Clinical trial NCT04292743
Conditions: Locally Advanced Pancreatic Ductal Adenocarcinoma Metastatic Pancreatic Ductal Adenocarcinoma
Sponsor: Georgetown University
Start date: 2020-12-02; Completion date: 2024-03-04
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This will be a single-arm, multi-center, open-label phase 1 study. The standard 3+3 design will be used to determine the maximum tolerated dose (MTD) from 4 possible dose levels of Eryaspase in combination with mFOLFIRINOX. We hypothesize that the addition of Eryaspase to FOLFIRINOX (5-fluorouracil \[5-FU\], leucovorin, irinotecan, and oxaliplatin) will be safe and demonstrate preliminary signs of efficacy in patients with advanced pancreatic cancer. Safety assessments include adverse events, physical examination abnormalities, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and coagulation panel).

Detailed description:
This is an open-label, multicenter, Phase 1 study of Eryaspase combination with FOLFIRINOX in patients with locally advanced or metastatic pancreatic adenocarcinoma. Subjects will undergo screening in order to determine eligibility.

The study will use a standard 3+3 method of dose escalation. Patients will be enrolled in cohorts of 3. Four dose levels are planned and include 25, 50, 75, and 100 mg of Eryaspase with reduced dose irinotecan. Subjects will be assigned to a dose level in the order of study entry with at least a 3-day stagger in enrollment between individual subjects. With the 3+3 design to be employed, doses are not escalated unless all patients receiving the current dose have been observed for at least 6 weeks and dose-limiting toxicities (DLTs) have been reported. The MTD is defined as the highest dose level where at most 1 of 6 patients experience a dose limiting toxicity (DLT). Three patients will be treated at dose level 0. If 0/3 experience a DLT, 3 new patients will be enrolled at the next higher dose level. If 1/3 experience a DLT, 3 additional patients will be enrolled at the same dose level. If 1/6 patients experience a DLT at any dose level except the highest dose level, 3 new patients will be enrolled at the next higher dose level; if 1/6 patients at the highest dose level experience a DLT, it will be deemed the MTD and the trial will stop. As soon as 2 patients experience a DLT at a given dose level, that dose will be concluded to be above the MTD, dose escalation will cease and 3 new patients will be enrolled at the next lower dose level. If 6 patients were previously treated at that lower dose, the study will halt and that lower dose will be declared the MTD. A subject who withdraws from the escalation phase of the study for reasons other than a DLT will be replaced.

FOLFIRINOX treatment will be given on Day 1 and 15 of the 4 weeks cycle and continued until unacceptable toxicity or disease progression, for a maximum of 12 cycles. Subjects will receive a single intravenous administration of Eryaspase on Day 1 and 15 of 4-weeks cycle.

The study visits are day 1, 8, 15, 22, during cycle 1 and day 1 and 15 during subsequent cycles with a 4-week follow-up period after the end of treatment. Subjects who show at least stable disease based on RECIST 1.1 at the end of the 12-week period (Day 85) are eligible for the continuation of FOLFIRINOX plus eryaspase treatment until disease progression or unacceptable toxicity.

Arms: arm 1: Eryaspase 75 Units/kg will be administered on day 1 and 15 of a 4 week cycle (intravenous infusion).

mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² (intravenous infusion) on Day 1 and 15 of the 4 weeks cycle for a maximum of 12 cycles. arm 2: Eryaspase 100 Units/kg will be administered on day 1 and 15 of a 4 week cycle (intravenous infusion).

mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² (intravenous infusion) on Day 1 and 15 of the 4 weeks cycle for a maximum of 12 cycles. arm 3: Eryaspase 50 Units/kg will be administered on day 1 and 15 of a 4 week cycle (intravenous infusion).

mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² (intravenous infusion) on Day 1 and 15 of the 4 weeks cycle for a maximum of 12 cycles. arm 4: Eryaspase 25 Units/kg will be administered on day 1 and 15 of a 4 week cycle (intravenous infusion).

mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² (intravenous infusion) on Day 1 and 15 of the 4 weeks cycle for a maximum of 12 cycles.
Interventions: intervention 1: Eryaspase intervention 2: FOLFIRINOX
Intervention descriptions: intervention 1: intravenous administration of Eryaspase, starting dose 75 units/kg, dose escalation to 100 units/kg, dose reduction 50 units/kg and 25 units/kg intervention 2: intravenous administration of FOLFIRINOX

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A Phase I dose escalation study of Eryaspase in 
combination with modified FOLFIRINOX in locally 
advanced and metastatic pancreatic ductal 
adenocarcinoma 
 
Georgetown Protocol # :  
 
STUDY00002008 
Clinicaltrials.gov # :   
 
NCT04292743 
IND # :  
 
 
 
19,437 
 
Protocol Version Date: 
 
2.2, 01 June 2022 
 
Principal Investigator (PI):  
Marcus S. Noel, MD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20007 
Telephone (202) 444-2223 
Fax (202) 444-7009 
E-Mail: Marcus.S.Noel@gunet.georgetown.edu  
 
Sub-Investigator(s):  
 
Benjamin Weinberg, MD 
 
 
 
 
 
Ruth He, MD 
 
 
 
 
 
John Marshall, MD 
 
 
Biostatistician: 
 
 
Hongkun Wang 
 
 
 
 
 
Hongkun.wang@georgetown.edu 
 
 
Funding Sources: 
 
 
Erytech 
 
Study Drugs:  
 
 
Eryaspase 
 
Clinical Phase: 
 
 
I 
 
 
 
 
Number of Patients:  
 
19 
 
 


Page 2 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 
SPONSOR-INVESTIGATOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: A Phase I dose escalation study of Eryaspase in combination with modified FOLFIRINOX 
in locally advanced and metastatic pancreatic ductal adenocarcinoma 
 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice. 
 
 
 
 
_____________________________________ 
 _____________________ 
Marcus Noel, MD                                     
     
 Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 
 
 


Page 3 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 
Table of Contents 
Table of Contents .......................................................................................................................... 3 
Figures and Tables ......................................................................................................................... 4 
1. Study Synopsis .......................................................................................................................... 5 
2. Schedule of Events .................................................................................................................. 10 
3. Introductions ........................................................................................................................... 11 
3.1 Background ............................................................................................................................ 11 
3.2 Preclinical Data ...................................................................................................................... 12 
3.3 Previous Human Experience .................................................................................................. 13 
3.4 Study Rationale ...................................................................................................................... 13 
3.5 Justification for Dose .............................................................................................................. 14 
4.0 Objectives .............................................................................................................................. 14 
4.1 Primary Objective ................................................................................................................... 14 
4.2 Secondary Objective ............................................................................................................... 14 
5.0 Study Design ......................................................................................................................... 14 
5.1 Overall Design ........................................................................................................................ 14 
5.2 Sample Size ............................................................................................................................ 14 
5.3 Cohorts/Escalation Scheme .................................................................................................... 15 
5.4 Definition of the Maximum Tolerated dose (MTD) .............................................................. 16 
5.5 Dose Limiting Toxicities  ....................................................................................................... 16 
5.6 Dose modification .................................................................................................................. 17 
5.7 Discontinuation of Eryaspase ................................................................................................. 20 
5.8 Duration of therapy ................................................................................................................ 20 
5.9 Duration of follow-up ............................................................................................................. 21 
5.10 Women of childbearing potential ......................................................................................... 21 
5.11 Study Pause Criteria ............................................................................................................. 22 
6.0 Study Population .................................................................................................................. 22 
6.1 Inclusion Criteria .................................................................................................................... 22 
6.2 Exclusion Criteria ................................................................................................................... 23 
6.3 Randomization and Method of Treatment Assignment ......................................................... 23 
6.4 Inclusion of Women and Minorities ....................................................................................... 23 
6.5 Multicenter Trial Management ............................................................................................... 24 
7.0 Study Procedures .................................................................................................................. 25 
7.1 Screening and Enrollment ...................................................................................................... 25 
7.2 Study Day -5 ........................................................................................................................... 25 
7.3 Study Day 1 ............................................................................................................................ 25 
7.4 Study Day 8 ............................................................................................................................ 26 
7.5 Study Day 15 .......................................................................................................................... 26 
7.6 Study Day 22 .......................................................................................................................... 26 
7.7 Study Day 1 and Day 15 of each subsequent cycle ................................................................ 27 
7.8 End of Treatment/Safety Follow-up ....................................................................................... 27 
8 Study Assessment .................................................................................................................... 27 
8.1 Efficacy Assessments ............................................................................................................. 27 
8.2 Safety Assessments ................................................................................................................ 28 
8.3 Regulatory and Reporting Requirements ............................................................................... 29 
9. Study Drugs and Treatment Plan ......................................................................................... 34 
9.1 Study Drug Description .......................................................................................................... 34 


Page 4 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
9.2 Study Drug Dosing ................................................................................................................. 35 
9.3 Other Medications and Supportive Care ................................................................................ 36 
9.4 Eryaspase Acquisition, Accountability, Preparation, Storage and Handling ......................... 37 
10. Study Monitoring ................................................................................................................. 39 
10.1 Data Safety Monitoring Committee at Georgetown ............................................................. 39 
11. Study Analysis ....................................................................................................................... 40 
11.1 Demographics and Baseline Characteristics ........................................................................ 40 
11.2 Safety Analysis ..................................................................................................................... 40 
11.3 Analysis of secondary endpoints .......................................................................................... 40 
12. Ethical Considerations ......................................................................................................... 41 
12.1 Institutional Review Board (IRB) ........................................................................................ 41 
12.2 Ethical Conduct of the Study ................................................................................................ 41 
12.3 Subject Information and Consent ......................................................................................... 41 
12.4 Protection of Patient Confidentiality .................................................................................... 41 
12.5 Investigator Responsibilities ................................................................................................ 41 
13. Data Management and Confidentiality .............................................................................. 41 
13.1 Data Sharing Plan ................................................................................................................. 41 
13.2 Data Security ........................................................................................................................ 42 
13.3 Data Disclosure .................................................................................................................... 43 
13.4 Record Retention .................................................................................................................. 43 
13.5 Use of Information and Publication ..................................................................................... 43 
14 References .............................................................................................................................. 44 
Appendix A: ECOG Performance Scale ...................................................................................... 46 
 
 
Figures and Tables 
Table 1:  Schedule of Events ....................................................................................................... 10 
Table 2:  Dose Escalation Schedule ............................................................................................ 15 
Table 3:  mFOLFIRINOX Dose Modifications  ......................................................................... 17 
Table 4:  Indications mFOLFIRINOX Dose Modifications  ....................................................... 17 
 
Table 4A Neutrophil Count Decreased ............................................................................ 17
 
Table 4B Platelet Count Decreased ................................................................................. 18 
 
Table 4C General Non-hematologic toxicities ................................................................ 18 
 
Table 4D Diarrhea ........................................................................................................... 19 
 
Table 4E Mucositis .......................................................................................................... 19 
 
Table 4F Oxaliplatin related neuropathy ......................................................................... 20 
 
Table 4G Hand-throat-skin reaction ................................................................................ 20 
Table 5:  Timeframe for reporting adverse events  ...................................................................... 33 
 
 
 
 
 
 
 
 


Page 5 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
1. 
Study Synopsis 
Title 
A Phase I dose escalation study of Eryaspase in combination with 
modified FOLFIRINOX in locally advanced and metastatic 
pancreatic ductal adenocarcinoma 
 
Short Title 
rESPECt 
Protocol Number 
STUDY00002008 
 
Clinicaltrials.gov 
number 
NCT04292743 
Phase 
1 
 
Investigational Agents Eryaspase 
 
FDA IND number 
19,437 
 
Indication 
locally advanced and metastatic pancreatic cancer 
 
Study Overview 
The treatment options for locally advanced and metastatic 
pancreatic cancer remain limited with poor survival1,2.  As 
such, there is a great need for further drug development.  In 
the previous phase II second-line trial the combination of 
Eryaspase plus gemcitabine or Eryaspase plus FOLFOX (5-
fluorouracil [5-FU], leucovorin, and oxaliplatin) was superior 
to that of chemotherapy alone3.   
 
Given this preliminary efficacy signal, this trial is designed to 
determine safety and perhaps an even larger signal of 
efficacy in the first-line setting.  FOLFIRINOX is the standard 
of care for the first-line treatment of patients with advanced 
disease worldwide and thus supports our first line design in 
combination with Eryaspase. 
 
Eryaspase is a dispersion for infusion of allogenic 
erythrocytes encapsulating recombinant E. coli L-
asparaginase, 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 appropriate for body weight. 
 
We hypothesize that the addition of Eryaspase to 
FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, 
and oxaliplatin) will be safe and demonstrate preliminary 
signs of efficacy in patients with advanced pancreatic cancer. 
 
Study Duration 
18 months 
 
Study Center(s) 
 
Georgetown University, Lombardi Comprehensive Cancer 
Center, Washington, DC 


Page 6 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 
Additional participating centers to be added upon activation 
 
Objectives 
Primary Objectives 
 The primary objective of this study is to determine the 
maximum tolerated dose, tolerability and safety of 
Eryaspase in combination with the dose-modified 
FOLFIRINOX in patients with newly diagnosed locally 
advanced or metastatic pancreatic adenocarcinoma 
 
Secondary Objectives 
 To determine the objective response rate (ORR), 
progression-free survival (PFS) and the overall 
survival (OS) 
 
Number of Patients 
Approximately 12-19 subjects, subject to determination of 
MTD 
 
Diagnosis and Main 
Inclusion and 
Exclusion Criteria 
Main Inclusion Criteria 
 Patients must be able to understand and willing to sign 
an IRB approved written informed consent document. 
 Patients must have histologically or cytologically 
confirmed pancreatic adenocarcinoma, which is locally 
advanced, or metastatic.  
 Subject must have received no previous surgery, 
chemotherapy, radiotherapy or investigational therapy 
for the treatment of locally advanced or metastatic 
disease. 
 If a subject has had adjuvant/neoadjuvant therapy for 
localized disease, tumor recurrence or disease 
progression must have occurred no sooner than 6 
months after completing the last dose of the 
aforementioned therapies. 
 Patient must have radiographically measurable 
disease according to RECIST 1.1. 
 Patient must be > 18 years of age. 
 Patient must have a life expectancy of > 3 months. 
 Patient must have an ECOG performance status ≤ 1.  
 Patient must have normal bone marrow and organ 
function as defined below: 
o Absolute neutrophil count           >1,500/mcl 
o Platelets                                       >100,000/mcl 
o Hemoglobin                                 >9.0 g/dL 
o Serum Albumin                           >3.0 g/dL 
o Creatinine should be below the upper limit of 
normal OR Creatinine clearance > 60 
mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal 
o Plasma antithrombin III > 65%, fibrinogen > 150 
mg/dL, international normalized ratio (INR) < 


Page 7 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
1.5, and partial thromboplastin time (PTT) < 
institutional ULN.  
o Total bilirubin ≤ 2.0 x institutional ULN 
 Patients who have had a stent placed for biliary 
obstruction can be included in the study. 
 Female subject of childbearing potential must have a 
negative urine or serum pregnancy test.  
 Women of childbearing potential and men must agree 
to use adequate contraception (hormonal or barrier 
method of birth control, abstinence) prior to study 
entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she must 
inform her treating physician immediately. 
 Male subjects with a female partner of childbearing 
potential must agree to use two adequate methods or 
a barrier method plus a method of contraception 
 
Main Exclusion Criteria 
 Patient must not have evidence of neuroendocrine 
tumor, duodenal adenocarcinoma, or ampullary 
adenocarcinoma. 
 Patient must not have a history of other malignancy ≤ 
3 years ago, with the exception of basal cell or 
squamous cell carcinoma of the skin, which were 
treated with local resection only or carcinoma in situ of 
the cervix or ductal carcinoma in situ. 
 Patient must not be receiving any other investigational 
agents 28 days prior to the screening process. 
 Patient must not have brain metastases. Such patients 
must be excluded from this clinical trial because of 
their poor prognosis and because they often develop 
progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other 
adverse events. 
 Patient must not have a history of allergic reactions 
attributed to compounds of similar chemical or biologic 
composition to asparaginase, 5FU, oxaliplatin, or 
irinotecan. 
 Patient must not have an uncontrolled intercurrent 
illness including, but not limited to, ongoing or active 
infection , symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, any 
clinically active malabsorption syndrome, inflammatory 
bowel disease, any condition that increases the risk of 
severe irinotecan gastrointestinal toxicity, or 
psychiatric illness/social situations that would limit 
compliance with study requirements 


Page 8 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 Has an active autoimmune disease, or a documented 
history of autoimmune disease or a syndrome that 
requires steroids or immunosuppressive agents. 
Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. 
o Has had an allogeneic tissue/solid organ 
transplant. 
o Has received or will receive a live vaccine 
within 30 days prior to the first administration of 
study medication. Seasonal flu vaccines that do 
not contain live virus are permitted 
o Has known active Hepatitis B or C. 
o Patient must not be pregnant and/or 
breastfeeding. 
 Patient must not be known to be HIV-positive on 
combination antiretroviral treatment.  
 
Study Design 
This will be a single-arm, multi-center, open-label phase 1 
study.  The standard 3+3 design will be used to determine 
the maximum tolerated dose (MTD) from 4 possible dose 
levels.  
 
mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² 
over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² 
plus Eryaspase 75 Units/kg administered on day 1 every 14 
days.  We will dose escalate to Eryaspase 100 units/kg and 
also build in 2 dose reduction levels. 
 
Safety assessments include adverse events, physical 
examination abnormalities, vital signs, and clinical laboratory 
tests (including blood chemistry, hematology, and 
coagulation panel). 
 
Study Statistical 
Analysis 
Demographics and Baseline Characteristics 
 All subject baseline characteristics and demographic 
data (age, sex, race, ethnicity, weight, height, body 
mass index, physical examination abnormalities, 
medical history, previous [within 6 months of 
screening]) and concomitant medications at study 
entry will be listed by study center and subject number 
and summarized with appropriate summary statistics. 
Establishing Maximum Tolerated Dose (MTD)  
 The standard phase I 3+3 design of dose 
escalation will be used to determine the maximum 
tolerated dose (MTD) from 5 possible dose levels, 
including at most 1 escalation level and 3 de-
escalation levels. 
 The maximum tolerated dose (MTD) is defined as 
the highest dose level where at most 1 of 6 


Page 9 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
patients experience a dose-limiting toxicity (DLT) 
during the first cycle. If 0 or 1 of 6 patients in Dose 
Level 1 experience DLT during the first cycle, 
Dose Level 1 will be presumed to be the MTD. 
Additional 6 patients will be included at the MTD 
level. 
Safety Analysis 
 All subjects who are enrolled and received at 
least one dose of study medication will be 
included in the safety population. 
 The primary safety endpoint is the subject 
incidence of Grade 3 or 4 adverse events. The 
number and percentage of all subjects who 
experience any adverse events (AEs) (Grade 1 
through 4), serious adverse events (SAEs), or 
clinically significant abnormal laboratory results 
will be reported. 
 Other safety endpoints include: 
o Clinically significant changes from baseline 
in all safety laboratory parameters; 
o Clinically significant changes from baseline 
in vital signs; 
o Incidence and type of clinically significant 
ECG abnormalities. 
 All clinical safety and tolerability data will be listed 
by subject and will be summarized. Treatment-
emergent adverse events will be listed and 
summarized by System Organ Class, by 
relatedness, and by maximum severity. Serious 
adverse events and adverse events leading to 
withdrawal will be listed and summarized. 
Individual vital signs and change from baseline in 
vital signs will be listed by subject, and study visit, 
and summarized descriptively. Laboratory data 
(actual values and change from baseline) will be 
listed by subject and study 
Efficacy Analysis 
 Analysis of secondary endpoints: Due to small 
sample sizes and dose heterogeneity, no 
statistical tests of hypotheses are planned for the 
study. Response data will be collected and 
summarized. Overall survival, and progression-
free survival will also be summarized as 
preliminary estimates of efficacy in this patient 
population using a Kaplan Meier estimator/curve. 
 
 
 
 


Page 10 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
2. 
Schedule of Events (Table 1) 
Table 1 
 
Study Procedures 
Screening 
Period up to 
3 weeks 
Up to 5-8 
days prior 
to C1D1 
Treatment (28-day/4-week cycles, ±1-day) 
End of Treatment Visit 
(+/- 7 days) 
Follow up 
(every 8 
wks, ± 1 
week) 
C1D1 
C1D8 C1D15 C1D22 
D1 and D15 on 
subsequent 
cycles 
Informed consent 
X 
  
  
  
  
  
  
  
  
Eligibility criteria 
X 
  
X 
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
Concomitant Medications Collection 
X 
 
X 
 
X 
 
X 
 
 
Physical exam (including height [screening only] and 
weight) 
X 
  
X 
X 
X 
X 
X 
X 
  
Vital signs (temperature, BP, and heart rate) 
X 
  
X 
X 
X 
X 
X 
X 
  
Performance status [1] 
X 
  
X 
X 
X 
X 
X 
X 
  
12-Lead ECG 
X 
  
X[2] 
  
 X[2] 
  
  
X 
  
Radiological assessments (CT or MRI) [3] 
X 
X (every 8 weeks [±3 days] from time of enrollment until disease progression, or death) 
 
AEs/SAEs [14] 
  
X (collected from the time of informed consent until 30 days after the last study treatment) 
  
Blood phenotype [4] 
X[4]  
 
 
 
 
 
 
 
  
Prescription with current weight 
  
X[5] 
X[5] 
 
X[5] 
 
X[5] 
 
  
Irregular antibody screening test (IAST) [6] 
X[6]  
 
X[6] 
 
X[6] 
 
X[6] 
 
  
Pre-eryaspase dose complete compatibility test [7] 
  
  
X[7] 
  
X[7] 
  
X[7] 
 
  
Eryaspase administration [8] 
  
  
X[8] 
  
X[8] 
  
X[8] 
 
  
FOLFIRINOX 
 
 
X 
 
    X 
 
X 
 
 
Hematology, biochemistry, and coagulation panels; 
CA19-9 [9] 
X[9,10] 
  
X 
  
X 
  
X 
X  
  
Pregnancy test, for patients of childbearing potential 
[11] 
X 
 
X 
  
 X 
  
X  
X 
  
Survival follow-up 
  
  
  
  
  
  
  
  
X[13] 
Subsequent anti-cancer treatments 
  
  
  
  
  
  
  
  
X 
  
Tables abbreviations and legends:  
D=Day; BP=blood pressure; ECG=electrocardiogram; CT=computed tomography; MRI=magnetic resonance 
imaging; IAST=irregular antibody screening test; CA19-9=cancer antigen 19-9; ASPNase = Asparaginase. 
[1] According to the Eastern Cooperative Oncology Group (ECOG) 
[2] Performed pre-dose Cycle 1 Day 1 and Day 15 
[3] Radiological assessment (CT C/A/P) to be completed within 3 weeks of screening and then every 8 weeks (±3 
days) from the time of enrolment until disease progression or until withdrawal from the study treatment, or death, 
using the same method throughout.  
[4] A complete erythrocyte phenotype (including D, C, E, c, e, and K antigens), ABO blood group status, and 


Page 11 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Rhesus factor, all assessed on 2 separate samples (can be collected on the same day), to be done at least 5 
working days before the first Eryaspase infusion. For group A and AB patients, sub-grouping A1/A1B and A2/A2B is 
required.  If A subgroup, screening of anti-A1 antibodies (Indirect Coombs method) should be performed for A2 and 
A2B patients. The A2 and A2B patients will require anti-A1 antibodies screening before each administration along 
with IAST and documented on IAST form. 
[5] A prescription form indicating the patient’s identifiers as well as his/her current weight, the investigator's 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 each Eryaspase infusion. Exact instructions are provided by 
the IMP Manual. 
[6] The IAST blood sample and results must be completed within 72 hours prior to each Eryaspase administration 
and a report provided to the sponsor as soon as possible prior to each Eryaspase infusion.  
[7] This should be performed by the blood bank at the local institution. If not compatible, eryaspase must not be 
administered and the sponsor should be notified immediately.  A collection of additional blood sample will be 
required for further investigation. 
[8] A ±1-day window is permitted for Eryaspase or FOLFIRINOX dosing for scheduling purposes. 
[9] Laboratory tests to be performed at the local laboratory as follows: Hematology: Complete blood count with 
differential (hemoglobin, hematocrit, erythrocyte count, white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean corpuscular volume, reticulocytes and platelet count). Serum Chemistry: Sodium, potassium, bicarbonate, 
calcium, chloride, magnesium, creatinine, albumin, total bilirubin (direct and indirect), alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, , glucose, urea, amylase, lipase, 
inorganic phosphorus, and total protein; Coagulation parameters – international normalized ratio (INR), Partial 
thromboplastin time, fibrinogen, plasma antithrombin III, D-dimer. Tumor marker: CA19-9 
[10] Baseline labs to be collected within the first 21 days of the screening period 
[11] For patients of childbearing potential, serum pregnancy test to be performed during the screening period and at 
End of Treatment and urine/serum pregnancy test to be performed prior to dosing of any chemotherapy agent 
[13] Survival follow to be conducted by phone, visit, or medical records review every 8 weeks (± 1 week) from end of 
treatment visit until patient’s death, loss to follow up, or study closure. Subsequent therapy should be collected 
during this follow up. 
Additional lab tests may be required (e.g., weekly monitoring per standard practice or label requirements should be 
followed) and should be reported if clinically significant 
[14] SAEs are not required to be reported until after they received the first dose. 
 
3. 
INTRODUCTION 
 
3.1 
Background 
 
Pancreatic cancer is a highly aggressive malignancy. In the United States, there will be 
an estimated 55,440 new cases of pancreatic cancer diagnosed in 2018, with the 
disease causing an estimated 44,330 deaths. The estimated 5 year survival is poor at 
8.5 %1,4  with a median survival of 10 to 12 months2. The poor prognosis for pancreatic 
cancer is related to a combination of late detection, as most patients present with 
locally advanced or metastatic disease; and standards of care that consist of relatively 
ineffective chemotherapeutic regimens.  Surgical resection is the only curative 
treatment for pancreatic cancer, however, only 15-20% of patients present with 
operable disease5,6. 
 
Improving survival in metastatic or unresectable disease remains a challenge; for 
decades many chemotherapy trials were conducted, however, most failed to 
demonstrate efficacy. For the past decade, we had only two studies that showed 
meaningful small improvements in survival and changed the practice. The 
PRODIGE4/ACCORD 11 trial compared FOLFIRINOX (fluorouracil with irinotecan 
hydrochloride, leucovorin calcium, and oxaliplatin) to single-agent gemcitabine in 
patients with metastatic pancreatic cancer. FOLFIRINOX demonstrated a significant 
survival advantage; median overall survival (mOS) of 11.1 months (m) vs. 6.8 m (HR 


Page 12 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
0.57, P <0.001,)2. While the MPACT trial evaluated gemcitabine/nab-paclitaxel 
combination to gemcitabine alone in patients with metastatic pancreatic cancer, nab-
paclitaxel was associated with improved survival; mOS of 8.5 m vs. 6.7 m (HR 0.57, P 
<0.001)7. Unfortunately, since these studies, we have not made any new progress that 
has changed the outcome of this devastating disease. Hence, new therapeutics that 
provide greater clinical efficacy in patients with pancreatic cancer are urgently needed. 
 
KRAS (Kirsten rat sarcoma virus) mutations are observed in more than 90% pancreatic 
ductal adenocarcinomas (PDAC)8,9. KRAS mutations provoke a constitutive activation 
of RAF/MEK/ERK and PI3K/AKT-mTOR pathways, reprogramming of metabolic 
pathways that allow continued cellular proliferation in the absence of nutrients required 
by normal cells10,11. Consequently, targeting cell metabolism is a novel approach in 
pancreatic adenocarcinoma12. 
 
What distinguishes the pancreatic tumor cell’s metabolism from normal cells is the 
dependence on metabolites that are utilized through the non-canonical metabolic 
pathway13. The amino acid glutamine, for instance, has an essential role in sustaining 
anabolic metabolism and biosynthetic pathways, including the de novo synthesis of 
asparagine14,15 . Asparagine is a non-essential amino acid, synthesized intracellularly 
from glutamine and aspartic acid by the enzyme asparagine synthetase (ASNS). 
However, this biosynthesis capacity varies between cells16. 
 
3.2 
Preclinical Data 
 
In leukemic cells, the asparagine synthetase (ASNS) is lacking, therefore, it depends on 
circulating asparagine in the serum17. The modulation of glutamine and asparagine metabolism 
was targeted with L-Asparaginase (L-ASNase). L-ASNase induces an antineoplastic effect 
through catalyzing the asparagine to ammonia and aspartic acid, consequently, depletion of 
serum asparagine leading to cycle arrest and cell death. Moreover, ASPNase deplete the serum 
glutamine as it acts as a substrate for the enzyme, and thus contributing further to cell growth 
inhibition and apoptosis18. Hence, L-ASNase has been tested and used in pediatric acute 
lymphoblastic leukemia (ALL) and has become one of the cornerstone components of 
chemotherapy regimens used in ALL. 
 
Interestingly, ASNS expressions are high in normal pancreatic cells. However, more than 50% 
of pancreatic adenocarcinoma has low or no expression of ASNS19,20. Therefore, the modulation 
of glutamine and asparagine metabolism has become an investigational therapeutic strategy of 
interest in pancreatic cancer. Unfortunately, L-ASNase has a narrow therapeutic index and was 
correlated with significant toxicity when it was tested in solid tumors, including pancreatic 
cancer21.  
 
Eryaspase is an encapsulated Escherichia Coli L-ASNase within erythrocytes. It’s a novel way 
of delivering L-ASNase that led to the delivery of effective doses with less toxic effects. 
Encapsulation of L-ASNase decreases the rapid degradation of L-ASNase in the blood, thus 
prolonging activity, with a half-life of approximately two weeks. Furthermore, encapsulation 
limits exposure to the immune system and, subsequently, decreases its intrinsic immunogenicity 
and hypersensitivity reactions22. 
 
3.3 
Previous Human experience 
 


Page 13 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Encapsulated L -asparaginase within erythrocytes investigated in GRASPALL 2005 
phase I/II,  a multicenter randomized controlled trial, investigated the safety profile of 
three dose levels (50, 100, and 150 IU/kg). The study results suggested a reduction in 
the number and severity of allergic reactions and a trend towards fewer coagulation 
disorders. Other adverse events were comparable to those observed with E. coli L-
asparaginase, and there was also no difference between the three doses22. 
 
In pancreatic cancer, two clinical trials have been conducted. The first clinical trial in 
pancreatic cancer was GRASPA 2008 trial (NCT01523808), a national, multicenter, 
open-label, phase 1 dose-escalation study, which investigated Eryaspase as a single 
agent in patients with metastatic pancreatic cancer progressed after two lines of 
therapy. Twelve patients were enrolled, and they received a single administration of 
Eryaspase as monotherapy (25, 50, 100, or 150 IU/Kg). No dose-limiting toxicity was 
reported. The recommended Phase 2 dose was determined to be 100 IU/Kg every two 
weeks23.   
 
Subsequently, a Phase 2, multicenter, open-label trial investigating Eryaspase in 
combination with gemcitabine or mFOLFOX6 (modified FOLinic acid-Fluorouracil-
Oxaliplatin-6 regimen) as second-line treatment in patients with metastatic pancreatic 
cancer was conducted. The trial was completed in 2017. The endpoint of the study was 
an improvement in progression-free survival (PFS) or overall survival (OS) in patients 
with no or low ASNS (0/1) expression as determined by immunohistochemistry (IHC), 
with a target hazard ratio (HR) < 0.85. Secondary endpoints included OS, PFS, 
objective response rate, safety, and QoL. A total of 141 patients were enrolled and 
randomized, 95 to Eryaspase plus chemotherapy and 46 to chemotherapy alone. The 
majority of patients (90%) received gemcitabine during the study. 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 OS3. These encouraging results prompted 
investigators to plan for the Phase III study. However, we sought to test the safety and 
tolerability of Eryaspase with FOLFIRINOX, the current first line, and standard of care 
chemotherapy. 
 
Eryaspase's safety and efficacy also have been under investigation in other clinical 
trials, acute lymphoblastic leukemia (ALL)24 and acute myeloid leukemia (AML)25. 
 
3.4 
Study Rationale 
 
As previously mentioned, the treatment options for unresectable and metastatic pancreatic 
cancer remain limited with poor survival.  As such, there is a great need for further drug 
development.  In the previous phase II second-line trial the combination of Eryaspase plus 
gemcitabine or Eryaspase plus FOLFOX was superior to that of chemotherapy alone. Given this 
preliminary efficacy signal, and this trial is designed to perhaps demonstrate an even larger 
signal of efficacy in the first-line setting. FOLFIRINOX is the standard of care for the first-line 
treatment of patients with the unresectable disease worldwide and thus justifies our combination 
of FOLFIRINOX plus Eryaspase. 
 
3.5 
Justification for Dose 
 
We plan to use modified dosing of FOLFIRINOX which has been an accepted practice across 
recent clinical trials, the infusion 5-FU, Oxaliplatin and are given at a full dose. The Irinotecan 


Page 14 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
is given at a modified dose in order to minimize Gastrointestinal and hematologic toxicity, and 
the bolus 5-FU is eliminated in order to minimize myelosuppression. Eryaspase has been 
previously evaluated in twelve patients at dose levels 25. 50. 100 and 150 units/kg without 
evidence of a dose limited toxicities. The recommended phase 2 dose was 100 units/kg.  We 
will start with a dose of 75 units/kg, with the goal of reaching 100 units/kg, however, will also 
build in a -1/-2 dose level of 50/25 units /kg. 
 
4. 
Objectives 
 
4.1 
Primary Objective 
 
 The primary objective of this study is to determine the maximum tolerated dose, 
tolerability and safety of Eryaspase in combination with the dose-modified 
FOLFIRINOX in patients with newly diagnosed locally advanced or metastatic 
pancreatic adenocarcinoma. 
 
4.2 
Secondary Objectives 
 
 To estimate the objective response rate (ORR) 
 To summarize progression-free survival (PFS)  
 To summarize overall survival (OS) 
 
5. 
Study Design 
 
5.1 
Overall Design 
 
This is an open-label, multicenter, Phase 1 study of Eryaspase combination with FOLFIRINOX 
in patients with locally advanced or metastatic pancreatic adenocarcinoma. Subjects will 
undergo screening in order to determine eligibility. The screening period will not exceed 28 
days. Eligible patients will receive Eryaspase and it will be administered on Day 1 and 15 of the 
4-week cycle combined with mFOLFIRINOX. 
 
5.2 
Sample Size 
 
The sample size for the standard 3+3 design is random with a total of anywhere from 9 
to 21 subjects possible, but 12-19 subjects most likely, with at most 1 escalation level 
and 2 de-escalation levels beyond the initial dose level.  
 
 
5.3 
Cohorts/Escalation scheme 
 
The study will use a standard 3+3 method of dose escalation. Patients will be enrolled in cohorts 
of 3. Four dose levels are planned and include 25, 50, 75, and 100 mg of Eryaspase with 
reduced dose irinotecan. Subjects will be assigned to a dose level in the order of study entry 
with at least a 3-day stagger in enrollment between individual subjects. With the 3+3 design to 
be employed, doses are not escalated unless all patients receiving the current dose have been 
observed for at least 4 weeks and dose-limiting toxicities (DLTs) have been reported. The MTD 
is defined as the highest dose level where at most 1 of 6 patients experience a dose limiting 
toxicity (DLT). Three patients will be treated at dose level 0. If 0/3 experience a DLT, 3 new 


Page 15 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
patients will be enrolled at the next higher dose level. If 1/3 experience a DLT, 3 additional 
patients will be enrolled at the same dose level. If 1/6 patients experience a DLT at any dose 
level except the highest dose level, 3 new patients will be enrolled at the next higher dose level; 
if 1/6 patients at the highest dose level experience a DLT, it will be deemed the MTD and the 
trial will be deemed the MTD and we will expand to an additional 6 patients at that dose level. 
As soon as 2 patients experience a DLT at a given dose level, that dose will be concluded to be 
above the MTD, dose escalation will cease and 3 new patients will be enrolled at the next lower 
dose level. If 6 patients were previously treated at that lower dose, the study will halt and that 
lower dose will be declared the MTD. A subject who withdraws from the escalation phase of 
the study for reasons other than a DLT will be replaced. 
 
FOLFIRINOX treatment will be given on Day 1 and 15 of the 4 weeks cycle and continued 
until unacceptable toxicity or disease progression, for a maximum of 12 treatments (6 months) 
of FOLFIRINOX. Subjects will receive a single intravenous administration of Eryaspase on 
Day 1 and 15 of 4-weeks cycle. 
 
The study visits are day 1, 8, 15, 22, during cycle 1 and day 1 and 15 during subsequent cycles 
with a 4-week follow-up period after the end of treatment. Subjects who show at least stable 
disease based on RECIST 1.1 at the end of the 12-week period (Day 85) are eligible for the 
continuation of FOLFIRINOX plus eryaspase treatment until disease progression or 
unacceptable toxicity. 
 
Table 2  
Dose Escalation Schedule 
Dose Level 
Dose 
Eryaspase 
FOLFIRINOX 
Level -2 
25 Units/kg 
5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², 
Irinotecan 150  mg/m²,leucovorin 400 mg/m2 
Level -1 
50 Units/kg 
5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², 
Irinotecan 150  mg/m²,leucovorin 400 mg/m2 
Level 0 (starting dose) 
75 Units/kg 
5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², 
Irinotecan 150  mg/m²,leucovorin 400 mg/m2 
Level 1 
100 Units/kg 
5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², 
Irinotecan 150  mg/m²,leucovorin 400 mg/m2 
 
 
 
 
 
5.4 
Definition of the Maximum Tolerated dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the highest dose level where at most 1 of 6 
patients experience a dose-limiting toxicity (DLT) during the first cycle. If 0 or 1 of 6 patients 
in Dose Level 1 experience DLT during the first cycles, Dose Level 1 will be presumed to be 
the MTD. 
 


Page 16 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
5.5 
Dose Limiting Toxicities (DLT) 
 
To the extent possible, any adverse events that are deemed to study drug-related and are 
ongoing at end of treatment will be followed up to resolution or until a determination is made 
that the unresolved event is stable. 
 
In general, Grade 1 and 2 toxicities do not require any dose modification for any of the 
chemotherapy agents or for Eryaspase. However, appropriate supportive care will be provided 
for the management of drug-related toxicities. 
 
Hematologic DLT is defined as any of the following that occurs during the first cycle (total of 
approximately 28 days) of treatment that is attributed as possibly, probably, or definitely related 
to Eryaspase alone or the combination of Eryaspase and FOLFIRINOX: 
 Grade 4 neutrophil count decrease > 7 day duration 
 Febrile neutropenia > Grade 3 of any duration 
 Grade 3 or Grade 4 platelet count decrease  
 Any Grade 4 platelet count decrease with bleeding  
 
Non-hematologic DLT is defined as any grade 3 or grade 4 adverse event, based on NCI 
CTCAE that occurs during the first cycle (total of approximately 28 days) of treatment that is 
considered possibly, probably, or definitely related to Eryaspase alone or the combination of 
Eryaspase and FOLFIRINOX with the following specific exceptions: 
 Grade 3 or 4 AST, ALT, alkaline phosphatase, or total bilirubin due to biliary 
obstruction or infection 
 Grade 3 or 4 nausea, vomiting, or diarrhea resolved with maximal supportive care within 
7 days 
 Grade 3 mucositis resolved with supportive care 
 Grade 3 fatigue lasting less than 7 days 
 Grade 3 or 4 laboratory abnormalities that are not clinically significant or do not require 
any clinical intervention. 
 
Any treatment-related toxicity that results in treatment delay for > 21 days cumulatively during 
the first cycle or > 14 days cumulatively during the second cycle will be considered a DLT, and 
the patient will be removed from the study. If the treatment delay during the first cycle is due to 
reasons other than treatment-related toxicity, the patient will be replaced as the subject will be 
considered to be inevaluable for DLT. 
 
 
 
 
5.6 
Dose modification 
 
Dose reduction or modification are only allowed after passing the 28 days DLT period. 
Recommended mFOLFIRINOX dose modifications are listed in Table 3, however modification 
may follow investigator or institutional guidelines. Modifications may be made to any or all 
chemotherapy agents, per investigator discretion.   
 
Table 3 


Page 17 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Recommended mFOLFIRINOX Dose 
Modifications 
Drug 
Initial dose 
Dose Reduction 
Level 1 
Dose 
Reduction 
Level 2 
5-FU 
2400 mg/m2 
1920 mg/m2 
1600 mg/m2 
Irinotecan 
150 mg/m2 
125 mg/m2 
90 mg/m2 
Oxaliplatin 
85 mg/m2 
68 mg/m2 
50 mg/m2 
 
 
Table 4. Indications for mFOLFIRINOX Dose Modifications 
 
Table 4A 
A 
Neutrophil Count Decreased 
 
 
Hold treatment until recovery to at least Grade 1 
for up to two weeks. If patient has not recovered 
to ≤ Grade 1 in two weeks, discontinue treatment. 
Follow drug specific modifications below for 
subsequent cycles 
 
Toxicity Grade 
 
5-FU 
 
Irinotecan 
 
Oxaliplatin 
 
2 
Consider holding, but 
can treat per 
Investigator discretion. 
Consider holding, but 
can treat per 
Investigator discretion. 
Consider holding, 
but can treat per 
Investigator 
discretion. 
 
3-4 
 
1st occurrence: 
reduce by 1 dose level 
 
1st occurrence: 
reduce by 1 dose level 
 
1st occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
3rd occurrence:  
discontinue the 
treatment 
 
3rd occurrence: 
discontinue the 
treatment 
 
3rd occurrence: 
discontinue the 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 18 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Table 4B 
 
Table 4C 
 
 
 
 
 
 
 
 
 
 
 
B 
 
Platelet Count Decreased 
 
Hold treatment until recovery to ≤ Grade 1 for up 
to two weeks. If patient has not recovered to ≤ 
Grade 1 in two weeks, discontinue treatment. 
Follow drug specific modifications below for 
subsequent cycles 
 
 
Toxicity Grade 
 
 
5-FU 
 
Irinotecan 
 
Oxaliplatin 
 
2 
Consider holding, but can 
treat per Investigator 
discretion. 
Consider holding, but 
can treat per Investigator 
discretion. 
Consider holding, but 
can treat per Investigator 
discretion. 
3-4 
 
1st occurrence: 
reduce by 1 dose level 
 
1st occurrence: 
reduce by 1 dose level 
 
1st occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
2nd occurrence: 
reduce by 1 dose level 
 
3rd occurrence:  
discontinue the treatment 
 
3rd occurrence:  
discontinue the 
treatment 
 
3rd occurrence:  
discontinue the 
treatment 
 
 
C 
General 
Non-hematologic toxicities 
 
 
All treatment related non-hematological toxicities 
(with the exception of hair loss) should resolve to 
Grade 1 prior to starting next cycle of therapy 
 
Toxicity Grade 
 
 
2 
 
Consider holding, but can treat per Investigator discretion. 
 
3 
 
Hold all drugs until resolution to ≤ Grade 1. Then resume 
treatment at the next lower dose level. 
 
 
4 
 
Discontinue all protocol treatment 
 


Page 19 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Table 4D 
 
D 
 
Diarrhea 
 
 
Patients should be instructed in the use of 
loperamide as treatment for diarrhea. Patient 
should not be retreated with irinotecan until 
recovery from diarrhea, without loperamide for at 
least 24 hours, has occurred 
 
Toxicity Grade 
 
 
 
2 
 
 
Consider holding, but can treat per Investigator discretion. 
 
 
 
 
3-4 
 
1st occurrence: Reduce irinotecan by 1 dose level 
 
 
2nd occurrence: Reduce oxaliplatin dose by 1 dose level and 5-
FU dose by 1 dose level 
 
3rd occurrence: Discontinue all protocol treatment 
 
 
Table 4E 
 
E 
 
Mucositis 
 
 
 
Toxicity Grade 
 
5-FU 
 
Oxaliplatin 
 
2 
 
Hold treatment 
until resolution to ≤ Grade 1,   
Continue at same dose level 
 
 
Hold treatment 
until resolution to ≤ Grade 1,   
Continue at same dose level 
 
3-4 
 
Hold treatment 
until resolution to ≤ Grade 1,   
Continue at next lower dose 
level 
 
Hold treatment 
until resolution to ≤ Grade 1,   
Continue at next lowest dose 
level 
 
 
 
 
 
 
 
 
 
 
 
 


Page 20 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Table 4F 
 
F 
 
Oxaliplatin related neuropathy 
 
 
 
 
Paresthesia or peripheral sensory neuropathy 
 
 
Toxicity Grade 
 
Duration of toxicity 
1–7 days 
 
Duration of toxicity 
more than 7 day 
 
Persistent (duration 
of toxicity more 
than 14 days) 
 
2 
 
No dose modification 
 
No dose modification 
 
Next lowest dose 
level for oxaliplatin 
 
3 
 
Next lowest dose 
level for oxaliplatin 
 
Next lowest dose 
level for oxaliplatin 
 
Discontinue 
 
4 
 
Discontinue 
 
Discontinue 
 
Discontinue 
 
 
Table 4G 
 
G 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 
 
Toxicity Grade 
2 
 
Consider holding, but can treat per Investigator discretion. 
 
Toxicity Grade 
3-4 
 
Reduce 5–5-FU by 1 dose level 
 
5.7 
Discontinuation of Eryaspase 
 
 DLT during dose escalation  
 Study completion  
 Patient withdraws from the study for any reason, including withdraws 
consent. 
 Progressive disease  
 Declared discontinuation due to missed Eryaspase doses. 
5.8 
 Duration of therapy 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 


Page 21 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 
In the absence of treatment delays due to adverse events, treatment may continue for 
a total of 12 treatments of FOLFIRINOX (approximately 6 months) or until one of the 
following criteria applies: 
 Documented and confirmed disease progression 
 Death 
 Adverse event(s) that, in  the judgment of the investigator, may cause severe or 
permanent harm or which rule out the continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from the study 
 The Sponsor-Investigator or Georgetown decides to close the study 
 
After 12 treatments of FOLFIRINOX, patients have the option to continue FOLFIRINOX 
plus Eryaspase or can transition to FOLFIRI (dropping Oxaliplatin) plus Eryaspase or 
5-FU (dropping Irinotecan and Oxaliplatin) plus Eryaspase, at the investigator’s 
discretion. 
5.9 
 Duration of follow-up 
Patients will be followed via chart review or phone interview every 8 weeks for a total of 
2 years or until death, whichever occurs first. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
5.10 Women of childbearing potential 
Women of childbearing potential (women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal, or women who have had a tubal ligation) are required to have a 
negative serum pregnancy test within 14 days prior to the first dose of Eryaspase. 
 
Female and male patients (along with their female partners) are required to use two 
forms of acceptable contraception, including one barrier method, during participation in 
the study and for 1 month following the last dose of Eryaspase. 
 
If a patient is suspected to be pregnant, Eryaspase should be immediately 
discontinued. In addition, a positive urine test must be confirmed by a serum 
pregnancy test. If it is confirmed that the patient is not pregnant, the patient may 
resume dosing.  
 


Page 22 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
If a female patient or female partner of a male patient becomes pregnant during 
therapy or within 1 month after the last dose of Eryaspase, the investigator must be 
notified in order to facilitate outcome follow-up. 
 
 
5.11 Study Pause Criteria 
 
The protocol will be paused with any criteria below being met: 
 Any death (other than due to progressive disease) 
 The occurrence of 2 or more grade 4 events 
 
6. 
Study Population 
 
6.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to participate in this study:  
 
6.1.1 Patient must be able to understand and willing to sign an IRB approved written 
informed consent document. 
6.1.2 Patient must have histologically or cytologically confirmed pancreatic 
adenocarcinoma, which is locally advanced, unresectable, or metastatic.  
6.1.3 Patient must have received no previous surgery, chemotherapy, radiotherapy or 
investigational therapy for the treatment of locally advanced or metastatic 
disease. 
6.1.4 If a patient has had adjuvant/neoadjuvant therapy for localized disease, tumor 
recurrence or disease progression must have occurred no sooner than 6 months 
after completing the last dose of the aforementioned therapies. 
6.1.5 Patient must have radiographically measurable disease according to RECIST 
1.1 
6.1.6 Patient must be > 18 years of age. 
6.1.7 Patient must have a life expectancy of > 3 months. 
6.1.8 Patient must have an ECOG performance status < 1.  
6.1.9 Patient must have normal bone marrow and organ function as defined below: 
o Absolute neutrophil count           >1,500/mcl 
o Platelets                                       >100,000/mcl 
o Hemoglobin                                 >9.0 g/dL 
o Serum Albumin                           >3.0 g/dL 
o Creatinine should be below the upper limit of normal OR Creatinine 
clearance (eGFR) >60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal 
o Plasma antithrombin III > 65%, fibrinogen > 150 mg/dL (1.5g/L), 
international normalized ratio (INR) < 1.5, and partial thromboplastin time 
(PTT) < institutional ULN. 
o Total bilirubin ≤ 2.0x institutional ULN 
6.1.10 Patients who have had a stent placed for biliary obstruction can be included in 
the study. 
6.1.11 Female subject of childbearing potential must have a negative urine or serum 
pregnancy test.  


Page 23 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
6.1.12 Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
6.1.13 Male subjects with a female partner of childbearing potential must agree to use 
two adequate methods or a barrier method plus a method of contraception 
 
6.2 
Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria will not be able to participate in this 
study:  
 
6.2.1 Evidence of neuroendocrine tumor, duodenal adenocarcinoma, or ampullary 
adenocarcinoma. 
6.2.2 History of other malignancy ≤ 3 years ago, with the exception of basal cell or 
squamous cell carcinoma of the skin, which were treated with local resection only or 
carcinoma in situ of the cervix of ductal carcinoma in situ. 
6.2.3 Receiving any other investigational agents 28 days prior to the screening process. 
6.2.4 Patient with evidence of brain metastases. Such patients must be excluded from this 
clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of neurologic 
and other adverse events. 
6.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to asparaginase, 5FU, oxaliplatin, or irinotecan. 
6.2.6 Any uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection , symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, any clinically active malabsorption syndrome, inflammatory bowel disease,
 
any condition that increases the risk of severe irinotecan gastrointestinal toxicity, 
or psychiatric illness/social situations that would limit compliance with study 
requirements 
6.2.7 Has an active autoimmune disease, or a documented history of autoimmune disease or 
syndrome that requires steroids or immunosuppressive agents. Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule. 
6.2.8 History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or 
intraabdominal abscess within 6 months prior to randomization. 
6.2.9 Has had an allogeneic tissue/solid organ transplant. 
6.2.10 Has received or will receive a live vaccine within 30 days prior to the first 
administration of study medication. Seasonal flu vaccines that do not contain live virus 
are permitted 
6.2.11 Has known active Hepatitis B or C. 
6.2.12 Patient is pregnant and/or breastfeeding. 
6.2.13 Known to be HIV-positive on combination antiretroviral. 
 
6.3 
Randomization and Method of Treatment Assignment 
 
There is only one treatment group in each part of the study. Therefore, no randomization will be 
performed 
 
 


Page 24 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
6.4 
Inclusions of Women and Minorities 
 
Both Men and Women and all minorities are eligible for participation. 
 
 
 
6.5 
Multicenter Trial Management 
 
6.5.1 Personnel 
 
At each site, personnel dedicated to this protocol will be: 
 
A study PI 
 
A research coordinator 
 
A data manager 
 
In addition, Georgetown University’s Multicenter Project Management Office will oversee the 
conduct of the trial at Lombardi-Georgetown and additional sites. Georgetown University’s 
Multicenter Project Management Office will be the main point of contact for Dr. Noel and the 
other site PIs for any study related concerns including data management and regulatory.  
 
6.5.2 Patient Enrollment 
 
Enrollment at the sites will be competitive.  If a patient is consented and being screened for 
enrollment, the local research coordinator must send an email within 24 hours containing the 
Patient registration form to the local PI, Dr. Noel, Georgetown University’s Multicenter Project 
Management Office and Erytech. If a patient is successfully screened, the local research 
coordinator must send all supporting documentation to Georgetown University’s Multicenter 
Project Management office by secure email to confirm eligibility. Patients should not start 
therapy until Dr. Noel and Georgetown University’s Multicenter Project Management office 
have reviewed the patient’s records and confirmed that the patient is indeed eligible for 
enrollment. 
 
6.5.3 Data Collection and Management  
 
Patient data will be entered into the on-line accessible database. This database is housed at 
Lombardi-Georgetown but is accessible anywhere there is internet access. The data manager 
and research coordinator at each site will attend an on-line training session so that they may 
learn how to enroll data into the data base. All screening data should be entered prior to starting 
therapy, and all ongoing patient data should be entered within 10 business days of each patient 
visit.   
 
6.5.4  
Conference Calls 
 
A weekly conference call will be held between Lombardi-Georgetown and the other sites to 
review patient enrollment, toxicity, and response assessment.   
 
 
 
 
 


Page 25 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
6.5.5 Trial Auditing 
 
Georgetown University’s Multicenter Project Management Office will arrange all primary 
source documents for the patients to be audited. This will include collecting copies of the 
primary source data for any patients treated at other sites. 
 
 
 
7 
Study Procedures 
 
7.1 
Screening and Enrollment 
 
For patients being considered for enrollment outside of Georgetown-Lombardi, all primary 
source documentation should be sent to Georgetown University’s Multicenter Project 
Management Office, and the principal investigator, Dr. Noel, for review and approval.  Patients 
must be approved for accrual prior to starting study medications. Patient IDs will be assigned at 
the time of registration. 
 
Informed consent must be obtained prior to the performance of study related 
evaluations. 
 
Within 21 days prior to study entry subjects will undergo the following evaluations: 
o Demographics, medical history, and concomitant medications 
o A physical exam, height, and weight measurements 
o Vital signs including temperature blood pressure and heart rate 
o A 12-lead ECG will be obtained 
o Subject performed status will be assessed via the ECOG scale 
o Samples will be collected for serum chemistry hematology, coagulation, and 
CA-19-9 
o Irregular antibody screening test (IAST) 
o Blood phenotype 
o Radiographic assessments will be obtained during screening and then 
repeated every 8 weeks from the time of enrollment until disease 
progression or death 
7.2 
Study Day -8 to Day -5 
The following procedures will be performed at least 5 days prior to Cycle 1 Day 1: 
o Prescription with current weight 
 
 
 
 
 


Page 26 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
7.3 
Study Day 1  
The following procedures will be performed: 
o 
Physical examination 
o 
Vital signs including temperature blood pressure and heart rate 
o 
Subject performed status will be assessed via the ECOG scale 
o 
12-lead ECG  
o 
Pre-Eryaspase dose complete compatibility test 
o 
Irregular antibody screening test (IAST) 
o 
Samples will be collected for serum chemistry hematology, coagulation, 
and CA 19-9 
o 
For all women of childbearing potential, a urine pregnancy test will be 
administered 
o 
Eryaspase Administration 
o 
FOLFIRINOX Administration 
7.4 
 Study Day 8 
The following procedures will be performed: 
o Physical examination 
o Vital signs including temperature blood pressure and heart rate 
o Subject performed status will be assessed via the ECOG scale 
o All adverse events will be recorded 
7.5 
Study Day 15 
The following procedures will be performed: 
o Physical examination 
o Vital signs including temperature blood pressure and heart rate 
o Subject performed status will be assessed via the ECOG scale 
o All adverse events will be recorded 
o 12-lead ECG 
o Pre-Eryaspase dose complete compatibility test 
o Irregular antibody screening test (IAST) 
o Samples will be collected for serum chemistry hematology, coagulation, 
and Ca 19-9 
o For all women of childbearing potential, a urine pregnancy test will be 
administered 
o Eryaspase Administration 
o FOLFIRINOX Administration 
 
 
 
 


Page 27 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
7.6 
 Study Day 22 
The following procedures will be performed: 
o Physical examination 
o Vital signs including temperature blood pressure and heart rate 
o Subject performed status will be assessed via the ECOG scale 
o All adverse events will be recorded 
7.7 
 Study Day 1 and Day 15 of each subsequent cycle 
The following procedures will be performed: 
o Physical examination 
o Vital signs including temperature blood pressure and heart rate 
o Subject performed status will be assessed via the ECOG scale 
o All adverse events will be recorded 
o Pre-Eryaspase dose complete compatibility test 
o Irregular antibody screening test (IAST) 
o Samples will be collected for serum chemistry hematology, coagulation, 
and CA19-9 
o For all women of childbearing potential, a urine pregnancy test will be 
administered 
o Eryaspase Administration 
o FOLFIRINOX Administration 
7.8 
End of Treatment/Safety Follow-up 
Subjects will complete an end of treatment (EOT) evaluation 4 weeks (+/- 7 days) after the last 
day of treatment on study or after tumor progression is documented. In addition, a positive 
urine test must be confirmed by a serum pregnancy test.  
 
Survival follow up will be conducted by phone, visit, or medical records review every 8 weeks 
(±1 week) from end of treatment visit until patient’s death, loss to follow up, or study closure. 
Subsequent anti-cancer treatment should be collected during this follow up.  
 
8 
Study Assessment 
 
8.1 
Efficacy Assessments 
 
8.1.1 Tumor Assessment 
 
Methods of evaluation of Measurable Disease 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including 
a ruler estimating the size of the lesion, is recommended. 
 


Page 28 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Conventional CT and MRI: These guidelines have defined measurability of lesions on CT 
scans based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slicing 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow up should be the same as was 
used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts and diseases. Ideally, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath hold scanning techniques, if possible. 
 
 
8.2 
Safety Assessments 
 
8.2.1 Physical Examinations, Vital Signs, and ECGs 
 
A physical examination will be performed during screening, Cycle 1 Days 1, 8, 15, and 
22, and Day 1 and Day 15 on all subsequent cycles.  
 
Vital signs will be measured at all study visits. Blood pressure, pulse rate, and body 
temperature will be measured in accordance with the study site’s standard operating 
procedures. Body weight and height will be measured at screening. Body height will be 
performed only at the screening period, and body weight will be measured at all visits. 
 
12-Lead ECGs will be acquired during the Screening period, and on Day 1 (pre-dose), 
Day 15 (pre-dose) of Cycle 1. The ECG recordings will be reviewed for any evidence of 
abnormalities. In particular, any evidence of QT/QTcF prolongation will be recorded as 
an adverse event. 
 
8.2.2 Clinical Laboratory Assessments 
 
The following tests will be performed at the local laboratories at the visits identified in 
the Time and Events tables. 
 
o Hematology: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count with differential, platelet count, mean cell hemoglobin (MCH), mean 
cell hemoglobin concentration (MCHC), mean corpuscular volume, reticulocytes 
 
o Serum Chemistry: liver panel (total and direct bilirubin, AST, ALT), GGT, renal 
panel (BUN, creatinine), albumin, sodium, potassium, magnesium, bicarbonate, 
chloride, calcium, inorganic phosphorus, glucose, total protein, alkaline 
phosphatase,, amylase, and lipase. 


Page 29 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
 
o Coagulation: Coagulation profile, plasma antithrombin III, fibrinogen, D-dimer, the 
international normalized ratio (INR), and partial thromboplastin time (PTT).  
 
o Pregnancy test (for all women of childbearing potential): Serum or Urine β HCG 
test 
 
o Tumor Marker: CA19-9 
 
o Complete compatibility testing: To be performed prior to Eryaspase 
administration by the blood bank at the Institution. If not compatible, eryaspase 
should NOT be administered and the sponsor notified immediately. Depending on 
the individual circumstances the patient may receive chemotherapy alone and 
resume eryaspase at the next dose or delay dose for Erytech to remanufacture and 
ship the new bag of eryaspase. If incompatibility persists the patient will NOT 
receive further eryaspase, but can continue chemotherapy alone. 
 
8.3 
Regulatory and Reporting Requirements 
 
8.3.1 Adverse Events (AE) 
 
Adverse events are defined as any untoward medical occurrence in a subject 
participating in a clinical trial who is administered an investigational product, at any 
dose; the adverse event does not necessarily have to have a causal relationship with 
this product. An adverse event could, therefore, be any unfavorable and/or unintended 
sign (including abnormal laboratory findings), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related 
to the investigational product. This definition includes intercurrent illnesses or injuries, 
and exacerbation of pre-existing conditions. 
 
All adverse events occurring in subjects who have received the treatment will be 
recorded on the CRF and will be reported in accordance with regulatory requirements. 
Adverse events reported prior to the commencement of administration of study 
medication will be considered pretreatment events. All adverse events will be 
monitored until resolution or, if the AE is determined to be chronic, until a cause is 
identified. To the extent possible, any adverse events that are deemed to study drug-
related and are ongoing at End of Treatment will be followed up to resolution or until a 
determination is made that the unresolved event is stable. If an adverse event remains 
unresolved at the conclusion of the study, a clinical assessment will be made by the 
Investigator and the Sponsor’s Medical Monitor whether continued follow-up of the 
adverse event is warranted. 
 
Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events.  
 
An elective surgery/procedure scheduled to occur during a study will not be 
considered an adverse event if the surgery/procedure is being performed for a pre-
existing condition and the surgery/procedure has been pre planned prior to study entry.  
However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., 


Page 30 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
surgery performed earlier than planned), then the deterioration of the condition for 
which the elective surgery/procedure is being done will be considered an adverse 
event. 
 
8.3.1.1 Grading Adverse Events 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP website.  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_5x7.pdf 
 
For AEs not listed, the following scale will be used: 
 Mild (Grade 1): no limitation of usual activities 
 Moderate (Grade 2): some limitation of usual activities 
 Severe (Grade 3): inability to carry out usual 
activities 
 Life-threatening (Grade 4): an immediate risk of death 
 Death (Grade 5) 
 
8.3.2 Unanticipated Problems 
 
An unanticipated problem is defined as: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol  and informed consent document; and (b) the 
characteristics of the subject population being studied;  
 Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and  
 Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Since it is anticipated that there will be deaths due to pancreatic cancer progression in 
this study, death will not necessarily be considered unexpected in this study. 
 
8.3.3 Relationship to Study Drug   
 
The investigator will use the following definitions to assess the relationship of the 
adverse event to the use of study drug: 
 
Related: A causal relationship between the medicinal product (and/or study 
procedures) and AE is a reasonable possibility. For example, the occurrence of the AE 
cannot be explained by other causative factors. The AE, however, can be explained by 
pharmacological effect of the medicinal product such as a similar event having been 
reported previously, alteration of the dose effect, or the timing or seriousness of the 
AE, etc. Positive re-challenge/de-challenge is supportive.  
 


Page 31 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Not Related: A causal relationship between the medicinal product (and/or study 
procedures) and AE is not a reasonable possibility: there is no temporal relationship 
between the medicinal product and event, or an alternative etiology is more 
reasonable. 
 
For every adverse event, the investigator must attribute whether the adverse event was 
due to study medication, or other causes. If an investigator's opinion of probably not or 
not related to study drug(s) is given, an “other” cause of event must be provided by the 
investigator for the adverse event.   
 
8.3.4 Serious adverse event (SAE) 
 
A Serious Adverse event (SAE) is defined as any untoward medical occurrence that at 
any dose: 
 Results in death 
 Is life-threatening (i.e., the patient was, in the opinion of the Investigator or 
Sponsor, at immediate risk of death from the event as it occurred) 
 Requires or prolongs hospitalization (unless planned for observation, protocol 
compliance, elective procedures, social reasons). This does not include an emergency 
room visit or admission to an outpatient facility. 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important and significant medical event that, based on appropriate medical 
judgment, may jeopardize the patient and/or may require medical or surgical 
intervention to prevent one of the other outcomes defining serious. 
 
Disease progression is an efficacy criterion and is therefore not considered an AE or 
SAE (even if fatal). Disease progression should be documented. If AEs/SAEs occur in 
relation to disease progression that are not consistent with the natural progression of 
the patient’s disease, these AEs/SAEs must be reported per AE/SAE reporting 
requirements. 
 
For patients enrolled outside of Georgetown University, serious adverse events will 
also be reported, and all supporting documentation emailed to Georgetown University’s 
Multicenter Project Management Office and to the study PI, Dr. Noel, within 24 hours.  
 
If an adverse event meets any of the following criteria, it will be reported to the Georgetown 
DSMC as a SAE by the Sponsor-Investigator or designee per DSMC reporting guidelines. 
 
SAEs will be collected and recorded from the time the patient receives the first dose in the study 
until he/she completes the End of Treatment visit. SAEs brought to the attention of the 
investigator at any time after cessation of the study drugs and considered by the investigator to 
be related or possibly related to the study drugs must be reported to the Sponsor-Investigator 
and Multicenter Project Management Office, if and when they occur.  
 
8.3.5 Serious Unexpected Suspected Adverse Reaction 
 
A serious unexpected suspected adverse reaction is defined as an unexpected serious 
adverse event where there is a reasonable possibility that the drug caused the serious 


Page 32 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
adverse event. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
 
8.3.6 Stopping Criteria 
 
We will follow guidelines for early termination of the study per the 3+3 study design. 
 
8.3.7 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements. It's the 
responsibility of the Site-Investigator to report any Unexpected Suspected Adverse Reaction to 
the FDA as follows: 
 
Report any unexpected fatal or life-threatening adverse experiences associated with the use of 
the drug (i.e., there is a reasonable possibility that the experience may have been caused by the 
drug) by telephone or fax no later than 7 calendar days after initial receipt of the information. A 
life-threatening adverse experience is defined as any adverse drug experience that places the 
subject (in the view of the investigator) at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Report any serious, unexpected adverse experiences, as well as results from animal studies that 
suggest significant clinical risk, within 15 calendar days after initial receipt of this information. 
 
All SAEs, regardless of relationship to the study/study drug, will be summarized and reported to 
the FDA at annual reports by the Sponsor-Investigator. 
 
A serious adverse drug experience is defined as any adverse drug experience occurring at any 
dose that results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant disability/incapacity (i.e., substantial disruption of a person’s 
ability to conduct normal life functions) 
 A congenital anomaly/birth defect 
 Any other experience which, based upon appropriate medical judgment, may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
An unexpected adverse drug experience is defined as any adverse drug experience, the 
specificity or severity of which is not consistent with the expectedness assessment with the 
Section 7 reference safety information of the current investigator brochure (or risk information, 
if an IB is not required or available).  
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at the 
following address or by fax: 
 


Page 33 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Document Control Center 
10903 New Hampshire Ave. 
Bldg WO71, Rm. G112 
Silver Spring, MD 20993-0002 
FAX: 1-800-FDA-0178 
 
8.3.8 Reporting of Pregnancy  
 
In cases of pregnancy or suspected pregnancy, the patient is to be discontinued immediately 
(within 24 hours) from the study and the female patient should be referred to an obstetrician- 
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling. Pregnancy, suspected pregnancy, a positive pregnancy test and pregnancy outcomes 
must be reported to the study PI, and the Multicenter Project Management Office. If the 
pregnancy results in spontaneous abortion or stillbirth, the event should be reported as an SAE. 
If there are any abnormal outcomes that meet the serious criteria, it must be reported as an SAE. 
Please follow the SAE reporting instructions. Pregnancy outcomes must be collected for the 
female partners of any males who took study drug in this study. Pregnancy of the patient’s 
partner is not considered to be an AE.  Consent to report information regarding these pregnancy 
outcomes should be obtained from the female partner.  
 
8.3.9 Overdose 
 
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
treatment that exceeds the dose described in the protocol. Overdoses are not considered AEs; 
however, all overdoses should be reported to the study PI and Multicenter Project Management 
Office.  An overdose should be reported even if it does not result in an AE. Overdoses do not 
need to be recorded on the eCRF; dosing information is recorded on the dose administration 
eCRF. If the overdose results in an AE, the AE must also be recorded as an AE.  An overdose 
does not automatically make an AE serious, but if the consequences of the overdose are serious, 
for example death or hospitalization, the event is serious and must be recorded and reported as 
an SAE. 
 
Table 5: The timeframe for reporting Adverse Events/Unanticipated Problems 
Deaths 
Any reportable death while on study or within 
30 days of study 
Immediately, within 24 hours, to PI, 
Georgetown Multicenter Project 
Management Office, ERYTECH (SUSAR, 
suspected unexpected serious adverse 
reactions, ONLY), and to the IRB (Per local 
IRB policy) 
Any reportable death while off study 
Immediately, within 24 hours, to PI, 
Georgetown Multicenter Project 
Management Office, ERYTECH (SUSAR 
ONLY), and to the IRB (Per local IRB policy) 
Adverse Events/Unanticipated Problems 
Any reportable adverse events/unanticipated 
problems as described in Sections 8.3.2, 
8.3.4 and 8.3.5 (other than death) 
Immediately, within 24 hours to PI, 
Georgetown Multicenter Project 
Management Office, and ERYTECH 


Page 34 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
(SUSAR ONLY),  
Within 7 calendar days (or within local IRB 
guidelines) to the IRB, and  
Within 7 or 15 calendar days to the FDA, as 
required 
All adverse events regardless of grade and 
attribution should be submitted cumulatively 
Entered into CRFs and 
Include in DSMC reports 
 
Erytech Reporting: 
Sites will report events/problems to the PI, Dr. Noel and the Georgetown Multicenter Project 
Management office and the Georgetown Multicenter Project Management Office will submit 
information as required to Erytech. 
 
Email:  
erytechpv@primevigilance.com 
 
9 Study Drugs and Treatment Plan 
 
9.1 
Study Drugs Description  
 
9.1.1 Eryaspase 
 
Eryaspase is a dispersion for infusion of allogeneic erythrocytes encapsulating 
recombinant E. coli L asparaginase, 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. 
 
Eryaspase was previously studied as a single agent in twelve patients with pancreatic 
cancer. No patient experienced dose limiting toxicities at any dose level. One patient 
experienced grade 3 lymphopenia one patient experienced grade 1 allergic pruritus.  
Eryaspase was later studied in combination with chemotherapy in 93 patients with 
pancreatic cancer, in comparison to the control arm of chemo alone grade 3 and 4 
hematological adverse event occurred with similar frequency between treatment arms. 
The most common adverse events were asthenia (68.8%), nausea (62.4%, anemia 
(45.2%), thrombocytopenia (43%), emesis (44.1%), abdominal pain (35.5%) and 
diarrhea (39.8%), however these are most likely secondary to chemotherapy26. 
 
In previous studies of Eryaspase in acute lymphocytic leukemia the most common 
adverse events were thrombocytopenia (13.6%), elevated transaminases (13.6%), 
anemia (8.8%), neutropenia (6.4%), and leukopenia (5.6%)26. 
 
Further information can be found in the current version of the Eryaspase Investigator’s 
Brochure.  
 
 
9.1.2 FOLFIRINOX (5-FU, Leucovorin, Irinotecan, and Oxaliplatin) 
 


Page 35 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
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 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. 
 
Oxaliplatin an antineoplastic antimetabolite agent. It is commercially available as an 
injectable solution for IV use. Oxaliplatin will be administered as per institutional 
procedure. 
 
9.2 
Study Drugs Dosing  
 
9.2.1 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 will 
follow the dose escalation schema.  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. A ±1-day window is permitted for 
Eryaspase dosing for scheduling purposes. 
 
Detailed instructions related to Eryaspase administration and contact information in 
case of any issues are provided in the IMP Manual. 
 
9.2.2 FOLFIRINOX (5-FU, Leucovorin, Irinotecan, and Oxaliplatin) 
 
o 5-fluorouracil 2400 mg/m² continuous infusion over 46 hours 
o Oxaliplatin 85 mg/m² (Intravenous infusion) 
o Irinotecan 150 mg/m² (Intravenous infusion)  
o Leucovorin 400 mg/m2 (Intravenous infusion) 
 
Institutional guidelines should be followed for the administration of FOLFIRINOX. It is 
recommended the administration be as follows:  


Page 36 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
1. Oxaliplatin is administered first over 2 hours,  
2. Leucovorin over 2 hours (30 minutes prior to Irinotecan),  
3. Irinotecan over 1.5 hours.   
 
9.3 
 Other Medication & Supportive Care 
 
9.3.1 Antiemetic Therapy  
 
Given the high incidences of nausea and vomiting associated with the FOLFIRINOX 
regimen, a combination of aprepitant, 5-HT3 antagonist, and dexamethasone before 
chemotherapy is strongly recommended. 
 
9.3.2 Irinotecan-induced cholinergic syndrome  
 
Atropine 0.25-1.0 mg IV may be given prior, during, or after infusion of irinotecan for 
irinotecan-induced cholinergic symptoms including lacrimation, rhinorrhea, diaphoresis, 
flushing, abdominal cramps, diarrhea, etc. 
 
9.3.3 Growth Factor Support 
 
Indications for use of GCSF should follow American Society for Cooperative Oncology 
(ASCO) guidelines. The choice of G-CSF support (filgrastim vs. pegfilgrastim) is at the 
discretion of the treating physician. Use of the erythropoiesis-stimulating agent is not 
allowed. It is strongly recommended that patients over the age of 65 receive growth 
factor support following initiation of treatment.  
 
9.3.4 Transfusion of blood products 
 
Transfusions are permitted. However, 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. 
 
9.3.5 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. 
 
9.3.6 Antidiarrheal medications 
 


Page 37 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Patients should be closely monitored for diarrhea. Dose modification is allowed for 
diarrhea. Patients should be instructed to take loperamide at the first sign of poorly 
formed or loose stools. Patients should take loperamide in the following fashion: 4 mg 
at the first onset of diarrhea, then 2 mg every 2 hours until diarrhea resolved. The total 
dose of loperamide should not exceed 16 mg/day. Patients are instructed to notify their 
treating physicians if diarrhea is not resolved within 24 hours. Additional antidiarrheal 
medications including Lomotil, tincture of opium, or octreotide can be used. 
 
9.3.7 Permitted Concomitant Medications 
 
Investigators may prescribe concomitant medications or treatments deemed necessary 
to provide adequate prophylactic or supportive care. 
 
9.4 
Eryaspase Acquisition, Accountability,  Preparation, Storage, and 
Handling  
9.4.1 Acquisition 
Eryaspase will be dispatched directly to each site only after receipt of the required information 
in accordance with ERYTECH procedures.   
 
Information to be provided at study start: Erythrocytes phenotype (including D, C, E, c, e, 
and K antigens), ABO blood group status, and Rhesus factor, all assessed on 2 separate 
samples, which can be collected on the same day. In addition, results of an irregular antibody 
screening test (IAST) are required. This information is required at least 5 working days before 
the first Eryaspase infusion.  For group A and AB patients, sub-grouping A1/A1B and A2/A2B 
is required.  If A subgroup, screening of anti-A1 antibodies (Indirect Coombs method) should 
be performed for A2 and A2B patients. The A2 and A2B patients will require anti-A1 
antibodies screening before each administration along with IAST and documented on IAST 
form. 
 
Information to be provided during the treatment phase: Results of IAST performed less 
than 3 days prior to each Eryaspase infusion.  
 
A prescription form indicating patient identifiers and body weight should be provided at the 
latest 5 working days prior to each Eryaspase infusion. 
 
The following information is required before Eryaspase can be shipped to the site: 
o The name and contact details of the recipient, who should be the Investigator or 
designee. 
o 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, 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). 
 


Page 38 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
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. Refer to the IMP manual for ERYTECH contact information. 
 
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. 
9.4.2 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. 
 
9.4.3 Formulation, Appearance, Packaging, and Labelling 
Eryaspase is packed in medical-grade polyvinyl chloride (PVC) bags. 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 erythrocytes, phenotype, 
patient identification Preparation number, etc.) to allow verification of the patient’s 
identity and blood group before administration. 
 
9.4.4 Preparation 
 
Prior to administration, a complete compatibility test (cross 
match test) between the 
patient's blood and Eryaspase, using the removable segment tubes, should be 
performed to confirm compatibility. In case a patient receives multiple bags of 
Eryaspase to achieve the intended prescribed dose, a separate test 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. 
 


Page 39 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
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.
 
10 
Study Monitoring 
 
10.1 
Data Safety Monitoring Committee at Georgetown 
 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the data and 
safety monitoring of this trial. As this study is an investigator-initiated phase I study utilizing FDA-
approved on label, and off label therapies, it is considered a high-risk study which requires real-time 
monitoring by the PI and study team and quarterly reviews by the LCCC Data and Safety Monitoring 
Committee (DSMC). The Principal Investigator, Dr. Noel, will review the data including safety monitoring 
at study teleconferences with participating sites. All SAEs are required to be reported to the local and to the 
Georgetown IRB, per each IRB policy. Based on SAEs, the IRB retains the authority to suspend further 
accrual pending more detailed reporting and/or modifications to further reduce risk and maximize the 
safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 3 months from the time the first patient is enrolled on the study. Results of 
the DSMC meetings will be forwarded to the IRB with recommendations regarding need for study closure. 
DSMC recommendations should be based not only on results for the trial being monitored as well as on 
data available to the DSMC from other studies. It is the responsibility of the PI to ensure that the DSMC is 
kept apprised of non-confidential results from related studies that become available.  It is the responsibility 
of the DSMC to determine the extent to which this information is relevant to its decisions related to the 
specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the DSMC 
recommends a study change for patient safety or efficacy reasons the trial PI must act to implement the 
change as expeditiously as possible. In the unlikely event that the trial PI does not concur with the DSMC 
recommendations, then the LCCC Associate Director of Clinical Research must be informed of the reason 
for the disagreement. The trial PI, DSMC Chair, and the LCCC Associate Director for Clinical Research 
will be responsible for reaching a mutually acceptable decision about the study and providing details of that 
decision to the IRB.  Confidentiality must be preserved during these discussions. However, in some cases, 
relevant data may be shared with other selected trial investigators and staff to seek advice to assist in 
reaching a mutually acceptable decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the DSMC 
will provide an adequate rationale for its decision. If the DSMC recommends that the trial be closed for any 
reason, the recommendation will be reviewed by the Associate Director for Clinical Research at LCCC.  
Authority to close a trial for safety reasons lies with the IRB, with the above described input from DSMC 
and the Associate Director for Clinical Research.  Of note, the DSMC will also review the safety data of 
the patients enrolled outside of Georgetown University. Georgetown University’s Multicenter Project 


Page 40 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
Management Office will be tasked with the job of collecting primary source documentation for patients 
enrolled outside of Georgetown University. In addition, the data managers at each site will be entering data 
into the Georgetown database, so that all data will be available for the DSMC at Georgetown to review.   
 
11 
STUDY ANALYSIS 
 
11.1 
Demographics and Baseline Characteristics 
 
All subject baseline characteristics and demographic data (age, sex, race, ethnicity, weight, height, body 
mass index, physical examination abnormalities, medical history, previous [within 6 months of screening]) 
and concomitant medications at study entry will be listed by study center and subject number and 
summarized with appropriate summary statistics 
 
11.2 
Safety Analysis 
 
All subjects who are enrolled and received at least one dose of study medication will be included in the 
safety population. 
 
The primary safety endpoint is the subject incidence of Grade 3 or 4 adverse events. The number and 
percentage of all subjects who experience adverse events (AEs), serious adverse events (SAEs), or 
abnormal laboratory results will be reported. 
 
Other safety endpoints include: 
Clinically significant changes from baseline in all safety laboratory parameters; 
Clinically significant changes from baseline in vital signs; 
Incidence and type of clinically significant ECG abnormalities. 
 
All clinical safety and tolerability data will be listed by subject and will be summarized by the study part. 
Treatment-emergent adverse events will be listed and summarized by System Organ Class, by relatedness, 
and by maximum severity. Serious adverse events and adverse events leading to withdrawal will be listed 
and summarized. Individual vital signs and change from baseline in vital signs will be listed by subject, and 
study visit, and summarized descriptively. Laboratory data (actual values and change from baseline) will be 
listed by subject and study. 
 
11.3 
Analysis of secondary endpoints 
 
Due to small sample sizes and dose heterogeneity, no statistical tests of hypotheses are planned for the 
study. Response data will be collected and summarized. Overall survival, and progression-free survival will 
also be graphically summarized using the Kaplan-Meier method. 
 
12 
Ethical Considerations 
 
12.1 
Institutional Review Board (IRB) 
 
GCP requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, the 
informed consent and all other forms of subject information related to the study (e.g., advertisements used 
to recruit subjects) and any other necessary documents be reviewed by an IRB. IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be obtained prior to 
the authorization of drug shipment to a study site.  Any amendments to the protocol will require IRB 
approval prior to implementation of any changes made to the study design.  Any serious adverse events that 


Page 41 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
meet the reporting criteria, as dictated by local regulations, will be reported to the IRB. During the conduct 
of the study, the investigator should promptly provide written reports to the IRB of any changes that affect 
the conduct of the study and/or increase the risk to subjects.  
 
12.2 
Ethical Conduct of the Study 
 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable regulations and 
guidelines governing clinical study conduct and the ethical principles that have their origin in the 
Declaration of Helsinki.  
 
12.3 
Subject Information and Consent 
 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions regarding this 
study. Each informed consent will be reviewed, signed and dated by the subject and the person who 
administered the informed consent. A copy of each informed consent will be given to the subject and each 
original will be placed in the subject's medical record. An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any study-related procedures and 
that the subject received a signed copy.   
 
12.4 
Protection of Patient Confidentiality 
 
All patient records, questionnaires, and tissue specimens will be de-identified using a letter and number 
assigned to their case at the time of enrollment on study.  No record or specimen will contain information 
which could identify the patient.  The key which connects patient identifiable information with this assigned 
number will be held by the Principal investigator.  For computer records, the key will be protected by a 
double password protection system.  Any paper records will be contained in a locked cabinet within a locked 
office to ensure patient’s privacy is protected.  
 
12.5 
Investigator Responsibilities 
 
Prior to trial initiation, the Investigator will provide the Sponsor with a fully executed and signed 
FDA Form 1572 and a Financial Disclosure Form. Financial Disclosure Forms also will be 
completed for all Sub-Investigators listed on the Form 1572 who will be involved directly in the 
treatment or evaluation of research subjects in this trial. 
 
The study will be conducted in accordance with the Declaration of Helsinki (amended by the 
59th World Medical Association General Assembly, October 2008) and Good Clinical Practice 
(GCP) according to International Conference on Harmonization (ICH) guidelines. Specifically, the 
study is based on adequately performed laboratory and animal experimentation; the study will be 
conducted under a protocol reviewed by a properly constituted IEC; the study will be conducted by 
scientifically and medically qualified persons; the benefits of the study are in proportion to the risks; 
the rights and welfare of the subjects will be respected; and each subject will give his/her informed 
consent before any protocol-specific tests or evaluations are performed. 
 
 
 
 
 
 


Page 42 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
13 
Data Management and Confidentiality 
 
13.1 
Data Sharing Plan 
 
Data sharing for this study will be conducted in compliance with the February 26, 2003 NIH Statement on 
Data Sharing (NOTICE: NOT-OD-03-032). The collaborating sites for this study generate a wide variety 
of scientific and clinical data and Data Sharing and Archiving will be handled by in accordance with NIH 
Statement on Data sharing, institutional internal document retention policies and all application rules, 
regulations and statutes. Subject to institutional policies, local IRB guidelines, and local, state and Federal 
laws and regulations including the Privacy Rule and the Bayh-Dole Act, we will make finished research 
data available through scientific presentations, publications (paper, web and other), depositing gene 
sequence, gene expression and other data in searchable electronic repositories, attendance at scientific 
meetings and extending invitations to scientists from other institutions for discussion. In accordance with 
the NIH policy, such data shall be made widely and freely available while safeguarding the privacy of 
participants and protecting Lombardi’s confidential and proprietary data.  
 
The participating sites will maintain awareness, and may participate in, discussions between members of 
multiple scientific and technical disciplines and their professional societies concerning data sharing, 
standards and best practices, and to create an environment that supports and develops data sharing tools. 
We will participate in or make ourselves aware of the outcome of any workshops the NIH or AACR will 
convene to address data sharing and which may address areas such as cleaning and formatting data, writing 
documentation, redacting data to protect subjects' identities and proprietary information, and estimating 
costs to prepare documentation and data for sharing.  
 
The NIH has recognized the need to protect patentable and other proprietary data and notes the restrictions 
on the sharing of data that may be imposed by agreements with third parties. Under the Bayh-Dole Act, 
grantees have the right to elect and retain title to subject inventions developed with Federal funding, and 
further, to commercialize any invention to which they retain title. Since it is not the stated intent of the NIH 
statement on Data Sharing to discourage, impede or prohibit the development of commercial products from 
federally funded research, our collaborating sites will continue to perform inventive activities, to seek 
patent protection for inventions that relate to data generated and may choose to defer publication or enter 
into agreements with third parties that may result in certain restrictions on data sharing. We note that 
seeking patent protection results in publication of the patent application into the public domain and, thus, 
may result in the data being broadly disseminated.  
 
All specimens submitted to any of the shared resource laboratories will be bar-coded upon receipt and 
assigned a unique identifier using a common software program. Tracking of specimens and their utilization 
will be carried out using a web-based system that will represent a modification of the systems presently in 
place at Georgetown (including but not limited to G-DOC, Georgetown Database of Cancer, Medidata 
Rave, REDCap), which will also give us the ability to track sample utilization. These systems have an 
“honest broker” interface which ensures HIPAA compliance and protection of any human subjects. As the 
same sample may well be used for genomic, proteomic, histopathological and clinical interrogation, 
assignment of a unique identifier as well as a common administrative structure ensures efficient cross-
database interrogation.  
 
13.2 
Data security 
 
The rights and privacy of people who participate in sponsored clinical research will be protected at all 
times. In the event that data is intended for broader use, it will be de-identified and would not permit 
linkages to individual research participants and variables that could lead to deductive disclosure of the 


Page 43 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
identity of individual subjects. No efforts will be made to identify individual cases, and any shared archive 
data will not be linked to other identifiable data. The following de-identification and security procedures 
will be followed to share information with collaborators part of the study: 
1) 
Deletion of 18 HIPAA identifiers 
a. Non-identifiable unique patient ID will be generated in G-DOC 
2) 
Secure netID-based single sign-on (netID is Georgetown’s LDAP based secure login system) 
3) 
Users will have to authenticate themselves prior to accessing controlled data 
4) 
Furthermore, based on their roles, users will require authorization to see specific studies 
5) 
Auditing and security assessments will be performed on a quarterly basis to ensure appropriate de-
identification procedures and use of data. 
 
For future studies involving new data types that are not covered in the descriptions above, NIH policy on 
data sharing will be followed where applicable. For example, Genome Wide Association Studies, if 
conducted, will comply with NIH Guidelines NOT-OD-07-088 (http://grants.nih.gov/grants/gwas/) for data 
release. Following these guidelines, GWAS data will be submitted to NCBI’s dbGAP 
(http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other tools as the NIH’s policy on GWAS evolves. 
 
13.3 
Data Disclosure 
 
GUMC (Georgetown University Medical Center) has a Confidentiality and Non-Disclosure policy that 
pertains only to proprietary information belonging to GUMC. The disclosure of research information such 
as microarray analysis results is at the discretion of the faculty and staff. Notably, investigators with NIH 
funding are expected to make their data and results public in a reasonable time frame (Please see the 
University plan for sharing and distributing biomedical research resources at 
http://otc.georgetown.edu/documents/inventors/NIHGrantLetter_ModelOrganismsUpdate_6-27-05.doc . 
To protect institutional intellectual property, the institution does have an internal review process prior to 
submission of journal manuscripts. This process will be propagated to other study sites as well. 
 
13.4 
 Record Retention 
 
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Sponsor CRA before 
disposal of any study records, and must notify the Sponsor of any change in the location, 
disposition, or custody of the study files. Records must be retained for the longest of the following 
two periods: 
 For two years following the date a marketing application is 
approved, or 
 For two years after the development of the drug is discontinued if there is no marketing 
application 
 
13.5  Use of Information and Publication 
 
It is understood by the Investigator that the information generated in this study will be used by the 
Sponsor in connection with the development of the product and therefore may be disclosed to 
government agencies in various countries. To allow for the use of information derived from the 
study, it is understood that the Investigator is obliged to provide the Sponsor with complete test 
results, all study data, and access to all study records. 
 
The Sponsor recognizes the importance of communicating study data, whether positive or 
negative, in accordance with ICH GCP Section 6.15 and Article 30 of the Declaration of Helsinki, 
version 2008. 


Page 44 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
14 
REFERENCES 
 
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30. 
2. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic 
cancer. N Engl J Med 2011;364:1817-25. 
3. Hammel P, Bachet J, El-Hariry I, et al. A phase IIb of eryaspase in combination with gemcitabine or 
FOLFOX as second-line therapy in patients with metastatic pancreatic adenocarcinoma (NCT02195180). 
JCO 2017;35:e15718. 
4. Pancreatic Cancer - Cancer Stat Facts. Anonymous . (Accessed Feb 28, 2019, at 
https://seer.cancer.gov/statfacts/html/pancreas.html). 
5. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014;371:1039-49. 
6. Tang K, Lu W, Qin W, Wu Y. Neoadjuvant therapy for patients with borderline resectable pancreatic 
cancer: A systematic review and meta-analysis of response and resection percentages. Pancreatology 
2016;16:28-37. 
7. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med 2013;369:1691-703. 
8. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by 
global genomic analyses. Science 2008;321:1801-6. 
9. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the 
exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549-54. 
10. Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic 
cancer cells. J Biol Chem 2007;282:14048-55. 
11. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and 
maintenance of pancreatic cancer in mice. J Clin Invest 2012;122:639-53. 
12. Perera RM, Bardeesy N. Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up. Cancer 
Discov 2015;5:1247-61. 
13. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016;2:e1600200. 
14. Kalyanaraman B. Teaching the basics of cancer metabolism: Developing antitumor strategies by 
exploiting the differences between normal and cancer cell metabolism. Redox Biol 2017;12:833-42. 
15. Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-
regulated metabolic pathway. Nature 2013;496:101-5. 
16. Richards NGJ, Kilberg MS. Asparagine synthetase chemotherapy. Annu Rev Biochem 2006;75:629-54. 
17. Horowitz B, Madras BK, Meister A, Old LJ, Boyes EA, Stockert E. Asparagine synthetase activity of 
mouse leukemias. Science 1968;160:533-5. 
18. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 
2010;35:427-33. 
19. Dufour E, Gay F, Aguera K, et al. Pancreatic tumor sensitivity to plasma L-asparagine starvation. 
Pancreas 2012;41:940-8. 
20. Cui H, Darmanin S, Natsuisaka M, et al. Enhanced expression of asparagine synthetase under glucose-
deprived conditions protects pancreatic cancer cells from apoptosis induced by glucose deprivation and 
cisplatin. Cancer Res 2007;67:3345-55. 
21. Lessner HE, Valenstein S, Kaplan R, DeSimone P, Yunis A. Phase II study of L-asparaginase in the 
treatment of pancreatic carcinoma. Cancer Treat Rep 1980;64:1359-61. 
22. Domenech C, Thomas X, Chabaud S, et al. l-asparaginase loaded red blood cells in refractory or 
relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 
randomized trial. Br J Haematol 2011;153:58-65. 
23. Bachet JB, Gay F, Marechal R, et al. Asparagine Synthetase Expression and Phase I Study With L-
Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma. Pancreas 
2015;44:1141-7. 


Page 45 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
24. Asparaginase Encapsulated in Erythrocytes for Patients With ALL and Hypersensitivity to PEG-
asparaginase - Full Text View - ClinicalTrials.gov. Anonymous . (Accessed Feb 28, 2019, at 
https://clinicaltrials.gov/ct2/show/NCT03267030). 
25. Thomas XG, Tavernier Tardy E, Guieze R, et al. GRASPA-AML 2012-01 study (NCT01810705): A 
multicenter, open, randomized phase 2b trial evaluating ERY001 (L-asparaginase encapsulated in red 
blood cells) plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly diagnosed acute 
myeloid leukemia (AML) elderly patients, unfit for intensive chemotherapy. JCO 2015;33:TPS7099. 
26. Eryaspase Investigator’s Brochure, Erytech Pharma, April 2018 
 
 
 
 
 
 
 


Page 46 of 46 
Version 2.1, 16 March 2022 
 
 
 
 
 
Confidential 
APPENDIX A: ECOG Performance Scale 
 
 
  
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade