes (whether target or non-target) must have reduction in 
SA to <10 mm.  
• Partial response (PR): At least 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters.  
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
• Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm.  


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• Non-evaluable (NE): Patient time points that have inadequate or missing images, 
including the inability to visualize >25% of target disease. 
7.6.1.4.2 
NON-TARGET LESION RESPONSE CRITERIA 
• CR: Disappearance (or normalization) of all non-target lesions.  
• All lymph nodes must be non-pathological in size (<10 mm SA). 
• Non-complete response, non-progressive disease (Non-CR/Non-PD): Persistence of 1 or 
more non-target lesion(s). 
• PD: Unequivocal progression of existing non-target lesions. 
• NE: Patient time points that have inadequate or missing images, including the inability to 
visualize >50% of non-target disease. 
• No disease (ND): No non-target disease noted. The absence of non-target lesions at 
follow-up time points is designated as ND and not SD when there is no non-target 
disease noted at baseline. 
7.6.1.4.3 
NEW LESION RESPONSE CRITERIA 
A separate assessment of the appearance of one or more new lesions will be provided in the read. 
If at least one new lesion is present, the patient is considered to have progressive disease overall. 
7.6.1.4.4 
RESPONSE ASSESSMENT IN CASE OF MISSING OR 
TECHNICALLY INADEQUATE SCANS 
If no lesions were identified at baseline in a specific body region (e.g., chest or abdomen) and the 
scan of that body region is unavailable at follow-up, then the response assessment will be based 
on the scans of the other regions. 
7.6.1.5 
DETERMINATION OF RADIOLOGICAL BEST OVERALL RESPONSE 
Best overall response (BOR) is the best response recorded from the start of treatment until the 
end of treatment (taking as reference for PD the smallest measurement recorded since the start of 
treatment). 
7.6.2 
Health Outcomes 
Patient-reported outcomes will be measured using a standardized instrument, the EORTC 
QLQ-C30, at the following time points: 
• Cycle 1 Day 1 before treatment. 
• Every 4 weeks during the treatment phase, Day 1 of each cycle before treatment. 
• At the End of Treatment visit. 
• Every 8 weeks during the follow-up phase until end of study. 
The following scores will be calculated: 5 functional scales, 3 symptom scales, a global health 
status/quality of life (QoL) scale, and 6 single items (Table 11). 


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Table 11 
EORTC QLQ-30 Scales and Items [43] 
 
Scale 
Number 
of Items 
Item 
Range* 
Version 3.0 
Item Numbers 
Function 
Scales 
Global health 
status/QoL 
QL2 
2 
6 
29, 30 
 
Functional scales 
Physical functioning 
(revised)† 
PF2 
5 
3 
1 to 5 
F 
Role functioning 
(revised)† 
RF2 
2 
3 
6, 7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social functioning 
SF 
2 
3 
26, 27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14, 15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnoea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhoea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
*Item range is the difference between the possible maximum and the minimum response to individual items; 
most items take values from 1 to 4, giving range = 3. 
†(revised) scales are those that have been changed since version 1.0, and their short names are indicated by a 
suffix “2” – for example, PF2. 
7.6.3 
Pharmacokinetic and Pharmacodynamic Assessments 
Eryaspase pharmacokinetics will be evaluated using sparse sampling, where possible. Whole 
blood and plasma concentrations of ASNase from these samples will be combined with previous 
data as part of a POP-PK analysis. The pharmacodynamic effect of eryaspase on amino acid 
levels will also be evaluated. 
For all patients who provide samples, PK and pharmacodynamics of eryaspase will be assessed 
at each measurement in terms of: 
• Total ASNase activity (U/L), 
• Plasma ASNase activity (U/L), 
• Plasma concentrations of asparagine (µmol/L), and 


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• Plasma concentrations of glutamine (µmol/L). 
See Section 7.8.5 for information related to the discontinuation of PD sample collection due to 
COVID-19  
7.6.4 
Immunogenicity 
The development of anti-ASNase antibodies and neutralizing antibodies will be determined for 
patients in the eryaspase arm. 
7.6.5 
Biomarker Assessments 
This study will collect samples for biomarker assessments in all patients. Sample types collected 
include tumor samples, whole blood samples and plasma samples. Biomarkers will be tested 
prospectively and summarized at baseline and, where applicable, at subsequent assessments. 
These assays will be performed at central laboratories. In addition, biomarkers identified in other 
clinical studies may also be assessed in the biomarker samples collected from patients enrolled in 
this study. Detailed instructions for processing, storage, and shipping of samples will be provided 
in the Laboratory Manual  
7.6.5.1 
ANALYSIS OF TUMOR TISSUES 
A paraffin-embedded tissue block (FFPE), or a minimum of 10 unstained slides, obtained from 
an archived or newly obtained tumor tissue sample (primary tumor or metastatic lesion) will be 
required.  
All tumor samples may be used to assess the effects of eryaspase and tumor-relevant pathway 
dysregulation (such as mutations, amplifications) that may be important in the development of 
progression of cancer as well as for the potential use in diagnostic development. Assays to 
evaluate biomarkers that may correlate with clinical outcome may be performed at central 
laboratories, such as: 
• Mutational analyses and detection of gene amplification of relevant oncogenes (e.g., 
KRAS, MYC, PI3KCA, and FGFR) and genes involved in activated pathways of survival 
and proliferation (e.g., Erk1/2, STAT3, AKT, and MAPK). 
• Expression profiling may be done by analysis of ribonucleic acid (RNA) extracted from 
tissue. 
• Depending on tissue availability, additional assays including immunohistochemistry 
(IHC), gene expression profiling, or protein activation may be performed. 
• If applicable, mechanisms of resistance to eryaspase treatment will be evaluated. 
 
 
7.6.5.2 
ANALYSIS OF PLASMA SAMPLES 
Plasma samples will be collected for the following biomarker analyses: 
• Circulating tumor DNA (ctDNA) may be analyzed in plasma samples to identify 
plasma-borne somatic mutations as predictors of clinical outcome with eryaspase. 
• Proteomic and transcriptomic analyses of biomarker samples may be conducted to 
identify profiles that can be related to treatment response. Examination of pre- and 


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post-treatment protein and transcript profiles may uncover novel blood-borne candidate 
biomarkers/profiles that could be used to predict response to eryaspase. 
• Markers of immunological response may be evaluated for correlation with response. 
7.6.5.3 
PHARMACOGENETIC ANALYSIS 
Pharmacogenetic analysis is the study of the variability in drug response due to hereditary 
factors. Individual genetic composition (genotype) may have an impact on the PK and the 
pharmacodynamic effects of the drug. Examples of pharmacogenetic analyses include 
genotyping of metabolizing enzymes such as uridine 5'-diphosphate glucuronosyltransferases 
(UGTs) and transports, evaluation of a whole-genome single nucleotide polymorphism (SNP), or 
other genetic marker sets. The information obtained is solely used to further characterize drug 
effects and does not have clinical, diagnostic, or therapeutic implications for the individual 
patients. This PGx research is not designed to determine whether other members of the patient’s 
family are at risk of developing pancreatic cancer. The Sponsor will be blinded as to the 
subject’s identity and since the analysis is done for research purposes only, individual results will 
not be shared with the Investigator and/or subject or the subject’s relatives. Any information 
obtained is not intended for inclusion in the medical record. This research will not change the 
care the subject receives in this study. 
A whole blood sample (5 mL) will be drawn using a tube containing ethylenediaminetetraacetic 
acid (EDTA) from patients who provide separate written informed consent for this optional 
procedure. Patient participation in the PGx analysis is voluntary, and refusal of consent will not 
disqualify the patient from participating in the study. Furthermore, a patient can withdraw 
consent for the PGx analysis at any time during the study. 
7.6.5.4 
SAMPLE COLLECTION, STORAGE, AND SHIPPING 
Detailed procedures for collection, processing, handling, storage, and shipment of samples for 
central laboratory analysis (PK, pharmacodynamics, immunogenicity, biomarkers, and PGx) will 
be provided in the Laboratory Manual. 
7.6.5.5 
BIOANALYSIS 
Samples will be analyzed using validated, where applicable, analytical methods. A description of 
the assays and validation data will be provided in separate analytical reports. 
7.6.5.6 
STORAGE OF BIOLOGICAL SAMPLES FOR POTENTIAL FUTURE 
ANALYSIS 
After the end of the study, biological samples or derivatives (such as DNA, RNA, and protein) 
will be stored at a central repository for the maximum number of years defined per local 
regulatory requirements to allow scientific research to be conducted in the future as new 
discoveries are made. 


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7.7 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The Investigator is required to report to the Sponsor or its representative all AEs occurring 
during the clinical study (Title 21 Code of Federal Regulations [CFR] Part 312.64[b] and 
International Council for Harmonization [ICH] E6 [R2]).  
7.7.1 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal 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 (new or exacerbated) temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
7.7.2 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
1. Results in death, 
2. Is life-threatening, 
3. Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. Results in persistent or significant disability/incapacity, 
5. Is a congenital anomaly/birth defect, or 
6. Is otherwise medically significant (any event not meeting the above criteria that, based 
upon medical judgment, jeopardizes the patient, and may require medical or surgical 
intervention to prevent one of the other outcomes listed in the definition of an SAE). 
NOTE: If the standard of care or institutional practice requires hospitalization of patients for the 
sole purpose of conducting study procedures or delivering study therapy, then such hospital 
admission will not be considered or reported as meeting SAE criteria. However, should an SAE 
develop during such a hospitalization, it will be considered serious and reported as such. 
NOTE: Disease progression should not be reported as an SAE for the purposes of this study. 
NOTE: in instances, where an adverse event changes to serious event; this date should be the 
onset date of the SAE. 
7.7.3 
Classification of Adverse Events 
7.7.3.1 
SEVERITY GRADING 
The severity of AEs is to be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. For AEs not listed in the 
CTCAE scale, the following definitions should be used: 
• Mild (Grade 1): The AE is noticeable to the patient but does not disrupt normal daily 
activities; it does not require discontinuation of the study drug, but may require additional 
therapy. 


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• Moderate (Grade 2): The AE is moderately uncomfortable and interferes with the 
patient’s daily activities; it does not require discontinuation of the study drug but may 
require additional therapy. 
• Severe (Grade 3): The AE is intolerable and disrupts normal daily activities, and may 
require additional therapy or hospitalization and/or discontinuation of the study drug. 
• Life-threatening (Grade 4): The AE exposes the patient to risk of death at the time of 
the event; this does not refer to an event that might have caused death if it had been more 
severe. Any event which is considered life-threatening is considered to be serious, and 
must be reported as described in Section 7.7.6. 
• Death related to AE (Grade 5): An event that results in death is considered a Grade 5 
AE, and by definition, is an SAE. Any event with a fatal outcome must be reported as 
described in Section 7.7.6. 
7.7.3.2 
CAUSALITY ASSESSMENT 
An Investigator who is qualified in medicine must assess the causal relationship between 
eryaspase, chemotherapy, or both and each occurrence of each AE/SAE. The Investigator should 
decide whether, in his/her medical judgment, there is a “reasonable possibility” that the event 
may have been caused by the study drug (IMP and non-IMP background treatment). 
• If no valid reason exists for suggesting a causal relationship between the study drug (IMP 
or non-IMP background treatment) and the occurrence of the AE, then the AE should be 
classified as “unrelated.” 
• If there is any valid reason for suspecting a possible causal relationship between the study 
drug (IMP and non-IMP background treatment) and the occurrence of the AE, then the 
AE should be considered “related.” 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study treatment administration, should be 
considered and investigated. The Investigator should also consult the IB in making his/her 
assessment. 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is critical that the 
Investigator provide an assessment of causal relationship for every event before the initial 
transmission of the SAE report to the Sponsor, as it is one of the criteria used when determining 
regulatory reporting requirements. 
The Investigator may change his/her opinion of causality in light of follow-up information; in 
this case an SAE follow-up report should be sent with the updated causal relationship 
assessment. 
Definitions of the causal relationship of an AE to the use of the study medication are as follows: 
• Related: There is a reasonable possibility of a causal relationship between the 
administration of the study drug (IMP and non-IMP background treatment) and the 
adverse event emergence. “Reasonable possibility” means there is evidence to suggest a 
causal relationship, e.g. temporal relationship, biological plausibility, between study 
intervention and the AE. 


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• Not Related: There is no reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and the event onset, or an alternate etiology has been established. 
7.7.3.3 
EXPECTEDNESS 
The drug safety group will be responsible for determining whether an AE is expected or 
unexpected, based on available reference safety information in the IB. An AE will be considered 
unexpected if its nature, severity, or frequency is not consistent with the reference safety 
information described for eryaspase in the IB. 
7.7.4 
Time Period and Frequency for Adverse Event Assessment and Follow-Up 
All AEs that are reported by a patient or observed by study personnel from the date of patient 
informed consent until 90 days after the last study treatment or start of new anti-cancer 
treatment, whichever is sooner, will be reported. 
Any medical condition that is present at the time that the patient is screened will be considered as 
a baseline condition and not reported as an AE.  
All AEs must be followed until they resolve, return to baseline, or are determined to be 
permanent at the EOT visit. 
7.7.5 
Recording Adverse Events and Serious Adverse Events 
All AEs, whether serious or non-serious, must be recorded in the source documents and in the 
eCRF using standard medical terminology. For each event, the Investigator will evaluate and 
report the onset date, resolution date, severity, causality, action taken, seriousness, outcome (if 
applicable), and whether or not it caused any change in study drug administration (dose delay, 
dose reduction, or study treatment discontinuation). Changes in the severity of an AE must be 
documented to allow the duration of the event at each level of severity to be assessed. AEs 
characterized as intermittent require documentation of the onset and duration of each episode. 
Whenever possible, diagnoses should be provided when signs and symptoms represent a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as “upper respiratory infection”). A specific disease or syndrome, rather than individual 
associated signs and symptoms, should be identified whenever possible. Where there is no link 
between different clinical symptoms occurring at the same time, each sign should be recorded as 
a separate AE. All reported information must be in English. 
When an AE occurs, it is the Investigator’s responsibility to review all documentation related to 
the event (e.g., hospital progress notes, laboratory and diagnostics reports). The Investigator will 
then record all relevant AE information in the eCRF. It is not acceptable for the Investigator to 
send photocopies of the patient’s medical records to the Sponsor in lieu of completion of the 
eCRF AE pages. 
In some instances, the Sponsor may request copies of medical records for certain patients. 
Should this occur, all patient identifiers, with the exception of the patient’s study identification 
number, will be redacted on the copies of the medical records before submission to the Sponsor. 


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7.7.6 
Serious Adverse Event Reporting 
7.7.6.1 
INVESTIGATOR REPORTING RESPONSIBILITIES FOR SERIOUS 
ADVERSE EVENTS 
If an AE meets the definition of “serious,” the Investigator must report it immediately (within a 
maximum of 24 hours from knowledge of the event), regardless of its presumed relationship to 
the IMP. To do so, the Investigator must complete the SAE Form, and forward it to 
PrimeVigilance, mandated by ERYTECH Pharma, at: 
Email: erytechpv@primevigilance.com 
eFax (US): +1(0) 8006470631  
eFax (EU): +44(0) 8000669250 
All reported information must be submitted in English. It is not acceptable for the Investigator to 
send photocopies of the patient’s medical records to the Sponsor in lieu of completion of the 
SAE form. 
If necessary, the Investigator will be asked for additional information which may include hospital 
records, laboratory reports, or other test results. 
SAEs must be followed until they resolve, or are determined to be permanent at the EOT visit, or 
until the patient dies or is lost to follow-up. The Investigator must forward any relevant 
follow-up information for SAEs (including outcome and diagnosis) in the same manner as the 
initial report within 24 hours of obtaining the information. 
7.7.6.2 
EXPEDITED REPORTING AND INVESTIGATOR SAFETY REPORTS 
The Sponsor is responsible for submitting all suspected unexpected serious adverse reactions 
(SUSARs) related to the IMP to Competent Authorities (and IECs/IRBs as required) and to 
Investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. 
It is the Investigator’s responsibility to notify the local IEC/IRB of all suspected unexpected 
serious adverse reactions or other specific safety information (e.g., summary or listing of SAEs) 
involving risk to human subjects as appropriate according to local requirements. 
The Investigator will acknowledge and file all safety updates received from the sponsor along 
with the IB in the Investigator’s Site File. 
7.7.7 
Events of Special Interest 
The following events are considered events of special interest: 
• Venous thrombotic events, 
• Hepatic toxicity, 
• Pancreatitis, and 
• Transfusion-related events. 


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7.7.8 
Reporting of Pregnancy 
If a female patient or the partner of a male patient becomes pregnant, the patient must inform the 
Investigator immediately. The Investigator must immediately report any pregnancy occurring 
during the trial to ERYTECH Pharma by completing the “Exposure during pregnancy case report 
form” and forward it to PrimeVigilance, mandated by ERYTECH Pharma, at: 
Email: erytechpv@primevigilance.com 
eFax (US): +1(0) 8006470631  
eFax (EU): +44(0) 8000669250 
Patients will give consent upon enrollment for this reporting of any pregnancy during the trial as 
well as information about the delivery and about the baby’s health until the age of 6 month. 
Pregnancy complications must be recorded as AEs. If the infant has a congenital anomaly/birth 
defect, this must be reported and followed as an SAE. 
 
7.8 
CHANGES IN PROTOCOL DUE TO COVID-19  
7.8.1 
BACKGROUND 
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus 
has been named “SARS-CoV-2” and the disease it causes has been named “Coronavirus Disease 
2019” (COVID-19). On January 31, 2020, Health and Human Services (HHS) issued a 
declaration of a public health emergency related to COVID-19 and mobilized the Operating 
Divisions of HHS. 
The COVID-19 worldwide pandemic has the potential to impact the conduct of clinical trials and 
challenges may arise due to issues such as quarantines, site closures, travel limitations, or 
interruptions to the supply chain of investigational products.  These challenges may lead to 
difficulties in meeting protocol-specified procedures, including administering or the use of 
investigational products or adhering to protocol-mandated visits and laboratory/diagnostic 
testing.   
Regulatory authorities in the EU and the US have provided guidance on how to handle the 
potential impacts of the COVID-19 pandemic when conducting clinical studies.  In the US, the 
Food and Drug Administration (FDA) published “FDA Guidance on Conduct of Clinical Trials 
of Medical Products during the COVID-19 Public Health Emergency”, and in the EU, the 
European Medicines Agency (EMA) published  “Guidance on the Management of Clinical Trials 
during the COVID-19 (coronavirus) pandemic”. 
Erytech followed the guidance in these documents and conducted a Risk Assessment of the 
COVID-19 pandemic on the conduct of Trybeca-1 to ensure the safety of subjects seen during 
the COVID-19 pandemic and maintain data quality and integrity.  


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7.8.2 
MODIFIED PROTOCOL REQUIRED PROCEDURES 
Erytech recognizes that subjects may encounter difficulties having all protocol required 
laboratory assessments completed due to possible local laboratory closures or shortages of lab 
personnel.  Please refer to Table 12 for a list of COVID-19 Minimum Safety Assessments that 
are to be completed.    
Inclusion criteria number 7 (requirement for archival or fresh tumor tissue) will be waived if 
archive tissue is not available and an elective biopsy cannot be scheduled due to COVID. 
 
7.8.3 
MINIMUM SAFETY ASSESSMENTS 
 
Table 12 
Minimum Safety Assessments 
Category 
Parameter 
Must Be 
Performed 
Hematology: (no waivers) 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
White blood cell (WBC) count with differential 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation:  
 
Fibrinogen 
Antithrombin III (AT III) 
 
 
X 
X 
 
Serum Chemistry and 
Tumor Markers: 
Albumin 
X 
Alkaline phosphatase 
waived 
Alanine aminotransferase (ALT) 
X 
Ammonia 
waived 
Amylase 
X 
Aspartate aminotransferase (AST) 
X 
Bicarbonate 
waived 
Calcium 
X 


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Table 12 
Minimum Safety Assessments 
Category 
Parameter 
Must Be 
Performed 
Chloride 
X 
Creatinine 
X 
Gamma-glutamyl transferase (GGT) 
X 
Glucose 
X 
Lactate dehydrogenase (LDH) 
waived 
Lipase 
X 
Potassium 
X 
Sodium 
X 
Total bilirubin 
X 
Total cholesterol 
waived 
Triglycerides 
waived 
Urea 
waived 
Uric acid 
waived 
CA19-9 
waived 
Other Laboratory Tests: 
(no waivers) 
Blood phenotype, Rh factor, and ABO blood 
group, all done on two separate samples 
Irregular antibody screening test (IAST) 
 
Pregnancy test for women of childbearing 
potential (serum at screening and at End of 
Treatment; urine on Cycle 1 Day 1 before 
treatment and as indicated during treatment for 
females of child-bearing potential) 
X 
X 
 
X 
 
X 
  
7.8.4 
 ON-SITE VISIT SCHEDULES 
Investigators should make every attempt to maintain patient’s treatment administration as 
planned for each treatment arm per protocol and patient assessments as outlined in the Schedule 
of Events.  Given the need to quarantine, travel restrictions and site closures, patients may be 
evaluated outside of the protocol parameters, including having laboratory or radiological 
assessments performed at another location. 
Disease assessments, particularly CT/MRI scans should be performed every 8 weeks [+ 3 days] 
from randomization per protocol, when possible.  Local imaging centers should be used if 
possible.   
 


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7.8.5 
 PHARMACODYNAMIC SAMPLES 
The laboratory that supplied the sulphosalicylic acid (SSA) vacutainer tubes for collecting 
pharmacodynamic (PD) samples was closed due to COVID-19.  All remaining SSA tubes were 
supplied to active sites.  A determination was made that no further PD samples would be 
obtained after SSA vacutainer supplies were exhausted. 
    
 
 
7.8.6 
PROTOCOL DEVIATIONS 
 
Investigators will apply due diligence to avoid protocol deviations if possible.  All protocol 
deviations due to delayed or missed visits and protocol required assessments or treatments 
related to COVID-19 will be collected on the COVID-19 Related Deviation Log (APPENDIX 
4).  This log will serve as source documentation for entry into the COVID-19 eCRF form within 
the electronic data capture system. 
 
7.8.7 
CLINICAL MONITORING 
 
On-site monitoring visits may be converted to remote monitoring visits according to the 
Monitoring Plan if on-site visits cannot be conducted due to COVID-19 restrictions on site 
closures, limited access to study staff and travel restrictions.  Access to source documents 
(medical records) may be provided electronically or other secure method to comply with 
applicable privacy and security laws for the use and disclosure of information related to the 
research set forth in this protocol if authorized by national competent authorities.   
 
Remote monitoring visits will be converted back to on-site visits upon a site’s availability to 
reopen safety. 
 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL HYPOTHESES 
The primary efficacy endpoint is Overall Survival (OS) and the study is designed to test the 
superiority of eryaspase plus chemotherapy over chemotherapy alone. The primary analysis will 
test the following hypotheses: 
• Null Hypothesis: The hazard ratio for OS between eryaspase plus chemotherapy and 
chemotherapy alone is equal to one 
• Alternative Hypothesis: The hazard ratio for OS between eryaspase plus chemotherapy 
and chemotherapy alone is less than one 
The key secondary efficacy endpoints are Progression-free Survival (PFS), Objective Response, 
Duration of Response (DoR) and Disease Control Rate (DCR). 
The null and alternative hypotheses for PFS will be as for OS 
The primary analyses of the endpoints objective response and disease control will test the 
following hypotheses: 
• Null Hypothesis: The Objective Response Rate (ORR)/Disease Control Rate (DCR) in 
the eryaspase plus chemotherapy group is equal to the Objective Response Rate 
(ORR)/Disease Control Rate (DCR) in the chemotherapy alone group 
• Alternative Hypothesis: The Objective Response Rate (ORR)/Disease Control Rate 
(DCR) is greater in the eryaspase plus chemotherapy group versus the chemotherapy 
alone group 
There will be no formal statistical testing for DoR as this is not a randomized comparison and 
these data will be evaluated through the presentation of descriptive statistics 
All statistical testing will be undertaken based on a one-sided 2½% significance level subject to 
adjustments for interim analysis. 
8.2 
SAMPLE SIZE DETERMINATION 
With a power of 88.4% and an overall one-sided type I error of 2.5%, and including one interim 
analysis for efficacy with an O’Brien-Fleming type stopping rule, a total of 390 deaths are 
required to detect a treatment effect hazard ratio of 0.725 for eryaspase plus chemotherapy 
versus chemotherapy alone. The hazard ratio in the Phase 2 study for eryaspase was 0.63 
(95% CI: 0.39 to 1.10), and 0.725 represents a conservative estimate based on these data that is 
viewed as being highly clinically relevant. 
The interim analysis for efficacy will take place once 261 (67%) events have been observed.  
Assuming a recruitment period of 26 months, a median overall survival in the control group of 
6.0 months, a 10% probability of dropping out during the course of the study, and a minimum 
follow-up of 9 months, the study size will be based on the recruitment of 482 patients. 


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8.3 
ANALYSIS POPULATIONS 
Intent to Treat population (ITT): All patients randomized, irrespective of whether they 
received study medication. 
Safety population (SP): All randomized patients who receive at least one dose of study 
medication (eryaspase or chemotherapy). 
Per Protocol population (PP): The PP population is a subset of the ITT population, and consists 
of all randomized patients who meet the major inclusion criteria and none of the major exclusion 
criteria and who receive at least one cycle of treatment. The major inclusion/exclusion criteria 
that are to be considered here will be defined in the Statistical Analysis Plan (SAP). 
8.4 
STATISTICAL ANALYSES 
8.4.1 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint is OS which is measured from the date of randomization to the date of 
death from any cause. Patients who are not known to have died will be censored at the date of 
last contact, and this will apply as of the date of data cut-off for any particular analysis. 
The primary analysis will be the comparison of OS between the two treatment arms in the ITT 
population using the one-sided stratified log-rank test, with stratification factors as used in the 
randomization. Data will be summarized in Kaplan-Meier curves together with medians and 
95% confidence intervals for those medians. The Cox Proportional Hazards model, stratified for 
the randomization factors, will be used to obtain a hazard ratio together with its 95% confidence 
interval. 
8.4.2 
Analysis of the Secondary Endpoints 
PFS will be compared between the two treatment arms using the same methods of analysis as for 
OS. 
The following efficacy analysis will also be performed in the ITT population: 
• ORR, defined as the proportion of patients who achieve objective tumor response (CR or 
PR) per RECIST 1.1. Each patient’s BOR will be summarized (CR, PR, SD, PD, or 
unknown). This comparison will be based on the Cochran-Mantel-Haenszel test, with 
stratification factors as for the analysis of OS and PFS. Results will be reported in terms 
of an odds ratio and associated 95% confidence interval. 
• DCR (disease control rate), defined as the proportion of patients who achieve CR, PR and 
SD, 
• DoR will be evaluated in patients who achieve CR/PR. It will be measured from the time 
CR/PR (whichever is first recorded) is first met until the first date that recurrence or PD 
is objectively documented. Kaplan-Meier curves will be provided in association with this 
analysis; however, there will be no p-value calculations, as this is not a randomized 
comparison. 


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• Extensive evaluation of the consistency of treatment effect for OS and PFS across the 
population as a whole will be undertaken by providing analyses in subgroups, with 
displays in forest plots and p-values for treatment by interactions. 
8.4.3 
Other Aspects of the Efficacy Analyses 
Additional disease control endpoints will be evaluated as exploratory analyses, namely DCR8, 
DCR12, and DCR16 defined as the disease control rates when SD is required to last for at least 
8 weeks, at least 12 weeks, and at least 16 weeks respectively. These analyses will follow the 
methodology for DCR outlined in Section 8.4.2. 
All primary and secondary efficacy analyses will be repeated in the PP population. 
Confirmatory testing for the primary and secondary efficacy endpoints will be performed 
hierarchically (OS followed by PFS followed by ORR followed by DCR) in order to account for 
multiplicity. Any statistically significant findings occurring below a non-significant result in the 
hierarchy will be considered as exploratory findings. 
8.4.4 
Planned Interim Analyses 
This study will have an event-driven interim analysis for OS, based on O’Brien-Fleming 
boundaries. The interim analysis for OS will take place following 261 deaths. The number of 
deaths required to trigger the final analysis will be 390. 
8.4.5 
Subgroup Analyses 
Hazard ratios and 95% confidence intervals will be calculated for OS within subgroups using the 
unadjusted Cox proportional hazards model in order to evaluate the consistency of treatment 
effect. These subgroups will include those defined by the stratification factors. Other subgroups 
may also be considered, with a full list being set down in the SAP. 
Subgroup analyses of PFS will be performed in a similar way. ORR and DCR will also be 
evaluated within these same subgroups, based on the calculation of unadjusted odds ratios and 
corresponding 95% confidence intervals. 
8.4.6 
Independent Data Monitoring Committee (IDMC) 
An IDMC, composed of at least two oncologists (at least one of whom specializes in pancreatic 
cancer) and a statistician, will be set up to review the safety of eryaspase during the study and to 
review the interim analysis for efficacy. The IDMC will develop and follow an IDMC plan and 
charter. 
The IDMC will review the safety of eryaspase in combination with irinotecan-based therapy or 
gemcitabine/Abraxane regimen after 10 or more patients have been enrolled per regimen and 
have received at least one cycle of study therapy. Thereafter, and at a frequency to be defined in 
the IDMC Charter, the IDMC will be provided with reports of baseline demographics, medical 
history, concomitant medications, AEs, SAEs, and other safety data for regular review and 
recommendations. 


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In addition, at the interim analysis, the IDMC will be provided with a report containing the 
results of the efficacy analyses. The IDMC will review these reports and will provide a 
recommendation to ERYTECH for the continuation, termination, or modification of the study. 


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9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
9.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
9.1.1 
Informed Consent Process 
Participation in the study is voluntary; each patient must indicate his/her agreement and 
willingness to participate by signing and dating the approved ICF prior to the initiation of any 
study-related procedures. 
The Sponsor or designee will provide an Informed Consent Form to Investigators in a separate 
document. The consent forms that are used, including the separate consent form for PGx, must 
be approved both by the Sponsor and by the reviewing IECs/IRBs. 
The ICF should be in accordance with the principles originating in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and Sponsor policy. 
Prior to the start of any protocol-specific evaluations or screening procedures, the Investigator 
(or designated staff) will explain the nature of the study and its risks and benefits to the patient. 
Each patient will receive a copy of the ICF, which includes patient information. Patients should 
be given ample time to read the information and the opportunity to ask questions. One copy of 
the signed ICF will be given to the patient, and another will be retained with the study records by 
the Investigator. The process of obtaining informed consent should be documented in the 
patient’s medical file. 
9.1.2 
Independent Ethics Committees and Regulatory Authorities 
This clinical study will be conducted in accordance with the current ICH GCP Guidelines, as 
well as the ethical principles founded in the Declaration of Helsinki and applicable local laws 
and regulations (including European Directive 2001/20/EC, EU Regulation No. 536/2014, and 
US Code of Federal Regulations (CFR) 21). 
Before the start of the study, the Sponsor or the Sponsor’s designee will submit the clinical study 
protocol, ICF, and any other appropriate documents to regulatory authorities in accordance with 
local legal requirements. All required documents will also be submitted to the relevant 
IECs/IRBs by the Sponsor, the Sponsor’s designee, or the investigative sites, as applicable. As 
required by local regulations or by the IECs/IRBs, the Sponsor or Investigator will also submit 
the financial arrangements for the study and/or other financial interests of the Investigator or 
applicable site staff in the investigational drug or the Sponsor company. 
The study will only be conducted at sites where IEC/IRB and regulatory authority approval has 
been obtained as required. 
All substantial amendments to the study protocol will also be submitted to the IECs/IRBs and 
authorities in accordance with local legal requirements. Amendments must be evaluated to 
determine whether the ICF should also be revised. Protocol amendments must not be 
implemented without prior IEC/IRB and regulatory approval, except where necessary to 
eliminate immediate hazards to the subjects or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in Sponsor contacts or telephone numbers). 


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The Investigator must keep a record of all communication with the IECs/IRBs and if applicable, 
between a national coordinating investigator and the IECs/IRBs. This also applies to any 
communication between the investigator (or sub-investigator, if applicable) and regulatory 
authorities. 
9.1.3 
Study Completion or Discontinuation and Closure 
The study will be considered completed with completion of the last visit of the last patient 
participating in the study. 
It is expected that each Investigator will complete the last study visit for the last patient at his/her 
site and submit all eCRFs to the Sponsor (or designee) in satisfactory compliance with the 
protocol within the time frame specified in the Clinical Trial Agreement. 
This study may be prematurely terminated if there is sufficient reasonable cause. If the study is 
prematurely terminated or suspended, the Investigator will promptly inform study participants 
and the relevant IEC/IRB, and the Sponsor will provide the reason(s) for the termination or 
suspension to competent regulatory authorities. Study participants will be contacted as 
appropriate, and will be informed of any changes to the study visit schedule. 
Circumstances that may warrant termination or suspension of the study include, but are not 
limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants, 
• Demonstration of efficacy that would warrant stopping, 
• Determination that the primary endpoint has been met, 
• Determination of futility, and 
• Sponsor decision to stop development of the IMP. 
The study may resume once concerns about safety, protocol compliance, and data quality have 
been addressed to the satisfaction of the Sponsor, IEC/IRB, and/or the applicable regulatory 
agency. 
Following study completion or termination, the Investigator will provide the Sponsor, the 
IEC/IRB, and the applicable regulatory agency with final reports and summaries as required by 
local regulations (e.g., for Investigational New Drug (IND) studies, the Investigator must submit 
a written report to the Sponsor and the Ethics Committee within 3 months after the completion or 
termination of the study). 
9.1.4 
Protocol Adherence 
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study patients. Under no circumstances should an Investigator collect additional data or conduct 
any additional procedures for any research-related purpose. 
Investigators will apply due diligence to avoid protocol deviations. 
All protocol deviations identified via monitoring and data review will be tracked, and all 
significant protocol deviations (i.e., major deviations that would exclude a patient from the PP 
population; to be defined in the SAP) will be reported in the Clinical Study Report (CSR). 
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9.1.5 
Definition of Source Data 
Source data are defined as data contained in original documents or certified copies of original 
records in the patient’s medical file (source documents), including but not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, pharmacy records, recorded 
data from automated instruments, X-rays, consultant letters and correspondence, and nurse’s 
notes. 
NOTE: Each patient’s involvement in the study should be clearly documented in his/her medical 
file; details should include the study protocol number, the patient’s study identification number, 
the patient’s consent to take part in the study (with the date of consent), and the dates of all study 
visits. Such essential documents must be retained by the Investigator in accordance with local 
regulations. 
9.1.6 
Access to Source Data 
By signing the ICF, the patient agrees that Investigators, monitors, and all mandated staff 
including the sponsor or its representatives and regulatory inspectors will have access to his/her 
personal data during and after the study to ensure the quality of data recorded for study purposes. 
By agreeing to participate in this clinical trial, the Investigator agrees to give full and direct 
access to all records (including electronic records) for patients enrolled in the study to the 
Sponsor or its representatives at the time of each monitoring visit or audit. The records will also 
be available for direct inspection, verification, and copying, as required by applicable laws and 
regulations, by officials of regulatory authorities (FDA, Agence nationale de sécurité du 
médicament et des produits de santé [ANSM], EMA, and others) and IECs/IRBs. 
The Investigator will comply with applicable privacy and security laws for the use and disclosure 
of information related to the research set forth in this protocol. 
9.1.7 
Confidentiality and Privacy 
To maintain patient confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all eCRFs, study reports, and communications relating to the study will 
identify patients by their assigned patient identification numbers and by dates of birth, if this is 
permitted by local laws and regulations. Access to patient names linked to such numbers shall be 
limited to the site and the Investigator, and shall not be disclosed to the Sponsor. 
In accordance with legal requirements, anyone having direct access to source data must respect 
data confidentiality and must ensure patient anonymity on documents that could be forwarded to 
the Sponsor. 
9.1.8 
Data Quality Control 
Steps taken by the Sponsor to ensure the accuracy and reliability of study data include the 
selection of qualified Investigators and appropriate study centers, review of protocol procedures 
with the Investigator and appropriate personnel before the study, training related to study 
conduct, periodic monitoring visits by the Sponsor or its designee, and when applicable, direct 
transmission of clinical laboratory data from the central laboratory to the Sponsor’s database. 


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The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. Study data for each enrolled patient will be entered into an eCRF by study site 
personnel using a secure, validated web-based electronic data capture (EDC) application. All 
users will be required to complete EDC training before they are given access to the system. 
Instances of missing, discrepant, or uninterpretable data will be queried to the Investigator for 
resolution, via auto-queries generated by programmed edit checks or via manual queries raised 
by site monitors and/or data managers. Any changes to the study data will be made in the eCRF; 
the EDC system will document these changes in an audit trail, which will be maintained within 
the clinical database. 
9.1.9 
eCRF Completion using Electronic Data Capture 
Guidelines for eCRF completion will be provided and will be reviewed with study personnel 
before the start of the study, and as needed during the study. 
It is the Investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported in the patient’s eCRF. All data entered in the eCRFs must be supported by 
source data. The Investigator or designee must complete eCRFs within 5 days after data are 
collected. 
The Sponsor or designee will review eCRF data for accuracy and completeness during on-site 
monitoring visits and after transmission of data to the Sponsor or designee; any discrepancies 
will be resolved with the Investigator or designee, as appropriate. After the data are uploaded 
into the clinical study database, they will be verified for accuracy. The Investigator must answer 
all queries as soon as possible. 
The Investigator will provide formal approval of all information in the eCRFs, including any 
changes made to the eCRFs, to endorse the final submitted data for patients for whom he or she 
is responsible. 
A copy of the final archival eCRF in the form of a compact disc (CD) or PDF will be provided to 
the Investigator for filing in his/her study file. The Sponsor will retain the eCRF data. 
9.1.10 
Key Roles and Study Governance 
The worldwide Sponsor of this clinical trial is ERYTECH Pharma. The Sponsor will enlist the 
support of a contract research organization (CRO), imaging management vendors, central labs, 
and statistical firms to perform the operational aspects of the trial. The Sponsor will supervise 
and practice oversight on all outsourced activities. All structures and associated procedures will 
be described in the Oversight Plan, which will include information about IMP, quality assurance, 
and vendor management.  
The Sponsor Medical Monitors will support the Investigators during the conduct of the study, 
and the Sponsor site monitor will support the site personnel and will provide the necessary 
protocol training, RECIST 1.1 training, and any additional training required for the successful 
conduct of this trial. 


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9.1.11 
Safety Oversight 
The Sponsor’s Global Drug Safety department or its designated representative will oversee, 
monitor and report AEs and SAEs to all relevant parties as required by the regulations and 
applicable laws. Continuous safety monitoring will be performed by Investigators and site 
clinicians. An IDMC will be appointed and will meet in regular intervals to monitor the safety of 
the study participants and provide recommendations to the Sponsor. 
9.1.12 
Clinical Monitoring 
In order to comply with GCP guidelines, the study sites must follow monitoring procedures 
developed by the Contract Research Organization (CRO) and approved by the Sponsor. 
The Sponsor or its designee will perform on-site monitoring visits as frequently as necessary and 
according to the Monitoring Plan developed for the study to ensure that the investigation is 
conducted according to the protocol design and regulatory requirements. The monitor will 
cross-check the data entered into the eCRFs and SAE Forms with the hospital or clinic records 
(source documents) for completeness and clarity. Data queries will be raised in the EDC system, 
findings from this review of eCRFs and source documents will be discussed with the 
investigational staff, and administrative matters will be clarified. 
At site initiation visits, the nature and location of all source documents will be identified to 
ensure that all sources of original data required to complete the eCRF are known to the Sponsor 
and investigational staff and are accessible for verification by the Sponsor site monitor. If 
electronic records are maintained at the investigational site, access to these records and methods 
of verification must be discussed with the investigational staff. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the data in the eCRF are consistent with the original source data. It is expected that 
during monitoring visits the relevant investigational staff will be available, the source 
documentation will be accessible, and a suitable environment will be provided for review of 
study-related documents. The monitors will meet with the Investigator on a regular basis during 
the study to provide feedback on study conduct. 
See Section 7.8.7 for further information regarding Clinical Monitoring related to COVID-19. 
9.1.13 
Site Audits and Inspections 
The Sponsor is responsible for implementing and maintaining quality assurance (QA) and quality 
control (QC) systems, and for performing systematic and independent auditing of study conduct, 
data generation, documentation, analysis, and reporting to determine whether the evaluated 
activities are being performed in compliance with the protocol, the Sponsor’s standard operating 
procedures, GCP, and applicable local regulatory requirements. 
Representatives of the Sponsor’s clinical QA department or designee may visit the site at any 
time during or after completion of the study to conduct an audit of the study in compliance with 
regulatory guidelines and company policy. Similar auditing procedures may also be conducted 
by agents of any IRB/IEC or regulatory body, either as part of a national GCP compliance 
program or to review the results of this study in support of a regulatory submission. The 


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Investigator should immediately notify the Sponsor if he or she is contacted by a regulatory 
agency concerning an upcoming inspection. 
The Investigator/institution will ensure direct access to all source data/documents and reports 
(including but not limited to written, electronic, magnetic, and optical records) for the purpose of 
monitoring, auditing, and inspection by the IRB/IEC or regulatory authorities. All parties will 
take reasonable precautions to maintain patient privacy. The Investigator and staff are also 
responsible for being present and available for consultation during routinely scheduled site audit 
visits conducted by the Sponsor or its designees or during inspections by regulatory authorities. 
9.1.14 
Data Handling and Record Keeping 
9.1.14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Patient data will be collected by the Investigator or designee using the eCRF provided by 
ERYTECH. 
It is the Investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported in the eCRFs. 
All data entered in the eCRFs must be supported by and consistent with source data, and any 
discrepancies must be explained. 
The Investigator or designee will complete eCRFs within 5 days after data are collected. 
The Investigator will provide formal approval of all information in the eCRFs, including any 
changes made to the eCRFs, to endorse the final submitted data for patients for whom the 
Investigator is responsible. 
Patient data necessary for analysis and reporting will be entered into a validated database system. 
Clinical data management will be performed in accordance with ERYTECH standards and data 
cleaning procedures. 
9.1.14.2 
STUDY RECORD RETENTION 
In compliance with the ICH GCP guidelines, the Investigator/institution will maintain all eCRFs 
(provided at the end of the study on electronic media for site records), source documents that 
support the data collected from each patient, and other study documents as specified in ICH GCP 
Section 8 (Essential Documents for the Conduct of a Clinical Trial) and applicable regulatory 
requirements. The Investigator/institution will take measures to prevent accidental or premature 
destruction of these documents. 
All documents must be retained by the Investigator for a minimum of two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational product. At the 
end of the two -year period, the Sponsor or its designee must be consulted prior to the destruction 
of study documents. These documents will be retained per country regulations. It is the 
Sponsor’s responsibility to inform the Investigator/institution as to when these documents no 
longer need to be retained. 


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If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the Investigator dispose of any study documents 
before having obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such documents. 
9.1.15 
Publication and Data Sharing Policy 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in 
relation to this trial will be considered the confidential and proprietary property of the Sponsor. 
The Investigator shall hold such information in confidence and shall not disclose the information 
to any third party without the Sponsor’s permission except to Investigator’s employees and staff 
who have been made aware that the information is confidential and who are bound to treat it as 
such. 
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study drug and that it therefore may be 
disclosed as required to other clinical Investigators, business partners and associates, and 
government agencies. The Investigator understands that to allow use of the information derived 
from the clinical study, the Investigator has the obligation to provide the Sponsor with complete 
test results and all data developed in the study. 
The Sponsor or designee will list this study on the public databases of clinical studies. 
www.clinicaltrials.gov and www.clinicaltrialsregister.eu. A clinical study report of the study will 
be made available after the conclusion of the study. The final report may be submitted to relevant 
regulatory authorities to support a request for product registration. It is the intention of the 
Sponsor to publish the results of this study in a peer-reviewed journal. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions defined in a separate written agreement between the Sponsor and the Investigator 
and/or the Investigator’s institution. 
9.2 
PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description 
0 
05th March 2018 
GRASPANC 2018-01 Study Protocol 
(Original) 
1.0 
05th September 2019 
GRASPANC 2018-01 Study Protocol 1.0 
(Global Amendment) 
2.0 
14th December 2020 
GRASPANC 2018-01 Study Protocol 2.0 
(Global Amendment) 
.


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38. Delaney M, Taune-Wikman A, Van De Watering LM, et al. Red blood cell transfusion 
antigen matching influence on gestational outcomes (AMIGO) study. Transfusion 
2015;55:25A  
39. Delaney M, Wendel S, Bercovitz RS, et al. Transfusion reactions: prevention, diagnosis, and 
treatment. The Lancet 2016;388(10061):2825-36 doi: http://dx.doi.org/10.1016/S0140-
6736(15)01313-6[published Online First: Epub Date]|. 
40. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines†. Annals of 
Oncology 2017;28(suppl_4):iv100-iv18 doi: 10.1093/annonc/mdx216[published Online 
First: Epub Date]|. 
41. Simons FER, Ardusso LRF, Bilò MB, et al. World Allergy Organization Guidelines for the 
Assessment and Management of Anaphylaxis. The World Allergy Organization Journal 
2011;4(2):13-37 doi: 10.1097/WOX.0b013e318211496c[published Online First: Epub 
Date]|. 
42. 2006 Update of ASCO Practice Guideline Recommendations for the Use of White Blood 
Cell Growth Factors: Guideline Summary. J. Oncol. Pract. Journal Translated Name 
Journal of Oncology Practice 2006;2(4):196-201 doi: 
10.1200/jop.2006.2.4.196[published Online First: Epub Date]|. 
43. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76  
44. Lan KKG, Demets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 
70:659--663.  
 


ERYTECH Pharma 
Amended Protocol GRASPANC 2018-01 
Investigational Product: Eryaspase 
Version 2.0 (14th December 2020) 
CONFIDENTIAL AND PROPRIETARY 
 
Page 117 of 119 
11 
APPENDICES 
APPENDIX 1 TNM CLASSIFICATION  
 


ERYTECH Pharma 
Amended Protocol GRASPANC 2018-01 
Investigational Product: Eryaspase 
Version 2.0 (14th December 2020) 
CONFIDENTIAL AND PROPRIETARY 
 
Page 118 of 119 
APPENDIX 2 PERFORMANCE STATUS (ECOG GRADING SCALE) 
Grade 
ECOG* 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
*ECOG, Robert Comis, MD, Group Chair. 
Reference: Oken MM, Creech RH, Tormey DC et-al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am. J. Clin. Oncol. 1983;5 (6): 649-55. 
 
APPENDIX 3 KARNOFSKY PERFORMANCE STATUS 
Definition 
Rating Description 
Able to carry on normal 
activity and to work; no special 
care needed. 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms 
of disease. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
Unable to work; able to live at 
home and care for most 
personal needs; varying amount 
of assistance needed. 
70 
Cares for self; unable to carry on normal activity or to do 
active work. 
60 
Requires occasional assistance, but is able to care for most 
of his personal needs. 
50 
Requires considerable assistance and frequent medical 
care. 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
The Karnofsky Performance Scale Index allows patients to be classified as to their functional 
impairment. This can be used to compare effectiveness of different therapies and to assess the 
prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most 
serious illnesses. 


ERYTECH Pharma 
Amended Protocol GRASPANC 2018-01 
Investigational Product: Eryaspase 
Version 2.0 (14th December 2020) 
CONFIDENTIAL AND PROPRIETARY 
 
Page 119 of 119 
APPENDIX 4 
COVID-19 RELATED PROTOCOL DEVIATION LOG 
 

SAP_001.pdf: 
 
Document No.: STAT GRASPANC 2018-01 SAP2.1 
 
Confidentiality 
This document is confidential and proprietary property of Erytech and to be used only as authorized by Erytech.  
No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Erytech 
  
STATISTICAL ANALYSIS PLAN 
GRASPANC 2018-01 
A Randomized, Phase 3 Study of Eryaspase in Combination with 
Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in 
Patients with Pancreatic Adenocarcinoma 
Protocol Number: 
(Version Date) 
GRASPANC 2018-01 
05Sep2019 (Protocol Amendment version 1.0) 
Name of Test Drug: 
Eryaspase (L-Asparaginase Encapsulated in Red Blood 
Cells) 
Phase: 
3 
Methodology: 
Open-Label, Randomized Trial 
Sponsor: 
ERYTECH Pharma 
60 avenue Rockefeller  
69008 LYON France  
Phone: +33 (0)4 78 74 44 38 
Sponsor Representative: 
Dr. Iman El Hariry 
Chief Medical Officer 
Sponsor Representative: 
 
Dr. Richard Kay 
RK Statistics Ltd 
Visiting Professor, School of Pharmacy and Pharmaceutical 
Medicine, Cardiff University 
Document Date: 
06 Oct 2021 
Document Version: 
2.1 
 


 
Document No.: STAT GRASPANC 2018-01 SAP2.1 
 
CONFIDENTIAL 
2 
SIGNATURE PAGE 
Protocol Title: 
A Randomized, Phase 3 Study of Eryaspase in 
Combination with Chemotherapy versus Chemotherapy 
Alone as Second-Line Treatment in Patients with 
Pancreatic Adenocarcinoma 
Sponsor: 
ERYTECH Pharma 
60 avenue Rockefeller  
69008 LYON France 
Phone: +33 (0)4 78 74 44 38  
Protocol Number: 
GRASPANC 2018-01 
Cytel, Inc. Author: 
David Bushnell 
Cytel, Inc. 
1050 Winter St; Suite 2700 
Waltham, MA 02451 
 
Signature:____________________________________ 
Date:________________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
Iman El Hariry, MD 
Chief Medical Officer 
ERYTECH Pharma 
60 avenue Rockefeller  
69008 LYON France  
 
Signature:____________________________________ 
Date:________________________________________ 
 
Sponsor Signatory: 
Richard Kay, PhD 
Statistician 
 
Signature:____________________________________ 
Date:________________________________________ 
 
 


 
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REVISION HISTORY 
 
Date 
Version number 
Reason for change 
Authored by 
09Dec2020 
1.0 
Signed 
Iman Elhariry 
David Bushnell 
11Jan2021 
1.1 
Minor Clarifications 
 
07 Oct 2021 
2 
Removed mITT per client 
request.  
Clarifications on date 
conventions and endpoint 
definitions. 
Some patient history, safety 
and exposure analysis added. 
Specified the intention of 
releasing final topline results 
and final outputs 
Changed ATC for Concomitant 
medications from ATC level 3 
to ATC level 2 
Provided details on adverse 
event retrieval terms for events 
of special interest 
David Bushnell 
18 Oct 2021 
2.1 
Added Appendix 2 to clarify 
protocol deviations 
Iman Elhariry 
 
 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ...................................................................................................................................... 10 
2. 
STUDY OBJECTIVES ................................................................................................................................. 10 
3. 
STUDY DESIGN........................................................................................................................................ 12 
3.1. 
OVERALL DESIGN......................................................................................................................................... 12 
3.2. 
ELIGIBLE PATIENTS ....................................................................................................................................... 16 
3.3. 
NUMBER OF SITES AND PATIENTS ................................................................................................................... 16 
3.4. 
SCREEN FAILURES ........................................................................................................................................ 16 
3.5. 
END OF STUDY DEFINITION ............................................................................................................................ 16 
3.6. 
RANDOMIZATION METHODOLOGY .................................................................................................................. 16 
3.7. 
STOPPING RULES ......................................................................................................................................... 17 
3.8. 
BLINDING ................................................................................................................................................... 17 
3.9. 
STUDY PROCEDURES .................................................................................................................................... 18 
4. 
GENERAL STATISTICAL CONSIDERATIONS AND DATA HANDLING ............................................................. 22 
4.1. 
SAMPLE SIZE DETERMINATION ....................................................................................................................... 22 
4.2. 
GENERAL METHODS..................................................................................................................................... 22 
4.3. 
GENERAL DATE CONVENTIONS ....................................................................................................................... 23 
4.4. 
COMPUTING ENVIRONMENT .......................................................................................................................... 26 
4.5. 
METHODS OF POOLING DATA ........................................................................................................................ 26 
4.6. 
EFFICACY, PK, PHARMACODYNAMIC AND SAFETY VARIABLES ............................................................................... 26 
 
Efficacy Variables ............................................................................................................................... 26 
 
PK, Pharmacodynamic and Immunogenicity Variables ..................................................................... 27 
 
Safety Variables ................................................................................................................................. 27 
 
Other Variables .................................................................................................................................. 27 
4.7. 
ANALYSIS POPULATIONS ............................................................................................................................... 27 
4.8. 
ADJUSTMENT FOR COVARIATES ...................................................................................................................... 28 
4.9. 
MULTIPLE COMPARISONS/MULTIPLICITY ......................................................................................................... 29 
4.10. 
SUBGROUP ANALYSES .................................................................................................................................. 29 
4.11. 
WITHDRAWALS, DROPOUTS, AND LOSS TO FOLLOW-UP ...................................................................................... 30 
4.12. 
MISSING, UNUSED, AND SPURIOUS DATA ........................................................................................................ 30 
 
Missing dates for study drug administration ................................................................................ 30 
 
Missing dates for adverse events .................................................................................................. 30 
 
Missing dates for other variables .................................................................................................. 31 
4.13. 
VISIT WINDOWS ......................................................................................................................................... 31 
4.14. 
PROTOCOL DEVIATIONS ................................................................................................................................ 31 
5. 
PATIENT DISPOSITION AND BASELINE DATA SUMMARIES ....................................................................... 32 
5.1. 
PATIENT DISPOSITION .................................................................................................................................. 32 
5.2. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................................................... 33 
 
Demographic Data ............................................................................................................................. 33 
 
Characteristics of Pancreatic Cancer ................................................................................................. 33 
 
Prior Cancer Therapy ......................................................................................................................... 34 
5.3. 
MEDICAL AND SURGICAL HISTORY .................................................................................................................. 34 
6. 
STATISTICAL ANALYSIS ............................................................................................................................ 35 
6.1. 
ANALYSIS OF PRIMARY EFFICACY ENDPOINT ...................................................................................................... 35 
 
Supportive and sensitivity analyses for OS ........................................................................................ 36 


 
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Planned Interim Analyses for Overall Survival ................................................................................... 37 
6.2. 
FINAL ANALYSIS AND TOPLINE RESULTS ........................................................................................................... 37 
6.3. 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ................................................................................................ 37 
 
Analysis of Progression-Free Survival (PFS) ....................................................................................... 38 
 
Analysis of Objective Response Rate (ORR) and Duration of Response (DoR) ................................... 44 
 
Analysis of Disease Control Rate (DCR) .............................................................................................. 46 
 
Analysis of New Metastatic Lesions ................................................................................................... 46 
6.4. 
OTHER SECONDARY ENDPOINTS ..................................................................................................................... 46 
 
PK, Pharmacodynamic and Immunogenicity Summaries .................................................................. 46 
 
CA19-9 tumor marker ........................................................................................................................ 47 
 
Tumor biomarkers ............................................................................................................................. 47 
 
Patient-reported outcomes (PRO) ...................................................................................................... 47 
6.5. 
SUBGROUP ANALYSES .................................................................................................................................. 50 
7. 
DRUG EXPOSURE .................................................................................................................................... 50 
7.1. 
DOSE REDUCTIONS ...................................................................................................................................... 53 
8. 
SAFETY AND TOLERABILITY ANALYSES .................................................................................................... 53 
8.1. 
ADVERSE EVENTS ........................................................................................................................................ 53 
 
Adverse Events of Special Interest (AESI) ........................................................................................... 56 
8.2. 
CLINICAL LABORATORY DATA ......................................................................................................................... 57 
8.3. 
PERFORMANCE STATUS ................................................................................................................................ 58 
8.4. 
VITAL SIGNS, PHYSICAL EXAMINATIONS AND PERFORMANCE STATUS ..................................................................... 58 
8.5. 
CONCOMITANT MEDICATIONS ....................................................................................................................... 58 
9. 
SUBSEQUENT ANTI-CANCER THERAPIES .................................................................................................. 59 
10. 
COVID-19 IMPACT .............................................................................................................................. 60 
10.1. 
BY-PATIENT COVID-19 LISTINGS ................................................................................................................... 61 
11. 
CHANGES TO PLANNED ANALYSES ...................................................................................................... 63 
12. 
REFERENCES ....................................................................................................................................... 64 
13. 
CLINICAL STUDY REPORT APPENDICES ................................................................................................ 65 
14. 
APPENDIX 1: RANDOMIZATION SPECIFICATION .................................................................................. 66 
15. 
APPENDIX 2: CONSORT DIAGRAM ...................................................................................................... 68 
16. 
APPENDIX 3: FINAL ANALYSIS LIST OF TABLES, LISTINGS AND FIGURES ............................................... 72 
17. 
APPENDIX 4: GROUPING RULES FOR ADVERSE EVENTS ....................................................................... 74 
18. 
APPENDIX 5: ADVERSE EVENTS OF SPECIAL INTEREST ......................................................................... 78 
18.1. 
TRANSFUSION EVENTS .................................................................................................................................. 78 
 
Transfusion reactions .................................................................................................................... 78 
 
Hemolytic disorders ...................................................................................................................... 78 
18.2. 
PANCREATIC EVENTS .................................................................................................................................... 79 
 
Clinical Pancreatitis ....................................................................................................................... 79 
 
Biochemical Pancreatitis ............................................................................................................... 79 
18.3. 
HEPATIC EVENTS ......................................................................................................................................... 79 
18.4. 
IMPAIRED COAGULATION .............................................................................................................................. 80 
 
Impaired coagulation parameters ................................................................................................ 80 
 
Embolic and thrombotic events .................................................................................................... 80 


 
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Hemorrhagic events ...................................................................................................................... 80 
 
Tables 
Table 2-1 
 Study objectives ............................................................................................................. 10 
Table 3-1. 
Schedule of Events .......................................................................................................... 18 
Table 4-1 
General data handling conventions ................................................................................. 23 
Table 6-1 
 Censoring rules for OS analysis ..................................................................................... 35 
Table 6-2 
Primary PFS analyses and censoring rules. ..................................................................... 39 
Table 6-3 
Sensitivity PFS analyses and censoring rules .................................................................. 41 
Table 6-4 
Evaluation of the discordance rate between the investigator and the 
independent review on assessing PFS data ..................................................................... 42 
Table 6-5 
Summary of all censoring rules for primary and supportive analyses ............................ 43 
Table 6-6 
Assessments considered for calculation of best percentage change for 
waterfall plots .................................................................................................................. 44 
Table 6-7 
Rules for defining best overall response (BoR) .............................................................. 45 
Table 6-8 
EORTC QLQ-30 Scales and Items ................................................................................. 48 
Table 6-9 
Worsening definition for EORTC QLQ-C30 .................................................................. 49 
Table 7-1 
Summary of the rules for defining drug exposure ........................................................... 52 
Table 10-1 
Trybeca-1 COVID-19 Minimum Safety Assessments .................................................... 60 
 
Figures 
Figure 3-1 
Study Schema .................................................................................................................. 13 
 
 
 


 
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ABBREVIATIONS 
 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine aminotransferase 
ASNase 
Asparaginase 
ASN 
Asparagine 
AST 
Aspartate aminotransferase 
AT III 
Antithrombin III 
ATC 
Anatomic Therapeutic Class 
BP 
Blood pressure 
BMI 
Body Mass Index 
BOR 
Best overall response 
CA19-9 
Cancer antigen 19-9 
CBC 
Complete blood count 
CFB 
Change from baseline 
CI 
Confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
DNA 
Deoxyribonucleic acid 
ctDNA 
Circulating tumor DNA 
DCR 
Disease control rate 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
European Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDR 
Early discrepancy rate 
EOT 
End of Treatment 
EORTC QLQ-C30 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 
EU 
European Union 
FDA 
Food and Drug Administration 
FOLFIRI 
FOLinic acid-Fluorouracil-IRInotecan regimen 
FOLFIRINOX 
FOLinic acid-Fluorouracil-IRInotecan-Oxaliplatin regimen 
mFOLFOX6 
Modified FOLinic acid-Fluorouracil-Oxaliplatin-6 regimen 
5FU 
5 Fluorouracil 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLN 
Glutamine 


 
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HCL 
Hydrochloride 
HR 
Hazard ratio 
IAST 
Irregular antibody screening test 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IR 
Independent radiological review 
ITT 
Intent to Treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
kg 
Kilogram 
KPS 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LDR 
Late discrepancy rate 
LV 
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging 
NALIRI 
NAnoliposomal irinotecan, folinic acid-fluorouracil-
IRInotecan regimen 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Non-evaluable 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PAC 
Pancreatic adenocarcinoma 
PFS 
Progression-free survival 
PGx 
Pharmacogenetics 
PH 
Proportional Hazards 
PK 
Pharmacokinetic 
POP PK 
Population pharmacokinetic 
PP 
Per Protocol 
PR 
Partial response 
PRO 
Patient reported outcome 
PS 
Performance status 
PTT 
Partial thromboplastin time 
QoL 
Quality of life 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 


 
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RMST 
Restricted mean survival time 
RS 
Raw score 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOC 
System organ class 
SOE 
Schedule of Events 
SP 
Safety population 
TEAE 
Treatment emergent adverse events 
TLFs 
Tables, listings and figures 
TNM 
Tumor, Node, Metastasis staging system 
TRYbeCA 
TRial of erYaspase in pancreatic CAncer 
U 
Units 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 


 
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1. 
INTRODUCTION  
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications, tables, figures and listings. It 
describes the planned analyses of the data collected during the study, including the safety and 
efficacy variables and populations, anticipated data transformations and manipulations, and 
other details of the analyses not provided in the study protocol, for the purpose of submission to 
the relevant authorities and for publication as appropriate. The results of all analyses in this SAP 
will be included in the Clinical Study Report (CSR). 
This SAP is based on the following study documents: 
• Protocol Amendment Version 1.0 dated 05SEP2019 
• Electronic Case Report Form (eCRF) for the study. 
 
The statistical analyses will be performed in accordance with International Conference on 
Harmonisation (ICH) E9 guidelines. This SAP conforms to the Cytel standard operating 
procedure STAT C002 Timing and Content of Statistical Analysis Plans using SAP template 
STAT C002 TP01 Version 2, dated 19FEB2016. 
The SAP should be validated and signed before study database extract for interim analysis.  
The CSR deliverables: (shells for tables, figures and listings) and further programming 
specifications are described in SAP documents “Table, Listings and Figures (TLFs) Shells” and 
“Programming Dataset Specifications”, respectively.  
2. 
STUDY OBJECTIVES 
The study objectives and corresponding endpoints as specified in the protocol are provided in 
Table 2-1. 
Table 2-1 
 Study objectives 
Objective 
Endpoint 
Analysis  
Primary  
 
Refer to section 
The primary objective of this study is 
to determine whether the addition of 
eryaspase to chemotherapy improves 
overall survival (OS) in second-line 
treatment of pancreatic 
OS in the Intent to Treat 
(ITT) population  
Section 6.1 


 
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adenocarcinoma compared to 
chemotherapy alone 
Key Secondary  
 
Refer to Section 
To compare progression-free survival 
(PFS) between the 2 treatment arms 
PFS based on local 
investigator’s assessment 
using modified RECIST 1.1 – 
ITT population 
The declaration of PD will be 
based on the investigator 
assessment as per modified 
RECIST 1.1 
Section 6.2 
To compare the disease control rate 
(DCR) between the 2 treatment arms. 
DCR – ITT population 
Section 6.2.3 
To compare the objective response 
rate (ORR) and duration of response 
(DoR) between the 2 treatment arms. 
ORR and DoR- ITT 
population 
Section 6.2.2 
Other Secondary 
 
 
To assess the effect of eryaspase on 
quality of life using the European 
Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (QLQ-C30). 
Patient reported outcome 
(PRO) – PRO population 
- 
Change from baseline 
(CFB) in the global health 
status scale score of the 
EORTC QLQ-C30 
Section 6.3.4 
To determine the pharmacokinetics of 
eryaspase. 
 
To assess the immunogenicity of 
eryaspase: the induction of anti-
asparaginase antibodies and 
neutralizing antibodies. 
Summary statistics for PK: 
Asparaginase activity, 
asparagine and glutamine 
concentration, and individual 
PK parameters based on 
population PK model– PK 
population 
Anti-asparaginase antibody 
induction – PK population 
Section 6.3.1 
To evaluate the safety and tolerability 
of eryaspase in combination with 
Type, frequency and severity 
of TEAE per CTCAE v5 – 
Safety population 
Section 8 


 
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chemotherapy versus chemotherapy 
alone 
Type, frequency and severity 
of laboratory toxicities per 
CTCAE v5 – Safety 
population 
To evaluate the relationship of clinical 
outcome with relevant biomarkers and 
genetic changes present in tumor 
tissues and blood and/or serum 
samples. 
Separate document 
NA 
To investigate the predictive 
relationship between genetic variants 
in select candidate genes in the 
patient’s somatic (blood) cell 
deoxyribonucleic acid (DNA) and 
their response to combination 
treatment in terms of safety and 
tolerability (pharmacogenetics [PGx]). 
Separate document 
NA 
 
3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is an open-label, multicenter, randomized Phase 3 study in patients with ductal 
adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer 
therapy for advanced disease and have measurable disease as defined by the Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. After provision of informed consent 
and conduct of screening assessments, patients who meet all inclusion and no exclusion criteria 
will be randomized in a 1:1 ratio to one of the following treatment arms, Figure 3-1: 
• Arm A (investigational arm): eryaspase in combination with either gemcitabine/abraxane or 
irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or 
(NALIRI) Onivyde/5-fluorouracil/leucovorin), 
• Arm B (control arm): gemcitabine/abraxane, or irinotecan-based therapy (FOLFIRI or 
Onivyde/5-fluorouracil/leucovorin). 
 
 


 
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Figure 3-1 
Study Schema 
The study will be divided into the following phases: 
• Screening Phase: Screening assessments should occur within 3 weeks of randomization 
for assessment of the patient’s overall eligibility. 
• Randomization Phase: Randomization will occur after the patient has been determined 
to be eligible. 
• Treatment Phase: The first dose of chemotherapy will be administered within 3 days 
after randomization. Treatment will continue until objective disease progression, 
unacceptable toxicity, or the patient’s withdrawal of consent. Unacceptable toxicity is 
defined as prolonged Grade 3 or 4 toxicity lasting more than 2 weeks. 
In the investigational treatment arm (Arm A), eryaspase will be administered on Day 1 and 
Day 15 of each 4-week cycle in combination with chemotherapy. Eryaspase will be 
administered by intravenous (IV) infusion over approximately 60 minutes, followed by one 
hour of rest and then followed by chemotherapy infusion. 
Chemotherapy will consist of one of the following two treatment regimens: 
o Gemcitabine and abraxane combination chemotherapy 
o Irinotecan-based therapy: FOLFIRI (FOLinic acid-Fluorouracil-IRInotecan regimen) 
or Onivyde/5-fluorouracil (5-FU)/leucovorin (LV) 


 
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The choice of the chemotherapy regimen for a particular patient will be determined by the 
prior treatment received in the first-line setting. Thus: 
o If a patient received prior gemcitabine/abraxane in the first-line setting, then on 
disease progression, the patient will be assigned to FOLFIRI (or Onivyde/5-FU/LV) 
in the current study. 
o If a patient received prior irinotecan-based therapy (FOLFIRINOX), then on disease 
progression, the patient will be assigned to gemcitabine/abraxane in the current 
study. 
• Follow-up Phase: Patients will be monitored for survival at 8-week intervals. Patients 
who discontinue treatment for reasons other than disease progression will continue to be 
assessed radiologically every 8 weeks until disease progression, or until withdrawal from 
the study, or death. 
An Independent Data Monitoring Committee (IDMC) will be established to review safety data 
at regular intervals, together with the interim and final analyses of efficacy. 
In addition, the safety of eryaspase in combination with irinotecan-based or abraxane-based 
regimens will be reviewed by the IDMC after at least 10 patients are enrolled per regimen and 
have received at least one dose of study therapy. The specific responsibilities and composition 
of the IDMC will be outlined in a separate document, the IDMC Charter. 
Assessments and timing of data collection are detailed in the Schedule of Events in Table 3-1. 
Clinical and laboratory parameters will be assessed in all patients to evaluate disease status and 
toxicity. Patients will have safety assessments (e.g. laboratory tests, physical exams, vital signs 
including temperature, heart rate, and blood pressure, electrocardiograms [ECGs as needed], and 
performance status score) performed on Day 1 and Day 15 of each cycle and at the End of 
Treatment visit. 
Adverse event reporting will begin at the time of informed consent signature. Adverse events 
and concomitant medications will be collected for at least 30 days (90 days in Amendment 1) 
after the last dose of study treatment or until start of a new anti-cancer treatment, whichever is 
sooner. 
Tumor assessments utilizing computed tomography (CT)/magnetic resonance imaging (MRI) 
scans will be repeated every 8 weeks (±3 days), calculated from the date of randomization, until 
disease progression, or until withdrawal from the study, or death. Every effort should be made 
to adhere to the assessment schedule. The same imaging technique should be used throughout 


 
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the study. Patients who discontinue treatment for reasons other than disease progression will 
continue to be assessed radiologically every 8 weeks until disease progression, or until 
withdrawal from the study, or death. For patients who discontinue treatment for reasons other 
than objective disease progression, and patients who start new anti-cancer treatment without 
evidence for objective disease progression, disease status evaluation will continue to be repeated 
every 8 weeks, calculated from the date of randomization, until objective disease progression. 
All radiological images must be collected in a de-identified manner, quality controlled, stored, 
and available for future review. 
Survival information will be collected by phone, follow-up visit, or medical records review 
every 8 weeks (±3 days) from the last dose of study treatment until the patient’s death, until the 
patient is lost to follow-up, or until study closure. Survival follow-up information will include 
collection of any subsequent anticancer therapy received after discontinuation from study 
medication. 
Patient reported outcomes (PRO) using quality of life (QoL) assessment (EORTC QLQ-C30) 
will be performed on Day 1 of each cycle, at the End of Treatment visit, and every 8 weeks 
during survival follow up. 
Blood and plasma samples will be collected in the eryaspase arm for pharmacokinetic (PK) and 
pharmacodynamic determination and for immunogenicity evaluation. 
Blood/plasma samples for pharmacokinetic (PK) and pharmacodynamic assessments will be 
collected at the following time points on Days 1 of Cycles 1 and 3 of study treatment: prior to 
eryaspase administration, at 5-10 minutes post-infusion, at 5-8 days post-infusion (at the 
Investigator’s discretion), and at Day 15 pre-dose. Samples will be analyzed for whole blood 
and plasma concentrations of asparaginase (ASNase) and amino acids (asparagine (ASN) and 
glutamine (GLN)). The sparse PK data will be combined with previous data as part of a 
Population PK (POP PK) analysis. 
Samples for assessment of anti-asparaginase antibodies and neutralizing antibodies will be 
collected pre-dose at Cycle 1 Day 1 and Day 15, at Day 1 of every second cycle thereafter, upon 
determination of disease progression, and at the End of Treatment (EOT) visit. 
Exploratory biomarker analyses will examine potential predictive biomarkers correlating with 
eryaspase activity. Tissue samples will be collected at study start. In addition, blood/plasma 
samples for biomarker analysis will be collected from all patients at Cycle 1 Day 1 and Day 15, 
at Day 1 of every second cycle thereafter, upon determination of disease progression, and at the 
End of Treatment (EOT) visit. 


 
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A blood sample for pharmacogenetic (PGx) analysis will be obtained once during the study, 
preferably during the screening phase, for patients who consent to this optional procedure. 
3.2. 
Eligible Patients 
Refer to study protocol for the inclusion/exclusion criteria. 
3.3. 
Number of Sites and Patients 
Approximately 100 study centers will participate in the study. 
The target sample size is approximately 482 patients.  
3.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, in order to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publication requirements and to respond to queries from 
regulatory authorities. 
This minimal information includes demography and reason for screen failure. 
Patients who do not meet the criteria for participation in this study because of abnormal 
laboratory findings at screening may be rescreened. Rescreened patients should be assigned the 
same patient number as for the initial screening. 
3.5. 
End of Study Definition 
A patient is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Events, 
Table 3-1. 
The end of the study is defined as completion of the last patient’s last visit. 
3.6. 
Randomization Methodology 
Patients will be randomized to receive either chemotherapy in combination with eryaspase or 
chemotherapy alone in a 1:1 ratio, using an IWRS. At screening, the IWRS system will assign a 
unique patient number that will remain constant over the duration of the study. If a patient is 
rescreened after initial screen failure, the IWRS will allocate the same number. Treatment arm 
will be automatically determined by the IWRS system. Patient will be randomized only once. 
Detailed instructions will be provided in the IWRS manual. APPENDIX 1 provides a brief 
summary of the randomization specifications. 


 
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Randomization will be stratified by the following factors: 
 ECOG PS score (0 or 1), 
 Chemotherapy regimen (gemcitabine plus abraxane or irinotecan-based therapy 
[FOLFIRI or onivyde, 5-FU, and leucovorin]), and 
 Time interval since diagnosis of advanced disease to date of randomization in the study 
(<6 months or ≥6 months). 
If stratification factors are missing from the randomization form, they will be imputed either 
by derived baseline value (ECOG and time interval since diagnosis) or actual treatment 
(chemotherapy regimen).  
3.7. 
Stopping Rules 
An interim analysis for efficacy is planned to take place once 261 (67%) events have been 
observed.  There will be no stopping rule for futility built in at the interim. The study could be 
stopped early for efficacy considerations. 
3.8. 
Blinding 
The study is an open-label pivotal trial. Investigators and patients will be unblinded to the 
treatment due to the nature of the investigational therapy. 
Consequently, it is not possible to completely blind everyone at the Sponsor and the contract 
research organization (CRO)/vendors involved with the study with respect to treatment 
assignment. In addition, as eryaspase is an off-shelf investigational agent, the manufacturing 
team will need to have access to information about individual patients. 
The operational, biostatistics and medical teams in Erytech, PPD (CRO) and Cytel will be 
blinded until the study is completed for the primary analysis.  
A separate, unblinded biostatistics team working in a restricted server directory will provide 
data and tables/listings/figures (TLFs) to the IDMC. 
 
 


 
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3.9. 
Study Procedures 
The schedule of event, as outlined in the study protocol, is provided in Table 3-1. 
Table 3-1. 
Schedule of Events 
Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
D8 
D15 
D21 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
X 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Pancreatic cancer disease history (including 
previous anti-cancer therapies) 
X 
 
 
 
 
 
 
 
 
Physical exam (including height [screening 
only] and weight)  
X 
 
X 
 
X 
 
X 
X 
 
Vital signs (temperature, BP, and heart rate) 
X 
 
X 
 
X 
 
X 
X 
 
Performance status1 
X 
 
X 
 
X 
 
X 
X 
 
12-Lead ECG2 
X 
 
X 
 
 
Radiological assessments (CT or MRI)3 
X 
 
X (every 8 weeks [±3 days] from time of randomization until disease 
progression, or death) 
Randomization4 
 
X 
 
 
 
 
 
 
 
QoL assessment (EORTC QLQ-C30) 
 
 
X 
 
 
 
 
X 
X5 
AEs/SAEs 
X (collected from time of informed consent until 90 days after the last study treatment or start of new anti-
cancer treatment, whichever is sooner) 
Concomitant medications 
X (record all medications taken 14 days prior to randomization to 90 days after the last study treatment or 
start of new anti-cancer treatment, whichever is sooner) 
Study Drug 


 
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Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
D8 
D15 
D21 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Blood phenotype6 
X6 
 
 
 
 
 
 
 
 
Prescription with current weight 
 
 
X7 
 
X7 
 
 
 
 
Irregular antibody screening test (IAST) 
 
 
X8 
 
X8 
 
 
 
 
IAST historical result if available 
X 
 
 
 
 
 
 
 
 
Pre-eryaspase dose complete compatibility 
test 
 
 
X9 
 
X9 
 
 
 
 
Eryaspase administration 
 
 
X 
 
X 
 
 
 
 
Chemotherapy 
 
 
Per standard of care 
 
 
Gemcitabine/abraxane 
 
 
X 
X 
X 
 
 
 
 
Irinotecan-based regimen 
 
 
X 
 
X 
 
 
 
 
Biological Exams 
Hematology, biochemistry, and coagulation 
panels; CA19-910 
X10,11 
 
X 
X16 
X 
X16 
X 
X 
 
Pregnancy test, for patients of childbearing 
potential12 
X 
 
X 
 
 
 
 
X 
 
Tumor tissue (for biomarker analysis, 
mandatory) 
X 
 
 
 
 
 
 
 
 
Pharmacogenetic (PGx) sample (optional) 
X (once during the study, preferably during the screening phase) 
 
 
Plasma biomarkers such as ctDNA, 
proteomics, and transcriptomics (central 
labs)  
 
 
X17 
 
X13 
 
 
X 
 
Pharmacokinetic (ASNase activity) and 
pharmacodynamic (amino acid) sample 
(eryaspase arm only) 
 
 
X14 
 
X14 
 
 
 
 


 
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Study Procedures 
Selection 
period 
(within 
3 weeks of 
Randomizati
on) 
Up to 
3 days 
prior to 
Cycle 1 
Day 1 
Treatment (28-day/4-week cycles) 
Cycle 1, 2, 3… 
End of 
Treatment 
Visit 
Follow-
Up every 
8 weeks 
D1 
D8 
D15 
D21 
D28 End of 
Cycle 
Evaluation 
(or D1 
subsequent 
cycle) 
Immunogenicity sample for anti-ASNase 
antibodies and neutralizing antibodies 
(eryaspase arm only) 
 
 
X17 
 
X13 
 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
X15 
Subsequent anti-cancer treatments 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: D=Day; Rand=Randomization; BP=blood pressure; ECG=electrocardiogram; CT=computed tomography; MRI=magnetic resonance imaging; 
QoL=quality of life; EORTC QLQ-C30= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; AE=adverse event; 
SAE=serious adverse event; IAST=irregular antibody screening test; CA19-9=cancer antigen 19-9; ctDNA=circulating tumor deoxyribonucleic acid; 
ASNase=asparaginase. 
1. Per Eastern Cooperative Oncology Group (ECOG)/Karnofsky scales. 
2. Performed during screening, pre-dose Cycle 2 Day 1 and then as clinically indicated. 
3. Radiological assessment to be completed within 3 weeks of randomization and then every 8 weeks (±3 days) from time of randomization until disease 
progression or until withdrawal from the study, or death, using the same method throughout. Tumor assessments will continue in patients, who start 
new cancer treatment without evidence of disease progression Every effort should be made to adhere to the evaluation schedule, irrespective of any 
treatment delays or modifications. Bone and/or brain scans are to be repeated every 12 weeks if clinically indicated. 
4. Randomization performed via interactive web response system (IWRS) within 3 days of 1st chemotherapy dose. 
5. During follow-up, questionnaire is to be completed every 8 weeks. 
6. A complete RBC phenotype (including D, C, E, c, e, and K antigens), ABO blood group status, and Rhesus factor, all assessed on two separate samples 
(can be collected on the same day), to be done as soon as possible but preferably at least 5 working days before the first eryaspase infusion. Exact 
instructions are provided in the Investigational Medicinal Product (IMP) Manual. 
7. Prescription form indicating the patient’s identifiers as well as his/her most recently collected weight, the Investigator recipient of the product, and 
the place and time of the delivery must be sent as soon as possible once the eryaspase infusion is scheduled, and at the latest 5 working days prior to 
Cycle 1 Day 1 and then 5 working days prior to each subsequent eryaspase infusion. Exact instructions are provided in the IMP Manual. 


 
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8. IAST must be completed within 72 hours prior to each eryaspase administration. The results (of the previous infusion) will be provided to the Sponsor 
along with the prescription form prior to subsequent eryaspase infusion. 
9. In case of incompatibility, collection of an additional blood sample will be required for further investigation. 
10. Laboratory tests to be performed at local laboratory as follows: 
Hematology: Complete blood count with differential (hemoglobin, hematocrit, RBC count, white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and platelet count). 
Biochemistry: Sodium, potassium, bicarbonate, calcium, chloride, creatinine, albumin, ammonia, total bilirubin, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase, glucose, urea, triglycerides, total cholesterol, amylase, 
lipase and uric acid; Coagulation parameters – international normalized ratio (INR), Partial thromboplastin time, fibrinogen, antithrombin III. 
Tumor marker: CA19-9 
11. Baseline labs to be collected within 14 days of randomization. 
12. For patients of childbearing potential, serum pregnancy test to be performed during screening period and at End of Treatment and urine pregnancy 
test to be performed prior to dosing of any chemotherapy agent Day 1 of each cycle. Additional pregnancy testing should be performed in case of 
delayed menstrual period and is recommended to be performed monthly and until the end of treatment exposure extended by 30 days, in case of 
sexual activity. 
13. Pre-dose Day 15 sample to be collected only during Cycle 1. 
14. Samples to be collected Cycles 1 and 3 of study treatment on Day 1 prior to eryaspase administration, 5-10 minutes post-eryaspase infusion, 5 to 
8 days post-infusion, and on Day 15 pre-dose. 
15. Survival follow to be conducted by phone, visit, or medical records review every 8 weeks (±3 days) from last treatment visit until patient’s death, loss 
to follow up, or study closure. Subsequent therapy should be collected during this follow-up. 
16. For patients under eryaspase arm, in addition to regular evaluation of liver function tests before treatment administration, patients will be monitored 
on weekly basis in the event of occurrence of ≥Grade 2 elevation of liver enzymes and bilirubin levels. 
17. Performed pre-dose Cycle 1 Day 1 and then pre-dose Day 1 of every second cycle thereafter i.e., Cycle 3 Day 1, Cycle 5 Day 1, upon determination of 
disease progression, or EOT, whichever is sooner.as clinically indicated. 
** 
Additional lab tests may be required (e.g., weekly monitoring per standard practice or label requirements should be followed) and should be reported 
in the electronic Case Report Form (eCRF) if clinically significant. 
 


 
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4. 
GENERAL STATISTICAL CONSIDERATIONS AND 
DATA HANDLING  
4.1. 
Sample Size Determination 
The primary objective of this study is to compare eryaspase in combination with chemotherapy 
versus chemotherapy alone in terms of OS. With a power of 88.4% and an overall one-sided 
type I error of 2.5% and including one interim analysis for efficacy with an O’Brien-Fleming 
type stopping rule, a total of 390 deaths are required to detect a treatment effect hazard ratio of 
0.725 for eryaspase plus chemotherapy versus chemotherapy alone. The hazard ratio in a Phase 
2 study for eryaspase was HR=0.60 (95% CI: 0.41 to 0.87) 1, and 0.725 represents a 
conservative estimate based on these data that is viewed as being clinically relevant. This 
translates to an approximate 2.28 months increase from an assumed median overall survival of 6 
months in the control arm. The choice of 6 months in the control arm is based on reported OS in 
Napoli-1 study 2, and the average OS improvement (2.3-10.2 months) in several randomized 
trials in second line setting 3. 
The interim analysis for efficacy will take place once 261 (67%) events have been observed. As 
of October 2021, the interim analysis for efficacy was conducted on 04 Feb 2021. The IDMC 
recommended that the study would continue to completion. The Sponsor continues to be blinded 
to any aggregate tables and figures. 
Assuming a recruitment period of 26 months, a median overall survival in the control group of 6 
months, a 10% drop-out rate, and a minimum follow-up of 9 months, the study size will be 
based on the recruitment of approximately 482 patients. Database lock was planned for 30 Jun 
2021 having observed the required number of events. Based on the time taken to clean the 
database this date was pushed back to 30 Aug 2021 and at this time the number of events was 
420. The final analyses will be based on this number of events in order to maximize the power 
to detect treatment differences. 
4.2. 
General Methods 
The primary statistical analyses will be performed using cleaned eCRF data obtained until a 
clinical cut-off date, which will be determined based on the reaching the pre-defined number of 
events. A further analysis will be undertaken once all patients have completed the study. 
All outputs will be incorporated into Microsoft Excel or Word files, sorted and labeled 
according to the International Conference on Harmonisation (ICH) recommendations, and 
formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic, 
PRO and safety parameters.  For categorical variables, summary tabulations of the number and 
percentage within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the mean, median, standard deviation, minimum and 
maximum values will be presented.  Time to event data will be summarized using Kaplan-Meier 


 
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methodology: median time-to-event, survival rates and rate differences between treatment at 
specified timepoints, and restricted mean survival time, all presented with associated 2-sided 
95% confidence intervals. Event types and censoring reasons will be summarized.   
All tumor measurement-related variables (PFS, ORR, DCR) will be based on both Investigator 
assessment and independent radiological reviews (IR).   
All efficacy analyses will use the intent-to-treat (ITT) principle (analysis of data by the groups 
to which patients were randomized).  Safety analyses will be based on the actual treatment 
received. 
All statistical testing will be undertaken based on a one-sided 2.5% significance level (or 
equivalently a two-sided 5% significance level) subject to adjustments for interim. Summary 
statistics will be presented, as well as confidence intervals (CIs) which will be provided at a 2-
sided 95% level, unless otherwise stated.  
4.3. 
General Date Conventions 
The general data handling conventions used in the derivation of variables used in data 
summaries and analysis are summarized in Table 4-1. 
Table 4-1 
General data handling conventions 
Term  
Definition/Rule  
Date of diagnosis of 
pancreatic cancer  
Date of initial pathological or radiological diagnosis. If both are 
available, then the date of pathological diagnosis will be used.  
 
Date of first 
administration of study 
treatment 
This is derived as the first date when a non-zero dose of any 
component of study treatment is administered.  
The first date of first administration is also referred as the start 
date of study treatment. 
 
Date of last 
administration of study 
treatment 
This is derived as the last date when a non-zero dose of any 
component of study treatment is administered. 
 
Study Day  
Study Day describes the day of the event or the assessment date, 
relative to the reference start date, which is either the 
randomization date or the start date of study treatment 
The reference start date is designated as the Study Day 1.  
Day-1 is the day that precedes Day 1. 
 
The study day will be calculated as follows: 
- 
If the event is on or after the reference start date, then: 
the date of the event = (Visit date, onset date of an event, 
assessment date, etc.) – reference start date + 1). 


 
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- 
If the event precedes the reference start date, then: the 
date of the event = (Visit date, onset date of an event, 
assessment date, etc.) – reference start date). 
 
The reference start date for all safety assessments, QoL 
assessment (EORTC QLQ-C30) and PK data will be the start date 
of study treatment. 
The reference start date for all efficacy assessments (tumor 
assessment, death, ECOG,) will be the randomization date. 
 
The reference start date for any non-safety screening 
assessment or events (baseline characteristics, medical history, 
cancer history, etc) will be the randomization date. 
 
Cycle  
Start date: Date of first study drug dose at each cycle. 
End date: The day before the start date of the following cycle. 
 
For the last cycle, the end date will be the start date of the cycle 
+ planned cycle length (4 weeks), or the death, or 
discontinuation date, whichever is earlier. 
 
Weeks 
Study days divided by 7 and rounding to one decimal place. 
 
Months  
Study days divided by 30.4375 days and rounding to one 
decimal place. 
 
Years  
Study days divided by 365.25 days and rounding to one decimal 
place. 
 
Baseline  
Baseline is defined as the period from the date of signing any 
informed consent document to the date of randomization or the 
start date of study treatment. 
 
For efficacy assessments (tumor assessment, death, ECOG), the 
latest non-missing value generated on or before the date of 
randomization will be used as the baseline value/assessment. 
 
For safety assessments (including QoL assessment (EORTC 
QLQ-C30)), the last available assessment on or before the start 
date of study treatment (likely Cycle 1 Day 1) is considered as 
the “baseline” value or assessment. 
In the case of patients who are randomized but not yet treated, 
randomization date will be used to select baseline 


 
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value/assessment; for demographic or baseline data summarized 
by ITT or PP population.  
 
If a patient has 2 “baseline” ECOG (or PRO) values at the same 
date, then the worst ECOG PS value will be taken as the 
“baseline”. 
 
Assessments specified to be collected post-dose on the first date 
of treatment are not considered as baseline values. 
 
If patients have no value as defined above then the baseline 
value will be missing. 
 
Post-baseline  
Any non-missing measurement after the first dose of study drug. 
  
Time to Event (i.e., PFS 
or OS)  
(date of the event) – (randomization date) + 1  
Age  
(date of informed consent – date of birth)/365.25 rounded down  
In case of partial birth date, impute missing day as 15th of the 
month; impute the missing month as June 30th; if year is 
missing, set age as missing. 
 
Total duration of 
treatment (weeks) 
(date of last dose) – (date of first dose) + 1) /7 
Last contact date 
Derived for patients not known to have died at the analysis cut-
off date, defined as the latest complete date from the following 
list, or the last contact date, whichever comes first:  
- 
Assessments dates (e.g. laboratory, vital signs, ECOG, 
PRO, ECG, tumor scans, PK, etc) 
- 
Medication and procedures dates (e.g. concomitant 
medications, medical or surgical procedures, new 
anticancer therapy) 
- 
Adverse events start and end dates 
- 
“last date patient alive” in the “survival” eCRF page 
- 
Study treatment start/end date 
- 
Randomization date 
The cut-off date will not be used for the last contact date, unless 
the patient is contacted on that date. 
 
Further, completely imputed dates (eg the analysis cut-off date 
imputed by the SAS program to replace the missing end date) 
will not be used to derive the last contact date. 
 
 


 
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4.4. 
Computing Environment 
All statistical analyses will be performed using Statistical Analysis Systems (SAS®) release 9.4 
or higher, unless indicated otherwise.  
Medical History and adverse events will be coding using MedDRA version 21.0.  The intensity 
of AEs will be graded according to the NCI-CTCAE (version 5.0).   
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary, version B3 June 2018. The dictionaries will remain static throughout the life of the 
project. However, an update to the most recent version will be performed before final database 
lock. 
4.5. 
Methods of Pooling Data 
Not applicable to the present study. 
4.6. 
Efficacy, PK, Pharmacodynamic and Safety Variables 
 
Efficacy Variables 
4.6.1.1. Primary efficacy variable 
The primary endpoint is Overall Survival (OS), which is measured from the date of 
randomization to the date of death from any cause. Patients who are not known to have died 
prior to data cut-off will be censored at the date of last contact or the date of data cutoff, 
whichever is earlier.  
4.6.1.2. Secondary efficacy variables 
Secondary efficacy variables include: 
• Progression-free Survival (PFS) is defined as the time interval from randomization to 
first disease progression (PD) per modified RECIST 1.1 based on the investigator review 
or death from any cause in the absence of PD, whichever occurs first.  
• The Objective Response Rate (ORR) is the proportion of patients who achieve tumor 
response (CR or PR) per modified RECIST 1.1.  
• Duration of Response (DoR) is defined as the time from first response of CR or PR until 
disease progression, as determined by modified RECIST 1.1. 
• Disease Control Rate (DCR) is defined as the proportion of patients who have CR, PR, 
or SD as determined by modified RECIST 1.1 criteria.  
• Emergence of new metastatic lesions, defined as the proportion of patients with 
radiological progression that included new metastatic lesions will be presented. 


 
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• Patient reported outcomes (PRO) using QoL endpoints include variables from various 
scales from the standardized instrument, EORTC QLQ-C30, at the following time 
points. 
 
PK, Pharmacodynamic and Immunogenicity Variables 
Eryaspase pharmacokinetics will be evaluated using sparse sampling. Whole blood 
concentrations of ASNase from these samples will be combined with previous data as part of a 
POP PK analysis. The pharmacodynamic effect of eryaspase on amino acid levels will also be 
evaluated. 
For all patients who provide samples, PK and pharmacodynamics of eryaspase will be assessed 
at each measurement in terms of: 
 Total asparaginase activity (U/L) 
 Plasma asparaginase activity (U/L) 
 Plasma concentrations of asparagine (μmol/L) 
 Plasma concentrations of glutamine (μmol/L) 
Immunogenicity variables include the presence of anti-asparaginase antibodies and neutralizing 
antibodies over time. 
 
Safety Variables 
Safety assessments performed during the study included measurement of vital signs, physical 
examination, ECOG performance status, clinical laboratory evaluations including standard 
blood chemistry, hematology, coagulation, and serum electrolytes, and monitoring of AEs. 
 
Other Variables 
This study will collect samples for biomarker assessments in all patients. Sample types include 
tumor tissue samples (archival or fresh), whole blood samples for pharmacogenetics and plasma 
samples for circulating tumor DNA (ctDNA). All biomarker analyses will be performed at 
central laboratories.  
4.7. 
Analysis Populations 
The primary population for analysis is the ITT population. All primary and secondary analyses 
will be repeated on the PP population and this will serve as sensitivity analysis. 
Intent to treat population (ITT):  
All patients randomized to study treatment (eryaspase, gemcitabine, abraxane, irinotecan and 
5FU). According to the ITT principle, patients will be analyzed according to the treatment and 


 
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strata they have been assigned to during the randomization procedure. The ITT population will 
be the primary population for the efficacy analyses.  
Safety population (SP):  
All randomized patients who receive at least one dose of study drug(s). Patients will be analyzed 
according to the actual study treatment received, where treatment received is defined as the 
randomized treatment if the patient took at least one dose of that treatment, or the first treatment 
received if the randomized treatment was never received. 
Per Protocol population (PP):  
The PP population is a subset of the ITT population consisting of patients who are sufficiently 
compliant with the protocol, with no protocol deviations that could confound the interpretation 
of the primary analysis conducted on the ITT population. Patients included in the PP population 
should meet the following criteria: 
• Received at least one dose of study drug to which they were randomized 
• No major protocol deviation in inclusion/exclusion criteria 
Patient inclusion in the PP population and the reasons for exclusion will be summarized. The 
reasons for exclusion will be determined during the data review meeting and documented prior 
to the performance of the primary OS analysis. 
Pharmacokinetic analysis population 
The pharmacokinetic analysis set will include all randomized patients who received at least one 
dose of eryaspase and who have at least one post-baseline PK assessment. Patients will be 
evaluated by the treatment actually received. 
PRO analysis Population 
The PRO population will consist of all patients who receive at least one dose of the study 
treatment and provide answers to at least some items of the EORTC QLQ-C30 at Cycle 1 Day 1 
(i.e, baseline) and a time point after the date of first dose of study treatment. 
4.8. 
Adjustment for Covariates 
Primary and secondary efficacy analyses include stratification factors (as defined by the IWRS) 
as covariates, together with gender and time since first diagnosis of pancreatic cancer to 
randomization as detailed below:  
 Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1). 


 
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 Chemotherapy regimen in this study (gemcitabine/Abraxane or irinotecan-based 
treatment [FOLFIRI or its equivalent onivyde/5-FU/LV]). 
 Time interval since initial diagnosis of advanced disease to date of randomization in the 
study (<6 months or ≥6 months). 
 Gender. 
 Time since first diagnosis of pancreatic cancer to randomization ((<12 months or ≥12 
months). 
4.9. 
Multiple Comparisons/Multiplicity 
All statistical testing will be undertaken based on a one-sided 2.5% significance level (or 
equivalently a two-sided 5% significance level) subject to adjustments for interim. 
Confirmatory testing for the primary and secondary efficacy endpoints will be performed 
hierarchically (OS followed by PFS followed by DCR followed by ORR (investigator 
assessment)) in order to account for multiplicity. Any statistically significant findings occurring 
below a non-significant result in the hierarchy will be considered as exploratory findings. 
4.10. 
Subgroup Analyses  
OS and PFS hazard ratios will be calculated for the following subgroups of patients and 
displayed in Forest Plots. In each case hazard ratios will be obtained from the Cox proportional 
hazards regression model including the stratification factors as covariates. For subgroups 
associated with those stratification factors the model will not include that factor. 
 Gender (Male, Female). 
 Age Group (< 65 years, >= 65 years). 
 Chemotherapy regimen (gemcitabine plus abraxane, irinotecan-based therapy FOLFIRI 
or onivyde, 5-FU, and leucovorin). 
 Eastern Cooperative Oncology Group (ECOG) performance status (0, >=1). 
 Time since diagnosis of advanced disease to date of randomization in the study (<6 
months or ≥6 months). 
 Time since first diagnosis of pancreatic cancer to date of randomization in the study : 
(<12 months or ≥12 months). 
 Geographical region (US or EU), which will be determined by the IWRS system based 
on site number. 
 Stage at study entry: III and IV. 
 CA19-9 at baseline (normal or elevated; < median nadir or >= median nadir). 
 Prior systemic adjuvant/neoadjuvant therapies: (Yes or No). 
 Prior systemic therapy (1 or 2 or 3). 
 Response to prior therapy in advanced setting: (CR+ PR+SD), progressive disease (PD). 


 
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 Hepatic metastasis (Yes/No). 
4.11. 
Withdrawals, Dropouts, and Loss to Follow-up  
Randomized patients who discontinue the study early for any reason will not be replaced and are 
not permitted to re-enter the study. Best efforts will be made to follow these patients for 
survival.   
4.12. 
Missing, Unused, and Spurious Data  
 
Missing dates for study drug administration 
When using dates from drug administration pages for the purposes of deriving treatment 
exposure, the following conventions will apply:  
 If the start date is missing, the date of randomization will be used to replace all first 
administration missing dates.  
 If the last administration date is missing, the date will be imputed with the date taken 
from one of the following eCRF pages, whichever is earlier: 
o The “Status of the Patient at the End of the Treatment” eCRF page. 
o Last known administration date 
o Last contact date for alive patients 
o Date of death for dead patients 
 
Missing dates for adverse events 
For missing or partial missing onset dates for adverse events, the following conventions will 
apply: 
 If the start date of an event is completely missing, then the event is assumed to be 
treatment-emergent (TE).  Treatment-emergent adverse event (TEAE) is an event that started 
on or after the first dose of study medication or that worsened after the first dose of study 
medication and with an onset date occurring during the treatment period. 
 If the start date has the month and year but day is missing, the event will be considered 
treatment-emergent if the month and year of the start date of the event are equal to, or 
greater than, the month and year of the date of first dose of study drug.  
 If the start date has the year, but day and month are missing, the event will be considered 
treatment-emergent if the year of the start date of the event is to the same as, or later 
than, the year of the date of the first dose of study drug. 


 
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  If the stop date is not missing, and the imputed start date is after the stop date, the 
imputed start date is equal to the stop date. If the imputed stop date is before the start 
date, the imputed stop date is equal to the start date. 
 
Missing dates for other variables 
When deriving all other variables that use dates, for dates that include missing values, the 
following conventions will be used. 
Value  
Imputation  
Missing day, month, and year  
Not imputed  
Missing day and month  
Day imputed to June 30th  
Missing day  
Day imputed to the 15th  
If the stop date is not missing, and the imputed start date is after the stop date, the imputed start 
date is equal to the stop date. If the imputed stop date is before the start date, the imputed stop 
date is equal to the start date. 
4.13. 
Visit Windows  
Specific visit windows will not be applied to this study given the variable number of courses 
each patient could have received. Screening assessments were to be completed within 3 weeks 
prior to randomization.  
Disease evaluations per modified RECIST 1.1 criteria will be taken every 8 weeks until disease 
progression, calculated from the randomization date. Survival follow-up would be conducted 
every 8 weeks from the last study assessment visit until the patient died, is lost to follow up, or 
the study closed.  
Patients who discontinue treatment for reasons other than disease progression will continue to 
be assessed radiologically every 8 weeks until disease progression, or until withdrawal from the 
study, or death. 
4.14. 
Protocol Deviations  
Protocol deviations will be identified by site monitors, the medical monitors and by the checks 
of the clinical database. Important deviations will be summarized for each treatment arm by the 
type of deviation. All protocol deviations will be listed. Major protocol deviations related to 
inclusion and exclusion criteria result in removal of a patient from the Per Protocol population, 
APPENDIX 2.   
Major protocol deviations will be defined as departure from the approved protocol that may 
impact the rights, safety of the patients or the integrity of the data. The sponsor, or designee, 
will be responsible for producing the final protocol deviation file (formatted as a Microsoft 
Excel file or using the RAVE output), in collaboration with Cytel; this file will include a 
description of the protocol deviation.  


 
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Data from patients who were randomized to one treatment and received the other treatment will 
be provided in a separate listing.  
5. 
PATIENT DISPOSITION AND BASELINE DATA 
SUMMARIES 
5.1. 
Patient Disposition 
Patients who give informed written consent but are not randomized are considered screen 
failures. Minimal data, such as demographic information and the reason for screen failure, for 
patients who fail screening will be recorded in the case report forms (CRFs).  
A tabulation of patient disposition will be provided, including the number of screen failures, the 
number of patients enrolled, number of patients in each chemotherapy subgroup, the number in 
each subset, population for analysis, and the primary reasons for withdrawal from treatment and 
study. Disposition will also be summarized by study site. Reasons for screen failure will also be 
summarized.  
A CONSORT diagram showing the flow of the participants through each stage of the study will 
be provided APPENDIX 3. A complete accounting of all patients participating in the study will 
be provided in overall summary table(s). This will include the final disposition of all study 
patients including the number of: 
 Total number of patients assessed for eligibility.  
 Number of patients excluded (screen failures), reasons for exclusion. 
 Number of patients provided written consent and randomized and are included in the 
efficacy analyses. 
 Number patients randomized to each treatment group: gemcitabine/abraxane, 
Gemcitabine/abraxane/eryaspase, NALIRI/FOLFIRI, and NALIRI/FOLFIRI/eryaspase. 
 Number of patients receiving at least 1 dose of study drug by treatment group and 
included in the safety analyses. 
 Discontinuation from study treatment by primary reason. 
 Discontinuation from study participation by primary reason.  
Distribution of patients by investigator with respect to the number of patients enrolled by 
treatment group and overall will be presented.  
A by-patient listing of study completion information, including the reason for premature 
treatment and study discontinuation, if applicable, will be presented. 


 
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5.2. 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics will be listed and summarized by treatment group 
and overall in each of the ITT and PP populations.  
Summaries will also be generated by treatment subsets in each arm (Gemcitabine/Abraxane, 
Irinotecan-based). 
 
Demographic Data  
Summary statistics (mean, median, standard deviation, minimum, maximum) will be presented 
for the continuous variables. 
 Age (years). 
 Age distribution. 
o 
Number (and %) of patients according to age in categories (<65 years; ≥65 
years). 
 Race: 
o   White (Caucasian/European Heritage, Arabic/North African Heritage). 
o   African American. 
o   Asian (Japanese or Japanese Descent). 
o   Asian (Others). 
o   American Indian or Alaska Native. 
o   Native Hawaiian or Other Pacific Islander. 
o   Others 
 Gender: (Male/Female). Number (and %) of patients.  
 Geographic region: Europe, USA. 
 Physical Examination at Baseline: Frequency table of patients with at least one abnormal 
finding.  
Blood group, Rhesus system, Phenotype and Irregular Antibody will be summarized by treatment 
group an listed by patient.  
 
Characteristics of Pancreatic Cancer  
Disease history for each patient will be summarized from the “Pancreatic Cancer History” eCRF 
page and the “Best Response Outcome” eCRF page. 
Summary statistics will be displayed by treatment group and overall. 
 Stage at Initial Diagnosis (I, II, III, IV, unknown). 
 Time from initial diagnosis to randomization in months (date of randomization – date of 
initial diagnosis +1)/30.4375). 


 
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 Stage at study entry (III, IV). 
 Time from diagnosis of advanced diagnosis to randomization in months (date of 
randomization – date of diagnosis of advanced (stage III or IV) disease +1)/30.4375). 
 ECOG Performance status: 0, 1, unknown (NOTE: ECOG PS should be based on 
reported status in eCRF at baseline.) 
 Number of prior systemic cancer therapies. 
 Sites of Metastasis (liver, lung, brain, peritoneal, others, unknown).  
 Number of metastatic sites (<3, >=3). 
 CA19-9 at baseline (normal vs. elevated), (< median, >= median). 
In addition, a separate table and associated listing will present the distribution of the 3 
stratification factors (in combination and according to the IWRS system) by treatment groups. 
 
Prior Cancer Therapy 
Cancer therapy will be summarized using data recorded in the “Prior Pancreatic Cancer 
Treatments, Prior Systemic Anti-cancer therapy, Prior Radiotherapy Treatment and Prior 
surgical treatment for pancreatic cancer” eCRF pages. Summary statistics will be displayed by 
treatment group and overall. This will include: 
 Prior surgery. 
 Prior radiotherapy. 
 Prior neoadjuvant therapy; and best response to prior neoadjuvant therapy (CR, + PR, 
SD, PD, unknown). 
 Prior adjuvant therapy. 
 Prior systemic therapy for advanced disease: 
o Gemcitabine + Abraxane – based chemotherapy 
o FOLFIRINOX and variants 
o Fluoropyrimidine-based, eg FOLFOX 
o Others  
 Best objective response to first-line therapy for advanced therapy (CR + PR, SD, PD, 
unknown). 
5.3. 
Medical and Surgical History  
Other medical history, both previous and current conditions, will be summarized by treatment 
group in the ITT population. Using data from the “Relevant Medical or Surgical History or 
Current Medical Conditions other than Pancreatic Cancer” eCRF pages. Medical history is 
coded with MedDRA. Medical history will be displayed in terms of frequency tables: ordered 
by primary system organ class (SOC) and preferred term (PT) in decreasing frequency order:  


 
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 A table with the number of patients having at least one previous medical history will be 
displayed by treatment group and overall. Previous conditions are medical history that 
stopped prior to the screening date. 
 The same table will be constructed for the number of patients having at least one 
ongoing medical history. Ongoing conditions are medical history still present at the first 
infusion date of any of eryaspase or chemotherapy. 
 A table with the number of patients having at least one previous cancer history by 
intervals of time since initial diagnosis of pancreatic cancer.  
Medical history will be listed by treatment group and patient number.  
In case of a partial or missing end date, medical history will be assumed to be ongoing except if 
the partial date indicates that the condition stopped prior to the selection visit. 
6. 
STATISTICAL ANALYSIS 
6.1. 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is OS which is measured from the date of randomization to the date of 
death from any cause.  
OS (months) = (earliest date of death or censoring – date of randomization + 1)/30.4375 
Patients who are not known to have died prior to data cut-off will be censored at the date of last 
contact or clinical cut-off, whichever comes first. The last contact date will be derived as the 
latest available date among those detailed in Table 6-1. 
Table 6-1 
 Rules for the last contact date for OS analysis 
Source Data 
Conditions 
Date of randomization 
No condition 
Last contact date/last date patient known to 
be alive from Long-Term Follow-Up eCRF 
• Use if patient status is reported to be 
alive 
• Do not use if patient status is reported 
unknown 
Start/end dates of new anticancer therapy 
Non missing chemotherapy term 
Start/end dates from drug administration eCRF Non missing dose.  
End of treatment date from the End of 
Treatment eCRF 
No condition 


 
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Tumor assessment (RECIST v1.1) date 
Evaluation is marked as done. 
Laboratory/PK collection dates 
Sample collection marked as done. 
Vital signs date 
At least 1 non missing parameter value 
ECOG performance status date 
Non missing ECOG performance status 
Start/end dates of adverse events 
Non missing verbatim term 
Physical examination 
At least 1 non missing parameter value 
 
For the primary analysis, OS will be summarized by treatment group for the ITT population. 
Summaries will include the number of patients who had an event during the study, the number 
of patients who didn’t have an event during the study (censored), with the date of censoring 
equal to the date that the patient was last known to be event-free.  
Median time-to-event will be estimated from a Kaplan-Meier analysis, with associated survival 
curves produced. The p-value for this analysis will be provided from the stratified log-rank test, 
with stratification factors as used in the randomization. Kaplan-Meir estimates will be given at 
6, 8 and 10 months along with the difference in those OS rates at each timepoint. The hazard 
ratio, its associated 95% CI and p-value will be estimated from a Cox proportional hazards 
model, including the stratification factors (according to IWRS) as covariates.   
Forest plots of the OS hazard ratios and the associated 95% CIs in subgroups will be constructed 
using the Cox PH model adjusting for the stratification factors as detailed in Section 4.9 (except 
where the subgroups are defined by a stratification factor, in which case that factor will be 
excluded) and the other two factors listen in Section 4.7. 
 
Supportive and sensitivity analyses for OS 
 A Cox PH model as for the primary analysis for OS but with stratification factors 
determined according to the baseline characteristics. In addition to the on ITT population, 
this analysis is repeated for actual treatment assignments (Safety population).  
 A Cox PH model will also be performed separately for each stratification factor, Gender and 
Time since first diagnosis of pancreatic cancer to randomization.  
 PP population. 
 Restricted mean survival time (RMST) may be computed using the area under the curve 
from baseline to 6, 12 and 18 months. RMST will be calculated for each treatment arm and 
the difference with its 95% CI will be displayed.  
 Sensitivity analyses to address different censoring rules: 
a) Explore the potential impact of the following 
 Censored at the date of subsequent anticancer therapy 


 
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b) Lost to follow-up 
 The impact of loss to follow-up on OS will be assessed on the number of 
patients who are lost to follow-up. If >5% of patients are lost for follow-
up for OS in either treatment arm, a sensitivity analysis will be performed 
for the comparisons between the 2 treatment arms in which patients who 
are lost to follow-up will be considered as having died at the last date 
they were known to be alive. 
 
Planned Interim Analyses for Overall Survival 
This study will have an event-driven interim analysis for OS, based on O’Brien-Fleming 
boundaries and the Lan-DeMets alpha-spending function. The interim analysis for OS is 
planned to take place following 261 deaths.  
An independent statistical group will conduct the interim analysis and assist the IDMC in 
rendering decisions on whether to recommend stopping the trial for efficacy or continuing the 
study as planned. For the OS interim analysis, if the one-sided p-value from the stratified log-
rank test is less than the corresponding significance level, then the study could be stopped for 
early success on OS, based on the IDMC recommendation. The actual significance levels will 
be determined based on the exact number of deaths at the time of the interim analysis. 
The key secondary endpoints may not be provided to the IDMC at the time of the interim 
analysis. The primary reason for this is due to the COVID-19 impact. Full data cleaning is 
increasingly delayed due to travel and sites visit restrictions. Therefore, to avoid undue delay of 
the interim analysis plan, the IDMC recognizes that these key secondary endpoints will not be 
available. This will only be performed once those data are fully cleaned and if OS in the ITT 
analysis set has achieved statistical significance.  
6.2. 
Final Analysis and Topline Results 
The final analysis will be conducted following the database lock. Data will be restricted by a 
cutoff date as close as possible to the date of planned database lock and determined by data 
cleaning logistics.  
Topline results will be generated ahead of full TLFs immediately following database lock. 
Additional analyses and tables may also be generated in support of topline results, APPENDIX 
4  
Analyses outside of those listed will be generated subsequently and the sponsor will remain 
blinded to these analyses and associated endpoints until the requisite tables, figures and listings 
have been generated. 
6.3. 
Analysis of Secondary Efficacy Endpoints 
The key secondary endpoints for this study are the PFS, DCR and ORR. The key secondary 
endpoints will be evaluated for confirmatory conclusions in this order only if the primary 
endpoint OS is statistically significant (one-sided p<0.025).  


 
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Analysis of Progression-Free Survival (PFS) 
PFS is defined as the interval time from the date of randomization until objective disease 
progression per modified RECIST 1.1, or death from any cause in the absence of disease 
progression, whichever occurs first.  
PFS = (earliest date of documented disease progression, death or censoring) – date of 
randomization) +1 
PFS will be compared between the two treatment arms using the same methods of analysis as 
for OS. In addition, the proportions of patients with PFS events (Total and split by radiological 
disease progression and death events) and censored PFS events (Total and reasons; no baseline 
tumor assessment, no progression, treatment discontinuation, new anticancer therapy, missed 
scans, data cutoff) will be summarized by treatment arm, Table 6-2. 
Forest plots of the PFS hazard ratios for the subgroups detailed in Section 4.9 will also be 
produced for the ITT population. The primary analysis of PFS is based on the investigator’s 
evaluation.  
6.3.1.1. Definitions for PFS analysis 
The following conventions will be used for the PFS analysis  
Definition of progression date: Progression Date is assigned to the first time at which 
progression can be declared; this will coincide with dates of radiological assessments. If 
multiple radiological assessments based on the sum of target lesion measurements are done at 
different times, the progression date is the earliest date of the first observation or radiological 
assessment of target lesions that shows a predefined increase in the sum of the target lesion 
measurements, or appearance of new lesion. 
For sensitivity analysis, the progression date is defined as the date of the protocol-scheduled 
clinic visit immediately after all radiological assessments (which collectively document 
progression) have been done. 
Definition of adequate tumor assessment.  
An adequate tumor assessment includes adequacy of target lesion assessments and adequacy of 
radiological tests both to evaluate non-target lesions and to search for new lesions. 
Partially missing tumor data.  
Unless disease progression is evident, partially missing tumor data or indeterminate lesions for a 
particular tumor assessment will result in an overall response of “unknown” or “not evaluable” 
and the tumor assessment will not be deemed adequate. If progression is assessed in the 
subsequent visits, data from partially missing assessments will be ignored. 
Completely missing tumor data.  


 
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There are several permutations in this situation: 
- 
completely missing adequate tumor assessments followed by death or by assessment visits 
showing progression.  
• If only a single missing assessment   The assessment will be ignored; use the 
subsequent assessment (or visit) 
• If 2 or more consequent assessments missed  use the last adequate assessment 
- 
completely missing adequate tumor assessments followed by subsequent assessment 
shows no progression.  ignore the missing assessment 
6.3.1.2. Censoring rules for the primary PFS analysis 
Table 6-2 provides the general primary rules for calculating PFS and censoring rules, in line 
with FDA guidance4. If a patient meets the criteria for more than one censoring rule, PFS will be 
censored at the earliest censoring date.  
Table 6-2 
Primary PFS analyses and censoring rules. 
Situation  
Date of Progression or Censoring  
Outcome  
Documented progression per 
modified RECIST 1.1 
Earliest date on which radiological 
progression is documented  
Progressed 
Incomplete or no baseline tumor 
assessment  
Change in imaging modality 
Randomization date  
Censored  
Progression documented between 
scheduled visits (unscheduled scan)* 
Earliest** of:  
 Date of progression 
assessment showing new 
lesion; or  
 Date of last adequate 
progression assessment  
Progressed 
No progression 
Date of last adequate assessment 
with no documented progression 
Censored 
Treatment discontinuation for 
clinical progression (undocumented 
progression) 
Date of last adequate assessment 
with no documented# progression  
Censored  
Treatment discontinuation for 
toxicity or other reasons (eg, 
withdrawal of consent) 
Date of last adequate$ assessment 
with no documented progression 
Censored  
New anticancer treatment started 
with no claim of adequate 
progression assessment 
Date of last adequate assessment 
with no documented progression 
before start of new treatment 
Censored  
Death before first radiological 
assessment  
Date of death  
Progressed 
Death between adequate progression 
assessment visits, or after patient 
missed one assessment visit 
Date of death  
Progressed  


 
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Death or progression after more than 
one missed consecutive scans 
Date of last adequate assessment 
with no documented progression 
Censored  
Death after 8 weeks of treatment 
discontinuation due to any reason 
without starting a new anticancer 
treatment  
Date of last adequate assessment 
with no documented progression 
Censored  
No progression at the time of final 
analysis  
Date of last adequate assessment 
with no documented progression 
Censored  
*An unscheduled scan is defined as a radiological assessment earlier or later than every 8 weeks (+/- 7 days).  
** Progression date assigned to the first time at which progression can be declared: For progression based on 
a new lesion, the Progression Date is the date of the first observation that the new lesion was detected. If 
multiple assessments based on the sum of target lesion measurements are done at different times, the 
Progression Date is the date of the first observation or radiological assessment of target lesions that shows 
a predefined increase in the sum of the target lesion measurements. 
# documented: evidence of disease progression per modified RECIST 1.1. 
$ adequate: progression assessment should be based on appropriate radiological assessments as described in 
the protocol and schedule of events. 
6.3.1.3. Supportive and sensitivity analyses for PFS 
These include the following: 
 A Cox PH model as for the primary analysis for PFS but with the stratification factors 
determined according to the baseline characteristics. 
 PP population. 
 Sensitivity analysis in relation to the investigator declaration of progression based on 
different definition of progression events and censoring rules, Table 6-3. These analyses 
will be performed for the ITT population, using the same statistical methods as the 
primary analysis. 
 Sensitivity analyses in relation to the IR based on the original (Table 6-2) and on the 
different definition of progression events and censoring rules (Table 6-5). These analyses 
will be performed for the ITT population, using the same statistical methods as the 
primary analysis.  
 Discordance between IR and investigator’s assessment using 2 measures, the early 
discrepancy rate (EDR) and the late discrepancy rate (LDR)5,6. 
6.3.1.3.1. Censoring rules will be used for sensitivity PFS analysis 
In the primary PFS analysis, censoring is based on the last adequate tumor assessment, Table 
6-2. In case of the sensitivity analysis in relation to progression declared by the investigator, the 
following situations will be considered progression events, and the progression date will be the 
patient visit date: 


 
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a. Clinical progression 
b. Starting new anticancer therapy 
c. General deterioration of health and/or performance status 
The impact of clinical deterioration, study drug discontinuation, and new anti-cancer therapy 
sensitivity analyses will be performed as described in Table 6-3. 
Table 6-3 
Sensitivity PFS analyses and censoring rules 
Situation  
Date of Progression or Censoring  
Outcome  
Progression per modified RECIST 
1.1 
Earliest date on which radiological 
progression is documented  
Progressed 
Incomplete or no baseline tumor 
assessment  
Randomization date  
Censored  
Progression documented between 
scheduled visits (unscheduled scan)* 
Next scheduled visit* 
Progressed 
No progression 
Date of last visit with adequate 
assessment  
Censored 
Treatment discontinuation for 
clinical progression (undocumented 
progression) 
Date of discontinuation   
Progressed  
Treatment discontinuation for 
toxicity or other reasons (eg, 
withdrawal of consent) 
Date of discontinuation   
Progressed  
New anticancer treatment started 
with no claim of adequate 
progression assessment 
Date of start of new anticancer 
treatment 
Progressed  
Death before first radiological 
assessment  
Date of death  
Progressed 
Death between adequate progression 
assessment visits, or after patient 
missed one assessment visit 
Date of death  
Progressed  
Death or progression after more than 
one missed consecutive scans 
Date of first missed visit 
Progressed  
Death after 8 weeks of treatment 
discontinuation due to any reason 
without starting a new anticancer 
treatment  
Date of death  
Progressed  
No progression at the time of final 
analysis or patient discontinued from 
the study for any reason other than 
progression  (no survival follow-up)  
Date of last visit with adequate 
assessment with no documented 
progression 
Censored  
* this is the date of the protocol-scheduled clinic visit immediately after all radiological assessments (which 
collectively document progression, or no progression) has been done. 


 
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6.3.1.3.2. Independent radiological review (IR) 
Analysis of PFS will be performed independent radiological review (IR) per modified RECIST 
1.1. The censoring rules in Table 6-2 and Table 6-3will also apply for the IR. 
A summary of the concordance between the investigator assessment and the independent 
radiological evaluation of disease progression will also be provided in Table 6-4. 
Table 6-4 
Evaluation of the discordance rate between the investigator and the 
independent review on assessing PFS data 
 
Independent radiological review 
Investigator 
assessment 
Disease 
progression 
No disease 
progression 
Disease 
progression 
A=A1+A2+A3 
B 
No disease 
progression 
C 
D 
A1; number of patients when there is an agreement on timing and occurrence of disease progression 
A2; number of patients when investigator declares disease progression later than independent review 
A3; number of patients when investigator declares disease progression earlier than independent review 
B: number of patients, whose disease declared disease progression by the investigator but not by the 
independent review 
C; number of patients, whose disease declared disease progression by the independent review but not by the 
investigator 
D: number of patients without disease progression as determined by the investigator and the independent 
review 
The early discrepancy rate (EDR) is defined as: 
EDR = (B + A3) / (A + B) 
The EDR represents the positive predictive value of investigator assessment and 
quantifies the frequency with which the investigator declares progression early relative to 
IR within each arm as a proportion of the total number of investigator’s assessed 
progressions. 
The late discrepancy rate (LDR) is defined as: 
LDR = (C + A2) / (B + C + A2 + A3) 
The LDR quantifies the frequency that investigator declares progression later than IR as a 
proportion of the total number of discrepancies within the arm. If the distribution of 
discrepancies is similar between the arms, then this suggests the absence of evaluation bias 
favoring a particular arm. 


 
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The EDR and LDR can be calculated for each treatment arm and the differential 
discordance around each measure can be defined as the rate on the experimental arm 
minus the rate on the control arm 5,6. A negative differential discordance for the EDR 
and/or positive differential discordance for the LDR are suggestive of a bias in the 
investigator favoring the eryaspase arm. 
Table 6-5 summarizes all rules and outcomes for both investigator and independent radiological 
review with censoring rules. 
Table 6-5 
Summary of all censoring rules for primary and supportive analyses 
PFS = Earliest Date of (Event or Censored) - Randomization Date + 1 
Primary analysis  
Supportive analysis 
(1) 
Supportive analysis 
(2) 
Supportive analysis 
(3) 
Purpose 
Investigator -based 
Sensitivity analysis 
Independent review 
Sensitivity analysis 
Population 
ITT 
ITT 
ITT 
ITT 
Situation 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
No Post-baseline censored date of rand. Censored 
date of rand. 
censored date of rand. censored date of rand. 
Documented PD 
PD 
Date of PD 
assessment 
PD 
Date of PD 
assessment 
PD 
Date of PD 
assessment 
PD 
Date of PD 
assessment 
PD on 
Unscheduled 
scan 
PD 
Date of PD 
assessment 
PD 
Next 
scheduled 
visit 
PD 
Date of PD 
assessment 
PD 
Next 
scheduled 
visit 
No 
progression 
censored last 
assessment 
with no PD 
Censored  
last 
assessment 
with no PD 
censored 
Date of last 
PD 
assessment 
Censored 
last 
assessment 
with no PD 
Clinical 
progression 
Censored  last 
assessment 
with no PD 
PD 
Date of 
discontinuati
on 
Censored  last 
assessment 
with no PD 
Censored last 
assessment 
with no PD 
Toxicity  
Censored  
last 
assessment 
with no PD 
PD 
Date of 
discontinuati
on 
Censored  last 
assessment 
with no PD 
Censored 
last 
assessment 
with no PD 
New 
anticancer 
therapy + no 
PD 
Censored last 
assessment 
with no PD 
PD 
Date of 
anticancer 
therapy 
Censored last 
assessment 
with no PD 
Censored 
last PD 
assessment 
visit with no 
PD 
Death  
PD 
Date of 
death 
PD 
Date of 
death 
PD 
Date of death 
PD 
Date of death  


 
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>1 
consecutive 
missing scan 
Censored Date of last 
assessment 
with no PD 
Censored 
Date of last 
assessment 
with no PD 
Censored Date of last 
assessment 
with no PD 
Censored Date of last 
assessment 
with no PD 
 
 
Analysis of Objective Response Rate (ORR) and Duration of 
Response (DoR) 
ORR, defined as the proportion of patients who achieve objective tumor response (CR or PR) 
per modified RECIST 1.1.  
ORR will be summarized by each treatment group using investigator’s assessment. The 
comparison between the 2 treatment arms will be based on the Cochran-Mantel-Haenszel 
(CMH) test, with stratification factors as for the primary analyses of OS and PFS. Results will 
be reported in terms of an odds ratio and associated 95% CI. 
In addition, ORR will be summarized by each treatment group using an independent 
radiological review of tumor response assessment.  
Subgroup analysis of ORR and DCR by Chemotherapy regimen will be performed.  
Waterfall plots will be used to display the percent change from baseline in the sum of longest 
diameters by treatment group for the ITT population. Only patients with measurable disease at 
baseline will be included in the waterfall plots. The following rules will be considered in the 
construction of the waterfall plots, Table 6-6; 
 Special consideration is needed for assessments where the target lesion response is CR, 
PR or SD, but the appearance of a new lesion or a worsening of non-target lesions results 
in an overall lesion response of PD. As a conservative approach, such assessments will 
be displayed as bars in the graph, and the % change in the sum of diameters of target 
lesions reflects the non-PD target lesion response, although the overall lesion response is 
PD. A patient with such assessments will be represented by a special symbol (e.g. *) in 
the waterfall graph. 
 Assessments with “unknown” target lesion response or overall response will be excluded 
from the waterfall plots 
All possible assessment scenarios are described in Table 6-6 
Table 6-6 
Assessments considered for calculation of best percentage change for 
waterfall plots 
Situation  
Target response 
Overall lesion response 
Calculate % CFB and include 
in waterfall plot 
1 
Unknown /non 
evaluable 
Any 
No 
2 
Any 
Unknown /non 
evaluable 
No 


 
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3 
CR/PR/SD 
PD 
Yes, flag assessment with * 
4 
PD 
PD 
Yes  
5  
CR/PR/SD 
CR/PR/SD 
yes 
 
6.3.2.1. General rules for assessing objective response 
Each patient’s best overall response (BOR) will be summarized (CR, PR, SD, PD, non-
evaluable or unknown). Patients with “unknown” or “non-evaluable” BOR will be summarized 
by reason for having unknown or non-evaluable status, such as:  
- 
No valid post-baseline assessment. 
- 
All post-baseline assessments have overall lesion response “unknown”. 
- 
New anticancer therapy started before first post-baseline assessment. 
- 
Change in the imaging modality, eg from CT to MRI or vice versa, or contract CT to 
non- contrast CT. The change in the imaging methodology will result in “unknown 
status” by default for the BOR assessment. 
If multiple radiological assessments based on the sum of target lesion measurements are done at 
different times, the overall response date is based on the latest date of the first radiological 
assessment of tumor response.  
Table 6-7 provides guidance for defining best overall response (BoR) for each tumor 
assessment.  
The best overall response will be determined after all the data for the patient are known. When 
stable disease (SD) is believed to be best response, it must be based on an assessment at least 5 
weeks (35 days) from the baseline scan. If the SD response occurs less than 5 weeks from the 
baseline, the patient’s best response will depend on the subsequent assessments. For example, a 
patient who had SD at the first assessment, progressive disease (PD) at the second assessment, 
and did not meet the criteria of SD determined at least 5 weeks from the baseline scan, will have 
a best response of PD. The same patient lost to follow-up after the first SD assessment will be 
considered non-evaluable 7.  
Table 6-7 
Rules for defining best overall response (BoR) 
Target  
Non-Target  
New Lesion 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 


 
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Target  
Non-Target  
New Lesion 
Response 
Not all 
evaluated 
Non-PD  
No 
non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
6.3.2.2. DoR  
DoR is measured from the first reporting of CR or PR per modified RECIST 1.1 until the first 
date of progression, death, or censoring, and will be based on the ITT population. The median 
DoR will be estimated for each treatment group using the Kaplan-Meier method and the 95% CI 
will be summarized similar to OS methods. A p-value for this analysis will not be provided. 
Summaries will include the proportion of patients with subsequent tumor progression after 
previously objective response and proportion of patients without subsequent tumor progression 
after previously objective response (censored at last known assessment).  If progression has not 
been documented, a patient’s DOR will be censored at the date of last assessment.  
DOR (months) = (earliest date of progression, death or censoring – date of first documented 
objective response + 1)/30.4375 
 
 
Analysis of Disease Control Rate (DCR) 
The DCR for each treatment group, along with 95% CIs will be calculated. The DCRs will be 
compared using a stratified CMH test with the same strata as for the primary analysis for OS. 
 
Analysis of New Metastatic Lesions 
Emergence of new metastatic lesions is evaluated through the proportion of patients with 
radiological progression that included new metastatic lesions, whether or not new metastatic 
lesions were also associated with disease progression in existing tumor lesions. In addition, the 
time to emergence of new metastatic lesions, defined as the time from the baseline scan to the 
first reporting of radiological PD that included new lesions, will also be evaluated by plotting 
Kaplan-Meier curves. Patients with no new metastatic lesions will be censored at the time of the 
most recent radiological assessment; patients that died will be censored to death date. A p-value 
for this analysis will not be provided.  
6.4. 
Other Secondary Endpoints 
 
PK, Pharmacodynamic and Immunogenicity Summaries 
PK, pharmacodynamics and immunogenicity analyses will be performed on the PK population. 


 
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For all patients who provided samples, PK and pharmacodynamics of eryaspase will be assessed 
at each measurement, by describing the following: 
 Total asparaginase activity (U/L) 
 Plasma asparaginase activity (U/L) 
 Plasma concentrations of asparagine (μmol/L). 
 Plasma concentrations of glutamine (μmol/L). 
Mean and median concentration-time profiles will be generated by cycle using nominal 
sampling time. Individual listings will be generated by course and include actual date and time, 
as well as patient demographics (age, gender, body weight).  Statistical tabular summaries of 
concentration data by time point will include mean, SD, median, minimum and maximum. 
Box and whisker plots will be generated for whole blood asparaginase concentrations collected 
at cycle 1 and cycle 3. These results would provide an assessment of trough (nadir) 
concentration following the first and third infusion of eryaspase.  
A spaghetti plot of individual plasma concentration profiles will be generated by time point.  
Immunogenicity assessments will include a screening assay, and if positive, a confirmatory 
binding assay, and if also positive then a neutralizing assay. Individual listings will be 
generated. An overall summary of baseline and post-baseline assays will be provided. Another 
summary will tabulate positive screening, confirmatory and neutralizing assays over time.  
 
CA19-9 tumor marker 
The CA19-9 levels will be summarized over time and change from baseline will be presented in 
tables as well as Spaghetti plots. A by-patient listing of these levels will also be summarized.  
Kaplan-Meier curves for OS and PFS will also be presented by treatment group and according 
to normal/elevated CA19-9 value at baseline. In addition, Kaplan-Meier curves for OS and PFS 
will be presented by treatment group and according to the median nadir levels over the course of 
the study. 
 
Tumor biomarkers 
Tumor biomarkers analysis will be described in a separate statistical analysis plan to be 
developed after study completion. 
 
Patient-reported outcomes (PRO)  
PRO, based on scales from the QLQ-C30 questionnaires, will be summarized at Cycle 1 Day 1 
(i.e, baseline) and each time it is measured according the protocol schedule, along with change 
from baseline (CFB). Box and whisker plots for the changes from baseline over time will also 
be plotted. 


 
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The following scores will be calculated: 5 functional scales, 3 symptom scales, a global health 
status/quality of life (QoL) scale, and 6 single items, Table 6-8. 
Table 6-8 
EORTC QLQ-30 Scales and Items 
Label 
Items (Questions) 
included 
Range of Response 
for items 
Global Health Status / QOL 
QL2 
29, 30 
6 
Functional Scales 
Physical functioning 
PF2 
1 - 5 
3 
Role functioning 
RF2 
6, 7 
3 
Emotional functioning 
EF 
21 - 24 
3 
Cognitive functioning 
CF 
20, 25 
3 
Social functioning 
SF 
26, 27 
3 
Symptom Scales/Items 
Fatigue 
FA 
10, 12, 18 
3 
Nausea and vomiting 
NV 
14, 15 
3 
Pain 
PA 
9, 19 
3 
Dyspnea 
DY 
8 
3 
Insomnia 
SL 
11 
3 
Appetite loss 
AP 
13 
3 
Constipation 
CO 
16 
3 
Diarrhea 
DI 
17 
3 
Financial difficulties 
FI 
28 
3 
 
All of the scales and single-item measures range in score from 0 to 100. For global health status 
and functional scales, 100 is associated with a high performance while for symptoms scales, 100 
is associated with high burden related to the symptoms. The calculation for each score is derived 
as follows. 
1. A raw score is calculated as the average of the items of the scale 
2. A linear transformation is applied to standardize the raw score so that the score ranges 
from 0 to 100. 
For example, the below algorithm demonstrates how various QLQ-C30 scales are computed:  
 
 
Functional scales/items: Score =    1- (RS-1)   X 100 
        Range 
 
Symptom scales/items: Score =     (RS-1)       X 100 
  
  


 
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49 
     Range 
 
Global health status/QoL:  Score =     (RS-1)       X 100 
      Range 
For all scales, the Raw Score, RS, is the mean of the component items. 
In case of missing items, the following rules will be applied: 
1. If at least half of the items from the scale are not missing, missing items will be ignored 
2. If not, the scale will be set to missing. For single item measures, the score is set to missing. 
QoL endpoints will be summarized by treatment at baseline and each study visit, along with 
CFB. Box and whisker plots for the changes from baseline over time will be plotted.  
A mixed model repeated measures (MMRM) model will be developed to analyze the CFB over 
study visits. Patients in the ITT population having at least a baseline value and one value after 
randomization were included in this analysis (PRO population).  
The model will consider CFB as the dependent variable and include the following variables: 
Treatment, visit, stratification factors, baseline value and their interactions with visit. Patient 
will be a random effect. Least square means and their 95% confidence intervals will be 
computed. Visits with less than 30 patients in either treatment are excluded from the model.  
6.4.4.1. Time to QoL first worsening/improvement analysis 
For each subscale score of EORTC QLQ-C30, time to first worsening will be defined as the date 
of randomization to the date of first worsening occurred, where worsening definition for each 
subscale score is summarized in Table 6-9. Patients who did not have any worsening will be 
censored at date of last measurement or at baseline if no measurement is available post-baseline. 
Partially completed questionnaires will still be utilized, with missing components ignored. 
Similarly, time to first improvement will be defined as the date of randomization to the date of 
first improvement occurred, where improvement definition for each subscale score is 
summarized in the table below. Patients who did not have any improvement will be censored at 
date of last measurement or at baseline if no measurement is available post-baseline. 
The analysis will be performed using the PRO population. Kaplan-Meier curves will be 
provided for both time to first worsening and time to first improvement. p-Values for these 
analyses will not be provided.  
Table 6-9 
Worsening/Improvement definition for EORTC QLQ-C30 
Score Name 
Worsening definition 
Improvement definition 
Global Health Status/QoL  
Change from baseline<=-10 
Change from baseline>=10 
Physical functioning 
Change from baseline<=-10 
Change from baseline>=10 


 
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Role functioning 
Change from baseline<=-10 
Change from baseline>=10 
Emotional functioning  
Change from baseline<=-10 
Change from baseline>=10 
Cognitive functioning 
Change from baseline<=-10 
Change from baseline>=10 
Social functioning 
Change from baseline<=-10 
Change from baseline>=10 
Fatigue 
Change from baseline>=10 
Change from baseline<=-10 
Pain 
Change from baseline>=10 
Change from baseline<=-10 
Nausea and Vomiting 
Change from baseline>=10 
Change from baseline<=-10 
Dyspnea 
Change from baseline>=10 
Change from baseline<=-10 
Insomnia 
Change from baseline>=10 
Change from baseline<=-10 
Appetite Loss 
Change from baseline>=10 
Change from baseline<=-10 
Constipation 
Change from baseline>=10 
Change from baseline<=-10 
Diarrhea 
Change from baseline>=10 
Change from baseline<=-10 
Financial difficulties 
Change from baseline>=10 
Change from baseline<=-10 
 
6.5. 
Subgroup Analyses 
A full list of subgroups is shown in section 4.9. Hazard ratios and 95% confidence intervals will 
be calculated for OS within subgroups using the Cox proportional hazards model with 
stratification factors as covariates as in the primary analysis of OS but excluding the factor used 
to define that subgroup where appropriate and displayed in a Forest plot in order to evaluate the 
consistency of treatment effect. The overall treatment effect and 95% confidence interval should 
also be included in the Forest plot. 
Subgroup analyses of PFS will be performed in a similar way. ORR and DCR will also be 
evaluated within these same subgroups, based on the calculation of adjusted odds ratios and 
corresponding 95% confidence intervals with the same rules regarding stratification factors as 
for OS. 
7. 
DRUG EXPOSURE 
Study drug exposure will be calculated based on the drug exposure eCRF pages and the End of 
Treatment eCRF page. 
Analyses of exposure to study drugs will be based on the Safety Population. Summaries will 
provide summary statistics (mean, median, standard deviation, and range) overall and by 
treatment group.   
A listing with visit (cycle) dates, drug administration start and end dates and times, end of study 
status will also be provided. Patients with missing or delayed doses will be listed by treatment 
group. 
The following information will be summarized separately for each study drug: 
 Study duration (months)  
 Duration of exposure (weeks): overall and for each study drug 


 
D o c u m e nt N o. : S T A T G R A S P A N C 2 0 1 8 - 0 1 S A P 2 . 1 
 
C O N FI D E N TI A L  
 
5 1  
 T otal c u m ulati ve d ose  f or eac h st u d y dr u g. 
 A bs ol ute a n d Relati ve d ose i nte nsit y i n wee ks . 
 T otal n u m ber of c ycles recei ve d, a n d t he n u m ber ( %) of patie nts treate d i n eac h c ycle . 
 N u m ber of patie nts wit h at least o ne misse d or dela ye d d ose f or eac h st u d y at a n y ti me 
d uri n g t he st u d y.  
o  T he reas o ns f or misse d/ dela ye d d oses f or eac h st u d y dr u g will als o be s u m marize d 
as f oll o ws: 
 Safet y reas o ns  of a d verse e ve nts, a b n or mal la b val ues  
 N o n safet y  reas o ns 
 Perce nta ge o f patie nts wit h dis c o nti n ue d treat me nt o verall a n d b y reas o n 
St u d y d ur ati o n  will be deri ve d i n m o nt hs a n d defi ne d as t he n u m ber of da ys bet wee n t he 
ra n d o mizati o n a n d t he last k n o w n st u d y visit, i.e., ( date of last visit - date of ra n d o mizati o n + 1) 
/ 3 0. 4 3 7 5.  
T re at me nt d ur ati o n  i n wee ks = last a d mi nistrati o n date – first a d mi nistrati o n date + 1) / 7 
F or patie nts w h o die pri or t o Da y 1 5 of t he last c ycle, t he d urati o n of e x p os ure will be calc ulate d 
as t he date of deat h  mi n us t he date of fi rst treat me nt pl us 1 da y. 
F or eac h st u d y dr u g, t he date of last d ose is as rec or de d i n t he E n d of Treat me nt e C R F pa ge 
T he c u m ul ati ve d ose recei ve d  f or eac h st u d y dr u g will be calc ulate d  as: 
 
     n  
 
C u m ulati ve d ose recei ve d  ( u nits) =  
 
D ose i 
 
i = 1 
 
W here d ose i = it h d ose recei ve d, a n d n = t otal n u m ber of d oses recei ve d 
Pl a n ne d  d ose i nte nsit y:  
T he pla n ne d d ose i nte nsit y f or eac h st u d y dr u g will be e x presse d as t he t otal i nte n de d d ose of 
t he st u d y dr u g per c ycle. 
A bs ol ute d ose  i nte nsit y: 
T he a bs ol ute d ose i nte nsit y f or eac h st u d y dr u g will be e x presse d as t he act ual d ose of t he st u d y 
dr u g recei ve d b y t he patie nt, di vi de d b y t he d urati o n of treat me nt i n wee ks f or eac h treat me nt 
A bs ol ute  D ose I nte nsit y =  
T otal  (c u m ulati ve) d ose of st u d y dr u g  ( U/ k g, or m g/ m 2) 
 D urati o n of e x p os ure ( wee ks) 
Rel ati ve d ose i nte nsit y : 
 T his will be e x presse d as t he rati o of a bs ol ute d ose i nte nsit y a n d i nte n de d d ose i nte nsit y , Ta ble 
7- 1  


 
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Relative Dose Intensity = 
Absolute dose intensity  
*100% 
 Planned dose intensity  
Table 7-1 
Summary of the rules for defining drug exposure 
Study Drug Duration of 
Exposure 
Absolute Dose Intensity  
Planned Dose 
Intensity per cycle 
(weeks) 
Eryaspase 
(Last dose date – First 
dose date +14)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+1)/7 
100 U/kg x 2 
Gemcitabine (Last dose date – First 
dose date +7)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
1000 mg/m2 x 3 
Abraxane 
(Last dose date – First 
dose date +7)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
125 mg/m2 x 3 
Onivyde 
(Last dose date – First 
dose date +14)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
70 (50 in case of 
UGT1A1*28)1 
mg/m2 x2 
Irinotecan 
(Last dose date – First 
dose date +14)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
180 mg/m2 x 2 
5 FU 
(Last dose date – First 
dose date +14)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
2400 mg/m2 x 2 
(NALIRI)  
(2400 + 400) mg/m2 
x 2 (FOLFIRI) 
Leucovorin 
(Last dose date – First 
dose date +14)/ 7 
Cumulative actual dose 
received divided by (last 
dose date – first dose date 
+ 1)/7 
400 mg/m2 (or flat 
dose 2 in some 
centers) x2 
1. A starting planned dose of 50mg/m2 in the presence of UGT1A1*28 would be considered a full 
planned dose at Cycle 1. 
2. Some site will use a flat dose, eg 200mg. These situations should not be considered as dose 
reductions  


 
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7.1. 
Dose Reductions 
A dose reduction is defined as actual dose less than 80% of planned protocol dose. When dose 
has been reduced in consecutive prior visit, the next dose is only considered as reduced if it is 
lower than the prior dose level. If a patient, due to a dosing error, received a higher dose than 
planned dose, and moves down to the planned starting dose, this dose will not be considered a 
dose reduction. 
Frequency tables on number of patients with at least one dose reduction of any study drug will 
be provided. Patients receiving less than 60% of planned dose will also be summarized. Time to 
first dose reduction is earliest date of a dose reduction – first dose date + 1. 
Dose reductions will be summarized as follows: 
 Number of dose reductions per patients  
 Level (<80% and <60%) of dose reduction  
 Time to first dose reduction  
 Which cycles a patient experienced a dose reduction 
8. 
SAFETY AND TOLERABILITY ANALYSES 
All safety summaries and analyses will be based upon the Safety population, which includes all 
patients who received at least 1 dose of study drug. 
The analysis of safety and tolerability data includes an overall summary of tolerability, AEs 
(incidence, intensity, seriousness, and relationship of AEs to the study drug), drug exposure 
(duration of treatment, dosing information), concomitant medications, clinical laboratory results, 
ECG findings, vital signs, physical examination, body weight, ECOG PS, and treatment and 
study termination status. 
Certain related adverse events and laboratory parameters that are similar in nature may be 
grouped manually to fully characterize the effect. For example, “neutrophil count decreased” 
and “neutropenia” will be combined as “neutropenia”. Trade and generic names for the prior 
cancer medications will also be grouped and presented under 1 name (e.g., gemcitabine, 
gemzar). 
In general, inferential statistical tests are not performed for AE incidence rates. 
8.1. 
Adverse Events 
All AEs and SAEs will be collected and reported in the patient’s eCRF throughout study 
duration (i.e.  for time patient signs the informed consent and at least 30 days (90 days in 
Amendment 1) after last administration of eryaspase or chemotherapy. All deaths and deaths 
occurring during the study (i.e. deaths after start of treatment and within 28 days after last dose 
of study treatment) as recorded in the “End of Study” eCRF section will be tabulated by 


 
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treatment group and chemotherapy regimen. In addition, dates will be provided in individual 
patient data listings together with related AE information (PT, verbatim term from eCRF, start 
date of AE, end date of AE, related to eryaspase (Yes/No), related to chemotherapy (Yes/No) 
and action taken). All AEs reported in the eCRF will be listed with the SOC, PT and 
Investigator’s verbatim term. 
AEs will be coded using the MedDRA version 21.0.  The NCI CTCAE will be used to grade the 
severity of AEs. For AEs not included in the NCI CTCAE, categorization by mild (Grade 1), 
moderate (Grade 2), severe (Grade 3), life threatening (Grade 4), or death (Grade 5) will be 
used.  
Treatment-Emergent Adverse Events (TEAE) are defined as AEs that started or worsened 
during the treatment period; The treatment period begins on the date of first administration of 
study treatment until at least 30 days after date of last administration of study treatment. 
The following tabular summaries of the incidence of treatment-related TEAEs by System Organ 
Class (SOC) and Preferred Term (PT) (in alphabetic order) with the number and percentages of 
patients experiencing at least one AE will be provided: 
 Overall AE summary table: 
o TEAE 
o Grade 3 or higher TEAE  
o TE SAE  
o TEAE leading to dose reduction  
o TEAE resulting in study drug discontinuation  
o TE SAE resulting in study drug discontinuation  
o TEAE with an outcome of death  
 Overall Study-drug related AE summary table: 
o Study-drug related TEAE  
o Study-drug related Grade 3 or higher TEAE 
o Study-drug related SAE 
o  Study-drug related leading to dose reduction 
o Study drug-related TEAE resulting in study drug discontinuation  
o Study drug-related TE SAE resulting in study drug discontinuation  
o Study drug-related TEAE with an outcome of death  
 All TEAEs: 
o By SOC and PT 
o By decreasing frequency of PT 


 
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o By decreasing frequency of PT in at least 5% of Patients 
o By SOC and PT and Maximum Severity (CTCAE Grade) 
o By PT and Maximum Severity (CTCAE Grade) 
 Study-drug related TEAEs: 
o By SOC and PT 
o By decreasing frequency of PT 
o By PT and Maximum Severity (CTCAE Grade) 
 Grade 3 or 4 TEAEs: 
o By SOC and PT 
o By decreasing frequency of PT 
o Related to study drug by decreasing frequency of PT  
 TEAE leading to study drug discontinuation: 
o By SOC and PT 
o By decreasing frequency of PT 
 TEAE leading to dose reduction: 
o By decreasing frequency of PT 
 TEAE resulting in death: 
o By SOC and PT 
o By decreasing frequency of PT 
 Serious TEAEs: 
o By SOC and PT 
o By decreasing frequency of PT 
o By PT and Maximum Severity (CTCAE Grade) 
o Study-drug related by SOC and PT 
o Study-drug related by decreasing frequency of PT 
o Leading to permanent discontinuation of study drug by PT 
 The time to first Grade 3 or 4 TEAE, by treatment group, presented using Kaplan-Meier 
methods. Data from patients without a reported Grade 3 or 4 TEAE by the data cutoff 


 
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will be censored at the end of the treatment-emergent period, or the data cutoff date, 
whichever occurs first. 
o Time to first Grade 3 or 4 TEAE (months) = (the date of first Grade 3 or 4 TEAE 
or censoring – date of first treatment + 1)/30.4375 
 Subgroup tabulations of Grade 3 or 4 TEAEs by treatment group will be created for: 
O Age: < 65 VS ≥ 65 
o Baseline body mass index (BMI): BMI≤ 18, 18<BMI ≤23, and BMI> 23  
The following general rules apply to adverse events:  
 If an AE is reported for a given patient more than once during treatment, the worst 
severity and the worst relationship to study treatment will be tabulated. 
 In table summaries, patients will be counted only once at the PT level if multiple 
incidences of the same event occur within a SOC. Patients will be counted only once at 
the SOC level if multiple events occur within that SOC. For example, a patient who 
experiences an event of anemia and an event of neutropenia will be counted twice at the 
PT level (anemia, neutropenia) and once at the SOC level (vascular disorders). 
 For the presentation of adverse events by PT, specific terms will be grouped (in bold) as 
in APPENDIX 5.  
 In case a patient had AEs with missing and non-missing grades, the maximum of the 
non-missing grades will be displayed. 
 
Adverse Events of Special Interest (AESI)  
Adverse events of special interest (AESI) will be summarized by treatment group, APPENDIX 
6. These will include: 
 Hepatic events 
 Diarrhea 
 Transfusion Reactions 
 Pancreatic Events 
 Impaired coagulation related events that include: Hemorrhagic/thrombo-
embolic/impaired coagulation parameters 
Using AE CRF information, each AESI table will present: number of patients with event, 
overall number of events, patients occurrences, event characteristics, maximum severity, 
outcome, action taken, number of dose interruptions, time to onset and duration of events.  
 Time to Event Onset is date of first TE-AESI – first dose date +1. 
 Event Duration is end date of TE-AESI - start date of TE-AESI +1. 
 


 
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8.2. 
Clinical Laboratory Data 
Local laboratories are being used for this clinical study for hematology and blood chemistry. For 
each individual laboratory used, laboratory reference ranges and units are collected. Reference 
ranges will be entered into the local laboratory normal range.  
The following tests will be performed centrally: PK and pharmacodynamic (asparaginase 
activity, asparagine and glutamine), and anti-asparaginase antibodies. 
The laboratory collection CRFs (hematology and serum chemistry) include fields for additional, 
non-protocol-required clinically significant laboratory tests, including laboratory test name, 
result, units, normal range low, and normal range high. 
NCI CTCAE version 5 will be used for grading applicable laboratory tests. 
Standard biological assessments will be performed at the local laboratory of the Investigator’s 
site at selection, before any eryaspase administration and at the end of each course of 
chemotherapy as follows: 
 Hematology: complete blood count (CBC). 
 Coagulation: partial thromboplastin time (PTT), fibrinogen, Antithrombin III (ATIII), 
international normalized ratio (INR). 
 Serum Electrolytes: bicarbonate, sodium, potassium, calcium, chloride. 
 Serum Biochemistry: ammonia, amylase, creatinine, albumin, glucose, triglycerides, 
lactate dehydrogenase (LDH), cholesterol, total bilirubin, ALT, AST, gamma glutamyl 
transpeptidase (γGT), alkaline phosphatase, lipase, urea, uric acid. 
For laboratory parameters (i.e., hematology, coagulation, serum electrolytes, and standard 
biochemistry), shift analyses will be performed on laboratory abnormalities of the highest NCI 
CTCAE grade or the worst severity if there is no NCI CTCAE grade. Shift from baseline grade 
to the worst CTCAE grade overall will be presented for all laboratory parameters that have an 
associated CTCAE grade. Both scheduled and on treatment unscheduled (see TEAE) values will 
be considered for worst CTCAE grade. These summaries will be presented by treatment group 
and overall. 
Normalized values will be graphed in a trellis plot, baseline value against maximum or 
minimum post-baseline value. Values are normalized by dividing by the high normal-range for 
all chemistry, except albumin; otherwise, values are normalized by dividing by the low normal-
range. The Trellis plot will use multiples of the upper or lower limit for axis scales.  
A Hy’s Law analysis will be performed on elevations of liver related assessments, summarized 
by treatment. Patients with the following results at the same post-baseline visit (a)ALT or AST 
> 3 x ULN and (b) ALP or BIL > 2 x ULN are counted. In addition, individual elevation of ALT 
> 3 x ULN, AST > 3 x ULN, ALP > 2 x ULN or BIL > 2 x ULN are also summarized.  


 
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All laboratory data will be provided in data listings. A subset listing will be presented for all 
clinically significant abnormal laboratory values. This listing will present all lab values for any 
parameter with at least one clinically significant abnormal value so that a time course for that 
lab parameter can be presented. 
8.3. 
Performance Status 
For ECOG Performance Status, shift tables from baseline score to worst post-baseline scores 
(PS 1, 2, 3, or 4) will be presented by treatment group and overall. 
By-patient listings of all ECOG measurements will also be presented in data listings. 
8.4. 
Vital Signs, Physical Examinations and Performance Status 
Vital signs parameters will include body temperature (°C), height (cm), weight (kg), heart rate 
(beats/min), systolic and diastolic blood pressures (mmHg) and will be evaluated by treatment 
group and overall. 
The actual value and change from baseline to each on study evaluation will be summarized for 
vital signs.   
By-patient listings of all vital sign measurements will also be presented in data listings  
Physical examination shifts from baseline to the worst post-baseline assessment will be 
presented.  Both scheduled and on treatment unscheduled (see TEAE) values will be considered 
for worst assessment. All physical examination findings will be presented in a data listing. 
8.5. 
Concomitant Medications 
Previous and Concomitant medication are summarized by treatment with the ITT population.  
Concomitant medications will be defined as all medications taken by the patient any time on-
study (on or after the first infusion date of any of eryaspase or chemotherapy) or within 28 days 
after the last administration date. Previous medication will be defined as all medications taken 
by the patient before the first infusion of any of eryaspase or chemotherapy. A table will be 
constructed for the number of patients having at least one subsequent anti-cancer therapies, 
defined as medications collect by the Post-Treatment Anti-Cancer Therapies CRF page. 
In case the date value does not allow allocation of a medication to previous or concomitant 
category, this medication will be considered as concomitant. 
Concomitant and previous medications, not including subsequent anti-cancer therapies, will be 
summarized using data recorded in the “Previous and concomitant treatments” eCRF pages. 
Subsequent anti-cancer therapies will also be summarized separately. 
Concomitant medications will be coded using the WHO Drug dictionary. Results will be 
tabulated by Anatomic Therapeutic Class (ATC) and Preferred Term. 


 
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For the presentation of concomitant medications, ATC level 2 will be used. In addition, 
medication names provided in the data base will be replaced by “Preferred Term”; these will be 
provided by the Sponsor in a spread sheet and will based on Generic name or the common name 
(as provided by WHO INN). 
Medications will be listed by patient number, start date of medication and drug name as 
recorded in the eCRF, separately for prior and concomitant medications. The use concomitant 
medications will be included in by-patient data listings. 
9. 
Subsequent Anti-Cancer Therapies  
Types of Subsequent Anti-Cancer Therapies will be determined by the sponsor’s designation of 
Post-Treatment Anti-Cancer Therapies CRF data. Results will be presented for the ITT 
population and the following categories, will be summarized by treatment group: 
 Subjects with Any Post-Treatment Anti-Cancer Therapies, Palliative radiation therapy or 
Systemic anti-cancer therapy 
 Combination chemotherapy and name of therapy.  
 Single agent chemotherapy and name of therapy.  
 Number of lines of subsequent chemotherapy 
 
 


 
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10. 
COVID-19 IMPACT 
The COVID-19 worldwide pandemic has impacted the conduct of this study. Challenges led to 
issues such as quarantines, site closures, travel limitations, or interruptions to the supply chain 
of investigational products.  These challenges may lead to difficulties in meeting protocol-
specified procedures, including administering or the use of investigational products or adhering 
to protocol-mandated visits and laboratory/diagnostic testing. 
Regulatory authorities in the EU and the US have provided guidance on how to handle the 
potential impacts of the COVID-19 pandemic when conducting clinical studies.  In the US, the 
Food and Drug Administration (FDA) published “FDA Guidance on Conduct of Clinical Trials 
of Medical Products during the COVID-19 Public Health Emergency”, and in the EU, the 
European Medicines Agency (EMA) published “Guidance on the Management of Clinical Trials 
during the COVID-19 (coronavirus) pandemic”. 
Erytech followed the guidance in these documents. Erytech recognizes that patients may 
encounter difficulties having all protocol required laboratory assessments completed due to 
possible local laboratory closures or shortages of lab personnel. Erytech implemented several 
emergency measures, including waiving some laboratory assessments to ease the burden on 
sites, without compromising the patients’ overall safety, Table 10-1. 
Table 10-1 
Trybeca-1 COVID-19 Minimum Safety Assessments 
Category 
Parameter 
Must Be 
Performed 
Hematology: (no 
waivers) 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
White blood cell (WBC) count with differential 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation:  
Partial thromboplastin time (PTT) 
Fibrinogen 
Antithrombin III (AT III) 
waived 
X 
X 
Albumin 
X 
Alkaline phosphatase 
waived 


 
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Category 
Parameter 
Must Be 
Performed 
Serum Chemistry 
and Tumor 
Markers: 
Alanine aminotransferase (ALT) 
X 
Ammonia 
waived 
Amylase 
X 
Aspartate aminotransferase (AST) 
X 
Bicarbonate 
waived 
Calcium 
X 
Chloride 
X 
Creatinine 
X 
Gamma-glutamyl transferase (GGT) 
X 
Glucose 
X 
Lactate dehydrogenase (LDH) 
waived 
Lipase 
X 
Potassium 
X 
Sodium 
X 
Total bilirubin 
X 
Total cholesterol 
waived 
Triglycerides 
waived 
Urea 
waived 
Uric acid 
waived 
CA19-9 
waived 
Other Laboratory 
Tests: (no 
waivers) 
Blood phenotype done on two separate samples 
Irregular antibody screening test (IAST) 
Pregnancy test for women of childbearing 
potential  
X 
X 
X 
 
10.1. 
By-Patient COVID-19 Listings 
A by-patient listing of COVID-19 impact codes by visit displays visits with abbreviated labels 
in separate columns for the ITT analysis set. Spanning headers above the visits display the 
analysis period. Each column denotes an analysis visit and displays the COVID-19 visit impact 
code. If a patient has multiple COVID-19 visit impact codes in an analysis visit window, then 
results are displayed sorted by visit date and comma-concatenated across all COVID-19 visit 
dates in the analysis visit window. 


 
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A by-patient listing of COVID-19 visit impact is provided for the ITT analysis set. The listing 
displays analysis period, analysis visit, COVID-19 visit date, study day derived from COVID-19 
visit date, treatment day derived from COVID-19 visit date, visit type (scheduled or 
unscheduled), visit impact type, visit impact characteristics, visit impact relationship with 
specify text, and premature study termination (yes; no; not applicable).  
 
 
 


 
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11. 
CHANGES TO PLANNED ANALYSES 
Not applicable 
 
 


 
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12. 
REFERENCES 
 
1. 
Hammel P, Fabienne P, Mineur L, et al: Erythrocyte-encapsulated asparaginase 
(eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic 
cancer: An open-label, randomized Phase IIb trial. European Journal of Cancer 124:91-101, 
2020 
 
2. 
Wang-Gillam A, CP L, Bodoky 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. The Lancet 387:545-557, 
2016 
 
3. 
Paluri RK, Kasi A, Young C, et al: Second-line treatment for metastatic 
pancreatic cancer. Clin Adv Hematol Oncol 18:106-115, 2020 
 
4. 
Guidance for Industry - Clinical Trial Endpoints for the Approval of Non-Small 
Cell Lung Cancer Drugs and Biologics, in Administration USDoHaHSFaD, (CDER) CfDEaR, 
(CBER) CfBEaR (eds), 2015 
 
5. 
Amit O, Mannino F, Stone AM, et al: Blinded independent central review of 
progression in cancer clinical trials: Results from a meta-analysis. European Journal of Cancer 
47:1772-1778, 2011 
 
6. 
Stone A, Gebski V, Davidson R, et al: Exaggeration of PFS by blinded, 
independent, central review (BICR).  
 
7. 
Eisenhauer EA, Therasse P Fau - Bogaerts J, Bogaerts J Fau - Schwartz LH, et 
al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  
 
 
 


 
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13. 
CLINICAL STUDY REPORT APPENDICES 
 
 
 


 
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14. 
APPENDIX 1: RANDOMIZATION SPECIFICATION 
 
 


 
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15. 
APPENDIX 2: PROTOCOL DEVIATIONS 
Major protocol deviations to exclude from Per Protocol Population 
Must be 18 years of age or older 
Inclusion Criterion #1 
Must have Stage III or IV disease 
Inclusion Criterion #3 
Must have received one line of systemic chemotherapy 
with or without targeted agents, immunotherapy, or 
radiotherapy for treatment of advanced pancreatic 
adenocarcinoma. 
NOTE: patients whose disease progresses on, or within 
3 months of neo(adjuvant) chemotherapy, may be 
considered eligible 
Inclusion Criterion #4 
Must have radiological evidence of disease progression 
following most recent prior treatment, defined as 
appearance of any new lesion or increase of >20% of 
one or more existing lesions 
Inclusion Criterion #5 
Must have measurable lesion(s) per RECIST version 1.1 
by CT scan with contrast (or MRI, if the patient is 
allergic to CT contrast media) 
Inclusion Criterion #6 
Must have adequate performance status (ECOG 0 or 1) 
Inclusion Criterion #8 
Resectable or borderline resectable pancreatic 
adenocarcinoma at the time of signing the informed 
consent 
Exclusion Criterion #1 
Histology other than pancreatic ductal adenocarcinoma 
(for example, but not inclusive: neuroendocrine, 
adenosquamous 
Exclusion Criterion #2 
More than 1 line of prior treatment in advanced or 
metastatic setting 
Exclusion Criterion #3 
Failure to obtain written informed consent from patient 
Inclusion Criterion #14 
 
 
Important protocol deviations (to be included in CSR) 
Must be 18 years of age or older 
Inclusion Criterion #1 


 
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Must have Stage III or IV disease 
Inclusion Criterion #3 
Must have received one line of systemic chemotherapy 
with or without targeted agents, immunotherapy, or 
radiotherapy for treatment of advanced pancreatic 
adenocarcinoma. 
NOTE: patients whose disease progresses on, or within 
3 months of neo(adjuvant) chemotherapy, may be 
considered eligible 
Inclusion Criterion #4 
Must have radiological evidence of disease progression 
following most recent prior treatment, defined as 
appearance of any new lesion or increase of >20% of 
one or more existing lesions 
Inclusion Criterion #5 
Must have measurable lesion(s) per RECIST version 1.1 
by CT scan with contrast (or MRI, if the patient is 
allergic to CT contrast media) 
Inclusion Criterion #6 
Must have adequate performance status (ECOG 0 or 1) 
Inclusion Criterion #8 
Must not be receiving therapy in a concurrent clinical 
study and must agree not to participate in any other 
interventional clinical studies during their participation 
in this trial while on study treatment. Patients taking 
part in surveys or observational studies are eligible to 
participate in this study. 
Inclusion Criterion #13 
Resectable or borderline resectable pancreatic 
adenocarcinoma at the time of signing the informed 
consent 
Exclusion Criterion #1 
Histology other than pancreatic ductal adenocarcinoma 
(for example, but not inclusive: neuroendocrine, 
adenosquamous 
Exclusion Criterion #2 
More than 1 line of prior treatment in advanced or 
metastatic setting 
Exclusion Criterion #3 
Presence of active or symptomatic untreated central 
nervous system (CNS) metastases. 
NOTE: Patients with asymptomatic or stable CNS 
metastases are eligible, provided that the CNS 
Exclusion Criterion #5 


 
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metastases are radiologically and clinically stable, and 
the patient is off steroids for at least 1 month prior to 
randomization.  
Bone as the only site of metastatic disease from 
pancreatic cancer (bone-only disease) 
Exclusion Criterion #7 
Incorrect stratification (distinguish between ECOG 
status, Chemo regimen, time interval since initial 
diagnosis of advanced disease errors) 
 
Failure to obtain written informed consent from patient 
Inclusion Criterion #14 
History of other malignancies  
Exclusion Criterion #14 
 
 
 


 
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16. 
APPENDIX 3: CONSORT DIAGRAM 
 


 
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17. 
APPENDIX 4: FINAL ANALYSIS LIST OF TABLES, 
LISTINGS AND FIGURES 
The full list of outputs is located in mock TLF shell document. Of the full list, the following will 
be provided for topline results: 
Table 14.1.1.1: Overall Patients Disposition - All Patients 
Table 14.1.1.4: Overall Deaths - ITT Population 
Table 14.1.3.1.1: Patient Demographics - ITT Population 
Table 14.1.3.1.2: Patient Demographics - PP Population 
Table 14.1.3.3.1: Baseline Characteristics of Pancreatic Cancer - ITT Population 
Table 14.1.3.3.2: Baseline Characteristics of Pancreatic Cancer by Backbone Chemotherapy - 
ITT Population 
Table 14.1.3.3.3: Baseline Characteristics of Pancreatic Cancer - PP Population 
Table 14.1.4.1: Prior Cancer Related Therapy and Disease Response - ITT Population 
Table 14.1.6.3: Subsequent Anti-Cancer Therapies - ITT Population 
Table 14.1.7.2.1: Summary of Overall Exposure to Eryaspase - Safety Population 
Table 14.2.1.1: Summary of Overall Survival by Treatment Group - ITT Population 
Table 14.2.1.2: Summary of Overall Survival by Treatment Group - PP Population 
Table 14.2.1.4: Restricted Mean Survival Time of Overall Survival by Treatment Group - ITT 
Population 
Table 14.2.1.5: Multivariate Cox Regression of Overall Survival - ITT Population 
Table 14.2.2.1: Summary of Progression Free Survival (Investigator Assessment) by Treatment 
Group - ITT Population 
Table 14.2.2.3: Summary of Progression Free Survival (Investigator Assessment) by Treatment 
Group - PP Population 
Table 14.2.3.1: Summary of Disease Response per RECIST Criteria (Investigator Assessment) 
by Treatment Group - ITT Population 
Table 14.2.3.1.1: Summary of Disease Response per RECIST Criteria (Investigator 
Assessment) by Treatment Group and subgroup: Chemotherapy regimen - ITT 
Population 
Table 14.3.1.1.1: Overall Summary of Treatment Emergent Adverse Events - Safety Population 
Table 14.3.1.2.1: Incidence of Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term - Safety Population 
Table 14.3.1.2.9: Incidence of Treatment Emergent Adverse Events Occurring in at least 5% of 
Patients in either Treatment Group by Preferred Term - Safety Population 
Figure 14.1.1.3: CONSORT Diagram for Patient- All Patients 


 
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Figure 14.2.1.1: Overall Survival by Treatment Group - Kaplan Meier Curves - ITT Population 
Figure 14.2.1.2: Overall Survival by Treatment Group - Kaplan Meier Curves - PP Population 
Figure 14.2.1.3.1: OS by Treatment Group - Kaplan Meier Curves - Safety Population  
“Sensitivity analyses: Actual Treatment and Stratification factors determined 
according to baseline characteristics" - Safety Population 
Figure 14.2.1.3.2: OS by Treatment Group - Kaplan Meier Curves - ITT Population  
Sensitivity analyses: Stratification factors determined according to baseline 
characteristics" - ITT Population 
Figure 14.2.1.3.3: OS by Treatment Group - Kaplan Meier Curves - ITT Population  
“Sensitivity Analysis: Censored at the date of subsequent anticancer therapy" - 
ITT Population 
Figure 14.2.1.3.4: OS by Treatment Group - Kaplan Meier Curves - ITT Population  
“Sensitivity Analysis: Lost to follow-up considered death - ITT Population 
Figure 14.2.2.1: PFS by Treatment Group - Kaplan Meier Curves - ITT Population 
Figure 14.2.2.3: PFS by Treatment Group - Kaplan Meier Curves - PP Population 
Figure 14.2.3.1: DoR by Treatment Group - Kaplan Meier Curves - ITT Population 
Figure 14.2.1.6: Forest Plot of OS Hazard Ratios in Subgroups - ITT Population  
Figure 14.2.1.7: Forest Plot of OS Hazard Ratios in Subgroups - PP Population 
Figure 14.2.2.8: Forest Plot of PFS Hazard Ratios in Subgroups - ITT Population 
Figure 14.2.3.3: Waterfall Plots: Percent Change from Baseline in Sum of Longest Diameter 
Best Response (RECIST 1.1) - ITT Population 
 
 


 
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18. 
APPENDIX 5: Grouping rules for Adverse Events 
The following is taken from Erytech’s “AE grouping rules-ISS's SAP 1.0.0-5 Jul21”:   
All analysis will be performed considering the grouped term identified with an “*” next to the 
grouped term, including those per SOC. In case of grouped term including PTs under different 
SOCs, the primary SOC of the grouped term will be considered. The exception to this rule is 
where the SOC is mentioned in brackets next to the grouped term. 
In addition, several tables with non-grouped PTs could be generated when specified. 
Ex.: Anaemia*: Anaemia, Haemoglobin decreased  
PT = Anaemia corresponds to SOC = Blood and lymphatic system disorders 
PT = Haemoglobin decreased corresponds to SOC = Investigations 
For “per PT” analysis: “Anaemia*” will be used to classify all cases under this grouped term 
denomination 
For “per SOC” tables: Anaemia* --- PT identical with grouped term denomination, so all cases 
grouped under Anaemia* will be counted in SOC Blood and lymphatic system disorders. 
 
For the presentation of adverse events by PT, specific terms will be grouped (in bold) with an 
“*” next to the grouped term as follow:  
 
Grouped preferred Term  
Relevant Preferred Term 
Abdominal pain* 
Abdominal pain, Abdominal pain lower, Abdominal pain upper, 
Gastrointestinal pain. 
Alloimmunisation* 
Alloimmunisation, Anti Kell antibody test positive, Antibody test 
positive, Anti-erythrocyte antibody positive, Anti-erythrocyte 
antibody, Anti A antibody positive, Anti B antibody positive, Cold 
agglutinins positive, Coombs direct test positive, Coombs indirect test 
positive, Coombs test positive, Rhesus antibodies positive, ABO 
incompatibility, Blood type incompatibility, Rhesus incompatibility. 
Anaemia* 
Anaemia, Haemoglobin decreased, Iron deficiency anaemia. 
Aspergillus infection* 
Aspergillus infection, Bronchopulmonary aspergillosis. 
Asthenia* 
Asthenia, Fatigue. 
Bacteraemia* 
Acinetobacter bacteraemia, Bacillus bacteraemia, Bacteraemia, 
Bacteroides bacteraemia, Citrobacter bacteraemia, Clostridium 
bacteraemia, Corynebacterium bacteraemia, Cronobacter bacteraemia, 
Device related bacteraemia, Enterobacter bacteraemia, Enterococcal 
bacteraemia, Escherichia bacteraemia, Granulicatella bacteraemia, 
Haemophilus bacteraemia, Klebsiella bacteraemia, Meningococcal 
bacteraemia, Pneumococcal bacteraemia, Pseudomonal bacteraemia, 
Salmonella bacteraemia, Serratia bacteraemia, Shewanella algae 
bacteraemia, Sphingomonas paucimobilis bacteraemia, 
Staphylococcal bacteraemia, Stenotrophomonas bacteraemia, 
Streptococcal bacteraemia, Yersinia bacteraemia. 
Blood albumin decreased* 
Hypoalbuminaemia, Blood albumin decreased. 
Blood chloride increased* 
Blood chloride increased, Hyperchloraemia. 


 
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Blood cholesterol 
decreased* 
Hypocholesterolaemia, Blood cholesterol decreased. 
Blood cholesterol 
increased* 
Blood cholesterol increased, Hypercholesterolaemia. 
Blood creatinine 
increased* 
Blood creatinine increased, Hypercreatininaemia. 
Blood fibrinogen 
decreased* 
Hypofibrinogenaemia, Blood fibrinogen decreased. 
Blood fibrinogen 
increased* 
Hyperfibrinogenaemia, Blood fibrinogen increased. 
Blood lactic acid 
increased* 
Blood lactic acid increased, Hyperlactacidaemia. 
Cellulitis* 
Administration site cellulitis, Anorectal cellulitis, Application site 
cellulitis, Breast cellulitis, Catheter site cellulitis, Cellulitis, Cellulitis 
enterococcal, Cellulitis gangrenous, Cellulitis of male external genital 
organ, Cellulitis orbital, Cellulitis pasteurella, Cellulitis 
staphylococcal, Cellulitis streptococcal, Eosinophilic cellulitis, 
External ear cellulitis, Implant site cellulitis, Incision site cellulitis, 
Infusion site cellulitis, Injection site cellulitis, Lacrimal sac cellulitis, 
Medical device site cellulitis, Perineal cellulitis, Periorbital cellulitis, 
Post procedural cellulitis, Pseudocellulitis, Puncture site cellulitis, 
Stoma site cellulitis, Vaccination site cellulitis, Vaginal cellulitis, 
Vessel puncture site cellulitis, Vulval cellulitis. 
Device malfunction* 
Device dislocation, Device leakage, Device malfunction, Device 
occlusion, Stent malfunction. 
Diarrhoea* 
Diarrhoea, Diarrhoea infectious, Faeces soft, Bacterial diarrhoea, 
Diarrhoea haemorrhagic, Diarrhoea infectious neonatal, Diarrhoea 
neonatal, Overflow diarrhoea, Post procedural diarrhoea, Viral 
diarrhoea. 
Dysphagia* 
Dysphagia, Odynophagia. 
Oedema* 
Oedema, Oedema peripheral, Lymphoedema, Localised oedema. 
Folliculitis* 
Folliculitis, Furuncle. 
Gastrointestinal 
haemorrhage*  
Gastrointestinal haemorrhage, Upper gastrointestinal haemorrhage, 
Gastric haemorrhage, Intestinal haemorrhage, Small intestinal 
haemorrhage, Rectal haemorrhage, Duodenal ulcer haemorrhage. 
General physical health 
deterioration* 
General physical health deterioration, Performance status decreased, 
Eastern Cooperative Oncology Group performance status worsened. 
Graft versus host disease* 
Acute graft versus host disease, Acute graft versus host disease in 
intestine, Acute graft versus host disease in liver, Acute graft versus 
host disease in skin, Acute graft versus host disease oral, Chronic 
graft versus host disease, Chronic graft versus host disease in eye, 
Chronic graft versus host disease in intestine, Chronic graft versus 
host disease in liver, Chronic graft versus host disease in skin, 
Chronic graft versus host disease oral, Graft versus host disease, Graft 
versus host disease in eye, Graft versus host disease in gastrointestinal 
tract, Graft versus host disease in liver, Graft versus host disease in 
lung, Graft versus host disease in skin. 


 
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Hyperbilirubinaemia* 
Hyperbilirubinaemia, Blood bilirubin increased. 
Hypercalcaemia* 
Blood calcium increased, Hypercalcaemia. 
Hyperglycaemia* 
Hyperglycaemia, Blood glucose increased. 
Hyperkalaemia* 
Blood potassium increased, Hyperkalaemia. 
Hypernatraemia* 
Blood sodium increased, Hypernatraemia. 
Hyperphosphataemia* 
Hyperphosphataemia, Blood phosphorus increased. 
Hypertriglyceridaemia* 
Hypertriglyceridaemia, Blood triglycerides increased. 
Hyperuricaemia* 
Hyperuricaemia, Blood uric acid increased. 
Hypocalcaemia* 
Blood calcium decreased, Hypocalcaemia. 
Hypoglycaemia* 
Hypoglycaemia, Blood glucose decreased. 
Hypokalaemia* 
Blood potassium decreased, Hypokalaemia. 
Hyponatraemia* 
Blood sodium decreased, Hyponatraemia. 
Hypophosphataemia* 
Blood phosphorus decreased, Hypophosphataemia. 
Injection site reaction* 
 
Injection site reaction, Injection site haematoma, Injection site 
inflammation, Injection site oedema, Infusion site pain.  
Gastrointestinal 
obstruction * 
Intestinal obstruction, Gastrointestinal obstruction, Small intestinal 
obstruction, Duodenal obstruction, Subileus, Intestinal pseudo-
obstruction, Ileus, Obstruction gastric. 
Leukocytosis* 
Leukocytosis, White blood cell count increased. 
Leukopenia* 
Leukopenia, White blood cell count decreased. 
Lymphopenia* 
Lymphopenia, Lymphocyte count decreased. 
Monocytopenia* 
Monocyte count decreased, Monocytopenia. 
Mouth haemorrhage* 
Mouth haemorrhage, Gingival bleeding. 
Neuropathy peripheral* 
Neuropathy peripheral, Paraesthesia, Peripheral sensory neuropathy, 
Hypoaesthesia, Dysaesthesia, Hyperaesthesia, Peripheral motor 
neuropathy, Peripheral sensorimotor neuropathy, Polyneuropathy, 
Sciatic nerve neuropathy. 
Neutrophilia* 
Neutrophilia, Neutrophil count increased. 
Neutropenia* 
Neutropenia, Neutrophil count decreased. 
Oral disorder* 
Stomatitis, Aphthous ulcer, Mouth ulceration, Tongue ulceration, 
Gingivitis, Mucosal ulceration, Mucosal inflammation, Oral disorder, 
Gingival disorder, Swollen tongue, Tongue oedema. 
Pancreatic enzymes 
abnormal* 
Amylase abnormal, Amylase creatinine clearance ratio abnormal, 
Amylase increased, Blood trypsin increased, Hyperamylasaemia, 
Hyperlipasaemia, Lipase abnormal, Lipase increased, Lipase urine 
increased, Pancreatic enzyme abnormality, Pancreatic enzymes 
abnormal, Pancreatic enzymes increased. 
Pancreatitis* 
Pancreatitis, Pancreatitis acute. 
Protein total decreased* 
Protein total decreased, Hypoproteinaemia 
Protein total increased* 
Protein total increased, Hyperproteinaemia 
Pyrexia* 
Pyrexia, Hyperthermia 


 
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Renal failure* 
Renal failure, Acute kidney injury, Postrenal failure, Prerenal failure. 
Respiratory tract 
congestion* 
Respiratory tract congestion, Lower respiratory tract congestion, 
Upper respiratory tract congestion. 
Sepsis* 
all PT which contain “sepsis” in the wording:  
Abdominal sepsis, Acinetobacter sepsis, Actinomycotic sepsis, 
Anthrax sepsis, Bacterial sepsis, Biliary sepsis, Brucella sepsis, 
Burkholderia cepacia complex sepsis, Campylobacter sepsis, Candida 
sepsis, Capnocytophaga sepsis,  Citrobacter sepsis,  Clostridial sepsis,  
Corynebacterium sepsis, Device related sepsis, Enterobacter sepsis, 
Enterococcal sepsis, Erysipelothrix sepsis, Escherichia sepsis, Fungal 
sepsis, Group B streptococcus neonatal sepsis, Haemophilus sepsis, 
Helicobacter sepsis, Herpes sepsis, Herpes simplex sepsis, Intestinal 
sepsis, Klebsiella sepsis, Leptospira sepsis, Listeria sepsis, 
Meningococcal sepsis, Micrococcal sepsis, Neutropenic sepsis, 
Nocardia sepsis, Pelvic sepsis, Plague sepsis, Pneumococcal sepsis, 
Post procedural sepsis, Postpartum sepsis, Pseudallescheria sepsis, 
Pseudomonal sepsis, Pseudosepsis, Pulmonary sepsis, Salmonella 
sepsis, SARS-CoV-2 sepsis, Sepsis, Sepsis neonatal, Sepsis 
pasteurella, Sepsis syndrome, Serratia sepsis, Shigella sepsis, 
Staphylococcal sepsis, Stenotrophomonas sepsis, Streptococcal sepsis, 
Umbilical sepsis, Urosepsis, Varicella zoster sepsis, Viral sepsis, 
Wound sepsis, Yersinia sepsis. 
Serum ferritin increased* 
Serum ferritin increased, Hyperferritinaemia. 
Sleep disorder* 
Sleep disorder, Insomnia. 
Transaminases increased* 
Alanine aminotransferase increased, Aspartate aminotransferase 
increased, Transaminases increased. 
Thrombocytosis* 
Thrombocytosis, Platelet count increased. 
Thrombocytopenia* 
Thrombocytopenia, Platelet count decreased. 
Upper respiratory tract 
infection* 
Upper respiratory fungal infection, Upper respiratory tract infection, 
Upper respiratory tract infection bacterial, Upper respiratory tract 
infection helminthic, Viral upper respiratory tract infection, Acute 
sinusitis, Nasopharyngitis, Sinusitis, Chronic sinusitis, Pharyngitis, 
Tracheitis, Rhinitis, Viral rhinitis. 
Upper limb fracture* 
Upper limb fracture, Humerus fracture, Forearm fracture. 
Urinary tract infection* 
Urinary tract infection, Campylobacter urinary tract infection, 
Cytomegalovirus urinary tract infection, Escherichia urinary tract 
infection, Genitourinary tract gonococcal infection, Genitourinary 
tract infection, Prophylaxis urinary tract infection, Providencia 
urinary tract infection, Streptococcal urinary tract infection, Urinary 
tract infection bacterial, Urinary tract infection enterococcal, Urinary 
tract infection fungal, Urinary tract infection neonatal, Urinary tract 
infection pseudomonal, Urinary tract infection staphylococcal, 
Urinary tract infection viral. 
 
 
 


 
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19. 
APPENDIX 6: ADVERSE EVENTS OF SPECIAL 
INTEREST 
This appendix explains AESI retrieval strategy, the content of the AESIs for the final outputs. 
The analysis will be performed on non-grouped AE database. However, the final AESI outputs 
for the AESI will apply the grouping rules as presented in Appendix 4. 
The methodology for the AESI data retrieval and analysis will be: 
 The programmer retrieves the relevant cases by applying the Standardized MedDRA 
Queries as defined below.  
 The listings will be reviewed by Erytech to ensure that the identified AEs terms are 
appropriate and eliminate the cases that are not of interest for the AESI categories. 
The following AESI categories will be presented: 
19.1. 
Transfusion events 
This category will include 2 subcategories: 
a) Transfusion reactions 
b) Hemolytic reactions 
 
Transfusion reactions 
The AE term retrieval for this sub-category will include all PTs as follows: 
 Allergic transfusion reaction 
 Delayed serologic transfusion reaction 
 Febrile non-hemolytic transfusion reaction 
 Hypotensive transfusion reaction 
 Transfusion reaction 
 Transfusion-related complication 
 Transfusion-related acute lung injury (TRALI) 
 Transfusion-related alloimmune neutropenia 
 Transfusion-related circulatory (volume) overload 
 Anaphylactic transfusion reaction 
 
Hemolytic disorders 
The AE term retrieval for this subcategory include the following PTs: 
 Acute hemolytic transfusion reaction 
 Autoimmune anemia 
 Autoimmune hemolytic anemia 
 Hemolytic anemia 


 
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 Delayed hemolytic transfusion reaction 
 Extravascular hemolysis 
 Hemolysis 
 Hemolytic transfusion reaction 
 Hemolytic uremic syndrome 
 Intravascular hemolysis 
 Iso-immune hemolytic disease 
 Microangiopathic hemolytic anemia 
19.2. 
Pancreatic events 
This category will be presented with 2 subgroups as defined below: 
 
Clinical Pancreatitis 
The AE term retrieval for this subcategory will use: 
 Acute Pancreatitis 
 Pancreatitis 
 
Biochemical Pancreatitis 
The AE term retrieval for this sub-category will include: 
 Amylase abnormal 
 Amylase increased 
 Blood trypsin increased 
 Hyperamylasemia 
 Hyperlipasemia  
 Lipase abnormal 
 Lipase increased 
 Pancreatic enzyme abnormality 
 Pancreatic enzymes abnormal 
 Pancreatic enzymes increased 
19.3. 
Hepatic Events 
This category will include the following search terms: 
 Jaundice 
 Jaundice hepatocellular 
 Hepatocellular injury 
 Hyperbilirubinemia 


 
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 Blood bilirubin increased 
19.4. 
Impaired coagulation 
This category will be presented with 3 subcategories as below: 
 
Impaired coagulation parameters 
AE term retrieval for this category will include: 
 Antithrombin III decreased 
 Blood fibrinogen abnormal 
 Blood fibrinogen decreased 
 Blood thrombin abnormal 
 Blood thromboplastin abnormal 
 Blood thromboplastin decreased 
 Coagulation factor decreased 
 Any of the coagulation factors abnormal/decreased: Factor IX level, Factor V level, 
Factor VII level,Factor X level 
 INR abnormal 
 INR decreased 
 Prothrombin level abnormal 
 Prothrombin level decreased 
 Prothrombin time abnormal 
 Prothrombin time prolonged 
 
Embolic and thrombotic events 
 This includes events (SMQ) [20000081] 
 
Hemorrhagic events 
 Hemorrhage terms 
 Gastrointestinal hemorrhage