Clinical trial NCT01810705
Conditions: Acute Myeloid Leukemia
Keywords: myeloid leukemia
Sponsor: ERYtech Pharma
Start date: 2013-02-01; Completion date: 2017-11-10
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy.

Detailed description:
L-asparaginase (ASNase) holds a key role in chemotherapy for Acute Lymphoblastic Leukemia (ALL) in children and young adults. In elderly patients, its efficacy is counterbalanced by its toxicity, which impairs its use. However, a study conducted with GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) in elderly ALL (study reference "GRASPALL-GRAAL SA2 2008") showed that efficacy/safety profile was positive, paving the way for introducing ASNase benefit into chemotherapy for elderly patients.

In adults, Capizzi (1988) reported a significant benefit of ASNase associated with high-dose cytarabine treatment (HiDAC) in Acute Myeloid Leukemia (AML). Indeed, there was an overall statistically superior complete remission rate for HiDAC/ASNase (40%) vs HiDAC (24%) and an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks vs 15.9 weeks).

Another study in elderly patients also displayed positive results for ASNase treatment (Petti, 1989), as well as recent single case reports that point out the potential benefit of ASNase in different AML or mixed lineage leukemia (Horikoshi, 2009; Rubnitz, 2009).

Our preclinical results also showed that an AML cell line and blast cells from the bone marrow of AML patients were sensitive to ASNase in vitro.

However, up to now, the toxicity of ASNase for elderly had prevented its use in this population that represents the majority of AML patients.

Considering the promising results of ASNase for AML treatment and the better safety profile offered by GRASPA (L-aspariginase encapsulated in red blood cells, erysapase), a multicenter, randomized, controlled IIb trial is open for recruitment. Efficacy and tolerability of GRASPA plus low-dose cytarabine will be evaluated versus low-dose cytarabine alone in treatment of AML patients over 65 year-old, unfit for intensive chemotherapy.

One hundred and twenty-three patients (65-85 year-old) newly diagnosed for AML are planned for inclusion in the study.

A 2:1 randomization will be respected (82 patients treated with GRASPA® plus low-dose cytarabine and 41 patients treated with low-dose cytarabine alone). Each patient will be followed for 24 months.

Arms: arm 1: patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control") arm 2: patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months
Interventions: intervention 1: GRASPA
Intervention descriptions: intervention 1: Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum

Protocol documents:
Prot_000.pdf: 
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STUDY PROTOCOL PHASE IIb 
GRASPA-AML 2012-01 
A Multicenter, open, randomized, controlled phase IIb trial evaluating 
efficacy and tolerability of GRASPA (L-asparaginase encapsulated in 
red blood cells, eryaspase) plus low-dose cytarabine vs low-dose 
cytarabine alone, in treatment of newly diagnosed acute myeloid 
leukemia (AML) elderly patients, unfit for intensive chemotherapy 
ENFORCE 1 study 
 
N° EUDRACT: 2012-002026-78 
 
Protocol Amendment no 4– date: 05 Oct 2015 
Protocol Version 07, dated 05 Oct 2015 
 
 
Coordinating investigator 
 
 
 
Dr. Xavier THOMAS 
Centre Hospitalier Lyon Sud 
Pavillon Marcel Bérard - Bat.1G 
165 chemin du Grand Revoyet 
69495 PIERRE BENITE 
+33 (0)4 78 86 22 35 
xavier.thomas@chu-lyon.fr 
Sponsor  
ERYTECH Pharma  
Bâtiment Adénine 
60 avenue Rockefeller 
69008 LYON 
France 
Phone: +33 (0)4 78 74 44 38 
Fax: +33 (0)4 78 75 56 29 
contact@erytech.com 
Sponsor Contact Person 
Elena Radu, MD – Senior Clinical Project Manager 
eradu@erytech.com 
 
Safety Contact Person  
 
Jerome Bailly, PharmD 
Phone: +33 (0)4 78 74 44 38 
declarationpv@erytech.com 
Fax: +33 (0)4 67 10 72 53  
(Vigipharm) 


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PROTOCOL SIGNATURE PAGE 
 
 
GRASPA-AML 2012-01:  
 
A Multicenter, open, randomized, controlled phase IIb trial evaluating efficacy and tolerability of GRASPA 
(L-asparaginase encapsulated in red blood cells, eryaspase) plus low-dose cytarabine vs low-dose cytarabine 
alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive 
chemotherapy. ENFORCE 1 study 
 
Sponsor: ERYTECH Pharma, 60 Avenue Rockefeller, 69008 Lyon, FRANCE 
 
 
 
 
 
 
 
 
 
 
 
 
Dr. Iman. El-Hariry 
Chief Medical Officer ERYTECH Pharma 
 
Date 
 
 
 
 
 
 
 
Dr.  Xavier Thomas 
Coordinating Investigator 
 
 
 
 
 
Date 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
GRASPA-AML 2012-01:  
 
A Multicenter, open, randomized, controlled phase IIb trial evaluating efficacy and tolerability of GRASPA 
(L-asparaginase encapsulated in red blood cells, eryaspase) plus low-dose cytarabine vs low-dose cytarabine 
alone, in treatment of newly diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive 
chemotherapy. ENFORCE 1 study 
 
Sponsor: ERYTECH Pharma, 60 Avenue Rockefeller, 69008 Lyon, FRANCE 
 
 
 
 
 
 
 
 
 
 
 
Dr. Iman. El-Hariry 
Chief Medical Officer ERYTECH Pharma 
 
Date 02/11/2015 
 
 
 
 
 
 
 
Dr.  Xavier Thomas 
Coordinating Investigator 
 
 
 
 
 
Date 
 
 
 




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Table of contents 
 
1. 
Synopsis ....................................................................................................................................................... 8 
2. 
Trial diagram ............................................................................................................................................. 14 
3. 
Introduction and rationale .......................................................................................................................... 15 
3.1 Acute Myeloblastic Leukemia (AML) ................................................................................................. 15 
3.2 L-asparaginase in AML treatment ........................................................................................................ 15 
3.3 GRASPA, a new formulation of L-asparaginase .................................................................................. 16 
3.4 GRASPA Current Clinical Experience................................................................................................. 17 
4. 
Objectives .................................................................................................................................................. 20 
4.1 Primary objective.................................................................................................................................. 20 
4.2 Secondary objectives ............................................................................................................................ 20 
4.3 Study endpoints .................................................................................................................................... 20 
4.3.1 
Primary endpoint ........................................................................................................................ 20 
4.3.2 
Secondary endpoints ................................................................................................................... 20 
5. 
Benefit – risk analysis ................................................................................................................................ 22 
5.1 Potential benefit for elderly patients with first AML diagnosis ........................................................... 22 
5.2 Potential risks for the patients .............................................................................................................. 23 
5.2.1 
Risk associated with L-asparaginase .......................................................................................... 23 
5.2.2 
Risk associated with erythrocytes administration ....................................................................... 23 
5.3 Benefit / Risk ratio................................................................................................................................ 24 
6. 
Trial design ................................................................................................................................................ 25 
6.1 Type of trial .......................................................................................................................................... 25 
6.2 Experimental plan ................................................................................................................................. 25 
7. 
Trial population ......................................................................................................................................... 25 
7.1 Inclusion criteria ................................................................................................................................... 25 
7.2 Exclusion criteria .................................................................................................................................. 26 
7.3 Assignment to patient numbers ............................................................................................................ 27 
7.4 Assignment to treatment schedule (randomization) ............................................................................. 27 
7.5 Sample size ........................................................................................................................................... 27 
7.6 Patient replacement .............................................................................................................................. 27 
8. 
Trial assessments ....................................................................................................................................... 28 
8.1 Visit flow chart and assessment ........................................................................................................... 28 
8.2 Inclusion period .................................................................................................................................... 32 
8.3 Registration procedure in IWRS (interactive web response system) ................................................... 32 
8.4 Study treatment administration ............................................................................................................. 32 
8.5 Dosage modification in case of toxicity ............................................................................................... 32 
8.5.1 
General dispositions.................................................................................................................... 32 
8.5.2 
Transfusion reactions .................................................................................................................. 33 
8.5.3 
Dosage modifications for cytarabine .......................................................................................... 33 
8.5.4 
Dosage modifications for GRASPA ........................................................................................... 33 
8.6 AML assessment .................................................................................................................................. 33 
8.7 Laboratory assessments ........................................................................................................................ 34 
8.7.1 
Biological parameters ................................................................................................................. 34 
8.7.2 
Pharmacokinetic, pharmacodynamic and Immunogenicity parameters ..................................... 34 
8.8 Patients Quality of Life ........................................................................................................................ 34 
8.9 Biomarker assessments ......................................................................................................................... 34 


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8.10 Study visits assessments and procedures .............................................................................................. 36 
8.11 End of study treatment.......................................................................................................................... 38 
9. 
Investigational product: GRASPA ............................................................................................................. 39 
9.1 Pharmaceutical form, qualitative and quantitative composition........................................................... 39 
9.2 Posology ............................................................................................................................................... 39 
9.3 Packaging and labeling ......................................................................................................................... 39 
9.4 Contra Indications ................................................................................................................................ 39 
9.5 Precaution for use ................................................................................................................................. 39 
9.6 Prescription ........................................................................................................................................... 40 
9.7 Supply, transportation, receipt and storage conditions ......................................................................... 40 
9.8 Administration ...................................................................................................................................... 41 
9.9 Traceability documentation on site ...................................................................................................... 41 
9.10 Return of empty package and accountability ....................................................................................... 42 
9.11 Case of non-administration of GRASPA.............................................................................................. 42 
9.12 End of study treatment.......................................................................................................................... 42 
10. Concomitant medication ............................................................................................................................ 43 
10.1 Cytarabine chemotherapy ..................................................................................................................... 43 
10.2 Concomitant treatments during study ................................................................................................... 43 
10.3 Interactions ........................................................................................................................................... 43 
10.3.1 
Contraindication: ........................................................................................................................ 43 
10.3.2 
To be avoided: ............................................................................................................................ 43 
11. Safety ......................................................................................................................................................... 44 
11.1 Adverse Events (AE) ............................................................................................................................ 44 
11.1.1 
Definitions .................................................................................................................................. 44 
11.1.2 
Collection, recording and reporting of AE ................................................................................. 44 
11.2 Serious Adverse Events (SAE) ............................................................................................................. 46 
11.2.1 
Seriousness criteria ..................................................................................................................... 46 
11.2.2 
SAE procedures (notification) .................................................................................................... 47 
11.2.3 
SAE follow-up ............................................................................................................................ 47 
11.3 Event linked to red blood cells during GRASPA administration ......................................................... 47 
11.4 Pregnancy - Lactation ........................................................................................................................... 47 
11.5 Trial premature withdrawal .................................................................................................................. 47 
11.6 Independent Data Monitoring Committee ............................................................................................ 48 
11.7 Development Update Safety Report (DSUR) ....................................................................................... 48 
12. Case Record Form (CRF) .......................................................................................................................... 49 
13. Monitoring procedures ............................................................................................................................... 49 
14. Data Management ...................................................................................................................................... 49 
15. Statistics ..................................................................................................................................................... 50 
15.1 Analysis sets (rules for statistical population definition) ..................................................................... 50 
15.2 Sample size calculation ........................................................................................................................ 50 
15.3 Statistical methods ................................................................................................................................ 50 
15.3.1 
Primary endpoint analysis ........................................................................................................... 50 
15.3.2 
Interim analysis ........................................................................................................................... 51 
15.3.3 
Secondary endpoint analysis ....................................................................................................... 51 
16. Ethics and regulatory ................................................................................................................................. 53 
16.1 Independent Ethics committees and regulatory authorities submissions ............................................. 53 
16.2 Informed Consent Form of trial subjects .............................................................................................. 53 


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16.3 Source data ........................................................................................................................................... 53 
16.4 Access to source data............................................................................................................................ 54 
16.5 Source data confidentiality ................................................................................................................... 54 
16.6 Source data electronic management ..................................................................................................... 54 
17. Duration and termination of trial ............................................................................................................... 55 
17.1 Trial duration ........................................................................................................................................ 55 
17.2 Trial location ........................................................................................................................................ 55 
17.3 Trial termination ................................................................................................................................... 55 
18. Protocol deviations .................................................................................................................................... 56 
19. Audits and Inspections ............................................................................................................................... 56 
20. Retention of clinical trial documentation ................................................................................................... 56 
21. Responsibilities .......................................................................................................................................... 57 
21.1 Trial execution ...................................................................................................................................... 57 
21.2 Central laboratory ................................................................................................................................. 57 
22. Financing and Insurance ............................................................................................................................ 57 
23. Trial report and publication policy ............................................................................................................ 57 
24. Quality assurance statement ....................................................................................................................... 58 
25. References .................................................................................................................................................. 59 
26. Appendices ................................................................................................................................................ 61 
 
List of appendices 
Appendix 1: SPC Cytarabine Hospira UK (ENG) and SPC Aracytine (FRA) ..................................................61 
Appendix 2: Inclusion and Randomization Process ...........................................................................................61 
Appendix 3: Samples preparation for centralized analyses ................................................................................61 
Appendix 4: EORTC QLQ-C30 version 3 Quality of life questionnaire ...........................................................61 
Appendix 5: Prescription of GRASPA ...............................................................................................................61 
Appendix 6: GRASPA Shipment and Administration Form with GRASPA guidelines ...................................61 
Appendix 7: SAE report form ............................................................................................................................61 
Appendix 8: Procedure to follow in case of an immediate event linked to red blood cells transfusion .............61 
Appendix 9: Declaration of Helsinki ..................................................................................................................61 
Appendix 10: Patient information sheet - Informed Consent Form ...................................................................61 
Appendix 11: History of changes .......................................................................................................................61 
 
List of figures 
Figure 1: Study diagram .....................................................................................................................................14 
Figure 2: Mechanism of action of GRASPA ......................................................................................................17 
Figure 3: GRASPALL2009-06 Study diagram ..................................................................................................18 
Figure 4: Safety reporting timeline guide ...........................................................................................................45 
 
List of tables 
Table 1: Clinical trials with GRASPA in ALL indication ..................................................................................17 
Table 2: Summary of key adverse events of interest that are study-related AEs in ≥ 10% of patients arranged 
by MedDRA Preferred Term ..............................................................................................................................19 
Table 3: Response criteria in AML ....................................................................................................................22 
Table 4: Calendar of study assessments .............................................................................................................29 
Table 5: Calendar of study PK/PD assessments .................................................................................................30 
Table 6: Calendar of study assessments – follow-up ..........................................................................................31 


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List of Abbreviations 
 
 
 
AE 
Adverse Event 
ALT  
Alanine Amino-Transferase 
ALL 
Acute Lymphoblastic Leukemia 
APL 
Acute promyelocytic leukemia 
AML 
Acute myeloid Leukemia 
AST 
Aspartate Amino-Transferase 
ASNS 
Asparagine Synthethase 
BM 
Bone Marrow  
CCG 
Children Cancer Group 
CBF-AML 
Core binding factor acute myeloid leukemia 
COG 
Children Oncology Group 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CR 
Complete Response 
CRi 
Complete Response with incomplete recovery 
CRA 
Clinical Research Associate 
CRF / e-CRF 
Case Report Form/electronic CRF  
CTCAE 
Common Terminology Criteria for Adverse Events 
D / d 
Day 
DNA 
Deoxyribonucleic acid 
IDMC 
Independent Data Monitoring Committee 
EDC 
Electronic Data Capture 
EFS 
Etablissement Francais du Sang (French Blood Bank) 
EORTC 
European Organization for Research and Treatment of Cancer 
FAB 
French American British (classification system for AML) 
GCP 
Good Clinical Practices 
GGT (γGT) 
Gamma-Glutamyl transpeptidase 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 
HiDAC 
High dose cytarabine 
HR 
Hazard Ratio 
IAST  
Irregular Antibody Screening Test 
IDMC 
Independent Data Monitoring Committee 
INR 
International Normalized Ratio 
IRB/IEC 
Institutional Review Board – Independent Ethics Committee 
ITT 
Intend To Treat 
IU 
International Units 
IWRS 
Interactive web response System 
kg 
Kilogram 
L-Asp 
L 
Asparaginase 
Liter 
LDAC 
Low-dose Cytarabine 
LDH 
Lactate dehydrogenase 
MDS 
Myelodysplastic syndrome 
mg 
Milligram 
mL 
Milliliter 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OS  
Overall Survival  
PBBC 
Peripheral Blood Blast Count 
PCV 
Per cell volume 
PFS 
Progression Free Survival 


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PK/PD(PK-
PD) 
Pharmacokinetics/pharmacodynamics 
PP 
Per Protocol 
PR 
Partial remission 
PS 
Performance status 
PT 
Prothrombin time 
PT 
Preferred Term 
(a)PTT 
(activated)Partial Thromboplastin Time  
PVC 
Polyvinyl Chloride 
QoL 
Quality of Life 
RBC 
red blood cells 
RD 
Resistant Disease 
RFS 
Relapse free survival 
mRNA 
Messenger Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper Limit Normal 
vs 
versus 
WHO 
World Health Organization 
 
 
 


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1. Synopsis  
Study Identifier 
GRASPA-AML 2012-01 
Study Title 
A multicenter, open, randomized, controlled phase IIb trial evaluating efficacy and 
tolerability of GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) 
plus low-dose cytarabine vs low-dose cytarabine alone, in treatment of newly 
diagnosed acute myeloid leukemia (AML) elderly patients, unfit for intensive 
chemotherapy. 
Investigational 
Product 
GRASPA®, eryaspase (proposed INN) 
Study Rationale 
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of 
hematopoietic progenitor cells and the most common malignant myeloid disorder in 
adults. The median age at presentation for patients with AML is about 65 years 
(Estey 2006). 
Standard therapy for older patients with AML has a poor outcome, and for those 
who cannot undergo intensive chemotherapy, any alternative to palliative treatment 
need to be investigated. 
For the last 30 years, L-asparaginase (L-Asp) has held a key role in chemotherapy 
for Acute Lymphoblastic Leukemia (ALL). Some leukemic cells, with asparagine 
synthetase deficiency, need plasma L-asparagine for protein synthesis. L-Asp 
hydrolyses L-asparagine leading to depletion of this amino acid. Normal cells are 
resistant to L-asparaginase because they can synthesize asparagine using asparagine 
synthetase. L-Asp is an integral component of induction treatment of ALL in  
children and young adults (< 55 years). 
Capizzi (1988) has reported a significant benefit of L-Asp in AML. One hundred 
ninety-five adult patients with refractory or first AML relapse were randomly 
assigned to receive high-dose cytarabine (HiDAC), 3 g/m2 as a three-hour 
intravenous (IV) infusion every 12 hours for four doses, followed by 6,000 IU/m² L-
Asp administered at hour 42, or HiDAC without L-Asp. Treatment was repeated on 
day 8. There was an overall superior complete remission (CR) rate for HiDAC/L-
Asp (40%) vs HiDAC (24%), p = .02. Subset analysis according to prior response 
and age showed the following CR rates: 54% from HiDAC/L-Asp treatment of 
refractory AML in patients less than 60 years, and 31% in patients greater than 60 
years; CR from HiDAC in the same refractory groups were 18% (less than 60) and 
0% (greater than 60). There was an overall survival benefit for patients treated with 
HiDAC/L-Asp (19.6 weeks) compared with HiDAC (15.9 weeks), p = .046, 
primarily attributable to effects in refractory patients. Toxicity in the two treatment 
arms was comparable. 
Another study with HiDAC plus asparaginase in elderly patients with newly 
diagnosed acute non-lymphocytic leukemia has been performed by the Italian 
Cooperative Group GIMEMA (Petti 1989). Overall, 43/125 evaluable patients 
(34.4%) achieved CR. 
Single case reports have been published that  demonstrate the potential benefit of L-
asparaginase in different AML or mixed lineage leukemia (Horikoshi 2009, Rubnitz 
2009) 
Antitumor activity of GRASPA as well as any L-asparaginase is based on depletion 
of plasma asparagine, which is an essential amino acid for cells survival in almost 
all lymphoblastic cells. This may also apply to other type of cancer cells including 
myeloid leukemia cells. 
A study with GRASPA in elderly ALL (GRASPALL-GRAAL SA2 2008) showed 
that efficacy/safety profile of 100 and 150 IU/Kg was positive, both doses achieving 


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sustained plasma asparagine depletion over 7 days with no excessive limiting 
toxicities.  
Study Design 
Open label, Randomized 1:2, controlled Phase IIb clinical trial. 
24-months follow-up 
Study Objectives 
Primary:  
To evaluate Overall Survival (OS) in AML patients 65 to 85 years old unfit for 
intensive chemotherapy, when treated with GRASPA plus low-dose cytarabine 
compared to low-dose cytarabine alone. 
Secondary: 
To evaluate: 
• 
Response to treatment  
• 
Progression-free Survival (PFS) 
• 
Relapse Free Survival 
• 
Patient transfusion needs 
• 
Patients Quality of life evolution 
• 
Number of hospitalization 
• 
Safety of GRASPA in combination with cytarabine 
• 
Pharmacokinetic and pharmacodynamic parameters of GRASPA 
• 
Immunogenicity of GRASPA 
• 
Asparagine Synthetase (ASNS) expression and sensitivity to L-
asparaginase in bone marrow cells (optional) 
• 
Biomarker cytogenetic testing (optional) 
Study population 
123 patients randomized 1:2, i.e. 41 patients treated with low-dose cytarabine alone 
in Arm A and 82 patients treated with GRASPA plus low-dose cytarabine in Arm B 
 
Main Inclusion 
Criteria 
• 
Patient > 65 years old and < 85 years old 
• 
Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic 
syndrome diagnosed within 6 months prior to study enrollment  
• 
Unfit for intensive chemotherapy (at risk to suffer treatment related 
pejorative toxicities /early death) due to the presence of one or more of the 
following criteria: 
o Dependence in activities of daily living owing to the presence of 
comorbidities other than those resulting from the deterioration 
caused by the neoplastic disease. 
o Presence in the patient's medical history of three or more of the 
following comorbidities, even if they are under control with proper 
treatment: 
 
Congestive heart failure 
 
Other chronic cardiovascular diseases 
 
Chronic obstructive pulmonary disease 
 
Cerebrovascular disease 
 
Peripheral neuropathy 
 
Chronic kidney failure 
 
Hypertension 
 
Diabetes mellitus 
 
Systemic vasculitis 
 
Severe arthritis 


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o Presence of geriatric syndromes such as fecal or urinary 
incontinence, spontaneous bone fractures, mild and moderate 
dementia, or patients who fall repeatedly. 
OR 
 
Patient unwilling to receive intensive chemotherapy 
 
• 
Eligible to receive low-dose cytarabine treatment 
• 
ECOG performance status ≤ 2  
• 
Female patients of childbearing potential and males must agree to use 
adequate contraception (e.g., hormonal or barrier method of birth control; 
abstinence) for the duration of study treatment and for 6 months after the 
last dose of Cytarabine or 3 months after last dose of GRASPA (whichever 
is the longest). 
• 
Negative serum pregnancy test at study entry for female subjects of 
childbearing potential 
• 
Subscription to social security insurance (if applicable, in accordance with 
local regulations) 
• 
Ability to understand, and willingness to sign, a written informed consent 
document and to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures 
 
Main Exclusion 
Criteria 
• 
Patients with M3 AML of FAB classification (APL, acute promyelocytic 
leukemia) 
• 
Patients with AML involving chromosome 16 abnormalities or 
translocation (8:21) (CBF-AML) 
• 
Patient with secondary AML subsequent to prior malignant blood disorder 
such as: 
o Myelodysplastic syndrome diagnosed more than 6 months before 
study entry 
o Myeloproliferative syndrome 
• 
Prior therapy to AML (standard therapy or investigational agents) 
• 
Inadequate organ function : 
o Uncontrolled or severe cardiovascular disease including myocardial 
infarction within 6 months of enrollment, New York Heart 
Association (NYHA) Class III or IV heart failure, uncontrolled 
angina, clinically significant pericardial disease, or cardiac 
amyloidosis.  
o Serum creatinine concentration > 2 x ULN (Upper Limit of 
Normal) 
o AST or ALT levels > 3.5xULN or 5xULN if related to AML 
o Total bilirubin > 2 x ULN 
o INR > 1.5, unless patient under chronic treatment with 
anticoagulants (in this case, INR should be within expected ranges 
for the specific condition) 
o Insulin-dependent or uncontrolled diabetes mellitus 
• 
Concurrent malignancies other than AML requiring chemotherapy 
• 
Severe active infection, HIV seropositivity, or known active type B or C 
viral hepatitis  
• 
Known or suspected hypersensitivity or intolerance to mannitol 
• 
Breastfeeding or lactating women 
 
Location 
EUROPE  


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Study duration 
Each patient will be followed for 24 months in the study. 
Study Treatment 
In the experimental group, the patients will receive one injection of GRASPA (100 
IU/kg) in combination with subcutaneous low-dose cytarabine (same posology as 
reference group hereafter), every 28 days. 
Control 
In the control arm, patients will be treated with subcutaneous low-dose cytarabine 
as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to 
local practice) for 10 consecutive days, every 28 days, for duration up to 24 months. 
Each period of 28 days constitute a cycle of chemotherapy. 
The dosage could be adjusted to 20 mg once daily in case of toxicities; higher dose 
is acceptable if required by patient’s status, at investigator's decision. 
Primary endpoint 
with time point 
assessment 
Primary endpoint:  
• 
Overall survival (OS) defined as the time elapsed between randomization 
and death from any cause 
• 
The primary analysis for OS will take place once all patients have 
completed 12 months in the study 
Secondary endpoint : 
• 
Percentage of patients with Complete remission (CR), Complete remission 
with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial 
remission (PR) 
• 
Progression-free survival (PFS) defined as the time elapsed between 
randomization and resistant disease or relapse or death from any cause 
• 
Relapse Free Survival defined only for patients who achieved CR or CRi as 
the time elapsed between date of CR/CRi and date of disease relapse or 
death from any cause 
• 
Percentage of patients who need transfusions (red cells and/or platelets), 
number of transfusion by patient 
• 
Patient quality of life (patient survey) 
• 
Number of hospitalizations (except scheduled protocol visit) 
• 
Safety of GRASPA® in combination with low-dose cytarabine, with 
specific attention to: 
o Grade 3 or 4 of Pancreatic toxicity 
o Grade 3 or 4 of hepatic toxicity, allergic or transfusion reaction or 
coagulation event 
o Grade 3 or 4 of hypoproteinemia or hyperglycemia/diabetes 
o All other non-hematologic Grade 4 toxicities 
 (NB grading reference used : NCI CTCAE version 4.0) 
• 
Pharmacodynamic and pharmacokinetic parameters of GRASPA: 
o Plasma concentrations of asparagine, aspartate, glutamine, 
glutamate  
o Whole blood L-asparaginase activity 
• 
Immunogenicity : titer of anti-L-asparaginase antibodies 
• 
Asparagine synthetase, Asparagine synthetase mRNA expression and in 
vitro sensitivity to asparaginase on the harvested bone marrow cells 
(optional) 
• 
Biomarker cytogenetic testing (optional) 
Treatment 
discontinuation 
Patients will discontinue study treatment in the following situations: 
• 
Disease relapse or presence of a resistant disease, unless the investigator 
considers that the patient has a clinical benefit from continuing the 
treatment. In this case, the investigator should continue to perform the same 


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study visits as long as considered clinical beneficial. 
• 
Occurrence of GRASPA-related toxicity, such as: 
o Grade 3 or 4 pancreatic toxicity  
o Grade 3 or  4 hepatic toxicity, allergic reaction, or coagulation 
event  
o other non-hematologic Grade 4 toxicity  
Patient assessment should continue as planned until evidence of relapse 
or presence of a resistant disease, in which case, patient will be 
followed up for survival. 
• 
Patient unwilling to continue 
• 
No evidence of study treatment benefit at investigator's decision 
Statistical plan 
Sample Size 
The sample size calculation has been based on the original primary efficacy 
endpoint (PFS) and a study that included an interim analysis for futility.  We 
assumed 75% improvement in median PFS in the GRASPA plus low-dose 
cytarabine group compared to median PFS in the low-dose cytarabine group 
(control). With a two-sided 5% level significance test and a power of 80%, taking 
into account the unbalanced group size (2 : 1) and interim analysis a total of 123 
patients should be enrolled (82 in the GRASPA plus low-dose cytarabine and 41 in 
the low-dose cytarabine group). 
Analysis plan 
The primary objective of the trial is to estimate whether GRASPA plus low-dose 
cytarabine is more promising than low-dose cytarabine alone with respect to OS in 
subjects 65-85 years old, with newly diagnosed AML unfit for intensive 
chemotherapy. The study however is not powered explicitly for OS and statistical 
significance in favor of GRASPA plus low-dose cytarabine is not anticipated. A 
decision as to whether GRASPA appears to be a promising drug in this indication 
will be based on the numerical values for the hazard ratio for OS. A hazard ratio of 
≤0.80 will indicate a 20% numerical reduction in the death rate on average over 
time in the GRASPA group compared to control. 
Efficacy data from this study will be summarized and analyzed on an intention-to-
treat (ITT) basis using randomized treatment while safety data for this study will be 
summarized using treatment received. 
The analysis of OS will be performed using a stratified log-rank test (stratification 
factor PS (performance status, 0, 1 vs 2). A secondary analysis will be performed 
using Cox's proportional hazards regression model, allowing for the effect of 
treatment and prognostic factors. For the main criterion of efficacy the significance 
level will be 0.05 using a two-sided test. OS will be summarized using Kaplan-
Meier methods. PFS will be analyzed as a secondary criterion of efficacy. 
The primary analysis of the primary endpoint and the main secondary endpoints for 
efficacy will take place once all patients have completed 12 months in the study. A 
further supportive set of analyses will take place following completion of 24 
months in the study for all patients. There will be no interim analysis for either 
futility or efficacy.  
 
External Data 
monitoring board 
An Independent Data Monitoring Committee (IDMC) will review the safety and 
tolerability of GRASPA at the following time points: 
- 
when 30 patients have been enrolled, to evaluate limiting toxicities as 
defined in stopping rules , 


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- 
when 60 patients have been enrolled. 
An original remit of the IDMC was to review the efficacy of GRASPA following 
60 PFS events accrued. The IDMC meeting will still take place following the 
accrual of these events, but with remit of safety review only. Thereafter, the IDMC 
will convene every 6 months for safety review. 
Specific attention will be paid on patients with type II diabetes treated with oral 
hypoglycemic agents: IDMC will assess 5 first of those patients enrolled after at 
least one month follow-up, and may reconsider study enrollment of such patients. 
To avoid any conflict between the evaluation of safety and the primary efficacy 
endpoint OS, deaths in the study will be presented to the IDMC only in terms of 
overall frequencies and individual patient narratives. In particular Kaplan-Meier 
curves and p-value comparisons of those curves will not be presented. 
The IDMC will work completely independently of the sponsor. Sponsor 
representatives will not attend those meetings of the IDMC where study data 
aggregated by treatment group will be considered. 
Date of Initiation 
Q1 2013  
Planned Date of 
completion 
 Q1 2018 (last patient last visit) 
Recruitment duration = 36 months + 24 months follow-up 
 


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2. Trial diagram 
 
Figure 1: Study diagram 
 
Patients included in the study will undergo successive courses of study treatment, for a duration up to 24 
months. A course is defined as 28 days, with Day 1 being the first day the patient receive low-dose cytarabine 
(Figure 1: Study diagram). 
Patient will have to attend a visit once a month, at the start of each course. 
When study treatment is stopped (see required conditions in section 8.9), the visits will take place every 3 
months until the 24 months study duration has been reached. 
 
Refer also to section 8 for study treatment and assessments.  
Randomization 
Low-dose Cytarabine (LDAC) 
GRASPA + LDAC 
Patients ≥ 65 and 
≤ 85 years with 
AML unfit for 
intensive 
chemotherapy 
Inclusion 
period   
24 months 
 
Course 1-C1 
C2 C3 C4 C5 etc…one course every 28 days 


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3. Introduction and rationale 
3.1 Acute Myeloblastic Leukemia (AML) 
Acute myeloid leukemia (AML) is a cancer involving hematopoietic progenitor cells, characterized by the 
rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the 
production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence 
increases with age. The median age at presentation for patients with AML is about 65 years. 
The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells, which causes 
decreased production of red blood cells, platelets, and normal white blood cells. The symptoms include 
fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. Several risk factors 
and chromosomal abnormalities have been identified, but the specific cause is not clear. As an acute leukemia, 
AML progresses rapidly and is typically fatal within weeks or months if left untreated. 
AML has several subtypes; treatment and prognosis varies among subtypes. Five-year survival varies from 
15–70%, and relapse rate varies from 33–78%, depending on subtype.  
In patients younger than 60 years, treatment consists in cytotoxic "chemotherapy" and might cure 20-75%, 
depending primarily on leukemia cell cytogenetic characteristics. Chemotherapy aimed at inducing a 
remission; patients may go on to receive additional chemotherapy or a hematopoietic stem cell transplant. 
However, chemotherapy produce such a result in less than 10% of elderly patients because of their inability to 
survive treatment and, mainly, the association of old age with cytogenetic abnormalities involving 
chromosomes 5 and 7 (Estey, 2006). 
Age over 60 years has constantly been identified as an independent adverse prognostic factor in AML, and 
there are very few long-term survivors in this age group. Poor outcomes in elderly AML patients have been 
attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, and 
higher frequency of adverse cytogenetic characteristics. Most AML patients over 60 years die within a year 
and overall survival in this age group has not increased significantly during the last three decades (Roboz, 
2011). 
Older patients with multiple poor-risk factors have a poorer prognosis and treatment outcome. In a 
retrospective analysis of 998 old patients treated with intensive induction at the M. D. Anderson Cancer 
Center, multivariate analysis identified age over 75 years, unfavorable karyotype, poor performance status, 
creatinine > 1.3 mg/dL, duration of antecedent hematologic disorders > 6 months, and treatment outside a 
laminar airflow room as adverse prognostic factors. Patients with 3 or more of these factors had expected 
complete remission rate of less than 20%, 8-week mortality > 50% and one year survival < 10% (Kantarjian, 
2006). 
Efforts have been made to develop efficacious regimens that are tolerable for older patients. The prototype for 
low-intensity induction over the last several decades has been low-dose cytarabine, which resulted in complete 
remission rate of 18% and improved overall survival when randomized to supportive care and hydroxyurea 
(Burnett, 2007). 
 
3.2 L-asparaginase in AML treatment 
L-asparaginase activity is based on its catalytic activity for degrading asparagine and glutamine in blood and 
tissue liquids into aspartic and glutamic acid and ammonia, which thus induce a cytotoxic response against 
asparagine-dependent tumors. Survival and growth of most of leukemic cells, such as lymphoblasts as well as 
certain solid cancer cell lines, are asparagine-dependent, using this amino acid as nutriment for protein 
synthesis. This degradation is mainly evidenced by their asparagine depletion levels. This asparagine 
depletion results in a regression of leukemic cell proliferation (Broome, 1981) by several mechanisms 
involved in the destruction of tumor cells following treatment: inhibition of protein biosynthesis and 
subsequently, induction of apoptosis (Story, 1993). 
Conversely, normal cells are resistant to L-asparaginase as they can synthesize asparagine using asparagine 
synthetase (ASNS) from other amino acids (glutamine or aspartic acid) when the level of serum asparagine is 
lowered. However some cancer cells are lacking ASNS and therefore when they are deprived of L-asparagine 
for growth and DNA replication, they become apoptotic and die. 


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A potential interest in AML has been identified from therapeutic use of free L-asparaginase and some 
bibliographic data. It has been demonstrated that AML blasts, especially M5 subtype cells, display a low level 
of ASNS (Codegoni 1995; Dubbers 2000; Kaspers 1999 Zwaan 2000). Kitoh et al. (1996) performed 
immunocytochemical staining in AML samples and showed that FAB M1, M4 and M5 cells were negative for 
ASNS. This supports the results of Okada et al. (2003) showing the relative sensitivity of M1, M4 and M5 
cells to L-asparaginase and strongly suggests that ASNS expression is inversely correlated with sensitivity to 
L-asparaginase in AML cells. 
Several cooperative groups have studied the combination of L-asparaginase with other induction 
chemotherapy regimen used in first-line and relapse AML, both in adults and in children. In adults, Capizzi 
(1988) has reported a significant benefit of L-asparaginase in AML. One hundred ninety-five adult patients 
with refractory or first AML relapse were randomly assigned to receive high-dose cytarabine (HiDAC), 3 
g/m² as a three-hour intravenous (IV) infusion every 12 hours for four doses, followed by L-asparaginase 
6,000 IU/m² (L-Asp) administered at hour 42, or HiDAC without L-Asp. Treatment was repeated on day 8. 
There was an overall superior complete remission (CR) rate for HiDAC/L-Asp (40%) vs HiDAC (24%), P = 
.02. Subset analysis according to prior response and age showed the following CR rates: 54% from HiDAC/L-
Asp treatment of refractory AML in patients less than 60 years, and 31% in patients greater than 60 years; CR 
from HiDAC in the same refractory groups were 18% (less than 60) and 0% (greater than 60). There was an 
overall survival benefit for patients treated with HiDAC/L-Asp (19.6 weeks) compared with HiDAC (15.9 
weeks), P = .046, primarily attributable to effects in refractory patients. Toxicity in the two treatment arms 
was comparable. 
Another pilot study with high-dose cytarabine plus asparaginase in elderly patients with acute non-
lymphocytic leukemia newly diagnosed has been performed by the Italian Cooperative Group GIMEMA 
(Petti et al., 1989). Overall 43/125 evaluable patients (34.4%) achieved CR. In addition a synergistic efficacy 
of L-asparaginase with cytarabine when used sequentially has been observed in this study. 
The Children Oncology Group (COG) published a review (Wells et al., 1993) to determine the impact of high-
dose cytarabine and L-asparaginase intensification on the outcome of childhood AML. Three consecutive 
Children Cancer Group (CCG) trials in AML: CCG 251 (1979 to 1983), CCG 213P (1983 to 1985), and CCG 
213 (1985 to 1989) with a total of 1,294 patients enrolled, were reviewed. Inclusion of the 7-day interval 
cytarabine/L-asparaginase intensification was accompanied by an overall improvement in 5-year survival rates 
from diagnosis when compared with historical controls (CCG 213, 36% vs CCG 251, 29%, P < .02).  
In children, L-Asparaginase is currently used in AML treatment protocols (protocol ELAM 02 2010). 
Others single case reports have been published recently, pointing out the potential benefit of L-asparaginase in 
different AML or mixed lineage leukemia (Horikoshi et al., 2009, Rubnitz et al., 2009, Takahashi et al., 
2012). 
 
3.3 GRASPA, a new formulation of L-asparaginase 
 
GRASPA is a ‘circulating microbioreactor’. As shown in Figure 2, plasma asparagine is actively pumped 
through the membrane of the erythrocyte into the intracellular compartment where it is cleaved by entrapped 
L-asparaginase. The erythrocyte membrane protects L-asparaginase against fast degradation/elimination, 
hence allowing for a long circulating activity and a longer half-life than with free L-asparaginase.  Thus, 
GRASPA combines the capacity of erythrocytes to actively ‘pump’ asparagine from blood plasma through 
sodium-coupled neutral amino acid transporters and the enzymatic activity of entrapped L-asparaginase to 
cleave asparagine into aspartic acid and ammonium leading to plasma asparagine depletion. This 
encapsulation concept is not considered as a ‘slow release’ of the L-asparaginase, since the activity of 
asparagine degradation takes place within the erythrocyte, until the latter is removed in the same manner as 
normally transfused erythrocytes, by macrophages or dendritic cells in the liver or spleen. The encapsulation 
of L-asparaginase eliminates the direct somatic contact with the L-asparaginase, and it is hypothesized that 
this provides the potential to reduce toxicity associated with the parent L-asparaginase and prolong the activity 
of the enzyme (Figure 2).   
Several tumor types depend on circulating asparagine for their growth and survival. In particular, leukemic 
cells are deficient in asparagine synthetase enzyme and are therefore incapable of synthesizing asparagine 


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(Stams et al. 2005, Kumar et al. 2014). The L-asparaginase treatment is based on the conversion of circulating 
asparagine into aspartic acid and ammonia, which deprives cancer cells of their source of asparagine and leads 
to their growth arrest and apoptosis. Normal cells are protected from asparagine requirement due to their 
ability to produce this amino acid with the help of the ASNS (Kawedia and Rytting 2014).  
 
Figure 2: Mechanism of action of GRASPA 
 
 
 
 
One main advantage of encapsulating L-asparaginase into erythrocytes is to reduce hypersensitivity reaction 
to asparaginase, as the L-asparaginase is protected from the immune system by the erythrocyte membrane. 
Additionally, its active site is  preserved, potentially resulting in lower production of neutralizing antibodies 
and reduction in the frequency and severity of hypersensitivity reactions. Although the enzyme retains its 
intrinsic immunogenic potential, it is no longer expressed as the erythrocyte membrane prevents its 
recognition by the immune surveillance systems of the host. 
 
3.4 GRASPA Current Clinical Experience 
Four clinical trials have been conducted with GRASPA in Europe, in pediatric, adult and elderly patients with 
ALL – Table 1.  
 
Table 1:  
Clinical trials with GRASPA in ALL indication 
 
Study reference  
Type of study /population  
Status  
GRASPALL 2005-01 
GRASPALL 2005-01: Administration of allogenic red blood 
cell-loaded L-asparaginase in patients with relapsed acute 
lymphoblastic leukemia (ALL)  
A Phase I/II multicenter, randomized study in adults and 
children over 1 year of age. 
N= 24 patients (GRASPA:9 children and 9 adults; native 
apsaraginase:3 children and 3 adults) 
Completed 
GRASPALL 
GRAALL SA2 2008 
An escalating dose Phase IIa study of GRASPA added to 
multi-agent chemotherapy during induction phase for the 
Completed 


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treatment of elderly patients, aged 55 years and over, 
presenting with Philadelphia chromosome-negative ALL. 
N= 30 patients  
GRASPALL 2009-06 
A multicenter, open, randomized, Phase IIb/III study, 
evaluating efficacy and safety of GRASPA versus native L-
asparaginase treatment in combination with multi-agent 
chemotherapy in patients with first recurrence of Philadelphia 
chromosome negative ALL  
N=80 patients (54 children and 26 adults). The randomized 
arms, n= 54 (GRASPA = 26; native asparaginase = 28) 
Completed  
GRASPALL2012-10-
EAP 
Expanded Access 
Program 
A multicenter, open, non-randomized study, evaluating safety 
of GRASPA in combination with multi-agent chemotherapy in 
patients under 55 years old with ALL at risk to receive other 
formulation of asparaginase. 
Ongoing 
(13 patients 
enrolled) 
 
 
The pivotal Phase III trial (GRASPALL 2009-06) is a randomized controlled trial, Figure 3. 
 
Figure 3: GRASPALL2009-06 Study diagram 
 
The co-primary endpoints were: 
1. Duration (in days) of L-asparaginase activity >100 IU/L; and 
2. Occurrence of study drug-related allergic reactions during the induction phase. 
Key secondary endpoints included: MRD, complete remission rate, anti-asparaginase antibodies, adverse 
events, Events Free Survival and OS.  
This trial enrolled 80 patients aged from 1 to 55 years, with either first relapse of Ph- ALL, or refractory to 
first-line treatment, and who were previously treated with native E.Coli L-asparaginase. 
The mean duration of asparaginase > 100 IU/L measured in whole blood was significantly higher in GRASPA 
arm compared to control arm, with a mean (± SD) of 20.5 (5.2) days and 9.4 (7.4) days, respectively, p = 
0.001. None of the patients (0/26) in the GRASPA arm had hypersensitivity reactions related to study drug 
during induction, compared to 13 (46.4%) in the control arm, p = 0.001.  Patients in GRASPA arm achieved a 
higher CR (65.4%, 95% CI: [51.6:89.8]) as compared to control arm (39.3%, 95% CI: [23.3:63.1]), p=0.026.  
The key adverse events of interest, generally considered to be a class-effect relevant to L-asparaginase, mainly 
included hypersensitivity reactions, coagulopathic events, pancreatic and hepatic events. The majority of these 
events occurred at a lower frequency with GRASPA compared to L-ASP, Table 2. 
 


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Table 2: 
Summary of key adverse events of interest that are study-related AEs in ≥ 10% of 
patients arranged by MedDRA Preferred Term 
Preferred Term [a] 
GRASPA 
N=26 (%) 
Control native asparaginase 
N= 28 (%) 
At least one AE 
19 (73.1) 
28 (100) 
Hypofibrinogenemia 
7 (26.9) 
18 (64.3) 
Elevated amylase and/or lipase enzyme elevation) 
7 (26.9) 
15 (53.6) 
Transaminase increased 
5 (19.2) 
6 (21.4) 
Hypoalbuminemia 
4 (15.4) 
9 (32.1) 
Anti-thrombin III decreased 
3 (11.5) 
20 (71.4) 
Hyperbilirubinemia 
2 (7.7) 
5 (17.9) 
Drug hypersensitivity reactions 
2 (7.7) 
16 (57.1) 
Hepatotoxicity 
1 (3.8) 
5 (17.9) 
GGT increased 
1 (3.8) 
4 (14.3) 
Activated partial thromboplastin time prolonged 
1 (3.8) 
3 (10.7) 
Extras of Table 14.3.1.10.1 GRASPALL 2009-06 CSR 
 


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4. Objectives 
4.1 Primary objective 
To evaluate Overall Survival (OS) in AML patients 65-85 years old and unfit for intensive chemotherapy, 
when treated with GRASPA plus low-dose cytarabine compared to low-dose cytarabine alone. 
 
4.2 Secondary objectives 
• 
Response to treatment 
• 
Progression-free survival 
• 
Relapse Free Survival  
• 
Patient transfusion needs  
• 
Patients Quality of life evolution 
• 
Number of hospitalizations 
• 
Safety of GRASPA in combination with cytarabine 
• 
Pharmacokinetic and pharmacodynamic parameters of GRASPA 
• 
Immunogenicity of GRASPA 
• 
Asparagine Synthetase (ASNS) expression and sensitivity to L-asparaginase in bone marrow cells 
(optional) 
• 
Biomarker cytogenetic testing (optional) 
 
4.3 Study endpoints  
4.3.1 Primary endpoint  
Overall survival (OS) is defined as the time elapsed between randomization and death for any cause. Patients 
not known to have this event are censored on the date they were last examined. 
 
4.3.2 Secondary endpoints 
• 
Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery 
(neutrophil or platelet regeneration, CRi), Partial remission (PR)  
• 
Progression-free survival (PFS) defined as the time elapsed between randomization and resistant 
disease or relapse or death from any cause  
• 
Relapse Free Survival defined only for patients who achieved CR or CRi as the time elapsed between 
date of CR/CRi and date of disease relapse or death from any cause  
• 
Percentage of patients who need transfusions (red blood cells and/or platelets), number of transfusions 
by patient 
• 
Patient quality of life evaluated using the EORTC QLQ-C30 version 3 scale 
• 
Number of hospitalizations (except scheduled protocol visit) required during the study 
• 
Safety of GRASPA in combination with low-dose cytarabine, with specific attention to : 
o Grade 3 or 4 of Pancreatic toxicity 
o Grade 3 or 4 of hepatic toxicity, allergic reaction or coagulation event 
o Grade 3 or 4 of hypoproteinemia or hyperglycemia/diabetes 
o All other non-hematologic Grade 4 toxicities 


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(NB grading reference used: NCI CTCAE version 4.0) 
• 
Pharmacokinetic and pharmacodynamic parameters: 
o Plasma concentrations of asparagine, aspartate, glutamine, glutamate 
o Whole Blood L-asparaginase activity 
• 
Immunogenicity by measuring titer of anti-L-asparaginase antibodies 
• 
Biomarker cytogenetic testing (optional) 
• 
Measurement of the following parameters on harvested bone marrow tumor cells (optional): 
o Asparagine synthetase protein expression 
o Asparagine synthetase mRNA expression 
o In vitro sensitivity to L-asparaginase 
(See also section 8.8 for details) 
 
Table 3 hereafter provides the definitions of response criteria in AML.  
 


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Table 3: Response criteria in AML 
Category 
Definition 
Complete 
remission (CR)* 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count > 1.0 × 109/L (1000/μL); 
platelet count > 100 × 109/L (100 000/μL); red blood cell transfusion 
independence 
CR with 
incomplete 
recovery (CRi) 
All CR criteria except for residual neutropenia (< 1.0 × 109/L [1000/μL]) 
or thrombocytopenia (< 100 × 109/L [100 000/μL]) 
Partial remission 
(PR) 
all hematologic criteria of CR; decrease of bone marrow blast percentage 
to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage 
by at least 50% 
    Resistant 
disease (RD) 
BM blasts increase of at least 5% vs nadir 
AND/OR 
PBBC increase of at least 15% in absolute count vs nadir OR at least 50% 
in percentage vs nadir – repeated at min 7 days interval 
Relapse¶ 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or 
development of extramedullary disease 
Stable disease 
Failure to achieve at least Partial Remission AND no Resistant Disease 
criteria 
* All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an 
aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may 
help to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be 
performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required. 
¶ In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a patient who has 
been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and 
recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related 
MDS/AML. (adapted Döhner et al 2010, Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European LeukemiaNet, Blood, 21 Jan 
2010, vol 15, no 3; 453 – 474) 
 
5. Benefit – risk analysis 
5.1 Potential benefit for elderly patients with first AML diagnosis  
In elderly AML patients with standard cytogenetic risk, treatment with intensive chemotherapy results in 
median overall survival of up to 12 months, whereas in the adverse cytogenetic category median survival is 
only 2-3 months (Lagadinou, 2010). The median age at presentation for patients with AML is about 65 years 
and in this age group, AML is associated with a poor prognosis. Therefore, AML in the elderly represents a 
major unmet medical need.  
Asparaginase has been used in some treatment protocols for AML in children. Capizzi (1988) has reported a 
significant benefit of Asparaginase in AML. However, its use remains hampered due to its toxicity. The use of 
L-asparaginase has a potential interest in AML, in light of the fact that AML blasts display a low level of 
ASNS (see section 3.2).   
GRASPA has been proposed as a new approach to maintain the activity of L-asparaginase while improving its 
safety profile. Recent experience of GRASPA in ALL with an elderly population >55 years, demonstrated a 


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tolerable safety profile. This study showed that GRASPA favorable safety profile of both doses 100 and 150 
IU/Kg (GRASPALL 2007-04). A recent PK/PD re-analysis of all completed studies with GRASPA 
demonstrated that age has no impact on the PK of different dosing levels; and therefore, a dosing schedule of 
150 IU/Kg every 2 weeks is proposed as a standard dose for all age groups.  
The objective of the development of GRASPA in AML is evaluate the overall survival benefit and the both 
progression free survival and event free survival and patient quality of life, as well as assess the impact on 
ASNS profile of myeloblasts as an exploratory objective.  
 
5.2 Potential risks for the patients 
The Potential toxicity of GRASPA results from 2 main mechanisms: (1) toxicity related to L-asparaginase, (2) 
toxicity associated with erythrocyte. 
5.2.1 Risk associated with L-asparaginase 
When L-asparaginase (free formulation as E. Coli L-asparaginase) is given, major effects observed include 
mainly hypersensitivity reactions related to the direct immunogenicity of the compound and pancreatic, 
hepatic or coagulation disturbances, probably related, in part, to asparagine depletion (Kurtzberg 2007).  
These toxicities are treatment-limiting especially in frail populations such as elderly patients. 
The encapsulation of L-asparaginase (GRASPA) eliminates the direct somatic contact with the L-
asparaginase, and it is hypothesized that this provides the potential to reduce toxicity associated with the 
parent L-asparaginase and prolong the activity of the enzyme.  On the basis of the pharmacological effects of 
L-asparaginase, GRASPA is expected to have a therapeutic benefit in AML. 
In study GRASPALL 2009-06, the incidence of allergic reactions was significantly lower in both GRASPA 
arms in the non-allergic (7.7%) and allergic patients (11.5%), as opposed to a rate of 57.1% in patients treated 
with native-asparaginase. There were no withdrawals due to hypersensitivity reactions, either in the allergic or 
non-allergic patient subsets. The most common drug-related events with GRASPA were hypofibrinogenemia 
(26.9%), asymptomatic pancreatitis (26.9%), elevated transaminases (19.2%), hypoalbuminemia (15.4%), and 
decreased anti-thrombin III (11.5%). By contrast, most of these events took place at greater incidence (64.3%, 
53.6%, 21.4%, 32.1%, and 71.4% for hypofibrinogenemia, asymptomatic pancreatitis, elevated transaminases, 
hypoalbuminemia, and decreased anti-thrombin III, respectively). These results indicate that GRASPA is 
anticipated to have a favorable safety profile in patients with AML unfit to receive intensive chemotherapy. 
5.2.2 Risk associated with erythrocytes administration 
Blood transfusion can cause adverse effects, either related to the patient’s particular condition, or to blood 
product, blood donor and blood transfusion procedure. These adverse events are well known (American 
Association of Blood Banks 1996; AFSSAPS 2003).  
The quantity of encapsulating erythrocytes administered as GRASPA are reduced compared to those used in 
usual blood transfusion practices. The volume of erythrocytes (leukocyte-depleted RBC in a SAG-mannitol 
suspension) injected per unit of RBC (280 ml) corresponds to approximately 4.6 ml/kg of an 18 g/dL 
suspension (HCT/PCV 60%). Comparatively, an administration of GRASPA at a dose of 100 IU/kg and 150 
IU/kg corresponds to 1.8 mL/kg, respectively 2.7 mL/kg of a 13 g/dL hemoglobin suspension (HCT/PCV 
50%). 
Safety data from 189 patients treated with GRASPA as of March 2015, all transfusion reactions occurred in 
5.8% of the patients, of which 1.1% were serious. None of the AE was related to GRASPA. 
Further, clinical studies with GRASPA have a clear guidance regarding monitoring of the patients during 
transfusions. In the event of transfusion reactions, transfusion must be stopped immediately and the necessary 
symptomatic treatments administered according to standard of care.  


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5.3 Benefit / Risk ratio 
As of March 2015, a total of 189 patients have been treated with GRASPA in various indications. GRASPA 
has been developed to reduce L-asparaginase toxicities and, based on accumulated data so far, was shown to 
have an improved tolerability profile as compared to native L-asparaginase, with an important reduction in 
allergic reaction as well as reduction of coagulation disorders. As provided earlier, the safety and tolerability 
of GRASPA has been demonstrated in a Phase III trial in patients with ALL aged between 1-55 years, as well 
as in a Phase II study in elderly patients with ALL, aged over 55 years. 
Therefore, based on the accumulated experience, the potential benefit of GRASPA outweighs the potential 
risks for assessing its clinical activity and tolerability in elderly patients with AML. 
 
 


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6. Trial design 
6.1 Type of trial 
This is a multicenter, open label, randomized, controlled phase IIb trial. 
 
6.2 Experimental plan 
The primary objective of the trial is to estimate whether GRASPA plus low-dose cytarabine is more promising 
than low-dose cytarabine alone with respect to OS in subjects 65-85 years old, with newly diagnosed AML 
unfit for intensive chemotherapy. The study however is not powered explicitly for OS and statistical 
significance in favor of GRASPA plus low-dose cytarabine is not anticipated. A decision as to whether 
GRASPA appears to be a promising drug in this indication will be based on the numerical values for the 
hazard ratio for OS. A hazard ratio of ≤0.80 will indicate a 20% numerical reduction in the death rate on 
average over time in the GRASPA group compared to control. 
Efficacy data from this study will be summarized and analyzed on an intention-to-treat (ITT) basis using 
randomized treatment while safety data for this study will be summarized using treatment received. 
The analysis of OS will be performed using a stratified log-rank test (stratification factor PS (0, 1 vs 2)) will 
be used to compare the two treatment arms.  
A secondary analysis will be performed using Cox's proportional hazards regression model, allowing for the 
effect of treatment and possible prognostic factors. For the main criterion of efficacy the significance level 
will be 0.05 using a two-sided test. OS will be summarized using Kaplan-Meier methods.  
PFS will be analyzed as a secondary criterion of efficacy using the same methods as for OS. 
The primary analysis of the primary endpoint and the main secondary endpoints for efficacy will take place 
once all patients have completed 12 months in the study. A further supportive set of analyses will take place 
following completion of 24 months in the study for all patients. 
There will be no interim analysis for either futility or efficacy. 
 
7. Trial population 
This trial will enroll patients corresponding to inclusion criteria AND exclusion criteria hereafter. 
 
7.1 Inclusion criteria 
To be eligible, patient must meet all the following criteria: 
• 
Patient > 65 years old and < 85 years old. 
• 
Newly diagnosed AML or post myelodysplastic syndrome (MDS) diagnosed within 6 months prior to 
study enrollment 
• 
Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death), 
due to the presence of one or more of the following criteria: 
o Dependence in activities of daily living owing to the presence of comorbidities other than 
those resulting from the deterioration caused by the neoplastic disease. 
o Presence in the patient's medical history of three or more of the following comorbidities, 
even if they are under control with proper treatment: 
 
Congestive heart failure 
 
Other chronic cardiovascular diseases 
 
Chronic obstructive pulmonary disease 
 
Cerebrovascular disease 


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 
Peripheral neuropathy 
 
Chronic kidney failure 
 
Hypertension 
 
Diabetes mellitus 
 
Systemic vasculitis 
 
Severe arthritis 
o Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone 
fractures, mild and moderate dementia, or patients who fall repeatedly. 
 
OR  
 
Patient unwilling to receive intensive chemotherapy 
• 
Eligible to receive low-dose cytarabine treatment 
• 
ECOG performance status ≤ 2. 
• 
Female patients of childbearing potential and males must agree to use adequate contraception (e.g., 
hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 6 
months after the last dose of cytarabine or 3 months after the last dose of GRASPA (whichever is the 
longest) 
• 
Negative serum pregnancy test at study entry for female subjects of childbearing potential 
• 
Subscription to social security insurance (if applicable, in accordance with local regulations) 
• 
Ability to understand, and willingness to sign, a written informed consent document and to comply 
with scheduled visits, treatment plans, laboratory tests, and other study procedures 
 
7.2 Exclusion criteria  
• 
Patients with M3 AML of FAB classification (APL, Acute Promyelocytic Leukemia)) 
• 
Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML) 
• 
Patient with Secondary AML subsequent to prior malignant blood disorder such as: 
o Myelodysplastic syndrome diagnosed more than 6 months before study entry 
o Myeloproliferative syndrome 
• 
Prior therapy to AML (standard therapy or investigational agents) 
• 
 Inadequate organ functions: 
o Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of 
enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled 
angina, clinically significant pericardial disease, or cardiac amyloidosis.  
o Serum creatinine concentration > 2x ULN (Upper Limit of Normal laboratory ranges),  
o AST or ALT levels > 3.5x ULN or > 5x ULN ,if related to AML 
o Total bilirubin levels > 2x ULN  
o INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be 
within expected ranges for the specific condition) 
o Insulin-dependent or uncontrolled diabetes mellitus 
• 
Concurrent malignancies other than AML requiring chemotherapy  


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• 
Severe active infection, HIV seropositivity, or known active type B or C viral hepatitis  
• 
Known or suspected hypersensitivity or intolerance to mannitol 
• 
Breastfeeding or lactating women 
          
7.3 Assignment to patient numbers 
For confidentiality purpose, complete name of patient enrolled will not be revealed and patient data will be 
identified with a dedicated patient number in trial records. 
Patient number will be composed of 6 digits: first 4 digits corresponding to site number, last 2 digits 
corresponding to the first number available following that of previous patient included in the trial in the same 
site. The number will be generated through Interactive Web Response System (IWRS), when minimal data 
patient are entered. 
In countries where this practice is authorized by local regulations, patients may also be identified with initials. 
 
7.4 Assignment to treatment schedule (randomization) 
The patients will be randomly and sequentially allocated to either one of the two treatments A or B. 
Randomization 1:2 will be performed by an Interactive Web Response System (IWRS, refer to Appendix 2 for 
randomization process). 
After confirmation of randomization, the system will display the treatment arm assigned namely A or B as 
follows:  
A: Low dose cytarabine (see section 10.1) 
B: Low dose cytarabine + GRASPA 
As poor performance status had been identified as a risk factor that increase probability of early death, and to 
avoid unbalance between groups, a stratified randomization will be done according to performance status (PS 
= 0 or 1 vs PS = 2). 
 
7.5 Sample size 
The study will enroll approximately 123 patients, see section 15.2 for sample size calculation. 
 
7.6 Patient replacement 
 The target recruitment is 123 patients. Randomization will continue until 123 patients are recruited and they 
receive at least one course of treatment


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8. Trial assessments 
8.1 Visit flow chart and assessment  


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Table 4: Calendar of study assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Bone marrow aspiration and extramedullary assessment may take place in the 4 weeks prior to randomization, for baseline status; samples for biomarkers assessments should be sent 
within max. 2 days after collection; 
(b) including occurrence of AE/SAE; concomitant treatment;  
(c) Irregular Antibodies Screening Test only for patients receiving GRASPA;  
(d) See PK-PD assessments  table 5 
(e) hematology (CBC) ; biochemistry ; coagulation parameters; serology tests only at inclusion; pregnancy test at inclusion and end of treatment, if applicable 
(f) for the first course = if biochemistry/hematology tests are available within 7 days, it is not necessary to repeat them; for coagulation tests – results should not be older than 3 days;  
for subsequent courses = to be performed within max. 3 days before next treatment course start;  
P : prescription of GRASPA;  
*: before the next treatment course;  
 
 
 
 
 
TREATMENT COURSE – 28 days cycle (+/- 3 days) 
Day 
D – 28 
max. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
13 
18 
23 
27 
Visit 
Inclusion 
1/2/3 
… 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Inclusion/exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
AML history/ assessment (a) 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 X* 
Clinical assessment (b) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Quality of life survey 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Randomization  
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Low-dose cytarabine 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
  
GRASPA  
  
  
 
  
  
  
  
  
  
P  
  
X 
  
  
 
  
IAST (c) 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
 
  
PK- PD (only for GRASPA receiving 
patients) (d) 
  
  
  
  
  
  
  
  
  
  
  
 X 
 X 
 X 
 
X  
Immunogenicity (only before GRASPA 
administration) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Biology (e)  
 X 
X (f) 
  
  
  
X 
  
  
  
X 
  
  
X 
X 
X 
X  
Patient diary distribution and/or 
review 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5: Calendar of study PK/PD assessments 
 
 
 
 
 
 
Course after amendment implementation – protocol version 07 
Course 1 and 2 
  
D11  
D13 
D18 
D27 
before admin 
15 min +/- 10 min 
  
  
  
after end of Graspa 
admin:  
5 min +/- 2 min 
48 h +/- 2h 
7 Days +/- 2h 
16 days after first 
admin +/- 2h 
1 h +/- 10 min 
  
  
  
3 h +/- 10 min 
  
  
  
6 h +/- 10 min 
  
  
  
 
 
 


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Table 6: Calendar of study assessments – follow-up 
 
Visit 
End of treatment 
every 3 Months until M24 (M3, …)* 
+/- 2 weeks 
AML assessment 
X 
X 
Clinical assessment, including Adverse events 
review and assessment and Concomitant 
medications 
X 
X 
Quality of life survey 
X 
X 
Subsequent AML therapy  
X 
X 
Patient diary return and review 
X 
 
 
 
*: a phone call, at minimum, will be performed at 4 months (+/- 1 week) after end of study treatment, for safety assessment 
 
Patient will have to attend visit every 28 days (+/- 3 days), at the start of each cycle, for a duration up to 24 months. Assessments required are provided in Table 4 and  
Table 5. 
When study treatment is stopped (see required conditions in section 8.9), the visits will take place every 3 months until 24-months study duration. Assessments required are 
provided in Table 6.) 
   


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8.2 Inclusion period 
The inclusion will take place before treatment beginning in order to obtain patient consent for study participation, 
verify the inclusion/exclusion criteria and gather the baseline data.  
 
8.3 Registration procedure in IWRS (interactive web response system) 
Registration takes place once the patient give his/her consent to participate in the study. Investigator must declare 
patient inclusion by entering patient data selection in IWRS (see details in Appendix 2) and, after checking all 
inclusion/exclusion criteria, ask for randomization.  
After confirmation of randomization, the system will display the treatment arm allocated and the investigator will 
receive an e-mail. 
A: Low-dose cytarabine 
B: Low- dose cytarabine + GRASPA 
 
8.4 Study treatment administration 
All patients enrolled, randomized in Arm A or B, will receive successive 28-day courses of subcutaneous low-dose 
cytarabine 40 mg daily (or 20 mg twice daily) for 10 days per course (from day 1-D1 to day 10-D10), each course 
occurring every 28 days +/- 3 days, for a duration up to 24 months. SPC for Cytarabine Hospira and Pfizer are 
attached in Appendix 1 as example. Please refer to country-specific approved Cytarabine SPC for country-specific 
information.  
Following the implementation of Amendment 4, patients randomized in arm B treatment will receive subcutaneous 
low-dose cytarabine, as described above, and GRASPA 100 IU/kg, given as an intravenous infusion at Day 11 of each 
28-day course.  
Required documents such as Investigator's prescription of GRASPA and Patient's pretransfusional status (refer 
to section 9.6) should be sent at ERYTECH Pharma 2 days before the schedule day of GRASPA administration, i.e. 
Day 9. 
In the event the patient cannot receive GRASPA treatment at the planned date (i.e. manufacturing failure) or if 
GRASPA treatment received on site is not suitable for administration (e.g. transport or cold chain impairment, rupture 
of bag…), investigator and ERYTECH Pharma will discuss the best treatment approach for the patient:  
• 
Restart manufacture for a new bag of GRASPA (delay GRASPA administration with max one week), if 
acceptable for the patient. 
• 
Switch the patient to appropriate alternative treatment, at investigator’s decision.  
o If the switch occurred before the first GRASPA administration, then the patient will be replaced, as 
defined in section 7.6.  
o If the switch occurred after at least one administration of GRASPA, treatment for next blocks 
afterwards will be at investigator’s decision (GRASPA will not be resumed if delayed more than 2 
weeks; refer to section  8.5.4 “Dosage modifications of GRASPA” and 8.11 “end of study 
treatment”). 
 
8.5 Dosage modification in case of toxicity 
8.5.1 General dispositions 
• 
The investigator will carefully monitor treatment toxicity according to standard practice and to the schedule to 
assessment (section 8.1). 
• 
Supportive therapy and adjustment to concomitant therapies may be prescribed by the investigator according 
to standard practice. 


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8.5.2 Transfusion reactions 
The clinical symptoms of a transfusion reaction are variable. A few clinical signs of adverse reaction due to 
transfusion are listed here: 
• 
Feeling of heat, malaise, feeling of burning along the vein 
• 
Chills, fever with or without lumbar and thoracic pain 
• 
Abrupt change in blood pressure, hypertension or hypotension 
• 
Respiratory distress with dyspnea 
• 
Urticarial, rash, localized or extensive edema 
• 
Nausea with or without vomiting 
• 
Hemorrhagic syndrome with bleeding at the site of injection and surgical wound. 
• 
Anaphylactic shock 
In case of any transfusion reaction, the first measure to be taken during the administration of GRASPA is to stop the 
transfusion immediately and then to administer the necessary symptomatic treatments, according to standard of care.  
 
8.5.3 Dosage modifications for cytarabine 
• 
Cytarabine dosage modifications should be applied according to the prescribing information and standard 
practice. At investigator judgment, if required by patient status, cytarabine dosage increase is acceptable.  
• 
A standard recommendation, in case of toxicity attributed to cytarabine, is to reduce the dosage of cytarabine 
to 20 mg daily.  
• 
In case of persistent or excessive toxicity attributed to cytarabine, cytarabine may be temporarily or 
permanently discontinued, as per investigator judgment. In such case, for patients in arm B, GRASPA should 
be continued as scheduled, every 14 days. 
 
8.5.4 Dosage modifications for GRASPA 
• 
If patient cannot receive GRASPA, for another reason than an adverse event, treatment may be postponed no 
later than one week after the initial scheduled day. A minimum two weeks interval between GRASPA 
infusions must be insured. 
• 
In case of allergic reaction during administration, stop the administration immediately and then to administer 
the necessary symptomatic treatments, according to standard of care. Further administration of GRASPA will 
be at investigator judgment, considering possibility of premedication anticipated for such case.  
• 
In case of any Grade 3 or 4 adverse event related to GRASPA occurring in two successive infusions, 
GRASPA should be discontinued. 
• 
 In the event of bilirubin levels >3 times upper limit of normal or transaminase levels >10 times upper limit of 
normal, treatment with GRASPA should be discontinued. 
 
8.6 AML assessment 
Initial bone marrow aspirate/biopsy must be available within four weeks prior randomization, for baseline blast count. 
AML assessment will be performed for each course, in order to allow AML disease evaluation and response to 
treatment based on adapted Dohner criteria (see Table 3 for Response criteria definitions) 
 


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8.7 Laboratory assessments 
8.7.1 Biological parameters  
Biological assessment will be performed according to the investigational center procedure at inclusion, and then, at 
D1, D5, D9, D13, D18, D23 and D27 of each course of chemotherapy (± 2 days). 
Following measurement should be performed: 
- Hematology: Complete Blood Count (CBC), platelets; 
- Coagulation parameters: Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), fibrinogen, 
antithrombin III, INR; 
- Chemistry: bicarbonate, sodium, potassium, calcium, creatinine, creatinine clearance (calculated by Cockroft & 
Gault formula) , albumin, bilirubin, alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline 
phosphatase, gamma glutamyl transpeptidase (GGT), lactate dehydrogenase, glucose, cholesterol, triglyceride, 
lipase, amylase; 
- Serologic test for HIV, B and C hepatitis will be made at inclusion only, if needed. 
-   Serum pregnancy test for women with childbearing potential – at inclusion and end of treatment.  
Assessed and signed anonymized lab reports must be sent to sponsor/representatives as soon as possible after 
receiving the results for protocol required tests as well as for any testing performed for management of AEs. 
 
8.7.2 Pharmacokinetic, pharmacodynamic and Immunogenicity parameters 
These procedures are applicable only to patients randomized on GRASPA treatment arm and they consist in the 
following tests: 
- 
Amino acids levels: asparagine, aspartate, glutamine, and glutamate  
- 
Whole blood asparaginase  
- 
Anti-L-asparaginase antibodies  
The Appendix 3: Samples preparation for centralized analyses summarizes parameters, procedures and central 
laboratories involved (a lab manual also is also edited and provided to investigational center). 
NOTE: on the scheduled days for GRASPA administration, samples should be taken at least 5 minutes prior 
administration. 
 
  
8.8 Patients Quality of Life 
Patients will complete quality of life (QoL) questionnaire (EORTC QLQ-C30, version 3, Appendix 4) at each visit. 
Also the number of transfusions (packed RBC or platelet) received by the patient will be recorded along the study as 
well as hospitalization (except scheduled for protocol visit). 
 
8.9 Biomarker assessments 
Bone marrow biopsy/aspirate will be collected at study entry and will be analyzed for biomarker analysis of 
potentially relevant biomarkers, utilizing proteomic, and transcriptomic techniques.  Assays designed to evaluate 
biomarkers that may correlate with clinical outcome will be performed, including: 
• 
Asparagine synthetase (ASNS) expression by two different methods: real-time qRT-PCR for the 
quantification of ASNS mRNA and western-blot for the quantification of ASNS protein expression 
(performed at The University of Texas MD Anderson Cancer Centre and Erytech Pharma respectively).  
• 
Mutational analyses and detection of gene amplification of relevant oncogenes, e.g FLT3, NPM1, IDH or KIT 


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• 
Depending on tissue availability, additional assays may be performed, including immunohistochemistry 
(IHC), gene expression profiling, and transcriptomic profiling. 
• 
Other potential biomarkers, as new scientific data emerge. 
 
Cells isolated from bone marrow by ficoll will be also cultured in presence of L-asparaginase. In-vitro sensitivity to L-
asparaginase will be assessed at ERYTECH Pharma by measuring the cytotoxicity using a colorimetric assay. 
 
Assessments could be repeated on further bone marrow aspirate if possible. 
Please refer to Appendix 3 (Samples preparation for centralized analyses) as well as to lab manual for details 
regarding procedure of samples collection, handling, storage, shipping and central laboratory involved.  
    
 
 
 


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8.10 Study visits assessments and procedures 
• 
Inclusion Visit (within max 4 weeks before treatment initiation):  
During the inclusion visit, the following procedures/assessments will be performed: 
- Patient information about potential study participation and obtaining the signed informed consent before 
any study related procedures;  
- Patient demographics: date of birth, gender; 
-   ECOG performance status 
- AML characteristics and assessment (see section 8.6): qualitative and quantitative parameters, primary 
diagnostic date, baseline values for bone marrow blast count, cytogenetic analysis, FAB and WHO 
classifications, including extramedullary AML assessment     
-    Medical history (relevant for the study condition) and concomitant medications 
-   General physical examination by systems and organs, including routine ECG, weight and height 
measurements 
-    Biological assessment (see section 8.7.1 for detailed items): date of sample taken; assessed and signed 
anonymized lab reports must be sent to sponsor/representatives - Inclusion and exclusion criteria 
validation 
- Patient registration in IWRS system 
-   Patient randomization - if all criteria are met.  
 
• 
Subsequent visits : from visit 1 onwards: 
- Disease evaluation (AML) (see section 8.6) 
- Clinical assessment: vital signs (height, weight, pulse, blood pressure systolic and diastolic), performance 
status (ECOG score), physical examination findings 
- Study treatment administration (low-dose cytarabine +/- GRASPA): details on date and time of 
administration are required 
- Patient quality of life: survey EORTC QLQ-C30, transfusion needs, hospitalizations from any cause 
(except scheduled protocol visit) 
- Biological assessment at D1, D5, D9, D13, D18, D23, D27 (see section 8.7.1 and table 4 for detailed 
items) – instructions to be provided to patient in case of lab testing outside the site hospital; assessed and 
signed anonymized lab reports must be sent to sponsor/representatives as soon as possible after sampling 
-   PK-PD and immunogenicity testing (see section 8.7.2, Table 4 and 5 and Appendix 3 for detailed 
instructions) – only patients on arm B (under GRASPA treatment) 
-   IAST (Irregular Antibodies Screening Test) at D9 - only patients on arm B (under GRASPA treatment)  
-   Review and assessment of any adverse event (refer to section 11 for details) 
- Record of any change in concomitant medications 
-   Distribution of patient diary and instructions provided to patients for completion – for each visit 
-   Collection and Review of previous patient diary completed 
 
• 
End of study treatment 
- Disease evaluation (AML) (see section 8.6) 
- Clinical assessment: vital signs, performance status (ECOG score), physical examination findings 


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- Patient quality of life: survey EORTC QLQ-C30, transfusion needs, hospitalizations from any cause 
(except scheduled protocol visit) 
-   Primary reason for treatment termination 
- Subsequent AML treatment if any 
-   Collection and Review of previous patient diary completed 
-   Review and assessment of any adverse event (refer to section 11 for details) 
 
• 
Follow-up visit after end of study treatment ( every 3 months +/- 2 weeks after End of Treatment visit – ex. 
M3, M6, M12…) 
- Disease evaluation, in the case relapse/recurrent status had not already occurred and the patient was 
discontinued from the treatment for other reason 
- Patient quality of life:  survey, transfusion needs, hospitalizations from any cause (except scheduled 
protocol visit) 
- Clinical assessment: Survival status 
-   Review and assessment of any adverse event (refer to section 11 for details) 
-   At minimum, a phone call will be performed 4 months (+/- 1 week) after end of treatment, for safety 
assessments 
 
 
 


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8.11 End of study treatment 
Patients will stop study treatment in following situations: 
• 
Disease relapse or presence of a resistant disease, unless the investigator considers that the patient has a 
clinical benefit from continuing the treatment. In this case, the investigator should continue to perform the 
same study visits as long as considered clinical beneficial. 
• 
Occurrence of GRASPA-related toxicity, such as: 
o Grade 3 or 4 pancreatic toxicity  
o Grade 3 or  4 hepatic toxicity, allergic reaction, or coagulation event  
o other non-hematologic Grade 4 toxicity  
Patient assessment should continue as planned until evidence of relapse or presence of a resistant disease, 
in which case, patient will be followed up for survival. 
• 
Patient unwilling to continue 
• 
No evidence of study treatment benefit at investigator's decision 
 


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9. Investigational product: GRASPA 
9.1 Pharmaceutical form, qualitative and quantitative composition 
GRASPA is a dispersion for infusion of eryaspase, packed in transparent PVC bag designed for blood product, 
containing a single dose for one administration.  
Each bag of GRASPA contains: 
-  Active substance: eryaspase, at a dose equivalent to 100 IU/kg of L-Asparaginase. 
-  Preservative solution: SAG Mannitol  
The Red Blood Cell (RBC) source material is from leukocyte-depleted packed red blood cells, prepared and qualified 
by a blood bank. Selected RBC source material is compatible with the patient (blood type and results of irregular 
antibodies screening test).  
The final volume of GRASPA bag depends on patient weight. 
 
9.2 Posology 
GRASPA is a ready to use suspension designed to be fully injected. 
The dose of GRASPA is 100 IU/kg. In this study protocol, patients will receive one infusion of GRASPA on Day 11 
of 28-day course of chemotherapy (see section 10.1).  
 
9.3 Packaging and labeling 
GRASPA is packaged in PVC (polyvinyl chloride) bags designed for blood product. Three removable segment-tubes 
are available and attached for checking before administration. 
Label statements are specific to the clinical trial, complying with legal requirements for medicinal product. In addition 
they display specific items necessary for traceability of source cell material and medicinal product (blood group, 
patient’s initials and birthdate). These mentions allow for checking the identity before administration. 
 
9.4 Contra Indications 
GRASPA should not be used in the following situation: 
- History of Grade 4 hypersensitivty reaction to L-asparaginase 
- Pregnancy/breastfeeding (see section 11.4) 
 
9.5 Precaution for use  
Anaphylaxis or serious allergic reactions: Patients should be constantly monitored during the infusion and at least one 
hour after the end of the infusion. Discontinue GRASPA with serious allergic reactions. 
Coagulation disorders: Blood count and clotting profile should be monitored before and during treatment with 
GRASPA. In cases of anti-thrombin III deficiency, administration of anti-thrombin III concentrate is preferable to 
transfusion of fresh frozen plasma (FFP) as it could counteract the GRASPA activity.  
Hepatotoxicity: Hepatic enzymes should be monitored before and regularly during treatment with GRASPA. 
Treatment with GRASPA should be discontinued in the event of bilirubin levels >3 times upper limit of normal or 
transaminase levels >10 times upper limit of normal. 
Pancreatitis: Serum lipase and amylase should be monitored regularly. Treatment with GRASPA should be 
discontinued in patients with Grade 4 pancreatitis. 
Glucose intolerance: L-asparaginase may cause hyperglycemia and patients with diabetes may have aggravation of 
their condition. Blood glucose levels should be monitored regularly. 


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Cardiac or renal impairment: Patients should be monitored for evidence of volume overload. The speed of infusion of 
GRASPA should be slowed as needed.  
If a patient receives a blood transfusion between the prescription of GRASPA and its administration, new 
compatibility tests must be performed. 
 
9.6 Prescription 
GRASPA is manufactured for one patient at a time according to investigator's prescription. 
To initiate the manufacture, ERYTECH Pharma should be provided with the documents listed hereafter:  
• 
Prescription Sheet indicating patient identifiers as well as his weight, the investigator recipient of the 
product, the place and the time of delivery. A template of the prescription sheet is available in Appendix 5: 
Prescription of GRASPA  
• 
Validated Erythrocyte phenotype and ABO blood group card with 2 determinations 
• 
an IAST (Irregular Antibody Screening Test) performed at the local immunohematology laboratory, less 
than 72h prior to GRASPA transfusion 
In the event the IAST is positive, or in case of previous or history of positivity, a compatibility test is mandatory. 
Therefore, a 5 mL sample of patient's blood should be sent to EFS Lyon (Service Immuno-hématologie, Hôpital 
Edouard Herriot pavillon I, place d’Arsonval – 69003 LYON. N° Fax: +33 (0)4 72 11 75 36 n° Tel: +33 (0)4 72 11 75 
31) 
 
9.7 Supply, transportation, receipt and storage conditions 
GRASPA bag is shipped to Investigator’s site in a qualified box allowing keeping medicinal product at controlled 
temperature +2°C to +8°C. The temperature evolution during shipment is continuously monitored by a recording 
sensor inside the pack.  
Details regarding GRASPA reception should be documented by the recipient on the document “GRASPA Shipment 
and administration Form” (Appendix 6): 
• 
Patient information consistency 
• 
The integrity of the bag of GRASPA (absence of visual leak), 
• 
The temperature indicator attached to the bag must show no sign that the product underwent out of range 
temperature. Otherwise, the investigator must contact ERYTECH Pharma for further instructions.  
• 
The expiry date is compatible with the date and time of administration 
• 
Presence of control card and Infusion double line (allowing the rinsing) 
Presence of a Packaging for bag return 
GRASPA should be managed and administered by the physician-investigator’s department as soon as possible 
upon receipt and within the expiry time stated on the label.  
The current shelf life of the product is 72 h from end of manufacture when stored between +2 °C to +8 °C (See the 
mention on the label). 
GRASPA can be kept at room temperature up to a maximum of 6 hours before the injection (including the injection 
time). The product remains stable as showed in the stability studies. Do not freeze. 
 
Instruction for receipt and administration of GRASPA are detailed in Appendix 6. Any issue happen, please contact 
ERYTECH Pharma for immediate appropriate recommendation. 
 


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9.8 Administration 
Before administration of GRASPA, the following controls must be performed and should be recorded on the 
document “GRASPA Shipment and administration Form” (Appendix 6):  
• 
The general appearance of the bag. The statements on the label are adapted according to the clinical trial.  
• 
The product for color; dark red color should be observed. If it provides evidence that the product underwent 
excessive or low temperatures during shipment, the investigator must contact ERYTECH Pharma for further 
instructions. He/she will then determine whether to urgently request a new preparation. 
• 
Presence of the document “GRASPA Shipment and Administration Form”. 
Consistency of information on  “GRASPA Shipment and Administration Form” and the patient: name, forename, 
date of birth. 
• 
An ultimate cross match blood test to check compatibility. Expiry date is compatible with date and time of 
administration. 
If there is any doubt, the product must not be administered. 
A compatibility test (cross-match) test between the patient’s blood and GRASPA (removable segment tubes) 
should be performed in your local laboratory and GRASPA must not be administered in case of discrepancy. 
GRASPA should not be administered beyond the maximum shelf life stated on the label. 
GRASPA should not be transferred to another container before injection. Since no data regarding 
incompatibility are available, GRASPA should not be mixed or administered simultaneously with any other 
product, solution or medicinal product. 
The administration should take place within the expiry time stated on the label of GRASPA. 
GRASPA is administered by intravenous route using line devices provided with the product, under medical 
responsibility. If a pump is used, only devices specifically approved for blood transfusion should be used. 
The rate of transfusion depends on the patient’s clinical conditions. The mean duration for administration is about 45 
minutes, longer in case cardiac impairment and must be adapted regarding the volume of the bag and patient’s clinical 
conditions.  
The entire content of the bag must be administered. The patient must remain awake and should be constantly 
monitored during the injection for occurrence of any adverse reactions and should be kept under observation for at 
least one hour post administration. In case of occurrence of a major symptom (e.g. malaise), GRASPA injection 
should be stopped immediately and the principal investigator must be informed. 
At the end of the injection, the lines should be rinsed with 20-40 ml of physiological saline solution (0.9% NaCl). 
The responsible person in charge of administration should record on “GRASPA Shipment and administration Form” 
(Appendix 6) information below:  
• 
date and the time of injection  
• 
name of the responsible person in charge of latest verifications before injection 
• 
Whether the entire content was injected and the lines accurately rinsed, with full explanation if it was not the 
case. 
Then this document should be faxed immediately to ERYTECH Pharma to confirm GRASPA administration. 
N° Fax: +33 (0)4 78 78 93 05 
 
9.9 Traceability documentation on site 
Traceability of reception controls and administration of GRASPA is documented with the document “Shipment and 
administration Form” (Appendix 6). 
This document should be archived in the patient medical file. 


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This document could be duplicated as needed and forwarded to the responsible persons concerned. 
The investigator is responsible for GRASPA accountability at the trial site.  
 
9.10 Return of empty package and accountability  
Empty bags must be returned to ERYTECH Pharma after GRASPA injection, using the material supplied to this 
attention. The bags will be checked for accountability and weighing at ERYTECH Pharma. 
 
9.11 Case of non-administration of GRASPA 
In case a bag of GRASPA is not administered to the patient, this event will be documented accordingly, providing full 
explanations for such case. Such case will be reported to EFS Lyon Rhône Alpes as well. These unused bags of 
GRASPA will be destroyed on site (biohazardous waste) or sent back to ERYTECH Pharma the same way as empty 
bags. 
In case of any issue, resulting in the quality of the product being compromised, the product must not be administered. 
Investigator should contact ERYTECH Pharma who will organize product return. Investigator will assess the delay in 
case of a new production need to be sent, and if it is not acceptable he will decide the best treatment for her/his patient. 
 
9.12 End of study treatment 
Refer to section 8.11 for details 
 


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10. Concomitant medication 
10.1  Cytarabine chemotherapy  
All patients enrolled are to be treated with low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 
mg twice daily according to local practice) subcutaneously for 10 days per course, each course occurring every 28 
days (+/- 3 days). 
The dosage could be adjusted to 20 mg once daily in case of toxicities at investigator's decision. Also, increased dose 
is acceptable if required by patient’s status, as per investigator judgement. 
 
10.2 Concomitant treatments during study 
Concomitant medications requiring precautions:  
 
- Oral Anticoagulants: fluctuations of coagulation factors and risk of thrombosis should be monitored with repeated 
measurements of INR 
- Erythropoiesis stimulating agents except if deemed necessary by the investigator 
- Growth Cell Stimulating Factors, except in case of severe infection at investigator's decision 
Prohibited concomitant medications: 
-  Other antineoplastic agents 
-  Other L-asparaginase marketed products 
-  Other investigational product 
 
10.3 Interactions 
10.3.1 Contraindication: 
A single GRASPA administration may lead to anti-L-asparaginase antibody production. These can trigger allergic 
reactions (mild reaction to anaphylactic shock) when another injection of L-asparaginase (whatever the form) 
administration is given. It is fully contra indicated to administrate any form of E. Coli L-asparaginase without a prior 
antibody test.  
Yellow fever Vaccination: risk of fatal systemic vaccine disease. 
 
10.3.2 To be avoided: 
Vaccination with live vaccines: increase risk of serious infection especially in immunodeficient patients. Inactivated 
vaccines are preferred when available. 
 


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11. Safety 
11.1  Adverse Events (AE) 
11.1.1 Definitions  
Adverse Event (AE): Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product. 
Any worsening, in frequency or severity, pre-existing condition should also be considered as an adverse event when 
occurring in patient administered a medicinal product. 
Adverse Drug Reaction: Any noxious and unintended response to a medicinal product related to any dose 
administered. The phrase response to a medicinal product means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. 
Unexpected Adverse Drug Reaction: An adverse reaction, the nature, or severity of which is not consistent with the 
applicable product information (e.g. Investigator's Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 
 
11.1.2 Collection, recording and reporting of AE 
11.1.2.1 
Collection of Adverse Events 
The following AE will be taken into account for this trial (grading reference used is the NCI-CTCAE version 
4.0):  
Any event will be recorded, irrespectively of the relationship with GRASPA / low dose cytarabine according 
investigator's opinion AND the grade. Similarly, any reaction linked to red blood cells (see section 11.3) during 
GRASPA administration will be recorded as an AE in the CRF.  
Laboratory tests abnormalities 
Any abnormal laboratory value should be reported as an AE. 
• 
EXCEPTION: When ALL the following criteria, the investigator may decide not to be reported such the 
abnormal value: 
o The abnormal parameter IS part of the schedule of assessment AND 
o Is NOT associated with clinical symptoms AND 
o Is considered NOT medically significant by the Investigator, AND  
o Does NOT result in change of GRASPA / Low-dose cytarabine or other concomitant treatment 
administration 
Disease Progression 
In this study, the signs and symptoms corresponding to the disease progression or worsening (AML) should not be 
recorded as AEs. Death related to disease progression should not be reported as SAE. 
The following should not be recorded as AEs, if recorded at screening:  
• 
Pre-planned procedure, unless the condition for which the procedure was planned has worsened from the 
first trial related activity after the subject has signed the informed consent. 
• 
Pre-existing stable conditions found as a result of screening procedures. Worsening of preexisting conditions 
must be reported. 
 


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If seriousness criterion is met, a SAE should be declared to ERYTECH Pharma drug safety, completing SAE report 
form (see section 11.2 and Appendix 7). 
11.1.2.2 
Recording procedure 
Any event meeting the definition of an AE / SAE must be collected and reported from subject signature of the 
informed consent and until 4 months after last GRASPA/ low-dose cytarabine administration (see Figure 4). 
Any AE / SAE related to GRASPA according to investigator's opinion must be collected and reported throughout 
study duration. 
Any SAE leading to death or life threatening must be collected and reported throughout study duration. 
Figure 4: Safety reporting timeline guide 
  
                                             
 
 
 
 
 
 
All AE / SAE must be followed until resolution or the end of the protocol. The Investigator should ensure that 
adequate medical care is provided to the subject for any adverse event. 
If there are several events and different symptoms combined to a main AE, then the only main AE (diagnostic 
preferable if available) should be recorded in the CRF. Where there is no link between different clinical symptoms 
occurring at the same time, each sign should be recorded as separate AE. 
Occurrence and follow-up of AE should be assessed at each visit, and essential data listed hereafter should be recorded 
in the patient's CRF and patient's medical file as well: 
• 
the severity or grade of the adverse event,  
• 
the causality: determination of whether an adverse event is related to the investigational treatment or 
procedure, or other agents are suspected of causing the adverse event, 
• 
the action(s) taken regarding investigational product (continued / interrupted / stopped) 
• 
the corrective treatment if any 
• 
the event outcome 
• 
the seriousness of the event 
11.1.2.3 
Intensity /AE grading 
Grade is used to denote the severity of the adverse event. The NCI Common Terminology Criteria for Adverse Event 
(NCI CTCAE) v. 4.0 will be used as reference for AE grading in this trial. If the term does NOT appear in the NCI 
CTCAE, the AE is graded using the following categories:  
• 
1 / Mild: minor; no specific medical intervention; asymptomatic laboratory findings only, radiographic only; 
marginal clinical relevance 
• 
2 / Moderate: minimal intervention; local intervention; noninvasive intervention (packing, cautery),  
• 
3 / Severe: significant symptoms requiring hospitalization or invasive intervention; transfusion; elective 
interventional radiological procedure; therapeutic endoscopy or operation). The term “severe” is often used 
to describe the intensity (severity) of a specific event. This is not the same as “serious,” which is based on 
patient/event outcome or action criteria (see section 11.2). 
ICF 
signature 
4 months after 
last GRASPA 
treatment 
administration 
24 months 
study period 
All GRASPA related (S)AEs and all 
fatal and life-threatening SAEs 
(except Death related to disease 
progression) 
All 
(S)AEs 


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• 
4 / Life-threatening or disabling: complicated by acute, life-threatening metabolic or cardiovascular 
complications such as circulatory failure, hemorrhage sepsis. Life-threatening physiologic consequences; 
need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, 
therapeutic endoscopy or surgery. 
• 
5 / Fatal 
 
11.1.2.4 
Causality assessment 
Causality is the determination of whether an adverse event is related to a medical treatment or procedure. Causality 
categories are: 
• 
Reasonable possibility: where the AE is clearly (certainly), likely to be (probably) or could be (possibly) 
related to the treatment or procedure. 
• 
No reasonable possibility: where the AE is clearly NOT (not related) or doubtfully (unlikely) related to the 
treatment or procedure.  
• 
In the case it is impossible to judge the AE causality, due to lack of information, or inconsistent information 
which cannot be investigated further, the AE/SAE will be reported as possibly related. 
 
11.1.2.5 
Outcome 
The event outcome is mandatory and should be recorded as soon as it gets resolved, where appropriate when the 
subject has completed the protocol at the latest. The outcome should be one of the following: 
• 
Recovering: the AE is improving 
• 
Not yet recovered: the AE is still ongoing when the subject has completed the protocol. 
• 
Recovered: fully recovered or by medical or surgical treatment the condition has returned to baseline level. 
• 
Recovered with sequelae: as a result of the AE, the subject suffered persistent and significant 
disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with sequelae should be 
declared as an SAE (see section 11.2). 
• 
Fatal: any AE resulting in death should be declared as an SAE (see section 11.2). 
 
11.2  Serious Adverse Events (SAE) 
11.2.1 Seriousness criteria 
An adverse event is classified as "serious" when at least one the following criterion is met: 
• 
Results in death: be aware that a death cannot be an event but always the outcome of an event. Exception is 
when death occurs suddenly, without the exact cause is stated. In this case only, the event should be recorded 
as "sudden death" with the seriousness criterion "fatal" indicated. 
• 
Is life-threatening: life-threatening in the definition of a serious adverse event refers to an event in which 
the subject was at risk of death at the time of event; it does not refer to an event which hypothetically might 
have caused death if it was more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is considered as serious according investigator judgment in other situation. Important adverse events/ 
reactions that are not immediately life-threatening or do not result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed above, should 
also be considered serious. 


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11.2.2 SAE procedures (notification) 
In addition to be recorded in patient's CRF, as well as any Adverse Event, Serious Adverse Event will be recorded 
in a separate SAE form (Appendix 10), and declared to ERYTECH Pharma, whether attributed to the protocol or not. 
Therefore, an SAE report must be completed and faxed without delay and in any case within 24 hours of obtaining 
knowledge about the event to: 
SAE FAX No: +33 (0)4 67 10 72 53 or email to erytech@vigipharm.fr 
(Vigipharm mandated by ERYTECH Pharma) 
If necessary, Investigator will be asked for additional information. SAE Follow-up report will be then completed and 
faxed to ERYTECH Pharma in the same way as the initial report. 
Any documentation regarding SAE, initial and follow-up report, should be archived together with patient's source 
documents. 
ERYTECH Pharma is responsible for declaring all Unexpected Serious Adverse Reactions (treatment related events) 
to Competent Authorities (and Ethical Committee(s) as needed), in accordance with the local requirements. 
Investigators will be informed as well. 
 
11.2.3 SAE follow-up 
Investigator should ensure that adequate medical care is provided to the subject for any adverse event.  
All SAE must be followed until the subject has recovered, stabilized, recovered with sequelae or died. The 
Investigator must forward follow-up information on SAE to ERYTECH Pharma without delay and in any case within 
24 hours of obtaining the new information. SAE Follow-up report should be faxed accordingly to: 
SAE FAX No: +33 (0)4 67 10 72 53 or email to erytech@vigipharm.fr 
(Vigipharm mandated by ERYTECH Pharma) 
 
11.3  Event linked to red blood cells during GRASPA administration 
Any adverse event that may be related to erythrocytes / blood transfusion should be assessed by the investigator 
according to the clinical background of the patient. In such cases, the Appendix 8 summarizes the corresponding 
procedure:  
- 
Any event linked to red blood cells will be recorded in the CRF as an AE. If seriousness criterion is met, a SAE 
should be declared to ERYTECH Pharma drug safety, completing SAE report form (see section 11.2.2 above). 
-  
The return of the bag of GRASPA to ERYTECH Pharma will be organized for immunologic and hematologic 
analyses. 
-  
If additional analyses are required in local laboratory, segment tubes can be removed from the bag of GRASPA 
for this purpose. 
 
11.4  Pregnancy - Lactation  
Since no preclinical or clinical data are available, GRASPA IS NOT TO BE USED during pregnancy and lactation. 
Cytarabine has known teratogen effects in several animal species and IS NOT TO BE USED during pregnancy and 
lactation 
 
11.5  Trial premature withdrawal 
The trial can be prematurely stopped (definitely or temporarily) when: 
• 
The treatment is considered as too noxious to continue with further clinical investigations 


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• 
Occurrence of new fact that can modify ERYTECH Pharma / Competent Authority approval on the trial, or 
for any unethical reason  
• 
ERYTECH Pharma decision to stop product development 
In case of any reason motivating such withdrawal, the Investigator should promptly inform the patients, ensure 
appropriate therapy and follow-up, and complete the CRF with all available data at the time of trial arrest. 
Trial withdrawal with the reason will be declared to Competent Authority (and EC if applicable) in accordance with 
local requirements. 
 
11.6  Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will review the safety and tolerability of GRASPA at the 
following time points: 
- 
when 30 patients have been enrolled, to evaluate limiting toxicities as defined in stopping rules , 
- 
when 60 patients have been enrolled. 
The original remit of the IDMC was to review the efficacy of GRASPA following 60 PFS events. The IDMC meeting 
will still take place following the accrual of these events, but with remit of safety review only. Thereafter, the IDMC 
will convene every 6 months for safety review 
Specific attention will be paid on patients with type II diabetes treated with oral hypoglycemic agents: IDMC will 
assess 5 first of those patients enrolled after at least one month follow-up, and may reconsider study enrollment of 
such patients. 
To avoid any conflict between the evaluation of safety and the primary efficacy endpoint OS, deaths in the study will 
be presented to the IDMC only in terms of overall frequencies and individual patient narratives. In particular Kaplan-
Meier curves and p-value comparisons of those curves will not be presented. 
The IDMC will work completely independently of the sponsor. Sponsor representatives will not attend those meetings 
of the IDMC where study data aggregated by treatment group will be considered. A specific document will be edited 
separately providing IDMC members details and conditions for such evaluation during IDMC meetings. 
 
11.7 Development Update Safety Report (DSUR) 
ERYTECH Pharma will forward to Competent Authority and Ethic Committee Development Update Safety Report on 
GRASPA with all available safety information, in accordance with local requirements. 
ERYTECH Pharma will keep investigators informed about data available impacting subject's safety. 
Occurrence of any new fact about research conduct or investigational product use, likely to cause subject's safety 
impairment will be taken into account to initiate appropriate action to guarantee subject's safety. ERYTECH Pharma 
will immediately inform Competent Authority and Ethic Committee as well as investigators. 


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12. Case Record Form (CRF) 
CRF will be used to collect data. Any assessment and corresponding results performed during protocol visits as stated 
in the schedule (detailed in section 8) will be recorded in patient medical file (source document) in order to be 
integrated in the Case Record Form. 
All laboratory data and Investigator observations must be reported to sponsor. Any imaging techniques must be 
summarized in the CRF where applicable. The original reports, traces and films must be retained by the Investigators 
for future reference. 
Some data may not be included in source document but could be recorded in the CRF directly. Such data need to be 
defined before study start. The CRF will be then considered as a part of source document. 
This trial will use an e-CRF, i.e. based on electronic data capture (EDC), designed and provided by ERYTECH 
Pharma or contractors. All requested data should be entered in the CRF on a regular basis, as soon as they are 
obtained, by the investigator or an authorized delegated person. The Investigator or authorized staff must ensure that 
all information recorded is consistent with the source information. 
At the end of the study, each CRF will be edited for archiving purposes, in accordance with local requirements. 
 
13. Monitoring procedures 
During the course of the trial, a dedicated CRA will visit investigational sites to monitor study conduct as it 
progresses. The purpose of these visits is to ensure:  
• 
Subjects enrolled were duly informed and gave their consent, 
• 
Adherence to protocol and GCP guidelines are followed, 
• 
CRF completion is accurate (consistency of data recorded versus source document), 
• 
SAE are notified accordingly if any, 
• 
Drug accountability is well documented, and documentation regarding investigational product is present and 
complete, 
• 
Any problems detected in the course of the monitoring visits are resolved. 
Therefore, the Monitor must be given direct access to source documents (original documents, data and records, see 
section 16). Direct access includes permission to examine, analyze, verify and reproduce any record(s) and report(s) 
that are important for clinical trial evaluation. 
Investigator must be available for discussions and clarifications over the phone as well. 
The following data can be recorded directly on the CRF and will be considered as source data: Vital signs. For all 
other data in the CRF, it must be possible to verify these against source documents. 
Computerized data controls will be performed as well and may raise queries where there are inconsistencies. 
Investigator will be then requested to answer queries as soon as possible. 
 
14. Data Management 
The subjects will be identified by subject number, initials, site, and trial identification number. Appropriate measures 
such as encryption or deletion will be enforced to protect the identity of human subjects in all presentations and 
publications as required by local/regional/national requirements. 
Electronic data transfer of any CRF or subject related data must be approved by the responsible Data Management 
Unit(s). In cases where data is transferred via non-secure electronic networks, data must be primarily encrypted. 


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15. Statistics  
15.1  Analysis sets (rules for statistical population definition) 
The intent-to-treat (ITT) efficacy population will be comprised of all randomized patients in the groups to which 
they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they 
actually received, and regardless of subsequent withdrawal from treatment or deviation from protocol. 
The per-protocol (PP) efficacy population will be comprised of all patients from the ITT population without major 
protocol deviation that have received trial product and have completed at least one course of treatment. 
The safety population will be comprised of all patients that have received at least one administration of trial 
products.  
Patients without progression or death will be included in the efficacy population with a time interval that is right 
censored. 
The responsibility for excluding patients from the analysis will be a joint decision by Sponsor, Statistician, 
Investigator and Trial Monitor. The patients to be excluded and the reasons for their exclusion must be documented 
and signed by those responsible prior to database release. The documentation must be stored together with the 
remaining trial documentation. 
 
15.2  Sample size calculation 
The sample size calculation is based on the original primary efficacy endpoint (PFS). We assumed 75% improvement 
in median PFS in the L-asparaginase (GRASPA) plus low-dose cytarabine group compare to median PFS in the low-
dose cytarabine group (control). An hypothesis of 24 months of accrual time and whole study duration of 48 months is 
used. No dropout rate was taken into consideration. 
With a two-sided 5% level significance test and a power of 80%, taking into account the unbalanced group size (2 : 1), 
a total of 117 patients should be enrolled to observe 117 events (78 in the L-asparaginase (GRASPA) plus low-dose 
cytarabine and 39 in the low-dose cytarabine group). 
The study size had been increased to 123 patients (41 patients in Arm A and 82 patients in Arm B) in order to 
incorporate an interim analysis for futility. This interim analysis however will not now be undertaken.  
 
15.3  Statistical methods 
A statistical analysis plan (SAP) will be prepared by the CRO and validated by the sponsor. Statistical analyses will be 
performed with SAS® version 9.2 or higher (SAS institute, North Carolina, USA).  
A primary report will be delivered after 12-months follow-up of last patient included. An addendum on 24-months 
follow-up period will be added for the final report. 
Any patient not known to have had an event (death/progression) at the time of analysis will be censored based on the 
last recorded date on which the patient was known to be event-free. 
For numeric secondary endpoints (e.g. quality of life scores) and depending on the number of missing/invalid data, a 
data replacement according to the Last Observation Carried Forward method will be performed as a sensitivity 
analysis.  
Missing days and/or months for dates pertaining to events far before the initiation of the study will be replaced by 15 
and/or June respectively for time calculations purposes.  
Other conventions may be specified in the study statistical analysis plan. 
 
15.3.1 Primary endpoint analysis 
The primary endpoint will be analyzed based on the ITT population. Efficacy data will also be analyzed on the Per-
Protocol population to assess sensitivity of results to protocol compliance.  


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The primary objective of the trial is to estimate whether GRASPA plus low-dose cytarabine is more promising than 
low-dose cytarabine alone with respect to OS in subjects 65-85 years old with newly diagnosed AML unfit for 
intensive chemotherapy. OS will be calculated from date of randomization to date of death (or censoring).  
OS will be summarized using Kaplan-Meier methods. The analysis of OS, will be performed using a stratified log-
rank test (stratification factor PS (0, 1 vs 2) to compare treatment groups).  
Hypothesis testing will be based on the following relations: 
H0 : θ = -log(λ) = 0 and the alternative hypothesis will be H1 : θ = θ1 >0 where λ is the hazard ratio (HR) between the 
GRASPA plus low-dose cytarabine and the low-dose cytarabine alone groups. In our case (assumption for the median 
survival times of 2 months and 3.5 months for low-dose cytarabine alone and GRASPA plus low-dose cytarabine 
respectively) this will mean that H1 : θ = - log(0.5714) = 0.5597. 
A secondary analysis will be performed using Cox's proportional hazards regression model, allowing for the effect of 
treatment and prognostic factors (ECOG, age and cytogenetic group). For the main criterion of efficacy the 
significance level will be 0.05 using a two-sided test.  
The primary analysis for OS will take place once all patients have completed 12 months in the study. It should be 
noted however that the study is not powered explicitly for OS and statistical significance in favor of GRASPA plus 
low-dose cytarabine is not anticipated. A decision as to whether GRASPA appears to be a promising drug in this 
indication will be based on the numerical values for the hazard ratio for OS. A hazard ratio of ≤0.80 will indicate a 
20% numerical reduction in the death rate on average over time in the GRASPA group compared to control. 
 
15.3.2 Interim analysis  
 
There will be no interim analysis. 
 
15.3.3 Secondary endpoint analysis 
Efficacy endpoints 
All efficacy secondary endpoints will be analyzed in the ITT and PP populations. 
Progression-free survival (PFS) will be analyzed as a secondary criterion of efficacy. PFS will be defined as the time 
from date of randomization and resistant disease or relapse or death from any cause. Any patient not known to have 
died at the time of analysis will be censored based on the last recorded date on which the patient was known to be 
alive (i.e. their status must be known at the censored date and should not be lost to follow up or unknown). PFS will 
be analyzed at the time of final analysis using a stratified log-rank test (stratification factor, PS). A Cox model will 
also be used to test the effect of treatment and will include terms for prognostic factors (PS, age and cytogenetic 
group).  
The analysis of objective response rate (i.e. CR or PR) will be performed using logistic regression including treatment 
factor and PS. Secondary analysis will be performed where the logistic regression model will allow for the effect of 
treatment, and will also include prognostic factors as for OS and PFS. Percentage of patients with CR, CRi, CRp and 
PR will be calculated and associated exact 95% CIs will be presented by treatment group. Median duration of response 
from onset of response (RFS) will be calculated and summarized by treatment group for the subset of responders. 
Absolute and relative change from baseline EORTC quality of life (QoL) questionnaire scores will be described in 
each treatment group. EORTC QoL questionnaire scores will be compared across time in each treatment group using a 
mixed model for repeated data. 
Time until QoL deterioration will be defined as a decrease in QoL score from baseline without any return to a better 
state during the study. A threshold of 10% decrease in QoL score will be primarily used. Other thresholds may be used 
as exploratory analyses. Death will also be considered as a QoL deterioration. Time to QoL deterioration will be 
summarized using Kaplan-Meier methods and will be compared between treatment groups using a stratified log-rank 
test (stratification factor, PS).  


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Percentage of patients who need transfusions (red blood cells and/or platelets), mean number of transfusions by patient 
and mean number of hospitalizations (more than over 24 hours) required during the study will be described with their 
corresponding 95% CI in each treatment group. 
The primary analysis of the main secondary endpoints for efficacy will take place once all patients have completed 12 
months in the study as for the primary endpoint. A further supportive set of analyses will take place following 
completion of 24 months in the study for all patients. 
 
Safety endpoints 
All subjects who received at least one dose of investigational products will be included in the safety analyses. Safety 
data will be summarized using actual treatment received, regardless of randomized treatment. 
Safety and tolerability will be assessed in terms of AEs, SAEs, laboratory data and vital signs which will be collected 
for all subjects. AEs will be coded according to the Medical dictionary for regulatory activities (MedDRA) version 
15.1 or higher. The intensity of AEs will be graded according to the NCI-CTCAE (version 4.0). 
AEs, AE leading to study treatment discontinuation, AE related to study treatment, and SAEs will be listed 
individually by subject, and summarized by System Organ Class (SOC) and Preferred Term (PT) by treatment group. 
Summary of AEs with NCI-CTCAE grade 3 or 4 and most frequent PT will also be provided. 
Specific attention will be given to NCI-CTCAE Grade 3 or 4 of pancreatic toxicity, Grade 3 or 4 of hepatotoxicity, 
allergic reactions or coagulation disorders, known to be potentially related to L-asparaginase as well as to 
hypoproteinemia and hyperglycemia/diabetes events.  
Vital signs and laboratory data will be listed and summarized by actual treatment group based on the safety analysis 
set. Summary of absolute values over time (one table per vital sign/laboratory parameter) and summary of change 
from baseline values over time (one table per vital sign/laboratory parameter) will be presented. Patients with vital 
sign/laboratory values of NCI-CTCAE grade 3 or 4 will be identified. 
Pharmacokinetics and immunogenicity will only be assessed on the subgroup of subjects having received GRASPA. 
Samples for amino acids (asparagine, aspartate, glutamine, and glutamate), and whole blood asparaginase will be 
taken on Days 11, 13, 18 and 27 of the first two cycles of treatment after amendment implementation. Summary of 
absolute values over time (one table per parameter) and summary of change from baseline values over time (one table 
per parameter) will be presented separately for patients recruited before and after the protocol amendment. Whole 
blood L-asparaginase concentrations from this study will be evaluated using a population pharmacokinetic 
analysis.  Prior to the analysis, the concentration data will be combined with concentration data collected in previous 
clinical studies.  The model building will be conducted using NONMEM (Icon Development Solutions, Ellicott City, 
MD, USA, 2009) and reported separately. 
 


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16. Ethics and regulatory 
The Sponsor and investigators must ensure that the study will be carried out in compliance with the protocol, the 
principles of ICH GCP and the declaration of Helsinki (appendix 9) 
 
16.1  Independent Ethics committees and regulatory authorities submissions 
The Sponsor must submit the protocol and appropriate related materials to Ethic Committee(s) and local Competent 
Authority according to national legislation. Approval from Ethic committee(s) and competent authorities must be 
granted prior to the study start. 
Any substantial amendment to the protocols will be implemented only after approval of these bodies as well. 
Regulatory Authorities will be provided with amendments if any, reports on SAEs, and the Integrated Clinical Trial 
Report according to national regulations. 
 
16.2  Informed Consent Form of trial subjects 
Prior to any trial related activity, the Investigator must give the subject (and/or parents or the subject’s legally 
acceptable representative, if applicable) oral and written information about the trial in a form that the subject can read 
and understand. This form (see Appendix 10: Patient information sheet - Informed Consent Form) aims at detailing 
study purpose and methods, background and present knowledge of investigational product, benefits, risks, study 
assessments including full exams performed, personal data access and treatment, subject's right regarding the 
possibility, at any time, to withdraw his/her consent for participating in the study, without penalty about treatment he 
would beneficiate afterwards. Subject must be given sufficient time and opportunity to inquire about details, discuss 
and decide on his/her participation with the investigator concerned. 
A voluntary, signed and dated Informed Consent Form must be obtained from the subject before any specific study 
screening procedure. Alternatively, the consent can be given orally in the presence of an independent witness who will 
sign the Informed Consent Form. Healthy subjects must always give signed informed consent. The written informed 
consent must be signed and dated by the person who conducted the informed consent procedure. The original will be 
filed in Investigator Study File; a copy of the document will be retained by the subject and another one will be 
collected by the sponsor (Assurance Quality Department) in secured sleeves. 
If information becomes available that may be relevant to the subject’s willingness to continue participating in the trial, 
the Investigator must inform the subject in a timely manner, and a revised written informed consent must be obtained. 
 
16.3  Source data  
Source data mean data the patient medical file contains, including but not limited to: medical history, concomitant 
medication (received or withdrawn), clinical assessment, vital signs, any original document such as exam reports, 
laboratory results, consultant letters and correspondence, nurse's notes… 
NB: patient's involvement in the study should be clearly documented in his/her medical file; details should include the 
study protocol number, the hospital/unit code, the patient's identification and randomization number, the patient's 
consent to take part in the study (with the date of consent), the dates of all study visits. 
Such essential documents must be retained by the investigator in accordance with local regulations (see section 20). 
Any or part of data source may be recorded in the CRF (see section 12) for study purpose. 
 
 


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16.4 Access to source data 
By signing Informed consent Form, the subject agrees that investigators, monitors and all mandated staff have access 
to his/her personal data to ensure control and quality of data recorded for corresponding study purposes only. 
By agreeing to participate in this clinical trial, the investigator agrees to give full and direct access to sponsor, or 
mandated staff or health authorities to source data for each patient enrolled, in the course of trial related monitoring, 
audits, IRB/IEC review and regulatory inspection. 
Subject may accede to his/her personal data on written request, for information or corrective purpose. 
 
16.5 Source data confidentiality 
Investigators and any study team member who have patient data access are subject to professional secrecy. 
Source data recorded will be treated on an anonymous way. For this purpose, complete patient first name and last 
name will not appear in any study record. Data will be related to subject identified by a single number (see section 7.3 
for assignment to subject number). 
In countries where it is authorized by local regulations, patients may also be identified with initials (first two letters 
from last name followed by first letter from first name). 
In accordance with legal requirements, anyone having direct access to source data must respect data confidentiality 
and follow any specific procedure to warrant subject anonymity on documents that could be forwarded to the sponsor. 
 
16.6 Source data electronic management 
Data from subjects enrolled will be encrypted so as to warrant subject anonymity, in accordance with laws regarding 
electronic data treatment. 


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17. Duration and termination of trial 
 
17.1  Trial duration 
Trial assessment will last 24 months for each patient. 
Patient treatment will consist in successive 28-days blocks of low intensive chemotherapy (number of blocks depends 
on treatment response). 
Investigational product is given/ provided during the whole period the patient is under low intensive chemotherapy. 
Recruitment period planed: 3 years 
Expected start date: Q1 2013  
Expected completion date: Q1 2018 
 
17.2  Trial location 
This trial will involve European Health Care Centers. 
The sites will be chosen according to their experience in conducting clinical trial and handling patients with AML. 
Additional countries could be opened if the medical practice allows the protocol to be followed. 
 
17.3  Trial termination 
Trial termination is defined as last patient last visit. 
The Sponsor or the Investigator may decide to stop the trial or part of the trial at any time. In this case agreement on 
procedures to be followed must be obtained.  
If a trial is prematurely terminated or suspended please refer also to section 11.5. 
 


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18. Protocol deviations 
Protocol deviations should not occur. If deviations occur, the Investigator must inform the Monitor, for implications of 
the deviation review and discussion. Any deviation must be documented, stating the reason and date, the action taken, 
and the impact for the subject and/or the trial. The documentation must be kept in Investigator Study File and the 
Sponsor File, and will be treated as per sponsor procedure. 
 
19. Audits and Inspections 
Data obtained in this trial as well as all or part of trial process may be audited or inspected by an independent qualified 
person mandated by ERYTECH Pharma or the Competent Authority. 
 
20. Retention of clinical trial documentation 
During the study, the Investigator must maintain accurate and updated trial records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. 
Trial records concerned are patient clinical source documents and Investigator Study File with required documents. 
Regarding patient clinical source documents, subject notes must be kept for the maximum time period permitted by 
the hospital, institution or private practice. Other source documents, copies of patients CRF and the Investigator’s 
Trial File must be retained for at least 15 years after study completion or longer in accordance with local regulations. 
If the Investigator cannot guarantee this archiving requirement for any or all the documents at the investigational site, 
arrangements must be made between the Investigator and ERYTECH Pharma, to store these in a secure archive 
facility outside the site; they can therefore be returned to the Investigator in the event of a regulatory audit. 
The Investigator should not destroy any documents without prior permission from ERYTECH Pharma, including 
when the 15-year archiving period is over. 
In case the documentation should be relocated, or if investigator is to be retired, ERYTECH Pharma should be notified 
regarding new location of the files or new responsible person for archiving. 
 
ERYTECH Pharma, as the owner of the study data, will maintain the documentation pertaining to the trial as long as 
the product is on the market and for a minimum of 15 years after the trial completion, or in accordance with national 
regulations, if they require a longer retention period. 
 


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21. Responsibilities 
The Investigator is accountable for the conduct of the trial at his/her site. If any responsibility is delegated, the 
Investigator should maintain a list of appropriate qualified persons to whom he/she has delegated relevant trial related 
tasks. 
 
21.1  Trial execution 
ERYTECH Pharma is responsible for trial execution. 
Some responsibility may be transferred at a later stage. If applicable, the transfer of responsibility will be documented. 
 
21.2  Central laboratory 
Regarding analyses performed in Central Laboratories, please see details in Appendix 3: Samples preparation for 
centralized analyses). The conditions for preparation, storage and shipment of blood samples from the sites to the Central 
Laboratory will be detailed in a “Laboratory Manual” that will be provided to all the sites before trial starting. 
 
22. Financing and Insurance 
In accordance with the national law into force, a contract of insurance is subscribed by the Sponsor near the company 
HDI GERLING Industrie Versicherungs-AG, Riethorst 2 – D 30659 Hannover, (contract no 01005345/14058). 
 
23. Trial report and publication policy 
All information supplied by ERYTECH Pharma in connection with this trial shall remain the sole property of 
ERYTECH Pharma and is to be considered as confidential information. No confidential information shall be disclosed 
to others without prior written consent from ERYTECH Pharma and shall not be used except in the performance of 
this trial. 
 
A Final Study Report will be prepared under the responsibility and supervision of ERYTECH Pharma. It will be 
signed by the Principal Investigator, indicating agreement with the analyses, results and conclusions of the report. 
 
The information obtained during this trial is considered confidential and will be used by ERYTECH Pharma for 
registration purposes and for the clinical development of the drug. 
 
The information obtained during this trial may be made available to other physicians who are conducting other clinical 
trials with the drug, if deemed necessary by ERYTECH Pharma. 
 
No permission to publish will be granted to any of the providers involved in the trial. 


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24. Quality assurance statement 
 
This study will be conducted in compliance with the protocol, current GCP rules and the applicable regulatory 
requirements. 
Quality control will be carried out as per standard operating procedures in force by ERYTECH Pharma. 
 
The amended protocol has been audited by ERYTECH Pharma Quality Assurance Department. 
 
 
 
 
 
 
 
 
 
Cécile Lacroix 
ERYTECH Pharma 
Quality Assurance Manager 
 
 
Date 




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25. References 
 
Alpar H.O & Lewis, D. A. Therapeutic efficacy of asparaginase encapsulated in intact erythrocytes. Biochem 
Pharmacol 1985, 342: 257-261. 
Broome JD. L-asparaginase : discovery and development as tumor-inhibitory agent. Cancer treat. Rep. 1981; 65 
(suppl. 4): 111-4. 
Burnett AK, Milligan D, Prentice AG et al. A comparison of low-dose cytarabine and hydroxyurea with or without 
all-trans retinoic acid for acut myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit 
for intensive treatment. Cancer, 2007, 109(6):1114-1124. 
Capizzi RL, Davis R, Powell B, Cuttner J, Ellison RR, Cooper MR, Dillman R, Major WB, Dupre E, McIntyre OR. 
Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute 
myelogenous leukemia-a Cancer and Leukemia Group B Study. J Clin Oncol, 1988, 6(3): 499-508. 
Codegoni A.M.et al. Human monocytic leukemia expresses low levels of asparagine synthase and is potentially 
sensitive to L-asparaginase. Leukemia. 1995 9(2): 360-361. 
Domenech C. 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, 15358-15365. 
CRS Study No 016/09-05.AE : Validation of methods for the determination of Asparaginase activity in human plasma 
and blood, and for the determination of Asparagine, Aspartic Acide, Glutamine and Glutamic Acid in human plasma 
and human CSF samples 
Döhner H, estey EH, Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010; 
115(3):453-474. 
Dübbers A. et al. Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest 
activity. Br J Haematol. 2000, 109(2): 427-429 
Estey H, Döhner H Acute myeloid leukemia. Lancet, 2006;368:1894-1907. 
Hamidi M. et al. Applications of carrier erythrocytes in delivery of biopharmaceuticals. J Control Release. 2007; 
118(2):145-160. 
ELAM 02 2010 protocole multicentrique de traitement des leucemies aigues myeloblastique de l'enfant et de 
l’adolescent. Etude randomisée d’un traitement d’entretien par interleukine 2 - Département de la Recherche Clinique 
et du Développement (DRCD) pour l’AP HP 
GRASPALL GRAALL SA2 2008 (GRASPALL2007-04):An escalating dose Phase IIa study of L-Asparaginase encapsulated in 
erythrocytes (GRASPA) in association with polychemotherapy during induction phase for treatment of elderly patients with Acute 
Lymphoblastic Leukaemia (ALL), aged 55 years and over, with Philadelphia chromosome-negative (ALL Ph-) – ERYTECH 
Pharma - EHA ABSTRACT 17 june 2012  
GRASPALL 2005-01: Administration of allogenic erythrocyte-loaded L-asparaginase in cases of relapse of acute lymphoblastic 
leukaemia (ALL) – ERYTECH Pharma 
GRASPALL 2009-06: A multicenter, open, randomized, Phase II/III study, evaluating efficacy and safety of erythrocytes 
encapsulating L-asparaginase (GRASPA) versus reference L-asparaginase treatment in combination with standard 
polychemotherapy in patients with first recurrence of Philadelphia chromosome negative Acute Lymphoblastic Leukemia (ALL 
Ph-) in adults and children over 1 year of age – ERYTECH Pharma 
Horikoshi A. et al. Effect of L-asparaginase combined with vincristine and prednisolone on acute myeloblastic 
leukemia (M0) associated with non-Hodgkin lymphoma. Acta Haematol. 2009; 122(1):54-57. 
Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with 
acute myeloid leukemia or high risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer, 
2006;106(5):1090-1098.  
Kaspers G.J.L. et al. Cellular drug resistance in childhood acute myeloid leukemia: a mini-review with emphasis on 
cell culture assays. In Drug resistance in Leukemuia and Lymphoma III, edited by Kaspers et al. Kluwer Academic / 
Plenum Publishers, New York 1999. 415-421. 
Kawedia, J. D. and M. E. Rytting (2014). "Asparaginase in Acute Lymphoblastic Leukemia." Clin Lymphoma 
Myeloma Leuk 14S: S14-S17.Kitoh T. et al. Immunocytochemical analysis of asparagine synthetase protein of 
leukemia cells: indication for L-asparaginase treatment. Blood 1996, 88(suppl 1):86a. 


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Konecna P. et al. Monitoring the asparaginase activity and asparagine levels in children with acute leukemia treated 
with on different asparaginase preparations. Scripta Medica. 2004, 77 (2):55-62 
Kravtzoff R. et al. Tolerance Evaluation of L-asparaginase loaded in erythrocytes. Eur. J. Pharmacol. (1996a) 51: 221-
225. 
Kravtzoff R. et al. Improved pharmacodynamics of L-asparaginase loaded in human erythrocytes. Eur J. Clin. 
Pharmacol. (1996b) 49: 465-70. 
Kumar, K., J. Kaur, S. Walia, T. Pathak and D. Aggarwal (2014). "L-asparaginase: an effective agent in the treatment 
of acute lymphoblastic leukemia." Leuk Lymphoma 55(2): 256-262. 
.Kurtzberg. Asparaginase. 2007 Chap 51, pp.699-705. www.cancer.org 
Lagadinou DE, Zoumbos CN and spyridonidis A. Challenges in treating older pateint with Acute myeloid leukemia. J 
Oncol, 2010, 2010:943823. 
Kwon Y.M. et al. L-Asparaginase encapsulated intact erythrocytes for treatment of acute lymphoblastic leukemia 
(ALL). J Control Release 2009, 1393: 182-189. 
Laguerre M. Thèse : Création de bioréacteurs par internalisation d’enzymes dans les globules rouges humains et 
murins. Université de Tours et Laboratoire de biopharmacologie transfusionnelle CRTS-CNRS de Tours. 1990. 
Millan CG, Marinero ML, Castaneda AZ, Lanao JM. Drug, enzyme and peptide delivery using erythrocytes as 
carriers. J Control Release. 2004 Feb 20;95(1):27-49. 
Naqi A., Deloach J.R., Andrews K., Satterfield W. and Keeling M. Determination of parameters for enzyme therapy 
using L-asparaginase entrapped in canine erythrocytes. Biotechnology and applied biochemistry; 1988; 10 : 365-72. 
O’Brien, P.C. Fleming, T.R. (1979). A multiple testing procedure for clinical trials. Statistical Methodology in the 
Pharmaceutical Sciences, 291-311 
Okada S. et al. In vitro efficacy of l-asparaginase in childhood acute myeloid leukaemia. Br J Haematol, 2003, 123(5): 
802-809. 
Petti M.C. et al. High-dose Ara-C (HiDAC) plus asparaginase in elderly patients with acute non-lymphocytic 
leukemia: a pilot multicentric study by the Italian Cooperative Group GIMEMA. Eur J Haematol. 1989, 42(1):24-31. 
Reinert R.B. et al. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase J 
Biol Chem. 2006 ; 281(42): 31222-31233 
Roboz GJ. Novel approaches to the treatment of acute myeloid leukemia.Hematology Am Soc Hematol Educ 
Program. 2011;2011:43-50. 
Rubnitz J.E. et al. Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. 
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Stams, W. A., M. L. den Boer, A. Holleman, I. M. Appel, H. B. Beverloo, E. R. van Wering, G. E. Janka-Schaub, W. 
E. Evans and R. Pieters (2005). "Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-
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Chemother. Pharmacol.; 1993 (32) : 129-33. 
Takahashi H, Koh K, Kato M, Kishimoto H, Oguma E, Hanada R. Acute myeloid leukemia with mediastinal myeloid 
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Tilly B. Thèse : L’asparaginase dans le traitement des leucémies aiguë lymphoblastique de l’enfant. Thèse de docteur 
en pharmacie, Nantes 2003. 
Updike S.J. Entrapment of L-asparaginase in erythrocytes. A strategy to improve treatment of acute lymphoblastic 
leukemia. Bibl Haematol. 1985;(51):65-74. 
Wells R.J. et al. Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid 
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Zwaan C.M. et al. Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB 
types and comparison with acute lymphoblastic leukemia. Blood. 2000 15; 96(8): 2879-2886. 
 
 
 
 


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26. Appendices 
 
Appendix 1: SPC Cytarabine Hospira UK (ENG) and SPC Aracytine (FRA) 
Appendix 2: Inclusion and Randomization Process 
Appendix 3: Samples preparation for centralized analyses 
Appendix 4: EORTC QLQ-C30 version 3 Quality of life questionnaire  
Appendix 5: Prescription of GRASPA 
Appendix 6: GRASPA Shipment and Administration Form with GRASPA guidelines 
Appendix 7: SAE report form  
Appendix 8: Procedure to follow in case of an immediate event linked to red blood cells transfusion 
Appendix 9: Declaration of Helsinki 
Appendix 10: Patient information sheet - Informed Consent Form 
Appendix 11: History of changes 
 


 
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Appendix 1: Summary of Product Characteristics: SPC Cytarabine Hospira UK (ENG) and SPC Aracytine 
Pfizer (FRA) 
 


RÉSUMÉ DES CARACTÉRISTIQUES DU PRODUIT 
ANSM - Mis à jour le : 26/06/2015 
1. DENOMINATION DU MEDICAMENT 
ARACYTINE 100 mg, poudre et solvant pour solution injectable 
2. COMPOSITION QUALITATIVE ET QUANTITATIVE 
Composition de la poudre 
Cytarabine .................................................................................................................................. 100,00 
mg 
Pour un flacon de 100 mg de poudre. 
Pour la liste complète des excipients, voir rubrique 6.1. 
3. FORME PHARMACEUTIQUE 
Poudre et solvant pour solution injectable. 
4. DONNEES CLINIQUES 
4.1. Indications thérapeutiques 
• Leucémies aiguës myéloblastiques de l'adulte et de l'enfant. 
• Leucémies aiguës lymphoblastiques et localisation méningée de la maladie. 
• Transformation aiguë des leucémies myéloïdes chroniques et des myélodysplasies. 
4.2. Posologie et mode d'administration 
La posologie et le mode d’administration varient selon le protocole d’associations thérapeutiques 
utilisées.  
Posologie 
Différents schémas thérapeutiques utilisant la cytarabine ont été proposés : 
Leucémies aiguës myéloblastiques et transformation aiguë des leucémies myéloïdes 
chroniques et des myélodysplasies :  
Les posologies données en mg/m2 de surface corporelle sont utilisables chez l’adulte et l’enfant.  
Induction : 
Chimiothérapie d’association (toujours avec une anthracycline, parfois avec d’autres anti-
néoplasiques) :  
100 mg/m2 /j pendant 7 à 10 jours 
Ou  
200 mg/m2 /j pendant 5 à 7 jours. 
Une deuxième cure peut être administrée en cas d’échec de la première. 
Entretien et consolidation : 
Une consolidation peut être faite avec le même protocole de chimiothérapie que celui qui a permis 
d’obtenir la rémission. La cytarabine peut être administrée à des doses inférieures, seule ou en 
association avec d’autres antinéoplasiques, par cures espacées de 4 à 6 semaines lors des 
traitements d’entretien. 
Dans les traitements d’entretien, la voie sous-cutanée peut être utilisée : 20 mg/m2 /jour, administrés 
en 1 ou 2 injections pendant 5 à 10 jours.  
Leucémies aiguës lymphoblastiques : 
Traitement d’induction et d’entretien : 


Les protocoles utilisés sont assez voisins de ceux du traitement des leucémies aiguës myéloïdes. 
Ils utilisent des associations comprenant principalement : cytarabine-vincristine-prednisolone. 
Traitement des localisations méningées par voie intrathécale : 
A titre préventif, on propose la cytarabine : 20 mg/m2, parfois associée au méthotrexate et à 
l’hydrocortisone. 
Pour l’enfant de moins de 3 ans, la dose de cytarabine est de 30 mg/m2. 
A titre curatif, on utilise habituellement la dose de 20 mg/m2 une à deux fois par semaine.  
L’alcool benzylique ne doit pas être utilisé pour la reconstitution de la solution dans le cas d’une 
administration intrathécale.  
ADAPTATION POSOLOGIQUE : 
• La fréquence des cures est fonction du résultat thérapeutique et de la toxicité hématologique et extra-
hématologique. 
• Des contrôles répétés, sanguins et médullaires devront être effectués, surtout en début de traitement. 
Les fonctions hépatiques et rénales seront également surveillées. 
• L’adaptation de la posologie se fait en fonction des résultats des examens sanguins et médullaires 
(myélogramme).  
• Habituellement le traitement est interrompu si : 
o Les plaquettes sont inférieures à 50 000/mm3, 
o Les polynucléaires neutrophiles sont inférieurs à 1 000/mm3.  
• La reprise du traitement se fait dès que les chiffres des numérations le permettent et dès que les 
cellules blastiques réapparaissent dans le sang ou dans la moelle. Le fait d’attendre la normalisation de 
la numération pour reprendre le traitement est préjudiciable au contrôle ultérieur de la maladie. 
• Les posologies seront aussi modifiées en cas de phénomènes toxiques autres qu’hématologiques et 
en cas d’association à d’autres agents chimiothérapiques. 
MODE D’ADMINISTRATION 
La cytarabine peut être utilisée par différentes voies d'administration. 
• Voie intraveineuse en injection directe ou en perfusion continue : lorsque la cytarabine est administrée 
rapidement, les doses injectées peuvent être plus importantes que celles qui le seraient par perfusion 
lente; ceci est dû à l'inactivation rapide du produit et à sa durée de contact très courte avec les cellules 
néoplasiques et normales sensibles. 
• Voie sous-cutanée : la cytarabine est particulièrement bien tolérée. On observe très rarement douleur 
et inflammation au point d'injection. 
• Voie intrathécale : la cytarabine est utilisée dans le traitement préventif et curatif des localisations 
méningées des leucémies aiguës lymphoblastiques de l'enfant. 
En cas d'utilisation par voie intrathécale, la reconstitution se fait avec du L.C.R. autologue ou avec une 
solution de chlorure de sodium isotonique ; l'utilisation doit être immédiate.  
L’alcool benzylique ne doit pas être utilisé pour la reconstitution de la solution dans le cas d’une 
administration intrathécale.  
Quelle que soit la voie d'administration, l'expérience clinique acquise suggère que les résultats 
obtenus par la cytarabine dépendent étroitement des modifications posologiques de façon à détruire 
le plus de cellules blastiques avec le moins d'effet toxique. Une association polychimiothérapique 
entraîne des modifications de posologie pour chacun des constituants du protocole. 
Modalités de manipulation : 


La préparation des solutions injectables de cytotoxiques doit être obligatoirement réalisée par un 
personnel spécialisé et entraîné ayant une connaissance des médicaments utilisés, dans des 
conditions assurant la protection de l’environnement et surtout la protection du personnel qui 
manipule. Elle nécessite un local de préparation réservé à cet usage. Il est interdit de fumer, de 
manger, de boire dans ce local. Les manipulateurs doivent disposer d’un ensemble de matériel 
approprié à la manipulation, notamment blouses à manches longues, masques de protection, calot, 
lunettes de protection, gants à usage unique stériles, champs de protection du plan de travail, 
conteneurs et sacs de collecte des déchets. Les excréta et les vomissures doivent être manipulés 
avec précaution. Les femmes enceintes doivent être averties et éviter la manipulation des 
cytotoxiques. Tout contenant cassé doit être traité avec les mêmes précautions et considéré comme 
un déchet contaminé. L’élimination des déchets contaminés se fait par incinération dans des 
conteneurs rigides étiquetés à cet effet.  
Ces dispositions peuvent être envisagées dans le cadre du réseau de cancérologie (circulaire 
DGS/DH/98 n°98/188 du 24 mars 1998) en collaboration avec toute structure adaptée et remplissant 
les conditions requises.  
Instruction pour une ouverture correcte des ampoules :  
Important : l’ampoule est prélimée en un point de l’étranglement. La tâche colorée sur l’olive permet 
l’orientation de celle-ci (figure 1). Saisir l’ampoule, le point coloré dirigé vers soi, l’ampoule s’ouvre 
facilement en plaçant le pouce sur le point coloré et en exerçant une légère flexion du haut vers le bas 
(figure 2). Ne pas ouvrir l’ampoule au niveau du trait. 
 
4.3. Contre-indications 
• Hypersensibilité à la cytarabine. 
• Celles communes à toute thérapeutique cytotoxique. 
• Aplasie médullaire préexistante. 
• Encéphalopathies dégénératives et toxiques, notamment après emploi du méthotrexate ou de 
traitement par les radiations ionisantes. 
• Patients avec une infection méningée évolutive. 
• Allaitement (voir rubrique 4.6). 
• Association avec le vaccin antiamarile (fièvre jaune) (voir rubrique 4.5). 
• Le solvant à base d’alcool benzylique ne doit pas être utilisé pour la reconstitution de la solution dans 
le cas d’une administration intrathécale. Dans les autres cas, la solution reconstituée avec ce 
solvant est contre-indiquée chez les nouveau-nés. 
4.4. Mises en garde spéciales et précautions d'emploi 


La cytarabine doit être administrée sous stricte surveillance médicale en particulier au cours du 
traitement d'induction : on pratiquera de façon répétée une numération de la formule sanguine, 
examens médullaires (myélogramme) afin d'apprécier les résultats thérapeutiques et la toxicité 
hématologique du traitement. 
La cytarabine est un puissant myélosuppresseur : Elle peut entrainer une hypoplasie ou une aplasie 
médullaire dont la sévérité dépend de la dose administrée et du schéma thérapeutique utilisé. 
Insuffisance médullaire préexistante : la cytarabine peut être administrée en cas de nécessité absolue. 
Le traitement doit dans ce cas être initié avec prudence. 
Les patients recevant ce traitement doivent être placés sous surveillance médicale stricte. 
Pendant la phase d’induction une numération des globules blancs et des plaquettes doit être réalisée 
quotidiennement. Des examens médullaires doivent être réalisés fréquemment une fois que les 
cellules blastiques ont disparu du sang périphérique. 
Il conviendra de considérer la possibilité de suspendre ou de modifier le traitement lorsque 
l’insuffisance médullaire médicamenteuse entraine une réduction du nombre de plaquettes à moins de 
50 000 ou de polynucléaires neutrophiles à moins de 1000/mm3. Il se peut que le nombre d’éléments 
figurés continue à diminuer après l’arrêt du traitement pour atteindre les valeurs les plus basses après 
une période sans traitement de 12 à 24 jours. Si cela est indiqué, la reprise du traitement peut se faire 
lorsque des signes nets de réparation médullaire apparaissent. 
Un équipement spécial doit être disponible afin de pouvoir gérer les complications, potentiellement 
fatales de l’insuffisance médullaire (infections résultant d’une granulopénie et autre diminution des 
défenses de l’organisme, hémorragies secondaires à la thrombopénie). 
On surveillera les fonctions hépatiques et rénales. Les patients ayant une insuffisance hépatique ou 
rénale présentent un risque plus important de toxicité sur le système nerveux central après 
administration de fortes doses de cytarabine. Il faudra donc utiliser le produit avec précaution en 
réduisant les doses chez les patients atteints d’insuffisance hépatique et rénale.  
Syndrome de lyse tumorale : Comme toute chimiothérapie antileucémique, la cytarabine induit une 
hyperuricémie secondaire à la lyse cellulaire : on surveillera le taux d'acide urique pendant le 
traitement et on préviendra l'hyperuricémie. 
Les patients recevant des doses élevées de cytarabine doivent être suivis afin de détecter des signes 
de neuropathie, car il peut être nécessaire de modifier le schéma d’administration et les doses pour 
éviter des troubles neurologiques irréversibles (voir rubrique. 4.8). 
La vaccination avec un vaccin vivant doit être évitée chez les patients recevant de la cytarabine (voir 
rubrique 4.5). 
L’association de ce médicament est déconseillée avec la phénytoïne (et par extrapolation la 
fosphénytoïne) (voir rubrique 4.5). 
Femmes en âge de procréer traitées (voir rubrique 4.6) :  
Les femmes en âge de procréer traitées par la cytarabine doivent utiliser un moyen de contraception 
efficace au cours du traitement et un mois après la fin du traitement.  
Hommes traités (voir rubrique 4.6) :  
Il est souhaitable que les hommes traités par la cytarabine ou leur partenaire utilisent une méthode 
contraceptive de manière à éviter une conception pendant le traitement du patient et dans les 3 mois 
suivant la fin du traitement.  
Les patients traités doivent être avertis de la nécessité de consulter en vue d’une conservation de 
sperme préalablement au traitement, en raison de la possibilité d’atteinte de la fertilité. 
Une ampoule de solvant de 5 ml contient 47,25 mg d’alcool benzylique. 
Ce solvant ne doit pas être utilisé pour la reconstitution de la solution dans le cas d’une administration 
intrathécale.  
Dans les autres cas, la solution reconstituée avec ce solvant peut provoquer des réactions toxiques et 
des réactions de type anaphylactoïde chez les nourrissons et les enfants jusqu’à 3 ans. 
Voie intrathécale : La cytarabine, lorsqu'elle est administrée par voie intrathécale, peut être associée à 
des nausées, des vomissements et à une grave toxicité du système nerveux central qui peut aboutir à 
un déficit permanent, incluant une cécité et d'autres toxicités neurologiques.  
Il est recommandé de ne pas dépasser la dose individuelle validée et d’être très prudent chez les 
patients ayant déjà reçu un traitement radiothérapique ou intrathécal. Voir rubrique 4.8. 


4.5. Interactions avec d'autres médicaments et autres formes d'interactions 
Interactions médicamenteuses : 
En raison de l’augmentation du risque thrombotique lors des affections tumorales, le recours à un 
traitement anticoagulant est fréquent. La grande variabilité de la coagulabilité au cours de ces 
affections, à laquelle s’ajoute l’éventualité d’une interaction entre les anticoagulants oraux et la 
chimiothérapie anticancéreuse, impose, s’il est décidé de traiter le patient par anticoagulants oraux, 
d’augmenter la fréquence des contrôles de l’INR (acénocoumarol, fluindione, phénindione, tioclomarol, 
warfarine). 
Interactions communes à tous les cytotoxiques :  
Association contre-indiquée (voir rubrique 4.3) :  
+ Vaccin antiamarile (fièvre jaune) : risque de maladie vaccinale généralisée mortelle.  
Associations déconseillées (voir rubrique 4.4) : 
+ Phénytoïne (et, par extrapolation, fosphénytoïne) : risque de survenue de convulsions par 
diminution de l’absorption digestive de la seule phénytoïne par le cytotoxique, ou bien risque de 
majoration de la toxicité ou de perte d’efficacité du cytotoxique par augmentation de son métabolisme 
hépatique par la phénytoïne ou la fosphénytoïne.  
+ Vaccins vivants atténués (sauf antiamarile) : risque de maladie vaccinale généralisée 
éventuellement mortelle. Ce risque est majoré chez les sujets déjà immunodéprimés par la 
maladie sous-jacente. 
Utiliser un vaccin inactivé lorsqu’il existe (poliomyélite).  
Associations faisant l'objet de précautions d’emploi : 
+ Antivitamines K : 
Augmentation du risque thrombotique et hémorragique au cours des affections tumorales. De 
surcroît, possible interaction entre les AVK et la chimiothérapie. 
Contrôle plus fréquent de l'INR. 
Association à prendre en compte : 
+ Immunosuppresseurs : immunodépression excessive avec risque de syndrome lymphoprolifératif. 
4.6. Grossesse et allaitement 
Grossesse  
Les femmes en âge de procréer traitées par la cytarabine doivent utiliser un moyen de contraception 
efficace au cours du traitement et un mois après la fin du traitement.  
Compte tenu des données disponibles, la cytarabine ne sera administrée pendant la grossesse que si 
la pathologie met en jeu le pronostic vital de la mère. En effet, les études sur les fonctions de 7/7 
reproduction réalisées chez différentes espèces animales ont montré que la cytarabine est 
embryotoxique et a des effets tératogènes principalement sur le cerveau et le squelette.  
Quelques cas de malformations congénitales des membres et de l’oreille externe ont été rapportés 
lors de l’exposition au premier trimestre de grossesse. En cas d’exposition au premier trimestre, une 
surveillance échographique orientée est donc recommandée.  
Des cas de prématurité ou de retard de croissance intra-utérin ont été signalés.  
A la naissance, la survenue d’ictère, d’insuffisance médullaire et d’hyperéosinophilie transitoires a été 
rapportée. Une surveillance biologique est donc indiquée dans les premières semaines de vie.  
Allaitement  


L’excrétion de la cytarabine dans le lait maternel n’est pas connue. En raison des effets indésirables 
potentiellement graves pouvant être entrainés par la cytarabine chez les enfants allaités, la prise de 
cytarabine doit être contre-indiquée au cours de l’allaitement. 
Fertilité  
La cytarabine est mutagène et peut induire une atteinte chromosomique des spermatozoïdes.  
Les patients traités doivent être avertis de la nécessité de consulter en vue d’une conservation de 
sperme préalablement au traitement, en raison de la possibilité d’atteinte de la fertilité.  
Il est souhaitable que les hommes traités par la cytarabine ou leur partenaire utilisent une méthode 
contraceptive de manière à éviter une conception pendant le traitement du patient et dans les 3 mois 
suivant la fin du traitement. 
4.7. Effets sur l'aptitude à conduire des véhicules et à utiliser des machines 
Les effets sur l’aptitude à conduire des véhicules et à utiliser des machines n’ont pas été étudiés. 
Cependant, sur la base des effets indésirables notifiés, les patients doivent être avertis de ne pas 
conduire et de ne pas utiliser de machine sans l’avis d’un professionnel de santé. 
4.8. Effets indésirables 
Investigations :  
Dans de rares cas, une hyperuricémie secondaire à la lyse blastique peut être induite par le traitement 
à la cytarabine; il sera donc nécessaire de surveiller le taux d'acide urique dans le sang et les urines. 
Affections cardiaques :  
Péricardite.  
Des cas de cardiomyopathie pouvant être fatale ont été rapportés suite à l’utilisation expérimentale 
d’un traitement associant de fortes doses de cytarabine et du cyclophosphamide utilisé dans le cadre 
de transplantation médullaire. 
Affections hématologiques et du système lymphatique : 
La cytarabine est un agent antinéoplasique qui entraîne une myélodépression. Son administration 
entraîne donc une aplasie ou une hypoplasie médullaire responsable d'anémie, granulopénie, 
thrombopénie, mégaloblastose et chute du taux de réticulocytes. 
La sévérité de l'aplasie dépend de la dose administrée et du schéma thérapeutique utilisé. En relation 
avec l'aplasie, des complications hémorragiques ou infectieuses graves peuvent venir compliquer 
secondairement la cure de chimiothérapie. 
Des infections virales, bactériennes, fongiques, parasitaires et saprophytiques peuvent être associées 
à l’utilisation de la cytarabine seule ou en association avec d’autres médicaments 
immunosuppresseurs affectant l’immunité cellulaire ou humorale. Ces infections peuvent être légères, 
mais elles peuvent aussi être graves et parfois fatales. 
Affections du système nerveux : 
Toxicité neurocérébelleuse pour de fortes doses. 
Atteintes cérébelleuses sous forme, au minimum, de dysarthrie et d’un nystagmus, au maximum d’une 
grande ataxie qui peut être d’apparition retardée et être définitive. Des épisodes de comas, des 
troubles du comportement et des neuropathies périphériques sensitives et motrices, ont aussi été 
rapportés. Des cas graves voire létaux ont été observés chez des malades ayant déjà reçu 
antérieurement d’autres traitements sur le système nerveux central (irradiation encéphalique) : on 
recommande de ne pas dépasser la dose individuelle validée et on sera très prudent chez les patients 
ayant déjà reçu un traitement radiothérapique ou intrathécal. 
La toxicité neurologique semble en rapport avec un débit rapide d’administration. 
Affections oculaires :  
Des atteintes réversibles de la cornée et des conjonctivites hémorragiques ont été décrites après 
utilisation de fortes doses de cytarabine. Ces phénomènes peuvent être prévenus ou diminués par 
l'instillation d'un collyre contenant des corticoïdes. 
Affections respiratoires, thoraciques et médiastinales :  
Une toxicité pulmonaire grave, parfois fatale, des syndromes de détresse respiratoire et des œdèmes 
pulmonaires ont été rapportés après utilisation de fortes doses de cytarabine. 


De rares cas de pneumopathies interstitielles ont été rapportés chez des patients traités avec des 
doses intermédiaires de cytarabine associée ou non à d’autres agents de chimiothérapie, sans que 
cela ait pu être associé de façon claire à la cytarabine. 
Affections gastro-intestinales :  
Nausées, vomissements, anorexie sont fréquents avec l’utilisation de la cytarabine, d’autre part risque 
de stomatite et de mucite. Les nausées et vomissements sont plus fréquents à la suite d’une perfusion 
rapide. Quelques rares cas d’ulcérations gastro-intestinales sévères avec perforation et péritonite, 
nécrose intestinale ont été décrits. 
Des cas de pancréatite aigüe ont été rapportés chez des patients traités avec de la cytarabine en 
association avec d’autres médicaments. 
Affections des reins et des voies urinaires :  
Insuffisances rénales et rétentions urinaires. 
Affections de la peau et du tissu sous-cutané :  
Rashs cutanés ou dermites exfoliatives. 
Alopécie totale. 
Ulcérations cutanées. 
Troubles généraux et réactions au site d’administration :  
Thrombophlébites et cellulites au point d’injection. 
Poussées fébriles.  
Affections du système immunitaire : 
Dans de rares cas : Syndrome cytarabine qui se caractérise par élévation thermique, myalgies, 
douleurs osseuses accompagnées dans certains cas par des douleurs thoraciques, rashs 
maculopapuleux, conjonctivite et sensation de malaise général. Ce syndrome survient 6 à 12 heures 
après l'administration du produit. 
Son traitement et sa prévention répondent aux corticoïdes. 
Réactions anaphylactiques :  
Œdème allergique. 
Affections hépato-biliaires :  
Abcès hépatique et altération fonctionnelle hépatique avec élévation de la bilirubine. 
Ictère. 
Affections des organes de reproduction et du sein :  
Aménorrhée, azoospermie. 
Effets secondaires et toxicité de la voie intrathécale de la cytarabine : 
Les effets les plus fréquemment rapportés après administration par voie intrathécale sont des 
nausées, des vomissements et de la fièvre. Ces réactions sont légères. 
Des accidents de neurotoxicité graves dont des paraplégies ont été rapportés lors d’administrations 
intrathécales combinées avec du méthotrexate et des corticostéroïdes et lors d’association d’injection 
intrathécale avec une administration systémique de fortes doses de méthotrexate et de cytarabine. 
Des cas de leucoencéphalites nécrosantes avec ou sans convulsion ont été rapportés. Certains de 
ces patients ont aussi été traités par méthotrexate et/ou hydrocortisone par voie intrathécale et par 
irradiation encéphalique. 
Deux cas de cécité ont été décrits chez des sujets mis en rémission après polychimiothérapie 
intraveineuse et traitement préventif des greffes méningées avec cytarabine intrathécale et 
radiothérapie de l'encéphale. 
Déclaration des effets indésirables suspectés 
La déclaration des effets indésirables suspectés après autorisation du médicament est importante. 
Elle permet une surveillance continue du rapport bénéfice/risque du médicament. Les professionnels 
de santé déclarent tout effet indésirable suspecté via le système national de déclaration: Agence 
nationale de sécurité du médicament et des produits de santé (Ansm) et réseau des Centres 
Régionaux de Pharmacovigilance www.ansm.sante.fr. 
4.9. Surdosage 
Il n'existe pas d'antidote spécifique. La dose de 4,5 g/m2 en perfusion IV d'une heure toutes les 12 
heures en 12 doses provoque une toxicité du système nerveux central irréversible et létale. 
5. PROPRIETES PHARMACOLOGIQUES 
5.1. Propriétés pharmacodynamiques 


Classe pharmacothérapeutique : Agents Antinéoplasiques – Antimétabolites – Analogue de la 
pyrimidine  
Code ATC : L01BC01 
Antimétabolite spécifique de la phase S du cycle cellulaire (phase de division cellulaire). 
La cytotoxicité de la cytarabine dépend de son métabolite actif l'ARA-CTP qui incorporé à l'ADN en 
bloque la synthèse. La molécule d'ADN comprenant de l'ARA-CTP présente des anomalies 
structurales aboutissant à des perturbations du métabolisme cellulaire et altérant sa reproduction. La 
cytotoxicité passerait aussi par une inhibition de l'ADN polymérase et par une action sur le système 
des kinases. 
L'utilisation de hautes doses de cytarabine a montré qu'elles permettent de vaincre la résistance des 
cellules leucémiques ne répondant plus aux doses conventionnelles du produit. 
Plusieurs mécanismes semblent intervenir pour vaincre cette résistance : 
• augmentation de la quantité de substrat, 
• augmentation du pool intracellulaire d'ARA-CTP: il existe une corrélation positive entre la rétention 
intracellulaire d'ARA-CTP et le pourcentage de cellules en phase S. 
5.2. Propriétés pharmacocinétiques 
Pharmacocinétique de la cytarabine utilisée à haute dose : la pharmacocinétique de la cytarabine à 
haute dose (H.D ARA C) est bicompartimentale (modèle à 2 compartiments). 
Après administration intraveineuse d'une dose de 2 à 3 g/m² toutes les 12 heures en perfusion d'une 
heure sur 5 à 6 jours (10 à 12 doses), les concentrations plasmatiques en fin de perfusion sont de 
l'ordre de : 19,96 + 8,02 µg/ml et 35 + 2,8 µg/ml. Les concentrations plasmatiques décroissent à l'arrêt 
de la perfusion, selon une courbe biexponentielle. Six heures après la fin de la perfusion les 
concentrations obtenues correspondent à celles mesurées au "steady-state" après une perfusion 
continue de 24 heures de 100 mg / m² de cytarabine. 
Par comparaison avec la cinétique de la cytarabine à dose conventionnelle, les hautes doses 
produisent un pic 200 fois supérieur. 
De même le pic d'apparition d'ARA-U métabolite inactif est retardé avec les hautes doses puisqu'il 
n'apparaît qu'au bout de 15 minutes. 
Aux doses conventionnelles : 
• la T ½ est de l'ordre de quelques minutes (10 en moyenne), 
• la T ½ B est de l'ordre de quelques heures (1 à 3). 
Liaison aux protéines : 14 % de la cytarabine environ est lié aux protéines plasmatiques. 
Clairance rénale plus lente avec les hautes doses, de l'ordre de 232 + 33,4 ml/min/m². 
La cytarabine administrée par voie générale (IV) passe la barrière hémato-encéphalique : après une 
dose de 1 à 3 g/m² en perfusion de 1 à 3 heures, les concentrations dans le liquide céphalo-rachidien 
sont de l'ordre de 100 à 300 ng/ml. 
Le produit diffuse aussi dans la salive, la rate, les reins, le tube digestif, le thymus, la moelle osseuse 
et les larmes. On ne sait pas si la cytarabine passe dans le lait maternel. 
Activation de la cytarabine en ARA-CTP métabolite actif : 
Passage de la membrane cellulaire par une diffusion facilitée selon le gradient de concentration à 
haute concentration, par un mécanisme utilisant un transporteur à faible concentration. 
Activation enzymatique par phosphorylations successives : les enzymes qui activent l'ARA-C sont 
celles qui assurent l'activation du ribonucléoside naturel, la déoxycytidine. 
Deux enzymes jouent un rôle important : déoxycytidine kinase (ARA-C → ARA-CMP) et 
déoxycytidilate kinase (ARA-CMP → ARA-CDP). 
Le métabolite actif formé est l'ARA-CTP (arabinofuranosylcytosine tri-phosphate). La formation de 
l'ARA-CTP est une condition nécessaire à la cytotoxicité du produit mais n'est semble-t-il pas la seule 
: d'autres mécanismes interviennent. 
Catabolisme : 
La cytarabine est dégradée en ARA-U (arabinofuranosyl uracile), métabolite inactif, par la cytidine 
déaminase, enzyme présente dans de nombreux tissus mais principalement dans le foie et aussi dans 


les cellules leucémiques et la moelle. Cette enzyme est la cible de nombreux phénomènes d'activation 
ou d'inhibition. 
5.3. Données de sécurité préclinique 
Les études de toxicité chez la souris, le rat et le chien par voie orale, intraveineuse, intrapéritonéale, 
sous-cutanée et intra-articulaire ont montré que les organes cibles sont : le système hématopoïétique 
(mégaloblastose, réticulocytopénie, leucopénie, thrombocytopénie, et anémie), le cerveau (destruction 
des fonctions cérébrales et cérébelleuses) et dans une moindre mesure le foie (élévation modérée 
des enzymes hépatiques à insuffisance hépatique) et les reins (néphrotoxicité). La sévérité de la 
toxicité est dose-dépendante. Les autres effets observés sont : une toxicité pulmonaire, gastro-
intestinale (diarrhées, ulcérations), cardiomyopathie, des conjonctivites et des rashs cutanés. 
Aucune étude de fertilité n'a été réalisée, mais des effets sur la fertilité mâle ont été rapportés chez la 
souris. La cytarabine est embryotoxique et tératogène (cerveau et squelette) et est responsable d’une 
toxicité péri- et post-natale chez de nombreuses espèces. Administrée à des rats nouveau-nés à la 
dose de 4mg/kg/j, la cytarabine a provoqué des retards de développement.  
La cytarabine est mutagène et clastogène. 
Aucune étude de cancérogenèse n'a été réalisée. 
6. DONNEES PHARMACEUTIQUES 
6.1. Liste des excipients 
Solvant: alcool benzylique, eau pour préparation injectable. 
6.2. Incompatibilités 
Il existe une incompatibilité physico-chimique de la cytarabine avec l'héparine, l'insuline, le 5-fluoro-
uracile, la nafcilline, l'oxacilline, la pénicilline G, le solu-B (solution injectable de vitamines du groupe 
B, vitamines C et PP) et l'hémisuccinate de méthylprednisolone. 
ARACYTINE ne doit pas être mélangé avec d'autres médicaments à l'exception de ceux mentionnés 
dans la rubrique 6.6. S'assurer de la compatibilité avant de le mélanger ou de l'associer à toute autre 
substance. 
6.3. Durée de conservation 
Avant reconstitution : 5 ans 
Après reconstitution : voir rubrique 6.4. 
6.4. Précautions particulières de conservation 
Après reconstitution: 48 heures à température inférieure à 25°C 
6.5. Nature et contenu de l'emballage extérieur 
Poudre: 
Flacon en verre incolore de type I de 10 ml fermé par un bouchon en caoutchouc bromobutyle. 
Solvant: 
Ampoule en verre incolore de type I de 5 ml. 
6.6. Précautions particulières d’élimination et de manipulation 
Ne pas utiliser une solution dans laquelle un léger trouble serait apparu. 
7. TITULAIRE DE L’AUTORISATION DE MISE SUR LE MARCHE 
PFIZER HOLDING FRANCE 


23-25, AVENUE DU DOCTEUR LANNELONGUE 
75014 PARIS 
8. NUMERO(S) D’AUTORISATION DE MISE SUR LE MARCHE 
• 302 672-1 ou 34009 302 672 1 9 : flacon de 10 ml (verre incolore) de poudre pour solution injectable 
-ampoule de 5 ml (verre incolore) de solvant, boîte de 1. 
• 553 151-2 ou 34009 553 151 2 4 : flacon de 10 ml (verre incolore) de poudre pour solution injectable 
-ampoule de 5 ml (verre incolore) de solvant, boîte de 25. 
9. DATE DE PREMIERE AUTORISATION/DE RENOUVELLEMENT DE L’AUTORISATION 
[à compléter par le titulaire] 
10. DATE DE MISE A JOUR DU TEXTE 
[à compléter par le titulaire] 
11. DOSIMETRIE 
Sans objet. 
12. INSTRUCTIONS POUR LA PREPARATION DES RADIOPHARMACEUTIQUES 
Sans objet. 
CONDITIONS DE PRESCRIPTION ET DE DELIVRANCE 
Liste I. 
 


SPC Cytarabine - Hospira 
 
1. Name of the medicinal product 
Cytarabine 20 mg/ml Injection  
 
2. Qualitative and quantitative composition 
Each 1 ml contains 20 mg of cytarabine.  
Presentations  
100 mg/5 ml  
500 mg/25 ml  
1 g/50 ml  
Amount cytarabine present  100 mg  
500 mg  
1 g  
For excipients see 6.1.  
 
3. Pharmaceutical form 
Solution for injection.  
Clear, colourless solution.  
 
4. Clinical particulars 
4.1 Therapeutic indications 
Cytarabine may be used alone or in combination with other antineoplastic agents. It is indicated alone 
or in combination for induction of remission and/or maintainance in patients with acute myeloid 
leukaemia, acute non-lymphoblastic leukaemias, acute lymphoblastic leukaemias, acute lymphocytic 
leukaemia, erythroleukaemia, blast crises of chronic myeloid leukaemia, diffuse histiocytic lymphomas 
(non-hodgkin's lymphomas of high malignancy), meningeal leukaemia and meningeal neoplasms. 
Clinicians should refer to the current literature on combination therapy before initiating treatment.  
4.2 Posology and method of administration 
Cytarabine 20 mg/ml Injection is a ready to use solution and is suitable for intravenous, subcutaneous 
and intrathecal use.  
Cytarabine 20 mg/ml Injection can be diluted with Sterilised Water for Injections BP, Glucose 
Intravenous Infusion BP or Sodium Chloride Intravenous Infusion BP. Prepared infusions, in the 
recommended diluents should be used immediately. Alternatively, the diluted infusion fluids may be 
stored at 2-8°C, protected from light, but portions remaining unused after 24 hours must be discarded.  
Remission Induction: Adults 
Continuous Dosing: The usual dose in leukaemia, is 2 mg/kg by rapid intravenous injection daily for 
ten days. If after ten days neither therapeutic response not toxicity has been observed, the dose may 
be increased to 4 mg/kg until a therapeutic response or toxicity is evident. Daily blood counts should 
be taken. Almost all patients can be carried to toxicity with these doses.  
Alternatively, 0.5 to 1 mg/kg may be infused daily in 1-24 hours for ten days, and then at a rate of 2 
mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs. Results from one 
hour infusions have been satisfactory in the majority of patients.  
Intermittent dosing: Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, 
for five consecutive days This course of treatment can be repeated after an interval of 2 to 9 days, and 
repeated until the therapeutic response or toxicity is exhibited.  
Evidence of bone marrow inprovement has been reported to occur 7-64 days days after the beginning 
of therapy.  
In general, if a patient shows neither remission or toxicity after a trial period, then cautiously 
administered higher doses can be administered. Generally patients tolerate higher doses given by 
rapid intravenous injection rather than slow infusion.  
As a single agent for induction of remissions in patients with acute leukaemia, cytarabine has been 
given in doses of 200 mg/m2 by continuous intravenous infusion for five days at approximately 2 week 
intervals.  


Maintainance therapy: To maintain remission, doses of 1 mg/kg may be given intravenously or 
subcutaneously, once or twice weekly.  
Leukaemic Meningitis: Therapy for established meningitis employs a wide variety of dose regimens 
but a recommended total daily dose not exceeding 100 mg, alternating with methotrexate (given either 
systemically or intrathecally) is recommended. Cytarabine has been given intrathecally at doses of 10-
30 mg/m2 three times a week until cerebro-spinal fluid findings return to normal.  
Myelosuppression, anaemia and thrombocytopenia occur almost to all patients given daily infusions or 
injections. Myelosuppression is biphasic and nadirs at 7-9 and 15-24 days. Evidence of bone marrow 
improvement may be expected 7-64 (mean 28) days after the beginning of treatment.  
Children: Children appear to tolerate higher doses of cytarabine than adults, and where the range of 
doses is given, children should receive the higher dose.  
Elderly: No data is available to suggest that a change in dose is necessary in the elderly. However, 
the elderly patient is more susceptable to toxic reactions and therefore particular attention should be 
paid to drug induced leucopenia, thrombocytopenia and anaemia.  
4.3 Contraindications 
Known hypersensitivity to cytarabine or to any of the excipients.  
Anaemia, leucopenia and thrombocytopenia of non-malignant aetiology (e.g. bone marrow aplasia), 
unless the benefits outweigh the risk.  
Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with 
ionizing radiation.  
During pregnancy, cytarabine should only be administrated on strict indication, where the benefits of 
the drug to the mother should be weighed against possible hazards to the fetus.  
4.4 Special warnings and precautions for use 
Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with 
pre-existing drug-induced bone marrow suppression. Patients receiving the drug should be kept under 
close medical supervision. Leucocyte, and platelet counts should be performed frequently and daily 
during induction. Bone marrow examinations should be performed frequently after blasts have 
disappeared from the peripheral blood.  
Facilities should be available for management of complications, possibly fatal, of bone marrow 
suppression (infection resulting from granulocytopenia and other impaired body defenses, and 
hemorrhage secondary to thrombocytopenia).  
One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitiation has 
been reported. This occurred immediately after intravenous cytarabine was administered.  
Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity 
(different from that seen with conventional therapy regimens of cytarabine) has been reported 
following some experimental cytarabine dose schedule. These reactions include reversible corneal 
toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe 
gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis 
and liver abscess; and pulmonary oedema.  
Rarely, neurological effects such as quadriplegia and paralysis have been reported with cytosine 
arabinoside and have been predominantly associated with intrathecal administration. Isolated cases 
have also been reported with high intravenous doses during combination chemotherapeutic regimens.  
Delayed progressive ascending paralysis resulting in death has been reported in children with AML 
following intravenous cytarabine at conventional doses in combination with other drugs.  
Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar 
effect should be borne in mind when designing the long-term management of the patient.  
Cytarabine should only be used under the constant supervision by physicians experienced in therapy 
with cytotoxic agents. Hyperuricaemia secondary to rapid lysis of neoplastic cells may occur in 
patients receiving cytarabine; serum uric acid concentrations should be monitored. The physician 
should be prepared to use such supportive and pharmacological measures as may be necessary to 
control this problem.  
Periodic determinations of renal and hepatic functions and bone marrow should also be performed 
and the drug should be used with caution in patients with impaired hepatic function.  


However, dosage reduction does not appear to be necessary in patients with impaired renal function. 
The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should 
be used with caution and at a reduced dose when liver function is poor. Frequent platelet and 
leucocyte counts are mandatory. Therapy should be suspended or modified when drug-induced bone 
marrow depression results in a platelet count of less than 50,000 or a polymorphonuclear count of 
under 1000 per mm3. Counts may continue to fall after the therapy has been discontinued and may 
reach lowest values after five to seven days. Therapy may be restarted when the bone marrow 
appears to be recovering on successive bone marrow studies. Therapy should not wait until the 
normal blood values are obtained to be re-initiated. If treatment is not resumed before blood values 
return to normal, the disease can get out of control.  
When intravenous doses are given quickly, patients may become nauseated and may vomit for 
several hours afterwards. The problem tends to be less severe when infused.  
Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and 
thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in 
combination with other drugs. Patients have responded to nonoperative medical management.  
Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has been 
reported.  
Immunosuppressant effects/Increased susceptibility to infections  
Administration of live or live-attenuated vaccines in patients immunocompromised by 
chemotherapeutic agents including cytarabine, may result in serious or fatal infections. Vaccination 
with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines 
may be administered; however, the response to such vaccines may be diminished.  
High dose therapy  
Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, 
daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukemia.  
Patients treated with high doses of cytarabine should be observed for neuropathy since dose 
adjustments may be needed to avoid irreversible neurologic disorders.  
Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome, and pulmonary 
edema have occurred following high dose schedules with cytarabine therapy.  
Cases of cardiomyopathy with subsequent death have been reported following experimental high dose 
therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant 
preparation.  
The risk of CNS toxicity increases if high dose cytarabine is given in combination with another CNS 
toxic treatment such as radiation therapy or in patients who have previously had CNS treatment as 
chemotherapy intrathecally. When given intrathecally, as with any other intrathecal drug, care must be 
taken with radiotherapy given either during or after treatment; it is well recognised that this can 
exacerbate the toxicity of radiotherapy.  
The safety of the drug has not been established in infants.  
4.5 Interaction with other medicinal products and other forms of interaction 
Cardiac Glycosides 
GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination 
chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary 
damage to intestinal mucosa caused by the cytotoxic agents. Reversible decreases in steady-state 
plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-
acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone 
with or without cytarabine or procarbazine. Limited data suggest that the extent of GI absorption of 
digitoxin is not substantially affected by concomitant administration of combination chemotherapy 
regimens known to decrease absorption of digoxin. Steady-state plasma digitoxin concentrations did 
not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients 
receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients 
may be considered as an alternative.  
Anti-Infective Agents 


One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against 
Klebsiella pneumoniae. In patients on cytarabine being treated with gentamicin for a K.pneumoniae 
infection, a lack of a prompt therapeutic response may indicate the need for re-evaluation of 
antibacterial therapy.  
5-Fluorocytosine:  
5-Fluorocytosine should not be administered with cytarabine as the therapeutic efficacy of 5-
Fluorocytosine has been shown to be abolished during such therapy.  
Immunosuppressive Agents:  
Due to the immunosuppresive action of cytarabine, viral, bacterial, fungal, parasitic, or saprophytic 
infections, in any location in the body, may be associated with the use of cytarabine alone or in 
combination with other immunosuppressive agents following immunosuppressant doses that affect 
cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal.  
4.6 Pregnancy and lactation 
Use in Pregnancy 
Cytarabine is teratogenic in some animal species. It should not be used in pregnant women (especially 
during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh 
the potential risks. Women who are, or who may become, pregnant during treatment with cytarabine 
should be informed of the risks.  
Men and women have to use effective contraception during and up to 6 months after treatment.  
Use in Lactation 
It is not known if cytarabine or its metabolite is distributed into breast milk, and it should not be used in 
mothers who are breastfeeding.  
Fertility  
Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted. Gonadal 
suppression, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine therapy, 
especially in combination with alkylating agents. In general, these effects appear to be related to dose 
and length of therapy and may be irreversible. Given that cytarabine has a mutagenic potential which 
could induce chromosomal damage in the human spermatozoa, males undergoing cytarabine 
treatment and their partner should be advised to use a reliable contraceptive method.  
4.7 Effects on ability to drive and use machines 
No documented effect on ability to drive or operate machinery.  
Nevertheless, patients receiving chemotherapy may have an impaired ability to drive or operate 
machinery and should be warned of the possibility and advised to avoid such tasks if so affected.  
4.8 Undesirable effects 
The following adverse events have been reported in association with cytarabine therapy.  
Frequencies are defined using the following convention:  
Very common (≥1/10); common (≥1/100 to <1/10);  
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);  
very rare (<1/10,000), not known (cannot be estimated from the available data).  
Undesirable effects from cytarabine are dose-dependent. Most common are gastrointestinal 
undesirable effects. Cytarabine is toxic to the bone marrow, and causes haematological undesirable 
effects.  
Infections and infestations  
Uncommon: Sepsis (immunosuppression)  
Neoplasms benign,malignant and unspecified (including cysts and polyps) 
Uncommon: Lentigo  
Blood and lymphatic system disorders  
Common: Anaemia, megaloblastosis, leucopenia, thrombocytopenia.  
Not known: Reticulocytopenia.  
These appear to be more evident after high doses and continuous infusions; the severity depends on 
the dose of the drug and schedule of administration  
Metabolism and nutrition disorders  
Common: Anorexia, hyperuricaemia  


Nervous system disorders  
Common: At high doses cerebellar or cerebral influence with deterioration of the level of 
consciousness, dysarthria, nystagmus  
Uncommon: Headache, peripheral neuropathy and paraplegia at intrathecal administration  
Not known: Dizziness, neuritis or neural toxicity and pain, neurotoxicity rash  
Eye disorders  
Common: Reversible haemorrhagic conjunctivitis (photophobia, burning, visual disturbance, increased 
lacrimation), keratitis  
Not known: Conjunctivitis  
Cardiac disorders  
Uncommon: Pericarditis  
Very rare: Arrhythmia  
Respiratory, thoracic and mediastinal disorders  
Uncommon: Pneumonia, dyspnea, sore throat  
Gastrointestinal disorders  
Common: Dysphagia, abdominal pain, nausea, vomiting, diarrhea, oral/anal inflammation or ulceration  
Uncommon: Oesphagitis, oesophageal ulceration, pneumatosis cystoides intestinalis, necrotising 
colitis, peritonitis  
Not known: Gastrointestinal haemorrhage  
Nausea and vomiting may occur and are generally more frequent following rapid intravenous 
administration than with continuous intravenous infusion of the drug.  
Hepatobiliary disorders  
Common: Reversible effects on the liver with increased enzyme levels  
Not known: Hepatic dysfunction, jaundice  
Skin and subcutaneous tissue disorders  
Common: Reversible undesirable effects to the skin, such as erythema, bullous dermatitis, urticaria, 
vasculitis, alopecia,  
Uncommon: skin ulceration, pruritus, burning pain of palms and soles  
Very rare: Neutrophilic eccrine hidradenitis  
Not known: Rash, freckling, skin bleeding  
Musculoskeletal and connective tissue disorders  
Uncommon: Myalgia, joint pain  
Renal and urinary disorders  
Common: Renal impairment, urinary retention  
Not known: Renal dysfunction  
General disorders and administration site conditions  
Common: Fever, thrombophlebitis at the injection site, cellulitis at injection site  
Not known: Irritation or sepsis at the injection site, chest pain and mucosal bleeding  
A cytarabine syndrome (immunoallergic effect) is characterised by fever, myalgia, bone pain, 
occasionally chest pain, exanthema, maculopapular rash, conjunctivitis, nausea and malaise. It usually 
occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or 
preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, 
corticosteroids should be contemplated. If treatment is effective, therapy with cytarabine may be 
continued.  
Adverse effects due to high dose cytarabine treatment, other than those seen with 
conventional doses include: 
Blood and lymphatic system disorders: 
Hematological toxicity has been seen as profound pancytopenia which may last 15-25 days along with 
more severe bone marrow aplasia than that observed at conventional doses.  
Nervous system disorders:  
After treatment with high doses of cytarabine, symptoms of cerebral or cerebellar influence like 
personality changes, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, 
somnolence, dizziness, coma, convulsions, etc. appear in 8-37 % of treated patients. The incidence in 


elderly (>55 years) may be even higher. Other predisposing factors are impaired liver and renal 
function, previous CNS treatment (e.g., radiotherapy) and alcohol abuse. CNS disturbances are in the 
most cases reversible.  
The risk of CNS toxicity increases if the cytarabine treatment - given as high dose i.v.- is combined 
with another CNS toxic treatment such as radiation therapy or high dose of a cytotoxic agent  
Eye disorders: 
Reversible corneal lesion and haemorrhagic conjunctivitis have been described. These phenomena 
can be prevented or decreased by installation of corticosteroid eye drops.  
Gastrointestinal disorders: 
Especially in treatment with high doses of cytarabine, more severe reactions may appear in addition to 
common symptoms. Intestinal perforation or necrosis with ileus and peritonitis have been reported. 
Pancreatitis has also been observed after high-dose therapy.  
Hepatobiliary disorders: 
Liver abscesses, hepatomegaly and Budd-Chiari-syndrome (hepatic venous thrombosis) have been 
observed after high-dose therapy.  
Respiratory, thoracic and mediastinal disorders:  
Clinical signs as present in pulmonary oedema/ARDS may develop, particularly in high-dose therapy. 
The reaction is probably caused by an alveolar capillary injury. It is difficult to make an assessment of 
frequencies (stated as 10-26 % in different publications), since the patients usually have been in 
relapse where other factors may contribute to this reaction.  
Reproductive system and breast disorders 
Amenorrhoea and azoospermia.  
Others: 
Following cytarabine therapy, cardiomyopathy and rhabdomyolysis have been reported.  
The gastrointestinal undesirable effects are reduced if cytarabine is administered as infusion. Local 
glucocorticoids are recommended as prophylaxis of haemorrhagic conjunctivitis.  
One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has 
been reported (see section 4.4 Special warnings and precautions for use).  
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via:  
United Kingdom 
Yellow Card Scheme  
Website: www.mhra.gov.uk/yellowcard  
4.9 Overdose 
There is no specific antidote for cytarabine overdose. Cessation of therapy followed by management 
of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as 
required. Twelve doses of 4.5 g/m2 by IV infusion over one hour every 12 hours induces irreversible 
and fatal central nervous system toxicity.  
Cytarabine may be removed by haemodialysis.  
 
5. Pharmacological properties 
5.1 Pharmacodynamic properties 
Cytarabine (ARA-C) is metabolised in vivo to ARA-CTP phosphorylated compound. This competitively 
inhibits DNA polymerase and may also inhibit certain acid kinase enzymes. Primarily the drug acts as 
a false nucleoside and competes for enzymes involved in the conversion of cytidine nucleotide to 
deoxycytidine nucleotide and also incorporation into the DNA.  
Cytarabine has no effect on non proliferating cells nor on proliferating cells unless in the S phase. It is 
a cell cycle specific antineoplastic drug.  
5.2 Pharmacokinetic properties 


Oral administration is ineffective due to rapid deamination in the gut. Cytidine deaminase is 
concentrated in the liver and intravenous doses show biphasic elimination with half lifes of 
approximately 10 minutes and 1-3 hours.  
After 24 hours 80% of a dose has been eliminated either as the inactive metabolite or as the 
unchanged cytarabine, mostly in urine but some in bile.  
CSF levels of 50% of plasma levels are achieved with intravenous infusion. Intrathecal dosing results 
in slower elimination (T1/2 2-11 hours).  
Cytarabine is rapidly and widely distributed into tissues, crosses the blood brain barrier and also the 
placenta.  
5.3 Preclinical safety data 
There is no pre-clinical data of relevance to the prescriber which are additional to that already included 
in other sections of the SPC.  
 
6. Pharmaceutical particulars 
6.1 List of excipients 
Sodium Chloride  
Water for Injections  
6.2 Incompatibilities 
Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. carbenicillin 
sodium, cephalothin sodium, fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium 
succinate, insulin-regular, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, 
penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of 
the drug, specific diluents used, resulting pH, temperature). Specialised references should be 
consulted for specific compatibility information.  
6.3 Shelf life 
Before use: 12 months.  
In use: Chemical and physical in-use stability has been demonstrated for 7 days at room temperature.  
From a microbiological point of view, the product should be used immediately. If not used immediately, 
in-use storage times and conditions prior to use are the responsibility of the user and would normally 
not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated 
aseptic conditions.  
6.4 Special precautions for storage 
Do not store above 25°C. Keep container in the outer carton .  
6.5 Nature and contents of container 
Clear Type I glass vials, rubber stopper.  
Clear Type I Onco-Tain® Vials, rubber stopper.  
Pack sizes 5's, 25's and 50's.  
Not all presentations and pack sizes may be marketed.  
6.6 Special precautions for disposal and other handling 
Not applicable.  
 
7. Marketing authorisation holder 
Hospira UK Ltd  
Queensway  
Royal Leamington Spa  
Warwickshire CV31 3RW  
United Kingdom.  
 
8. Marketing authorisation number(s) 
PL 04515/0040  
 


9. Date of first authorisation/renewal of the authorisation 
7th July 1992/10th October 2006  
10. Date of revision of the text 
June 2015  
 


APPENDIX 2 - INCLUSION AND RANDOMIZATION PROCESS 
(NB screening shot are corresponding to protocol version dated 21/01/2013) 
Connect to www.graspa-ml.com and choose "patients" section, then "new patient" 
Enter patient data selection and validate 
 
Answer inclusion exclusion criteria and validate 
 
 
 
Only if authorized 
according local regulations 


Answer question and validate 
 
Confirm or cancel patient randomization (If cancel is chosen, patient will be marked as screening failure) 
 
If confirm is chosen the system display randomization arm on the screen :  
Patient 1004-07 is randomized in Arm B - Low-dose Cytarabine + GRASPA® 100 UI/kg. 
 
 
 
 
Randomization number: 0XX 
An email confirmation is also sent to the investigator example below : 
From : graspa.ml@icta.fr [mailto:graspa.ml@icta.fr]  
Sent by  : vendredi 29 novembre 2013 17:20 
To:  Investigator 
Subject : GRASPA-ML_Study_Centre 1004_Confirmation of Randomisation - Patient 1004-07 
This is the confirmation of the data you have entered into the Interactive Web Response System for the 
following patient: 
 
Connection to IWRS: 
- Date of connection: 29/11/2013 
 
Centre and Patient: 
- Centre: 1004 - Investigator 
- Patient number: 1004-07 
- Sex: Male 
- Date of birth: 12/12/1945 
- Date of consent form signature: 29/11/2013 
- Start Date for Cytarabine (Day 1): 02/12/2013 
 
Randomization: 
Your patient 1004-07 has been randomized: 
 
in Arm B – Low-dose Cytarabine + GRASPA® 100 UI/kg 
(randomization number 075) 
 
ICTA PM / ERYTECH PHARMA will contact you in the coming days for the arrangement of GRASPA 
prescription and delivery. 
The GRASPA-ML study team 
 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
 
Appendix 3: Samples preparation for centralized analyses  
Amino acids: asparagine, aspartate, glutamine, and glutamate - At D11, D13, D18 and D27 of chemotherapy 
course 
Procedure: 
One sample of 4mL of blood should be taken and immediately refrigerated (put in an iced water bath) 
Centrifuge the blood sample no later than 15 minutes after sampling, at 800-1,000 G and at 4°C for 10 minutes 
Harvest the serum and process the sample 
Add ≥ 100 µL (1 part) 10% sulfosalicylic acid to ≥ 400 µL (4parts) of serum to precipitate proteins, mix thoroughly 
(vortex mixer) and centrifuge 5 minutes at 2,500 G at 4°C 
Fill the supernatant into a propylene tube and freeze between ≤ -20°C and -80°C, store at this temperature until shipping. 
Samples will be transferred on dry ice for analysis to: 
SGS Cephac 
90, Av. des Hauts de la Chaume BP28 
86281 Saint Benoît Cedex, France 
Whole blood asparaginase - At D11, D13, D18 and D27 of chemotherapy course 
Procedure: 
Two sample of 2mL of blood should be taken and freeze between ≤ -20°C and -80°C; store at this temperature until 
shipping. 
Samples will be transferred on dry ice for analysis to: 
SGS Cephac 
90, Av. des Hauts de la Chaume BP28 
86281 Saint Benoît Cedex, France 
Immunogenicity: Anti-L-asparaginase antibodies - At D11 each course of chemotherapy, before GRASPA 
administration 
Procedure: 
One sample of 2mL of blood should be taken 
Centrifuge the blood sample no later than 15 minutes after sampling, at 800-1,000 G and 4°C for 15 minutes 
Fill the supernatant into 2 propylene tubes and freeze between ≤ -20°C and -80°C, store at this temperature until 
shipping. 
Samples will be transferred on dry ice for analysis to: 
CHU Hôtel Dieu 
Laboratoire d'immunologie biologie 
9 quai Moncousu 
44093 Nantes cedex 1 (France) 
 
Biomarker assessments on bone marrow aspirate of patients.  
Procedure 
Two Bone marrow samples will be collected as follows:  
-2 mL will be collected in EDTA tube (for culturing cells after ficoll separation)  
-2 mL will be collected in PAXgene tube (for extraction of RNA) 
Patient samples will be transferred (ambient temperature) for analysis to 
ERYTECH Pharma – R& D department 
60 av Rockefeller, Bât Adenine 
69008 Lyon (France) 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
 
 
 
 
 
Within 15 
min max 
Within 15 
min max 
Add 100 µl of 10% 
sulphosalicylic acid 
(1 part per 4 part of serum) 
 
Mix thoroughly 
Whole blood 
Asparaginase 
anti-asparaginase 
Antibodies 
2 X 2 ml 
(Lithium Heparin) 
1 X 4 ml 
(Lithium Heparin) 
Store between-80°C and -20°C 
Store between -80°C and -20°C 
Fax the Analysis Form to trigger pick-up of samples to ship 
Fax No: + 33 (0)1 48 92 22 02 (CEMO) 
Shipment to SGS Cephac 
Ambient immediate 
shipment to Erytech 
R&D dep.(Lyon) 
2X  > 100 µl 
Centrifugation 
+4°C  
2500G 5 min 
1 X  > 400 µl 
1 X 2 ml 
(Dry tube) 
Fill the 
supernatant into 
propylene tubes 
PUT IN COLD 
SYSTEM 
IMMEDIATELY  
Amino 
Acids 
1 Back-up 
Centrifugation 
+4°C 
800-1000G 15 min 
Centrifugation 
+4°C 
800-1000G 10 min 
1 Back-up 
Fill the 
supernatant into 
propylene tubes 
Harvest the serum and 
process the sample 
1 Back-up 
2X  > 100 µl 
Asparagine 
Synthetase 
(explorator test on 
bone marrow) 
Shipment to Hotel Dieu 
Hospital (Nantes) 
Immunology department 
1 X 2 ml (EDTA tube) 
1 X 2 ml (Paxgene  
mRNA tube) 


 
GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
 
Dosage and Central Laboratories 
 
 
Analysis 
Reference for measurement 
Central Laboratory 
Responsible 
Amino Acids : 
Asparagine, Aspartate, Glutamine, Glutamate 
 
Whole blood Asparaginase  
R. Pieters et al, Blood. 2008 Dec 
15;112(13):4832-8 
Lanvers  C, C et al. J. Anal Biochem 
2002; 309: 117–126 
SGS Cephac 
90, Av. des Hauts de la 
Chaume BP28 
86281 Saint Benoît Cedex, 
France 
Patricia Blain - Study Director 
Phone: +33 5 49 57 50 20 
Fax:      +33 5 49 57 22 39 
Anti-asparaginase Antibodies 
B Wang, LJ Hak, MV Relling et al. 
"Elisa 
to 
evaluate 
plasma 
anti-
asparaginase IgG concentrations in 
patients with acute lymphoblastic 
leukemia" 
J 
of 
Immunological 
Methods 239 (2000) 75-83. 
Hôpital Hôtel Dieu 
Laboratoire d’Immunologie 
Biologie 
9, Quai Moncousu 
44093 NANTES Cedex 1 
FRANCE 
Dr Marie AUDRAIN  
Tel : +33 (0)2 40 08 40 67 
Fax : +33 (0)2 40 08 42 14 
marie-audrain@chu-
nantes.fr 
Asparagine Synthetase exploration/ Biomarker assessments 
Erytech study No EGG0-6-05 
ERYTECH Pharma 
60 Av Rockefeller, bât 
Adénine 5ème etage 
69008 LYON 
FRANCE 
Willy BERLIER 
Tel : +33(0)4 78 78 15 72 
Fax : +33 (0)4 78 78 93 09 
wberlier@erytech.com 
 
MD Anderson Cancer Center 
7435 Fannin St, Room 
2SCR3.3027 
Houston, TX  77054 
 
Philip LORENZI, M.D.  
Tél: +1 713 792 9999 
E-mail: 
pllorenzi@mdanderson.org 
 
 


 
GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
 
Appendix 4: EORTC-QLQ-C30_V3 


ENGLISH 
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
bbbb
bbbb
bbbb
bbbb 
Your birthdate (Day, Month, Year): 
cecec
cecec
cecec
cececdde 
Today's date (Day, Month, Year):  
31 cecec
cecec
cecec
cececdde 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


ENGLISH 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 


 
GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 5: Prescription of GRASPA 
 


GRASPA-AML 2012-01, Prescription form, version 2.0, dated 11 Oct 2015_FR 
 
PG-CLI-001-F7 
Indice A 
Revise le 25/03/2013 
This document, exclusive property of ERYTECH PHARMA, must not under any circumstances whatsoever, be transmitted to a third party,  photocopied, or reproduced without prior authorization 
ETUDE GRASPA-AML2012-01 
PRESCRIPTION DE GRASPA® 
(eryaspase, dispersion pour perfusion) 
 
IDENTIFICATION DU CENTRE 
IP nom : …………………………..…….. 
Adresse du centre : ………………..……. 
………………………………………. …. 
No centre : ………………. 
N° FAX : ………………………. 
 
FAXER A 
 
ERYTECH PHARMA 
 
 
N° FAX : +33(0)4 78 78 93 05 
 
IDENTIFICATION DU PATIENT 
NOM 
 
Monogramme 
|__|__| - |__|  
 
Nom 
 Prénom 
N° Patient 
|__|__|__|__| - |__|__|  
 
N° Centre  
N° Patient 
PRENOM 
 
Né(e) le 
|__|__| |__|__| |__|__|__|__| 
 
Jour 
 mois 
année 
 
Sexe 
 M   
 F 
Poids du patient 
|__|__|__| Kg 
 
 PRESCRIPTION  
1 poche de GRASPA® compatible 
sur la base du  dossier pré transfusionnel du patient  ci-joint 
Dose | 1 | 0 | 0 |  UI/Kg 
Préciser si caractéristique particulière (ex CMV négatif):  
 
Date et heure prévue 
d’administration 
|__|__| |__|__| |__|__|__|__| 
 
Jour 
 mois 
année 
|__|__| H |__|__| mn 
ELEMENTS DU DOSSIER PRE TRANSFUSIONNEL DU PATIENT 
Nombre total de pages (comprenant la prescription) : ___ pages  
  Photocopie de la carte de groupe sanguin valide 
ATTENTION LE PRODUIT SERA EXPEDIE UNIQUEMENT APRES RECEPTION DES RAI de moins 
de 72h, A faxer dans les 2 jours précédent l'administration. 
 
En cas de difficulté, appeler immédiatement le Pharmacien ERYTECH Pharma au +33(0)4 78 78 93 04 
Date : 
 
Nom du prescripteur :  
Signature : 
LIVRAISON PHARMACIE  
ADRESSE :  ..............................................................................................................................................................  
 ...................................................................................................................................................................................  
Tél.:  ................................................................................ Fax.:  ................................................................................  
CONTACT POUR LA RECEPTION DE GRASPA® (MENTION OBLIGATOIRE POUR L’EXPEDITION) 
Nom(s), fonction(s):  .................................................................................................................................................   
Cadre réservé ERYTECH pour confirmation 
Dose | 1 | 0 | 0 | UI/Kg 
Dose totale : |__|__|__|__|__| UI  
Date Signature : 
RAI ATTENDUES POUR LE  
 


GRASPA-AML 2012-01, Prescription form, version 2.0, dated 11 Oct 2015_EN 
PG-CLI-001-F7 
Indice A 
Revise le 25/03/2013 
This document, exclusive property of ERYTECH PHARMA, must not under any circumstances whatsoever, be transmitted to a third party,  photocopied, or reproduced without prior authorization 
GRASPA-AML2012-01 STUDY 
PRESCRIPTION OF GRASPA® 
(eryaspase, dispersion for infusion) 
 
SITE IDENTIFICATION  
PI name: …………………….…….. 
Site address: ……………………… 
……………………………………. 
Site No.: …………………………. 
FAX No: ………………………… 
 
TO BE FAXED AT: 
 
ERYTECH PHARMA 
 
FAX No : +33(0)4 78 78 93 05 
 
PATIENT IDENTIFICATION 
LAST NAME 
 
Patient Initials 
|__|__| - |__| 
 
Last Name 
First name 
Patient No 
|__|__|__|__| |__|__|  
 
Site No 
Pat No  
FIRST NAME 
 
Date of Birth 
|__|__| |__|__| |__|__|__|__| 
 
day 
 month 
year 
 
Gender 
 M 
 F 
Weight 
|__|__|__| Kg 
 
PRESCRIPTION  
1 compatible bag of GRASPA®, according patient 
pretransfusionnal status 
Dose:| 1 | 0 | 0 |  IU/Kg 
Precise specific conditions required if any (i.e. CMV negative):  
 
Administration scheduled 
on the  
|__|__| |__|__| |__|__|__|__| 
 
day 
 month 
year 
at 
|__|__| h |__|__| min 
PATIENT PRETRANSFUSIONNAL STATUS TO BE ATTACHED :  
Number of pages (including this prescription sheet) : ___ pages  
  Completed “BLOOD GROUP FORM”  
WARNING: GRASPA® WILL BE SENT ONLY AFTER RECEPTION OF IAST RESULTS LESS THAN 
72 H (3 DAYS) PRIOR GRASPA® INFUSION 
In case of any difficulty, please contact ERYTECH Pharma Pharmacist Tel No +33(0)4 78 78 93 04 
Date : 
 
Investigator Name : 
Signature : 
DELIVERY ADDRESS  
ADDRESS :  ..............................................................................................................................................................  
 ...................................................................................................................................................................................  
Tel.:  ................................................................................ Fax. / Mail.:  ....................................................................  
CONTACT (MANDATORY FOR SHIPMENT) Name(s), function(s): 
………………………………………………………………………………….. .....................................................   
Reserved as per confirmation by ERYTECH 
Dose: | 1 | 0 | 0 |   IU/Kg 
Total Dose : |__|__|__|__|__| IU 
Date & Signature : 
DATE IAST expected :  
 


 
GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 6: Transport and injection forms 
 


DOCUMENT DE TRANSPORT 
ET D’INJECTION DE GRASPA® 
ETUDE : 
GRASPA-AML2012-01 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
1- ERYTECH PHARMA - ENVOI DE GRASPA® 
Date de 
Prescription 
|__|__| |__|__| |__|__|__|__| 
jour 
mois 
année 
Par le Dr/Pr.: 
 ............................................................... 
Mise en 
expédition 
|__|__| |__|__| |__|__|__|__| 
jour 
mois 
année 
Par (transporteur) : 
 ............................................................... 
2- PHARMACIE - RECEPTION DE GRASPA® 
Date de réception  
 |__|__| 
|__|__| |__|__|__|__| 
jour 
mois 
année 
Horaire |__|__| h |__|__| min 
Contrôle qualité de la poche 
Conforme  Non Conforme 
Documents et matériel joints 
Présent Absent 
Identification de patient 
Carte de contrôle 
Intégrité 
Transfuseur double voie (Tubulures de 
rinçage) 
Température 
Emballage pour retour de poche 
Personne ayant réceptionné le produit (Nom, fonction) :  ___________________________ 
Date et heure de sortie du froid : 
|__|__| |__|__| |__|__|__|__| 
jour 
mois 
année 
par (Nom, fonction) :  ___________________________ 
à  |__|__| h |__|__| min 
Fin de mise à froid, produit à injecter dans les 6 heures. 
3- UNITE DE SOIN - ADMINISTRATION DE GRASPA®
Vérification de la prescription : 
 Oui 
 Non 
Vérification patient/étiquette produit : 
 Oui 
 Non 
Contrôle ultime au lit (compatible) :  
 Oui 
 Non 
 Date d’administration : 
|__|__| |__|__| |__|__|__|__| 
 jour  
 mois  
 année 
Début :   |__|__| h |__|__| min 
Fin : |__|__| h |__|__| min 
Produit administré : 
 Oui Totalement 
 Partiellement 
 Non 
Rinçage des tubulures : 
 Oui 
 Non 
Cause de non conformité, non injection ou non rinçage 
Administration effectuée par : 
Date : |__|__| |__|__| |__|__|__|__| 
jour 
mois 
année 
Signature 
RAPPEL :   Retour de la poche à ERYTECH Pharma selon modalités 
DOCUMENT COMPLETE A FAXER SANS DELAI AU +33(0)4 78 78 93 05 (Pharmacien ERYTECH Pharma) 
ORIGINAL


MODALITES DE RECEPTION ET
D’ADMINISTRATION DE GRASPA® 
ETUDE : 
GRASPA-AML2012-01 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
Etape 1 : 
RECEPTION DE LA POCHE 
Réception de la poche sous responsabilité pharmaceutique par le Pharmacien 
de la PUI.  
Effectuer les contrôles à réception selon la rubrique « Réception de 
GRASPA® » au verso de ce document. 
Etape 2 : 
ADMINISTRATION 
Appliquer les règles de vérification ultime (identité, examen du produit, 
contrôle ultime de compatibilité au lit du patient entre le GRASPA® et le sang 
du malade) 
Dans le cas où le patient a reçu une transfusion non programmée 
depuis la prescription de GRASPA®, réaliser avant l’injection une 
épreuve de compatibilité auprès de votre laboratoire d’immuno-
hématologie (segment à disposition sur le produit). 
En cas d'anomalie, le produit ne devra pas être transfusé. 
Transfuser la totalité de la poche 
Rincer les tubulures avec du sérum physiologique (20 à 40 ml de NaCl 0,9%) 
Etape 3 : 
TRACABILITE 
Compléter la section « Administration de GRASPA® » au verso de ce document. 
Faxer le Document de transport et d’injection de GRASPA® complété (sections 
remplies) sans délais au +33 (0)4 78 78 93 05 
Conserver le Document de transport et d’injection de GRASPA® dans le dossier 
médical du patient 
Etape 4 : 
RETOUR DE LA POCHE (à ERYTECH Pharma) 
Après administration, placer la poche vide dans le sachet prévu à cet effet (ne 
pas joindre les tubulures) 
Se reporter à la procédure de retour pour effectuer l’enlèvement par le 
transporteur
ORIGINAL


GRASPA®
SHIPMENT AND ADMINISTRATION FORM 
GRASPA-AML2012-01 
English version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
1- ERYTECH PHARMA - SHIPMENT OF GRASPA®
Prescription 
date 
|__|__| |__|__| |__|__|__|__| 
 day  
month 
 year 
By Dr/Prof.: 
 .............................................................................  
Shipping 
date 
|__|__| |__|__| |__|__|__|__| 
 day  
month 
 year 
By (carrier) : 
 .............................................................................  
2- RECEPTION OF GRASPA®  To be filled in by the Recipient 
Reception Date  |__|__| |__|__| |__|__|__|__| 
day 
month 
year 
Time |__|__| h |__|__| min 
Quality Control of the bag 
Conform 
 Non Conform 
Related supply 
Present Absent 
Patient Identification 
Integrity 
Infusion double line (allowing rinsing) 
Temperature 
Packaging for bag return 
Recipient 
Name: 
Signature: 
Removing from +2+8°C - Date/Time : 
|__|__| |__|__| |__|__|__|__| 
day 
month 
year 
by (Name) :  ___________________________________  
at |__|__| h |__|__| min 
To be administered within 6 hours 
3- ADMINISTRATION OF GRASPA® 
Consistency with prescription  
 Yes 
 No 
Check patient identification vs label : 
 Yes 
 No 
Ultimate cross match blood test :  
 Yes* 
 No    *by (name, title)______________________________ 
Administration Date : 
|__|__| |__|__| |__|__|__|__| 
day 
month 
year 
Start  :   |__|__| h |__|__| min 
End  :  |__|__| h |__|__| min 
Product administered : 
 Yes totally 
 Partially 
 Not administered 
Infusion line rinsing : 
 Yes 
 No 
Reason for non-conformity, administration failure, rinsing failure, or any relevant comment 
Administration performed by: 
Date : |__|__| |__|__| |__|__|__|__| 
day 
month 
year 
Signature 
PLEASE FAX THIS DOCUMENT COMPLETED TO +33(0)4 78 78 93 05 (ERYTECH Pharmacist) 
ORIGINAL


 GRASPA® GUIDELINES 
GRASPA-AML2012-01 
English version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
Step 1 : 
RECEPTION OF GRASPA® 
Under medical responsibility.  
Check items as indicated in section «Reception of GRASPA®» in the 
«GRASPA® shipment and administration form ». 
Step 2 : 
ADMINISTRATION 
Prior to the administration, an ultimate compatibility cross match test should be 
performed between patient blood and GRASPA® received using segment tube. 
If the patient received a blood transfusion in between GRASPA® 
prescription and scheduled date of administration of GRASPA®, a new 
compatibility test should be performed in your local laboratory. 
In case of discrepancy the product must not be administered. 
The entire content of the bag must be infused. 
Rinse the perfusion line with NaCl 0,9% (around 20 to 40 mL). 
Step 3 : 
DOCUMENTATION 
Complete the «Administration of GRASPA®» section of the document 
«GRASPA® shipment and administration form». 
Fax completed «GRASPA® shipment and administration form» form shortly 
after administration to +33(0)4 78 78 93 05. 
Keep the document «GRASPA® shipment and administration form» completed 
together with patient medical file. 
Step 4 : 
RETURN OF THE BAG (To ERYTECH Pharma) 
After administration, put the bag of GRASPA® into the supplied packaging for 
return (please do not insert perfusion lines).  
Follow the instructions to have the package picked. 
ORIGINAL


                     
RICHTLINIEN FÜR GRASPA® 
GRASPA-AML2012-01 
German version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
Schritt 1: 
ANNAHME DES BEUTELS 
Unterliegt ärztlicher Verantwortung.  
Kreuzen Sie die entsprechenden Punkte im Abschnitt «Reception of 
GRASPA®» des Dokuments «GRASPA® shipment and administration form» 
an.  
Schritt 2: 
VERABREICHUNG 
Vor der Infusion ist mittels Segmentröhrchen und Blutgruppenkarte eine 
endgültige Kreuzprobe zur Überprüfung der Kompatibilität zwischen 
Patientenblut und zu verabreichendem GRASPA® durchzuführen.  
Hat der Patient zwischen der Verordnung und der eigentlichen Infusion von 
GRASPA® eine Bluttransfusion erhalten, muss im Labor Ihrer Einrichtung 
ein erneuter Kompatibilitätstest durchgeführt werden. Im Falle von 
abweichenden Ergebnissen darf das Produkt nicht infundiert werden.  
Es muss der gesamte Beutelinhalt infundiert werden.  
Spülen Sie die Perfusionsleitung mit 0,9% iger Kochsalzlösung (etwa 20 bis 40 
ml).  
Schritt 3: 
DOKUMENTATION 
Füllen Sie Abschnitt «Administration of GRASPA®» im Dokument «GRASPA® 
shipment and infusion form» aus.  
Faxen Sie das Dokument «GRASPA® shipment and administration form» mit 
den ausgefüllten Abschnitten zeitnah nach der Infusion an folgende Nummer: 
+33(0)4 78 78 93 05.  
Bewahren Sie das ausgefüllte Dokument «GRASPA® shipment and 
administration form» zusammen mit der Krankenakte des Patienten auf.  
Schritt 4: 
RÜCKGABE DES BEUTELS (an ERYTECH Pharma) 
Stecken Sie nach Verabreichung von GRASPA® den Beutel in die mitgelieferte 
Verpackung für Rücksendungen (legen Sie bitte keine Perfusionsleitungen 
bei).  
Folgen Sie den Anweisungen, um das Päckchen abholen zu lassen. 
ORIGINAL


                     
INSTRUCCIÓN POR GRASPA® 
GRASPA-AML2012-01 
Spanish version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
Etapa 1: 
RECEPCIÓN DE LA BOLSA 
Recepción de la bolsa bajo responsabilidad médica  
Al recibir el producto, realice los controles de la sección «Reception of 
GRASPA®» en el documento Envío de GRASPA® y Administración 
«GRASPA® shipment and administration form»  
Etapa 2: 
ADMINISTRACIÓN 
Antes de la administración, una prueba de compatibilidad definitiva debe ser 
realizada, entre la sangre del paciente y GRASPA® recibido, usando un tubo de 
segmento y la tarjeta sanguínea  
En el caso de que el paciente haya recibido una transfusión no 
programada desde la prescripción de GRASPA®, hasta la fecha 
programada de la administración de GRASPA, un nuevo test de 
compatibilidad debe ser realizado en su laboratorio local.  
El producto no debería ser administrado en caso de discrepancias.  
Infunda toda la bolsa  
Purgar la línea de perfusión con suero fisiológico (de 20 a 40 ml de NaCl al 
0,9%) 
Etapa 3: 
DOCUMENTACIÓN 
Rellene la sección «Administration of GRASPA®» del documento Envío de 
GRASPA® y Administración «GRASPA® shipment and administration form».  
Envíe cuanto antes, después de la administración por fax el Documento 
«GRASPA® 
shipment 
and 
administration 
form» 
cumplimentado 
al +33 (0)4 78 78 93 05 
Conserve este Documento en la historia clínica del paciente  
Etapa 4: 
DEVOLUCIÓN DE LA BOLSA (a ERYTECH Pharma) 
Tras la administración, coloque la bolsa vacía en el sobre previsto para ello (no 
incluya las líneas de perfusión)  
Consulte el procedimiento de devolución para realizar la recogida por el 
transportista 
ORIGINAL


 MODALITA DI RICEVIMENTO E 
DI SOMMINISTRAZIONE DI 
GRASPA® 
GRASPA-AML2012-01 
Italian version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
Fase 1:
RICEVIMENTO DELLA SACCA 
Ricevimento della sacca sotto responsabilità medica  
Eseguire i controlli alla consegna descritti dalla voce «Reception of GRASPA®» 
del Documento «GRASPA® shipment and administration form» 
Fase 2:
SOMMINISTRAZIONE 
Attenersi alle regole di verifica finale (identità, esame del prodotto, controllo 
finale di compatibilità subito prima della somministrazione al paziente fra 
GRASPA® e il sangue del malato) 
Nel caso in cui il paziente abbia ricevuto una trasfusione non programmata 
dalla prescrizione di GRASPA®, eseguire prima dell’iniezione un test di 
compatibilità presso il laboratorio di immunoematologia della vostra struttura 
(segmento disponibile sul prodotto).  
In caso di anomalie, il prodotto non deve essere trasfuso. 
Somministrare per trasfusione tutto il contenuto della sacca 
Sciacquare i tubi con soluzione fisiologica (20-40 ml di NaCl al 0,9%) 
Fase 3:
TRACCIABILITÀ 
Compilare la sezione «Administration of GRASPA®» a tergo di questo 
documento. 
Inviare immediatamente per fax il Documento «GRASPA® shipment and 
administration form» completato (sezioni compilate) al +33 (0)4 78 78 93 05 
Conservare il Documento di trasporto e di iniezione di GRASPA® nella cartella 
clinica del paziente 
Fase 4:
RESTITUZIONE DELLA SACCA (a ERYTECH Pharma) 
Dopo la somministrazione, mettere la sacca vuota nel sacchetto previsto per 
tale scopo (non aggiungere i tubi) 
Richiamarsi alla procedura di restituzione per provvedere al ritiro da parte del 
trasportatore 
ORIGINAL


GRASPA® 
VALMISTEEN VASTAANOTTO JA ANTO 
GRASPA-AML2012-01 
Finnish version 
Référence : SOP-LOGI-002-F4 
Indice : B 
Date d’application : 24/11/2014 
Ce document est la propriété de ERYTECH PHARMA. Il ne peut être ni reproduit, ni communiqué à un tiers sans autorisation d'une personne mandatée spécialement à cet effet par ladite société 
1. vaihe:
PUSSIN VASTAANOTTO 
Pussin vastaanotto vastuullisesti lääketieteellisten käytäntöjen mukaan  
Suorita vastaanottotarkistukset « Reception of GRASPA® » ja injektioasiakirjan 
kohdan «GRASPA® shipment and administration form» mukaisesti 
2. vaihe:
ANTO 
Tarkista 
valmiste 
äärimmäisen 
tarkkojen 
tarkistussääntöjen 
mukaan 
(tunnistetiedot, valmisteen tutkiminen, GRASPA®-valmisteen ja sairaan 
henkilön veren yhteensopivuuden tarkistaminen viime kädessä potilaan 
vierellä). 
Jos 
potilas 
on 
saanut 
GRASPA®-valmisteen 
määräämisen 
jälkeen 
verensiirron, jota ei ole etukäteen merkitty ohjelmaan, teetä ennen injektiota 
yhteensopivuustutkimus 
immuno-hematologisessa 
laboratoriossa 
(osio 
valmisteen päällä).  
Jos havaitaan poikkeamia, valmistetta ei saa antaa potilaaseen. 
Anna pussin koko sisältö. 
Huuhtele letkut fysiologisella keittosuolaliuoksella (20 - 40 ml 0,9-prosenttista 
NaCl-liuosta). 
3. vaihe:
JÄLJITETTÄVYYS 
Täytä kappale « Administration of GRASPA®» joka on tämän asiakirjan toisella 
puolella. 
Lähetä «GRASPA® shipment and administration form» ja injektioasiakirja 
täydennettynä 
(osiot 
täytettyinä) 
viipymättä 
faksilla 
numeroon 
 +33 (0)4 78 78 93 05 
Säilytä 
GRASPA®-valmisteen 
kuljetus- 
ja 
injektioasiakirja 
potilaan 
asiakirjojen joukossa 
4. vaihe:
PUSSIN PALAUTTAMINEN (ERYTECH Pharmalle) 
Kun valmiste on annettu, aseta tyhjä pussi sille varattuun kuljetuspussiin (älä 
laita letkuja mukaan). 
Pyydä kuljetusyritystä noutamaan lähetys palautusprosessia koskevien ohjeiden 
mukaisesti. 
ORIGINAL


 
GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 7: Serious Adverse Event report form  
 


SERIOUS ADVERSE EVENT FORM: 
 
Complete and fax within 24 hours: +33(0)4 67 10 72 53 (VIGIPHARM) / email erytech@vigipharm.fr  Page 1/2 
PROTOCOL : GRASPA-AML 2012-01 
EUDRACT NO : 2012-002026-78 
IND NO : (For US only) 
IRB NO : (for US only) 
 
Référence : PO-PV-001-F1 
Indice : G 
Date d’application : 10/11/2014 
This document, exclusive property of ERYTECH PHARMA, must not under any circumstances whatsoever, be transmitted to a third party, photocopied, or reproduced without prior authorization 
Date of Report : |__|__| |__|__| |__|__|__|__| 
 
Day 
Month 
Year 
25a. Type of report : 
 Initial  
 Additionnal n° |__|__| 
Principal Investigator : 
Address : 
1. Patient Initials:  
 
|__|__| - |__| 
 
Last name 
First name 
Patient No:  
 
|__|__|__|__| - |__|__| 
 
Site No 
Patient No 
Inclusion date:  
 
|__|__| |__|__| |__|__|__|__| 
 
Day 
Month 
Year 
1a. Country 
2. Date of birth: |__|__| |__|__| |__|__|__|__| 
 
Day 
Month 
Year 
3. Gender:  
 F 
 
 M 
weight : |__|__|__| kg 
 
I. EVENT INFORMATION 
7. + 13. EVENT (primary diagnostic):  ................................................................................................................................................  
4.-6. Onset Date: |__|__| |__|__| |__|__|__|__| 
End Date : |__|__| |__|__| |__|__|__|__| 
 
Day 
Month 
Year 
Day 
Month 
Year 
Outcome: 
 Recovering 
 Not recovered 
 Fatal 
 Unknown 
 Recovered (without sequelae)  
 Recovered with sequelae, precise  :  ............................................................................................................................  
8.-12. Seriousness (tick appropriate boxes) : 
 Death 
 Date : 
|__|__| |__|__| |__|__|__|__| 
 Hospitalization or prolonged hospitalization 
 
 Start date: 
|__|__| |__|__| |__|__|__|__| 
 
 Date of discharge :  
|__|__| |__|__| |__|__|__|__| 
 Persistent/significant disability 
 Life-threatening 
 Result in congenital anomaly 
 Serious according investigator judgment  
Intensity : 
 Mild (grade 1) : minor, no specific medical intervention 
 Moderate (grade 2) : minimal or local intervention (non invasive) 
 Severe (grade 3) : significant symptoms requiring hospitalization or invasive intervention 
 
Or  
 
Highly Severe (grade 4) : Life-Threatening, need for intensive care or emergent invasive  
 
procedure  
 
Or  
 
Death (grade 5) 
7. + 13. Description of tthe event (manifestations, symptoms, laboratory results…): 
 
 
 
 
 
 
 
Action taken regarding the event: 
 None   
 Corrective treatment, precise below : 
 
 
 
 
 
Attached Documents:  
 None 
 Hospitalization report, nb of pages:…….. 
 Exams report, nb of pages:…….. 
 Laboratory results, nb of pages:…….. 
 Other, precise : ...........................................................................................................................................................................................................................  


SERIOUS ADVERSE EVENT FORM: 
 
Complete and fax within 24 hours: +33(0)4 67 10 72 53 (VIGIPHARM) / email erytech@vigipharm.fr  Page 2/2 
PROTOCOL : GRASPA-AML 2012-01 
EUDRACT NO : 2012-002026-78 
IND NO : (For US only) 
IRB NO : (for US only) 
 
Patient initials : |__|__| - |__|  
Patient No : |__|__|__|__| - |__|__| 
 
Last name First name 
Site No 
Patient No 
 
Référence : PO-PV-001-F1 
Indice : G 
Date d’application : 10/11/2014 
This document, exclusive property of ERYTECH PHARMA, must not under any circumstances whatsoever, be transmitted to a third party, photocopied, or reproduced without prior authorization 
II. STUDY TREATMENT INFORMATION 
14. Treatment :  
 GRASPA®  
 NA 
15. Dose (per 
infusion) 
16. Route 
Number of 
infusions 
18. 1st infusion date :  
18. last infusion date :  
………UI/kg. 
…… 
|__|__| 
|__|__| |__|__| |__|__|__|__| 
 
Day Month 
Year 
|__|__| |__|__| |__|__|__|__| 
 
Day  Month 
Year 
Action taken regarding study treatment : 
 None, Dose not changed (drug continued) 
 Drug withdrawn (drug stopped) 
 Dose reduced ( or drug transitory discontinued) 
 Not applicable 
20. Did event abate after stopping 
treatment  
 Yes  
 No  
 Not applicable 
Relationship to study treatment :  
No Reasonable Possibility : 
 Not applicable  
 
 Not related    
 Unlikely 
Reasonable Possibility : 
 Possible  
 Probable  
 Certain / Definite 
 Not assessable 
21. Did event reappear  after 
reintroduction : 
 Yes  
 No  
 Not applicable 
14. Treatment  
 CYTARABINE 
15. Dose (per 
administration) 
16. Route 
Number of 
administration 
18. 1st administration date :  
18. last administration date :  
………. 
…… 
|__|__| 
|__|__| |__|__| |__|__|__|__| 
 
Day Month 
Year 
|__|__| |__|__| |__|__|__|__| 
 
Day  Month 
Year 
Action taken regarding study treatment : 
 None, Dose not changed (drug continued) 
 Drug withdrawn (drug stopped) 
 Dose reduced ( or drug transitory discontinued) 
 Not applicable 
20. Did event abate after stopping 
treatment  
 Yes  
 No  
 Not applicable 
Relationship to study treatment :  
No Reasonable Possibility : 
 Not applicable  
 
 Not related    
 Unlikely 
Reasonable Possibility : 
 Possible  
 Probable  
 Certain / Definite 
 Not assessable 
21. Did event reappear  after 
reintroduction : 
 Yes  
 No  
 Not applicable 
 
III. MEDICAL HISTORY AND ASSOCIATED MEDICATION 
23. Relevant medical history: 
 None 
 
 
 
 
22. Concomitants medication (except those for event treatment) : 
 None 
Drug(s)  
(generic name)  
Dose 
(daily) 
Route 
Indication 
Start Date 
(dd/mm/yyyy) 
Stop Date 
(dd/mm/yyyy) 
On going 
Related to the 
event 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
 
 
 
 
 
 
Yes 
 No 
 
Investigator completing the report (Name and address) : 
 
 
Signature 
 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 8: IMMEDIATE EVENT POSSIBLY LINKED TO RED BLOOD CELLS INJECTION 
 
 
* 
Chills / Fever 
Shock  
Hyperthermia  
Dyspnea 
Urticaria 
Acute pulmonary oedema  
Nausea, vomiting   
Hypertension 
Anxiety 
Oligo anuria 
Unexplained bleeding 
Jaundice 
Pains 
Other suggestive clinical signs 
 
Suspected Event 
possibly linked to 
red blood cells* 
Confirmed 
event linked 
to red blood 
cells
Resume 
Transfusion 
Return GRASPA® bag to 
Erytech Pharma for analyses 
purposes (immunologic and 
hematologic) 
Additional analyses 
required in local lab, 
remove segment 
tubes from Graspa® 
bag 
GRASPA® 
NO 
YES 
Record as an AE in the 
CRF  
+ SAE report if 
seriousness criterion is 
met 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 9: Declaration of Helsinki 


Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of
Clariﬁcation added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clariﬁcation added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki
as a statement of ethical principles for medical research involving human subjects,
including research on identiﬁable human material and data.
            The Declaration is intended to be read as a whole and each of its constituent
paragraphs should be applied with consideration of all other relevant paragraphs.
2.         Consistent with the mandate of the WMA, the Declaration is addressed
primarily to physicians. The WMA encourages others who are involved in medical
research involving human subjects to adopt these principles. 
General Principles
3.         The Declaration of Geneva of the WMA binds the physician with the words,
WMA Declaration of Helsinki - Ethical
Principles for Medical Research Involving
Human Subjects
1/8


“The health of my patient will be my ﬁrst consideration,” and the International Code of
Medical Ethics declares that, “A physician shall act in the patient's best interest when
providing medical care.”
4.         It is the duty of the physician to promote and safeguard the health, well-being
and rights of patients, including those who are involved in medical research. The
physician's knowledge and conscience are dedicated to the fulﬁlment of this duty.
5.         Medical progress is based on research that ultimately must include studies
involving human subjects.
6.         The primary purpose of medical research involving human subjects is to
understand the causes, development and eﬀects of diseases and improve preventive,
diagnostic and therapeutic interventions (methods, procedures and treatments). Even
the best proven interventions must be evaluated continually through research for their
safety, eﬀectiveness, eﬃciency, accessibility and quality.
7.         Medical research is subject to ethical standards that promote and ensure
respect for all human subjects and protect their health and rights.
8.         While the primary purpose of medical research is to generate new knowledge,
this goal can never take precedence over the rights and interests of individual
research subjects.
9.         It is the duty of physicians who are involved in medical research to protect the
life, health, dignity, integrity, right to self-determination, privacy, and conﬁdentiality of
personal information of research subjects. The responsibility for the protection of
research subjects must always rest with the physician or other health care
professionals and never with the research subjects, even though they have given
consent.
10.       Physicians must consider the ethical, legal and regulatory norms and
standards for research involving human subjects in their own countries as well as
applicable international norms and standards. No national or international ethical, legal
or regulatory requirement should reduce or eliminate any of the protections for
research subjects set forth in this Declaration.
11.       Medical research should be conducted in a manner that minimises possible
harm to the environment.
12.       Medical research involving human subjects must be conducted only by
2/8


individuals with the appropriate ethics and scientiﬁc education, training and
qualiﬁcations. Research on patients or healthy volunteers requires the supervision of a
competent and appropriately qualiﬁed physician or other health care professional.
13.       Groups that are underrepresented in medical research should be provided
appropriate access to participation in research.
14.       Physicians who combine medical research with medical care should involve
their patients in research only to the extent that this is justiﬁed by its potential
preventive, diagnostic or therapeutic value and if the physician has good reason to
believe that participation in the research study will not adversely aﬀect the health of
the patients who serve as research subjects.
15.       Appropriate compensation and treatment for subjects who are harmed as a
result of participating in research must be ensured.
Risks, Burdens and Beneﬁts 
16.       In medical practice and in medical research, most interventions involve risks
and burdens.
           Medical research involving human subjects may only be conducted if the
importance of the objective outweighs the risks and burdens to the research subjects.
17.       All medical research involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and groups involved in
the research in comparison with foreseeable beneﬁts to them and to other individuals
or groups aﬀected by the condition under investigation.
           Measures to minimise the risks must be implemented. The risks must be
continuously monitored, assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects
unless they are conﬁdent that the risks have been adequately assessed and can be
satisfactorily managed.
           When the risks are found to outweigh the potential beneﬁts or when there is
conclusive proof of deﬁnitive outcomes, physicians must assess whether to continue,
modify or immediately stop the study.           
Vulnerable Groups and Individuals
3/8


19.       Some groups and individuals are particularly vulnerable and may have an
increased likelihood of being wronged or of incurring additional harm.
           All vulnerable groups and individuals should receive speciﬁcally considered
protection.
20.       Medical research with a vulnerable group is only justiﬁed if the research is
responsive to the health needs or priorities of this group and the research cannot be
carried out in a non-vulnerable group. In addition, this group should stand to beneﬁt
from the knowledge, practices or interventions that result from the research.
Scientiﬁc Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally
accepted scientiﬁc principles, be based on a thorough knowledge of the scientiﬁc
literature, other relevant sources of information, and adequate laboratory and, as
appropriate, animal experimentation. The welfare of animals used for research must
be respected.
22.       The design and performance of each research study involving human subjects
must be clearly described and justiﬁed in a research protocol.
           The protocol should contain a statement of the ethical considerations involved
and should indicate how the principles in this Declaration have been addressed. The
protocol should include information regarding funding, sponsors, institutional
aﬃliations, potential conﬂicts of interest, incentives for subjects and information
regarding provisions for treating and/or compensating subjects who are harmed as a
consequence of participation in the research study.
           In clinical trials, the protocol must also describe appropriate arrangements for
post-trial provisions.
Research Ethics Committees
23.       The research protocol must be submitted for consideration, comment,
guidance and approval to the concerned research ethics committee before the study
begins. This committee must be transparent in its functioning, must be independent of
the researcher, the sponsor and any other undue inﬂuence and must be duly qualiﬁed.
It must take into consideration the laws and regulations of the country or countries in
which the research is to be performed as well as applicable international norms and
4/8


standards but these must not be allowed to reduce or eliminate any of the protections
for research subjects set forth in this Declaration. 
           The committee must have the right to monitor ongoing studies. The researcher
must provide monitoring information to the committee, especially information about
any serious adverse events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of the study, the
researchers must submit a ﬁnal report to the committee containing a summary of the
study’s ﬁndings and conclusions. 
Privacy and Conﬁdentiality 
24.       Every precaution must be taken to protect the privacy of research subjects
and the conﬁdentiality of their personal information.
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in
medical research must be voluntary. Although it may be appropriate to consult family
members or community leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26.       In medical research involving human subjects capable of giving informed
consent, each potential subject must be adequately informed of the aims, methods,
sources of funding, any possible conﬂicts of interest, institutional aﬃliations of the
researcher, the anticipated beneﬁts and potential risks of the study and the
discomfort it may entail, post-study provisions and any other relevant aspects of the
study. The potential subject must be informed of the right to refuse to participate in
the study or to withdraw consent to participate at any time without reprisal. Special
attention should be given to the speciﬁc information needs of individual potential
subjects as well as to the methods used to deliver the information.
           After ensuring that the potential subject has understood the information, the
physician or another appropriately qualiﬁed individual must then seek the potential
subject’s freely-given informed consent, preferably in writing. If the consent cannot be
expressed in writing, the non-written consent must be formally documented and
witnessed.      
           All medical research subjects should be given the option of being informed
about the general outcome and results of the study.
5/8


27.       When seeking informed consent for participation in a research study the
physician must be particularly cautious if the potential subject is in a dependent
relationship with the physician or may consent under duress. In such situations the
informed consent must be sought by an appropriately qualiﬁed individual who is
completely independent of this relationship.
28.       For a potential research subject who is incapable of giving informed consent,
the physician must seek informed consent from the legally authorised representative.
These individuals must not be included in a research study that has no likelihood of
beneﬁt for them unless it is intended to promote the health of the group represented
by the potential subject, the research cannot instead be performed with persons
capable of providing informed consent, and the research entails only minimal risk and
minimal burden.
29.       When a potential research subject who is deemed incapable of giving informed
consent is able to give assent to decisions about participation in research, the
physician must seek that assent in addition to the consent of the legally authorised
representative. The potential subject’s dissent should be respected.
30.       Research involving subjects who are physically or mentally incapable of giving
consent, for example, unconscious patients, may be done only if the physical or
mental condition that prevents giving informed consent is a necessary characteristic
of the research  group. In such circumstances the physician must seek informed
consent from the legally authorised representative. If no such representative is
available and if the research cannot be delayed, the study may proceed without
informed consent provided that the speciﬁc reasons for involving subjects with a
condition that renders them unable to give informed consent have been stated in the
research protocol and the study has been approved by a research ethics committee.
Consent to remain in the research must be obtained as soon as possible from the
subject or a legally authorised representative.
31.       The physician must fully inform the patient which aspects of their care are
related to the research. The refusal of a patient to participate in a study or the
patient’s decision to withdraw from the study must never adversely aﬀect the patient-
physician relationship.
32.       For medical research using identiﬁable human material or data, such as
research on material or data contained in biobanks or similar repositories, physicians
must seek informed consent for its collection, storage and/or reuse. There may be
exceptional situations where consent would be impossible or impracticable to obtain
6/8


for such research. In such situations the research may be done only after
consideration and approval of a research ethics committee.
Use of Placebo
33.       The beneﬁts, risks, burdens and eﬀectiveness of a new intervention must be
tested against those of the best proven intervention(s), except in the following
circumstances:
           Where no proven intervention exists, the use of placebo, or no intervention, is
acceptable; or
           Where for compelling and scientiﬁcally sound methodological reasons the use
of any intervention less eﬀective than the best proven one, the use of placebo, or no
intervention is necessary to determine the eﬃcacy or safety of an intervention 
           and the patients who receive any intervention less eﬀective than the best
proven one, placebo, or no intervention will not be subject to additional risks of serious
or irreversible harm as a result of not receiving the best proven intervention. 
           Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.       In advance of a clinical trial, sponsors, researchers and host country
governments should make provisions for post-trial access for all participants who still
need an intervention identiﬁed as beneﬁcial in the trial. This information must also be
disclosed to participants during the informed consent process.
Research Registration and Publication and Dissemination of
Results
35.       Every research study involving human subjects must be registered in a publicly
accessible database before recruitment of the ﬁrst subject.
36.       Researchers, authors, sponsors, editors and publishers all have ethical
obligations with regard to the publication and dissemination of the results of research.
Researchers have a duty to make publicly available the results of their research on
human subjects and are accountable for the completeness and accuracy of their
reports. All parties should adhere to accepted guidelines for ethical reporting. Negative
and inconclusive as well as positive results must be published or otherwise made
7/8


publicly available. Sources of funding, institutional aﬃliations and conﬂicts of interest
must be declared in the publication. Reports of research not in accordance with the
principles of this Declaration should not be accepted for publication.
Unproven Interventions in Clinical Practice
37.       In the treatment of an individual patient, where proven interventions do not
exist or other known interventions have been ineﬀective, the physician, after seeking
expert advice, with informed consent from the patient or a legally authorised
representative, may use an unproven intervention if in the physician's judgement it
oﬀers hope of saving life, re-establishing health or alleviating suﬀering. This
intervention should subsequently be made the object of research, designed to
evaluate its safety and eﬃcacy. In all cases, new information must be recorded and,
where appropriate, made publicly available.
© World Medical Association, Inc. - All Rights reserved.
© Asociación médica mundial - Todos los derechos reservados.
© L'Association Médicale Mondiale - Tous droits réservés.
8/8


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 10: Patient Information Sheet - Informed Consent Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 1/8 
 
 
 
PATIENT INFORMATION SHEET ON THE STUDY GRASPA-AML 2012-01 
 
TITLE: A Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA (L-asparaginase encapsulated in 
red blood cells, eryaspase ) Plus Low-dose Cytarabine vs. Low-dose Cytarabine Alone, in Treatment of Newly 
Diagnosed Acute Myeloid Leukaemia (AML) Elderly Patients, Unfit for Intensive Chemotherapy. ENFORCE 
1 study 
Protocol Nº: GRASPA-AML 2012-01 
Study sponsor: ERYTECH Pharma 
 
 
 
INTRODUCTION 
 
Your doctor has told you that you have Acute Myeblastic Leukaemia (AML). The purpose of this 
information sheet is to describe the disease and its treatments and to invite you to take part in some clinical 
trial. 
The information given on this form is intended to help you to understand exactly what will be asked of you so 
that you can decide whether or not you want to take part in this study.  
Please read this form and ask all the questions you want to ask before you decide whether or not to take part 
in the study. You can take as much time as you want before making your decision and you are free to discuss 
this with persons of your choice. Your participation in this study is completely voluntary and if you decide not 
to take part this decision will not disadvantage you in any way. 
For this study, the Investigators and the hospital will receive financial funding to cover the research work 
What is acute myeloblastic leukaemia (AML)? 
 
The term leukaemia describes several types of cancer affecting the bone marrow where blood cells are 
produced. Leukaemia occurs when blood cells that are still immature (precursors) become cancerous or can 
no longer mature or specialise normally. These cells are called “blasts” or “blastic cells”.  
In contrast to chronic forms of leukaemia, which progress very slowly, acute forms of leukaemia can occur 
from one day to the next and progress rapidly. They are characterised by abnormal multiplication of precursors. 
Uncontrolled multiplication of abnormal blasts leads to invasion of the bone marrow which can no longer 
function properly. In particular it can no longer produce normal blood cells. This is known as medullary 
insufficiency. 
In the acute forms of leukaemia, a distinction is made between acute lymphoblastic leukaemia (ALL), which 
affects the lymphocyte line (a category of white cells involved in the immune system) and forms of acute 
myeloblastic leukaemia (AML), which may affect the precursors of all the other cells produced by the bone 
marrow (the red cells that transport oxygen to the tissues, the white cells that fight infection and the platelets 
that play a role in blood clotting). 
The latter form of leukaemia can lead to anaemia (reduction in red cells and haemoglobin) which causes 
fatigue, paleness, shortness of breath and palpitations. Because of the drop in other white cells called 
polymorphonuclear neutrophils (neutropenia), the body is more sensitive to infections, particularly pulmonary 
infections. Finally, the lower number of platelets (thrombopenia) may cause bleeding, particularly of the 
mucosa (nosebleeds, bleeding gums) and skin (haematoma or bruises as a result of minor bumps). The 
accumulation of blasts in the bone marrow and in other organs may cause other problems: bone pain, 
enlargement of the lymph nodes, spleen and liver. 
 
 
What is the treatment for AML? 
 
The treatment for this disease varies according to the patient’s age. While patients aged less than 60 
years can benefit from “intensive” chemotherapy combining several anticancer medicines, older patients are 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 2/8 
 
less robust and far less able to tolerate the adverse effects caused by this kind of treatment which is then as 
dangerous as the disease itself. Treatment for these patients, described as “non-eligible" for intensive 
chemotherapy, is based on a single low-dose chemotherapy product, which is used to limit the harmful side 
effects while eliminating as many of the cancer cells as possible.  
You are in this category of patients and your doctor has offered you a treatment based on low-dose cytarabine, 
given in 10-day courses repeated every month (about 28 days). If side effects occur on this treatment, your 
doctor will offer you appropriate medicines for the situation and may have to change the cytarabine dose or 
discontinue this medicine. 
 
Why is this study being conducted? What is the benefit for the patients? 
 
Patients over 60 years old cannot always be given intensive chemotherapy. It is necessary to evaluate 
every possible alternative treatment to be able, in the absence of the ability to cure the disease completely, to 
slow disease progression, bring relief to patients and prolong their life expectancy under good conditions. 
In this study, we propose to evaluate the addition of the product GRASPA, containing L-asparaginase, to 
“conventional” treatment with low-dose cytarabine. Approximately 120 patients will participate in this study 
which will take place in France and other European countries. 
L-asparaginase decreases the quantity of asparagine, an amino acid necessary for the leukaemia cells to 
survive. There is a higher chance of eliminating the cancer cells by depriving them of asparagine with L-
asparaginase. This compound is a basic treatment used for 40 years in acute lymphoblastic leukaemia. Certain 
research studies suggest that L-asparaginase could be equally active in acute myeloblastic leukaemia. L-
asparaginase is currently used in treatment protocols for this disease in children. 
ERYTECH Pharma has developed a form of L-asparaginase that is encapsulated in red blood cells. This 
product is called GRASPA. It is not yet on the market. It resembles a bag of blood and is given in the same 
way as a blood transfusion. Studies have already been conducted in animals and humans with this product. 
They show that GRASPA is less rapidly eliminated than L-asparaginase and thus has a longer action in the 
body and is better tolerated by patients. Allergic reactions are decreased in particular. All the same, 
administration of GRASPA may cause adverse effects and your doctor may have to stop using it if you 
experience the effects listed below for L-asparaginase. 
As the studies on GRASPA are still on going, expected efficacy is not fully known and you may have no 
benefit to be treated with this product. 
 
 
Undesirable effects with GRASPA®  
 
Adverse events that may occur with GRASPA® are those related to transfusion and those related to L-
asparaginase. 
Major clinical signs of adverse reaction due to transfusion are feeling of heat, feeling of burning along the 
vein, chills, fever, abrupt change in blood pressure, malaise, nausea with or without vomiting, difficulty to 
breath, urticaria, rash, localized or extensive oedema, anaphylactic shock 
Most frequent and potentially severe adverse reactions related to L-asparaginase toxicity are the following: 
Immediate-type hypersensitivity reactions, troubles in liver and pancreas function, troubles in coagulation, 
thrombosis, diabetes mellitus, and general disorders such as fever, pains (abdominal, back, and joint pain) and 
gastrointestinal disturbance.  
Even if the participants in this study are aged 65 years and above, it is important to remember that pregnant 
women or women breastfeeding a baby cannot take part in this study in view of the toxic effects of the 
anticancer medicines administered in the courses of treatment and transmission of these effects to the baby. 
 
Women of childbearing potential and males must agree to use adequate contraception (e.g., hormonal or 
barrier method of birth control; abstinence) for the duration of study treatment and for 6 months after the last 
dose of cytarabine or 4 months after the last dose of Graspa (whichever is the longest) 
 
 
What is the purpose of this study?  


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 3/8 
 
 
The purpose of this study is to evaluate the efficacy and tolerability of GRASPA administered in 
combination with low-dose cytarabine compared to cytarabine alone.  
Efficacy (response to treatment) is mainly evaluated by measuring the overall survival for a period of 24 
months. Tolerability is mainly assessed by studying the nature and frequency of the adverse events.   
The study has also an exploratory part which is optional, consisting in performing an analysis of potentially 
relevant biomarkers, utilizing proteomic and transcriptomic techniques on bone marrow biopsy/aspirate. Also 
cells isolated from the bone marrow samples will be cultured and tested for sensitivity to asparaginase. The 
aim of this part is to better understand mechanisms of action, improve treatments or develop new medicines. 
You will be asked to sign a separate Informed Consent Document, if you agree to participate in this exploratory 
study also.    
 
What will the study involve? 
 
If you agree to take part, your doctor will carry out some investigations to check the selection criteria 
for patients in the study (in particular a screening test for hepatitis B and C and AIDS) and then you will start 
the study treatment that you are given (you do not have to pay for it). This study compares treatment arms A 
and B described below. Which one you are allocated is decided at random with 2 chances in 3 of having 
treatment B (with GRASPA): 
- Treatment arm A: subcutaneous administration of low-dose cytarabine as 40 mg daily (either one single dose 
of 40 mg or 20 mg twice daily) for 10 consecutive days (Day 1to day 10, D1 to D10), which makes up a course. 
The courses are repeated every month (about 28 days +/- 3 days). This is equivalent to normal management 
for treatment of a disease like yours in patients aged over 60 years. 
-Treatment arm B:  Administration of Cytarabine similarly as for treatment arm A with addition of GRASPA, 
administered at a dose of 100IU/kg as in intravenous infusion,  immediately after cytarabine treatment (D11).. 
The courses are repeated every month (about 28 days +/- 3 days). 
The study treatment will be reduced/stopped if you cannot tolerate it or if your doctor thinks that another 
treatment would be more suitable for your condition, depending on your state of health, the progression of 
your disease or the side effects that occur or if you do not want to continue with the treatment. 
 
 
What will you be asked to do? 
 
Your total participation in the study will be 24 months maximum from the day when you start the study 
treatment (but your doctor will continue to monitor your disease beyond this period, after the end of the study). 
Similarly, the treatment, if still beneficial and well tolerated, can be given to you beyond this period. You will 
be asked to attend the consultations with your doctor for follow-up of the disease and the repeat administrations 
of treatment. You should also undergo investigations such as blood samples and bone marrow punctures. 
The follow-up visits will take place once a month while you are receiving the study treatment. Your doctor 
will perform a clinical examination and monitor your tolerance of the treatment and its efficacy (blood samples 
and bone marrow analyses). After you stop the study treatment, the follow-up visits will take place every 3 
months up to the 24 months’ duration of the study period. 
 
During the inclusion visit, the following procedures/assessments will be performed: 
- Assessment of general health status (performance status) 
- You will be asked about your medical history and details of AML status will be collected (including 
collection of characteristics of AML, ex. results of cytogenetic analysis etc.) as well as other medication 
you could take concomitantly 
-   A general physical examination by systems and organs, weight and height measurements will be performed 
-   Blood samples will be collected for laboratory tests: hematology, biochemistry, serology test (including 
HIV, hepatitis B and C, if needed) 
 
Subsequent visits: monthly visits during treatment period and End of treatment visit: 
- Disease evaluation (AML)  


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 4/8 
 
- Clinical assessment: vital signs (height, weight, pulse, blood pressure systolic and diastolic), performance 
status, physical examination  
- You will be asked to complete a questionnaire about your quality of life called EORTC QLQ-C30, 
- Blood samples will be collected for laboratory tests: hematology, biochemistry at D1, D5, D9, D13, D18, 
D23 and D27 
- You will be asked if you had any adverse events since the last visit and if there was any change in 
concomitant medications you may take. Please pay attention: before administration of any new drug, please 
ask your study doctor about as there could be drugs which interfere with study medication.  
-   You will receive at each visit a patient diary to be completed with the dates of cytarabine administration 
and with all adverse events that you felt – you must return this diary at each visit and your doctor can ask 
you details about these 
 
Follow-up visit after end of study treatment: every 3 months +/- 2 weeks after End of Treatment visit – ex. 
M3, M6, M12…) 
- Disease evaluation (AML) if needed,  
- You will be asked to complete a questionnaire about your quality of life called EORTC QLQ-C30- 
-   You will be asked if you had any adverse events since the last visit and if there was any change in 
concomitant medications you may take. 
-   Additionally, at minimum, your doctor will call you 4 months (+/- 1 week) after end of treatment, to ask 
you about any new adverse events 
For patients given treatment B: in addition to the blood samples described above, your doctor will take specific 
additional blood samples. These samples will be used to measure the total quantity of L-asparaginase 
remaining in your blood, its activity, the level of asparagine depletion, as well the levels of aspartate, glutamine 
and glutamate (these are blood components, whose levels are modified by GRASPA) (analysis known as 
pharmaco-kinetics and pharmaco-dynamics tests, PK/PD) and the potential existence of antibodies to 
asparaginase ( known as immunogenicity analysis). 
These additional PK/PD tests will be performed only for the next two courses after the acceptance of this 
consent and will be performed as follows:  
- D9: a sampling for PK/PD analysis 
- D11 : a sampling for immunogenicity analysis and samplings for PK/PD analysis at : 15 minutes +/- 10 
min before  GRASPA administration, then after administration at 5 min +/- 2 min, 1 h +/- 10 min, 3h 
+/- 10 min, 6 h +/- 10 min  
- D18 - 7 days later, after administration, a sampling for PK/PD analysis  
- D27 – at course end, 16 days after GRASPA administration, a sampling for PK/PD analysis 
These additional tests will be performed in the following laboratories: 
- Total L-asparaginase and aminoacids :  
SGS Cephac Europe 
90 Avenue des Hauts de la Chaume, B.P. 28, 
86281 Saint Benoît Cedex, France 
- Anti-asparaginase antibodies : Hôpital Hôtel Dieu – Nantes, France – will be tested during all treatment 
 
The total additional quantity of blood taken will be about 6 ml per PK/PD sampling and 2 ml for 
immunogenicity sampling. Certain blood samples collected may be stored for a single final assay (L-
asparaginase, asparagine, aspartate, glutamine and glutamate and antibodies above mentioned) at the end of 
the study. Samples will be kept frozen in analysis laboratory until the end of the study and will be then 
destructed, under sponsor responsibility. No further analysis will be carried out without the patient is informed, 
however some samples may be used for calibration of measuring equipment, without analysis. No collection 
of blood samples is expected beyond this period. 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 5/8 
 
The biological samples collected during the study will be treated in accordance with the Law 14/2007 on 
Biomedical Research. 
If you do not receive the treatment with GRASPA, these additional blood samples will not be requested. 
 
Your doctor will assess the effect of the study treatment and disease status every month by taking a blood 
sample combined or not with other routine tests used for assessing the status of your disease. Samples of bone 
marrow (called a biopsy or bone marrow puncture) will also be taken every 2 months.  
This procedure may be painful, but only for a few seconds. You may feel a sharp sting and burn when the 
anesthetic numbs your skin over the aspiration or biopsy site. You may hear a crunching sound and feel 
pressure and some pain when the needle enters the bone. During an aspiration, you may feel a quick, shooting 
pain down your leg as the sample is taken. 
The biopsy site may feel stiff or sore for several days after the biopsy. You may have a bruise on the site. 
Serious problems from a bone marrow aspiration or biopsy are not common. Problems may include: 
- Bleeding from the biopsy site (People with bleeding problems have a higher chance for this),  
- Infection of skin or the bone (osteomyelitis) at the biopsy site, 
- Injury to your heart, a lung, or a major blood vessel if the sample is taken from the breastbone (sternum). 
This complication is very rare. Samples are not often taken from the breastbone, so most people do 
not have to worry about this risk. 
 
If you agree, a part of the bone marrow samples, taken before and after the treatment begins, will be sent to 
ERYTECH Pharma for the purposes of exploratory research, as explained previously.  
 
Legal issues 
 
Your doctor has told you about the disease and its normal treatment. He has invited you to take part in 
this study, GRASPA-AML 2012-01, the sponsor of which is ERYTECH Pharma.  
 
Your participation in this study is entirely voluntary.  
 
If you do not want to take part in this research, you will continue to benefit from suitable medical 
management of your disease. 
 
If you agreed to take part in this study, we shall ask you to sign the consent form on the last page. 
Your signing this, before you are involved in the study, does not affect your legal rights in any way. If you 
wish, you can ask your doctor to tell you about the overall results of the study. In addition, your doctor will let 
you have any new information about the study or study treatment for the whole time the study is being 
conducted. 
 
This study will be conducted in accordance with national legislation relating to the rights of patients 
involved in biomedical research (Protection of personal data will be complied with   laid out in Organic Law 
15/1999, enacted on 13 December and the Royal decree 1720/2007) 
Your doctor and / or the institution will receive financial compensation for their participation 
 
This study protocol has been also approved  by the Ethics Committee and regulatory authorities. 
 
 
According to the LOPD 15/1999, you have the right to cancel the data or to ask to be shown what data about 
you has been collected and if you think anything is incorrect you may ask to have it corrected. 
 
 
Erytech Pharma S.A., the sponsor of this biomedical research, whose head office is situated at Bâtiment 
Adénine, 60 Avenue Rockefeller, 69008 Lyon, has taken out insurance in accordance with the legal provisions 
which covers its civil liability and that of anybody involved, with HDI Gerling, Industrie Versicherungs-AG, 
Riethorst 2 – D 30659 Hannover, (policy no.XXXXXX). 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 6/8 
 
 
Right to refuse to take part or to leave the study 
 
You are free to agree or to refuse to take part in this research. If you do not wish to take part in this study 
you will receive appropriate treatment for your disease without administration of GRASPA. 
 
If you decide to take part, you are still free to stop the research at any time without having to give reasons 
and without incurring any disadvantages in relation to the care you will be given. Your decisions will not affect 
the care you will receive. 
 
The doctor who monitors you during this study may decide at any time to discontinue your participation 
in the research if he considers that the research may harm you, if you do not follow the instructions that your 
monitoring while on treatment requires or if the study as a whole has to be stopped.  
 
Confidentiality 
 
As part of the biomedical research that ERYTECH Pharma has invited you to take part in, your personal 
data will undergo data processing so that the research results can be analysed with regard to the aim of the 
research. Your consent to participate in this study also includes your consent to use your medical and clinical 
data for research purposes. 
The sponsor, ERYTECH Pharma is responsible of the recording of collected data 
 
To this end, your medical data will be sent to the Sponsor of the research or to the persons or companies 
acting on his behalf and, if necessary, to health authorities (in France or abroad) comply with that laid out in 
Organic Law 15/1999, enacted on 13 December and the Royal decree 1720/2007. These data will be identified 
by a code number to guarantee your anonymity. 
 
Your participation in the study remains strictly confidential. All the information you give your doctor, 
as well as the medical data, will also be confidential. However, in this connection, the persons appointed by 
the authorised institutions and the authorised members or their representatives can check your personal data to 
ensure that this study has been conducted in accordance with the applicable legislation and health authority 
regulations. 
 
The information from the data in your file will be used for this study only and for the publications that 
may be based on the results obtained. Your identity will be protected in any case. The medical data about you 
cannot be used for purposes other than those of this research or be communicated to third parties without your 
permission. 
 
In accordance with the provisions of the Law, you have the right to access your personal data and an 
opportunity to correct them. You also have the right to object to transmission of the data covered by 
professional confidentiality that may be used as part of this research and may undergo data processing.  
 
 
 
Ask the doctor who has invited you to take part in this study if you think that the explanations you have 
been given are inadequate and you want more detailed information. 
 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 7/8 
 
 
WRITTEN INFORMED CONSENT FORM FOR PARTICIPATION  
IN GRASPA-AML 2012-01 STUDY 
 
 
After discussing and obtaining answers to all my questions, I the undersigned 
(patient’s surname and first name), 
…………………………………………………………………………….. 
AGREE FREELY AND VOLUNTARILY TO TAKE PART IN THE BIOMEDICAL 
RESEARCH ENTITLED: A Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA (L-
asparaginase encapsulated in red blood cells, eryaspase) Plus Low-dose Cytarabine vs. Low-dose 
Cytarabine Alone, in Treatment of Newly Diagnosed Acute Myeloid Leukaemia (AML) Elderly 
Patients, Unfit for Intensive Chemotherapy, ENFORCE 1 study, sponsored by ERYTECH Pharma 
which I was invited to take part in by Professor / Dr. (doctor’s surname and first 
name)
 
 
 ................................................................................................................................................................  
Telephone number to reach your physician, including for emergency needs: TEL 
:………………………………….. 
the investigator in this study from whom I can request any additional information at any time. 
On the understanding that: 
 
− The doctor who invited me to take part in this research on the conditions described in the 
information letter has given me all the information I wanted about the nature, aim, duration and 
foreseeable effects of the study and I have been informed of what is expected of me. 
− The potential benefits and risks of the study have been explained to me and I have been able to 
ask all the questions I wanted during the discussion with the doctor. All my questions have been 
answered to my satisfaction and I can ask for additional information at any time. 
− I understand that I am free to choose whether or not to take part in this research and I can decide 
to end my participation at any time, for any reasons whatsoever and without bearing any liability; 
however, in this case I undertake to inform my doctor as soon as possible. The fact that I am 
taking part in this research will not affect my relationship with my doctor who will offer me, if I 
want and if necessary, another appropriate treatment. 
− My consent does not release the investigator and sponsor from all their responsibilities and I 
retain all my rights guaranteed by in compliance with as stipulated in Royal Decree 223/2004, 
which regulates clinical trials. . I have also been informed of the existence of insurance covering 
the procedures associated with the study and that this study has been submitted for approval to 
the Ethics Committee and health authority  
− The data about me collected during this research, including this consent form or laboratory 
results, will remain strictly confidential but can be subject to data processing conducted by the 
organisers of this research comply with that laid out in Organic Law 15/1999, enacted on 13 
December and the Royal decree 1720/2007. However, the persons involved with this study will 
be entitled to consult them. 
− I agree that the results of this study may be communicated to the authorities concerned, the study 
sponsor and the scientific community (within or outside France/Europe). I know and I agree that 
the sponsor or its representatives and the authorities can inspect my medical data to check the 
information collected.  
 
 


Patient Information sheet & Informed Consent Form Template English version 2.0, dated 11/10/2015                                           
Study GRASPA-AML 2012-01 
 
 
 
 
Page 8/8 
 
− My participation on this research means that I will not be able to participate in another biomedical 
research for the duration of this research. 
Two copies: one for the patient and one for the doctor  
Person agreeing to participate: 
Surname
 ..........................................................................  First name .........................................................  
Patient’s 
signature
 ..........................................................................  
(patient must personally write his/her name, 
sign and date) 
 
Date |__|__| |__|__| |__|__|__|__| 
 
I hereby confirm that I have fully informed the patient named in the above of the nature, purpose, 
practical details as well as the risks associated with the study. The patient has read the information 
form and has kept a copy of it. He/she has given his/her voluntary agreement to participate in the 
biomedical research study GRASPA AML 2012-01. 
Surname
 ..........................................................................  First name .........................................................  
Investigator’s 
signature
 ..........................................................................  
Date |__|__| |__|__| |__|__|__|__| 
 


Information Letter & Consent for research on bone marrow sample - version 11 Oct 2015 
 
STUDY GRASPA-AML 2012-01 
 
 
Page 1/2 
 
 
INFORMATION LETTER FOR USE OF THE BONE MARROW SAMPLE 
 
 
Dear Sir or Madam, 
Your doctor is going to take a bone marrow sample. This sample will be used to establish the 
diagnosis of your disease and to tailor its treatment.  
We are writing to ask for your permission to use a part of this bone marrow sample  for the purposes 
of scientific research which could help to understand mechanisms of action, improve treatments or 
develop new medicines. You are free to agree or to refuse your permission for use of your sample in 
this purpose. You can also change your mind at any time without giving reasons; in this case, no 
further analysis will be performed and without penalty or loss of benefits to which you are otherwise 
entitled, however, the results of the analysis already done can be used for scientific purposes. 
This research consists in performing genetic tests (tests on cells which look for changes in DNA or 
RNA) and biomarker tests (tests that look for substances such as proteins that tell the drug is working 
in your body) utilizing specific techniques. The researchers will study how changes in the cells’ 
information and biomarker levels might affect the disease’s response to study treatment, the course 
of the disease and your response to treatment. 
Also cells isolated from the bone marrow sample will be cultured and tested for sensitivity to 
asparaginase (one of a drug we are testing used to treat acute myeloid leukemia). 
Your sample will be anonymized and your name will not be recorded. 
The samples will be sent to ERYTECH Pharma, a pharmaceutical company in Lyon, where part of 
analysis will be done as well as to the MD Anderson Cancer Center (Houston, Texas, USA) and/or 
another central laboratory (within Europe or United States of America- USA-) who performs specific 
method of analysis under ERYTECH responsibility. The analyses conducted by ERYTECH Pharma 
on your sample are part of a clinical trial with reference GRASPA-AML 2012-01. If you meet all the 
selection criteria for patients, your doctor may invite you to take part in this clinical trial. He will 
then explain the aims of the study to you, give you the information documents and ask you for your 
consent to take part. If you agree, further bone marrow samples will be taken for evaluation of the 
disease and part of these samples will be sent to Erytech Pharma for use in the same conditions and 
purpose as described above. 
 
DECLARATION OF CONSENT 
 
I the undersigned 
Full Name: ……………………………………… 
 
Date of birth:   …………………………………… 
Declare that I have understood the information given above and agree for the use of a part of 
the bone marrow sample for the purpose of scientific research and I understand and agree that 
this (these) sample(s) will be sent to ERYTECH Pharma and to other laboratory(ies) (within 
Europe or USA). 
 
Signature of the patient: 
 ........................................................ 
 
Date ................................................ 
(patient must personally write his/her name, sign and date) 


Information Letter & Consent for research on bone marrow sample - version 11 Oct 2015 
 
STUDY GRASPA-AML 2012-01 
 
 
Page 2/2 
 
 
 
I hereby confirm that I have fully informed the patient named in the above of the nature, 
purpose and practical details of this research. The patient has read the information form 
and has kept a copy of it. He/she has given his/her voluntary agreement to participate. 
Investigator’s 
name: 
………………………………… 
 
Investigator’s 
signature
 ........................................................................... 
 
Date  |__|__| |__|__| |__|__|__|__| 
 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
Appendix 11: History of changes 
 
Version, date 
Main changes 
Version 1, 03 Aug 2012 
initial version 
 
Version 2, 30 Nov 2012 
protocol changes requested by France Regulatory Authority, mainly: 
- 
Establish a minimum treatment cycles number: defined to 1 
- 
Limit the age of patients at inclusion to ≤ 85 years 
- 
Precise the “unfit for intensive chemotherapy” to non-eligible to 
receive intensive chemotherapy: added “at risk to suffer treatment 
related pejorative toxicities /early death” 
- 
Clarification of Inclusion criteria “Evidence of post-menopausal 
status for female patients” : added “absence of menstruation for 
12 months” 
- 
Precise the contraindications of Aracytine in exclusion criteria as 
per France SPC of Aracytine: added in the protocol 
- 
Clarification of exclusion criteria:  
o 
History of grade 3-4 pancreatitis or grade 3-4 
thromboembolic event (according NCI-CTCAE 
Version4.0) 
o 
Patient presenting evolutive cancer other than AML, except 
in situ basal-cell carcinoma or in situ cervix cancer 
- 
Note on primary endpoint: changed from EFS to PFS 
- 
Note that the protocol should include only patients with life 
expectancy of ≥ 3 months: added in the protocol in inclusion 
criteria 
- 
Change the SCP of CYTOSAR  to SPC of Aracytine 100mg in 
appendix 1 
 
Version 3, 05 Dec 2012 
added protocol changes requested by France Regulatory Authority:  
o 
Request addition of HIV, hepatitis B and C testing at 
screening 
o 
Added creatinine clearance as lab test 
o 
Updated Appendix 8 of drugs causing hemolysis 
 
Version 4, 21 Jan 2013 
- 
Location: France changed to Europe 
- 
Clarification of secondary endpoint “hospitalization”: except schedule 
protocol visit 
- 
Clarification of secondary endpoint on PK/PD – instead of Free and 
encapsulated L-asparaginase activity, Total L-asparaginase activity 
will be measured; consequently, the section on Plasma L-Asp 
measurement was deleted and the one on total L-Asp changed 
accordingly. 
- 
Correction of immunogenicity timepoints needed: only at Day (D)11, 
and not at D11 and D18.  
- 
Added “Disease (AML) progression, as well as death as consequence 
of disease evolution” as an exception to AE reporting.  
 
Version 5, 20 Nov 2013 
- 
Clarification of patient age for inclusion: “Patient over (or equal to) 65 
years old and less than (or equal to) 85 years old” 
- 
Clarification to exclude this particular patients that have poorer 
prognostic: 
o 
“Patient with Secondary AML consecutive to anterior malignant 
hemopathy as: 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
 
Myelodysplastic syndrome diagnosed more than 6 months 
before study entry 
 
Myeloproliferative syndrome” 
- 
Revision of the restriction regarding cardiac insufficiency from LVEF < 
50% of the theoretical value to ≤40 %, considering that the study 
treatment tested have no cardiotoxic effect and also the age of 
population targeted 
- 
Clarification of randomization and stratification procedure 
- 
Clarification on dose adaptation to confirm that patients discontinuing 
GRASPA or LDC (for an AE) are maintained in the study: 
“Dosage adaptation: 
• Low-dose cytarabine (LDC)  
The dosage could be adjusted to 20 mg daily in case of toxicities at 
investigator's decision. 
Investigator may also consider temporary or definitive withdrawn of 
LDC if necessary. In such case, for patients in arm B, GRASPA should 
be continued as scheduled, every 28 days. 
• GRASPA  
If patient cannot receive GRASPA for other reason than toxicity, 
GRASPA should be postponed no later than one week after the initial 
schedule day, and, in any case should be resumed at the next block. 
If GRASPA cannot be resumed and must be definitively withdrawn for 
any reason, patient should be kept under LDC.” 
 
- 
Clarification on attention to be paid to diabetic patients treated with 
oral hypoglycemic agents and not only with sulfamides. 
- 
Modified collection of patient initials: to be restricted as per local 
regulations 
- 
Updated SAE form, as per internal review.  
 
Version 6, 05 May 2014 
- 
Clarification of study title to align with inclusion criteria: “elderly 
patients” instead of “over 65 years” 
- 
Clarification of inclusion criteria “Subscription to social security 
insurance”: added “(if applicable in accordance with local regulations)” 
as this is required by French authorities, but not necessarily by other 
countries.  
- 
Addition/clarification of following exclusion criteria as per BfArM 
request: 
o 
“Total bilirubin > 2 ULN  
o 
INR > 1.5 
o 
Insulin-dependent or uncontrolled diabetes mellitus 
o 
Active cancer other than AML, except in situ basal-cell 
carcinoma or in situ cervix cancer 
o 
Severe active infection, HIV seropositivity, or active type B 
or C viral hepatitis” 
o 
Sexually active man of potential fertile couple not willing to 
use highly effective contraceptive method 
- 
Added section “8.5 Dosage modification in case of toxicity” as per 
BfArM request 
- 
Clarification of concomitant treatment requests  
- 
Modifications of section “Adverse Events Reporting” as per BfArM 
request, mainly: 


GRASPA-AML 2012-01  
 
Protocol Version 07, dated 05 Oct 2015 
– CONFIDENTIAL – 
 
o 
Collection of all clinically significant AEs 
o 
SAE reporting within max 24h 
- 
Clarification of DSMB review timepoints 
 
Version 7, 05 Oct 2015 
- 
Change of primary endpoint from Progression free survival (PFS) to 
Overall survival (OS) 
- 
Change of PK/PD sampling to allow for more samplings after GRASPA 
infusion 
- 
Added “eryaspase” as proposed INN, instead of “L-asparaginase 
encapsulated in erythrocytes” 
- 
Re-definition of response criteria in AML and clarification of 
assessment requirements 
- 
Clarification of some inclusion/exclusion criteria, mainly: 
- 
Unfit for intensive chemotherapy 
- 
Contraception period 
- 
Accepted lab tests upper values  
- 
Updated contraindications, concomitant medication and precautions 
for use sections to be in line with the proposed GRASPA SPC  
- 
Updated/clarification of study flow chart 
- 
Updated statistical plan section as well as other relevant sections 
according to changes above 
 
 

SAP_001.pdf: 
Erytech Pharma 
Protocol GRASPA-AML 2012-01 Version 2.0 
Confidentiality 
This document is confidential and proprietary property of Erytech and to be used only as authorized by Erytech. 
No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Erytech 
STATISTICAL ANALYSIS PLAN 
GRASPA-AML 2012-01 
A Multicentre, open, randomized, controlled phase IIb trial evaluating 
efficacy and tolerability of GRASPA (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) patients, over 
65 years, unfit for intensive chemotherapy. 
Protocol Number: 
(Version Date) 
2012-002026-78 
05Oct2015 
Name of Test Drug: 
GRASPA (L-asparaginase encapsulated in red blood cells, 
eryaspase) 
Phase: 
2b 
Methodology: 
Open-label, Double-blind, Controlled Trial 
Sponsor: 
ERYTECH Pharma 
Bâtiment Adénine  
60 avenue Rockefeller  
69008 LYON France  
Phone: +33 (0)4 78 74 44 38 
Sponsor Representative: 
Dr. Iman El Hariry 
Chief Medical Officer 
Sponsor Representative: 
Dr. Richard Kay PhD 
Statistical Consultant 
Document Date: 
26OCT2017 
Document Version: 
Final 




Erytech Pharma 
Protocol GRASPA-AML 2012-01 
Version 2.0 
CONFIDENTIAL 
Sponsor Signatory: 
Iman El Hariry, MD 
Chief Medical Officer 
ERYTECH Pharma 
60 avenue Rockefeller 
69008 Lyon FRANCE 
Signature: 
Date: 27Nov2017 


Erytech Pharma 
Protocol GRASPA-AML 2012-01 
Version 2.0 
CONFIDENTIAL 
4 
TABLE OF CONTENTS 
Section 
Page
1.
INTRODUCTION AND OBJECTIVES OF ANALYSIS......................8
1.1. 
Introduction .................................................................................... 8 
1.2. 
Objectives of Statistical Analysis .................................................. 9 
1.2.1. 
Primary objective .............................................................. 9 
1.2.2. 
Secondary and exploratory objectives .............................. 9 
2.
STUDY DESIGN ...................................................................................... 10
2.1. 
Synopsis of Study Design ............................................................. 10 
2.2. 
Randomization Methodology ...................................................... 11 
2.3. 
Stopping Rules and Unblinding .................................................. 11 
2.4. 
Study Procedures ......................................................................... 12 
2.5. 
Efficacy, Pharmacokinetic, and Safety Variables ..................... 15 
2.5.1. 
Efficacy Variables ........................................................... 15 
2.5.2. 
Pharmacokinetic Variables ............................................. 15 
2.5.3. 
Safety Variables .............................................................. 16 
3.
SUBJECT POPULATIONS .................................................................... 17
3.1. 
Population Definitions ................................................................. 17 
3.2. 
Protocol Violations ....................................................................... 17 
4.
STATISTICAL METHODS ................................................................... 18
4.1. 
Sample Size Justification ............................................................. 18 
4.2. 
General Statistical Methods and Data Handling ...................... 18 
4.2.1. 
General Methods ............................................................. 18 
4.2.2. 
Computing Environment ................................................. 19 
4.2.3. 
Methods of Pooling Data ................................................ 19 
4.2.4. 
Adjustments for Covariates ............................................. 19 
4.2.5. 
Multiple Comparisons/Multiplicity ................................ 19 
4.2.6. 
Subpopulations ................................................................ 19 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up .................... 20 
4.2.8. 
Missing, Unused, and Spurious Data .............................. 20 


 
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Section 
Page
4.2.9.
Visit Windows ................................................................20
4.3. 
Interim Analyses .......................................................................... 20 
4.4. 
Subject Disposition ....................................................................... 20 
4.5. 
Demographic and Baseline Characteristics ............................... 20 
4.6. 
Efficacy Evaluation ...................................................................... 21 
4.6.1. 
Analysis in the ITT population ..... Error! Bookmark not 
defined. 
4.6.2. 
Sensitivity analyses ......................................................... 21 
4.6.3. 
Secondary criteria ........................................................... 22 
4.6.4. 
Exploratory criteria ......................................................... 26 
4.6.5. 
Biomarker assessments ... Error! Bookmark not defined. 
4.7. 
Pharmacokinetic Evaluations ..................................................... 27 
4.8. 
Safety Analyses ............................................................................. 27 
4.8.1. 
Adverse Events ............................................................... 27 
4.8.2. 
Laboratory Data .............................................................. 30 
4.8.3. 
Vital Signs and Physical Examinations .......................... 32 
4.8.4. 
Concomitant Medications ............................................... 33 
5. 
CHANGES TO PLANNED ANALYSES .............................................. 34 
6. 
References ................................................................................................. 35 
7. 
CLINICAL STUDY REPORT APPENDICES ..................................... 36 
7.1. 
Statistical Tables, Figures, and Lisitings to be Generated ....... 36 
7.2. 
Data Listings to be Generated ..................................................... 43 
 


 
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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse events 
aPTT 
Activated Partial Thromboplastin Time 
ASNS 
Asparagine Synthetase 
ATIII 
Antithrombine III 
AML 
Acute Myeloid Leukemia 
BLLQ 
Below Lower Limit of Quantification 
BM 
Bone Marrow 
BMBC 
Bone Marrow Blast Count  
BMI 
Body Mass Index 
C 
Course 
CR 
Complete Remission 
CRi 
Complete Remission with incomplete recovery 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
D 
Day 
dps 
decimal places 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
HLT 
High Level Terms 
HLGT 
High Level Group Terms 
ICH 
International Conference on Harmonisation 
ICTA 
International Clinical Trial Association 
ITT 
Intention To Treat 
IU 
International Unit 
IWRS 
Interactive Web Response Services 
LDAC 
Low dose cytarabine 
LLT 
Lowest Level Terms 
LOCF 
Last Observation Carried Forward 
MEDDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messager Ribonucleic Acid 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
LDAC 
Low Dose Cytarabine 
LPLV 
Last Patient Last Visit 
NCI CTCAE 
National Cancer Institute   
Common Terminology Criteria for Adverse Events 
PFS 
Progression Free Survival 
PBBC 
Peripheral Blood Blast Count 


 
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Abbreviation 
Definition 
PP 
Per Protocol 
PD 
Progressive Disease 
PR 
Partial Remission 
PT 
Preferred Term 
QOL 
Quality Of Life 
RBC 
Red Blood Cells 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TFL 
Tables Figures Listings 
WHO 
World Health Organization 


 
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1. 
INTRODUCTION  
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study data 
and outlines the statistical programming specifications, tables, figures and listings. It describes the 
planned analyses of the data collected during the study, including the safety and efficacy variables and 
populations, anticipated data transformations and manipulations, and other details of the analyses not 
provided in the study protocol, for the purpose of submission to the relevant authorities and for 
publication as appropriate. The results of all analyses in this SAP will be included in the Clinical Study 
Report (CSR). 
This SAP is based on the following study documents: 
 
Protocol Version 7 dated  05OCT2015 
 
Protocol Amendment n°4 dated 05OCT2015  
 
Electronic Case Report Form (eCRF) for the study. 
The statistical analyses will be performed in accordance with International Conference on Harmonization 
(ICH) E9 guidelines. This SAP conforms to the Cytel standard operating procedure STAT C002 Timing 
and Content of Statistical Analysis Plans. 
The SAP should be validated and signed before the study database is locked.  
Specifications of outputs (i.e. TLFs shells) will be described in a separate document.  
The primary analyses were to be undertaken when all enrolled patients had completed treatment and 
follow-up period for 2 years. However, based on the outcome of the AML Advisory Board meeting 
conducted on 24th January 2017, there was a consensus that the study was not adequately powered for the 
key endpoint of overall survival (OS) and that the purpose of the statistical analyses was therefore to 
identify a signal strong enough to support proceeding to phase 3.  
This is a phase 2 proof of concept study and all efficacy parameters will be considered as the basis for 
conclusions regarding the activity of GRASPA in this population. P-values will be calculated for analyses 
of the primary endpoints in all patients. A two-sided 0.05 level of significance will be used as a guidance 
for interpretation of the data, but strict statistical significance will not be the only basis on which efficacy 
will be judged. In particular, the conclusions will not be based solely on the primary analysis of the primary 
endpoint. As indicated at the advisory board meeting, a Hazard Ratio (HR) less than 0.8 would indicate an 
interesting level of activity (approximately an increase in median OS from 6.4months to 8.0 months), 
which would warrant further investigation in a Phase 3. The activity of GRASPA will be concluded 
collectively in relation to the clinical relevance as indicated by the magnitude of effect across a range of 
endpoints (the totality of evidence). 


 
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2. 
OBJECTIVES OF STATISTICAL ANALYSIS 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s).  Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided.  The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
2.1.1. 
Primary objective 
The primary objective is to evaluate Overall Survival (OS) in AML patients 65 to 85 years unfit 
for intensive chemotherapy, when treated with GRASPA plus low-dose cytarabine (LDAC) 
compared to low-dose cytarabine alone (LDAC). 
2.1.2. 
Secondary and exploratory objectives 
The secondary and exploratory objectives are to evaluate: 
 Response to treatment 
 Progression Free Survival (PFS) 
 Relapse Free Survival  
 Patient transfusion needs 
 Patients’ quality of life evolution 
 Number of hospitalizations 
 Safety of GRASPA in combination with cytarabine 
 Pharmacokinetic and pharmacodynamic parameters of GRASPA® 
 Immunogenicity of GRASPA 
 Asparagine Synthetase (ASNS) expression and sensitivity to L-asparaginase in bone 
marrow cells (optional) 
 Biomarker cytogenetic testing (optional) 


 
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3. 
STUDY DESIGN 
3.1. 
Synopsis of Study Design 
This is a multicentre, open label, randomized 1:2 (control versus GRASPA), controlled phase IIb 
trial in Europe, evaluating efficacy and tolerability of GRASPA. The trial follows the scheme 
below: 
 
In both treatment and control arms, patients will be treated with subcutaneous LDAC as 40 mg 
daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 
consecutive days per course, each course occurring every 28 days +/- 3 days, for a duration up to 
24 months. Each period of 28 days constitutes a cycle of chemotherapy. The dosage could be 
adjusted to 20 mg once daily in case of toxicities; a higher dose is also acceptable if required by 
the patient’s status, at the investigator's decision. 
In the experimental group, the patients will receive subcutaneous LDAC, as described above, and 
GRASPA (100 U/kg) given as an intravenous infusion at Day 11 of each 28 day course. 
Patients will be required to attend a visit once a month, as the course begins. 
When study treatment is stopped (main expected reasons are limiting toxicity, PD, or no evidence 
of treatment benefit), the visits will take place every 3 months until 24-months study duration has 
been reached. 
An Independent Data Monitoring Committee (IDMC) was set-up for regular data reviews for 
safety: they reviewed the tolerance of GRASPA when 30 patients had been enrolled, to evaluate 
limiting toxicities defined as one of the following: 
 grade 3 or 4 pancreatic toxicity 
 grade 3 or 4 hepatic toxicity, allergic reaction, or coagulation event 


 
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 other non-hematologic grade 4 toxicity or requiring treatment change at 
investigator's decision 
Specific attention is paid on type II diabetic patients treated with oral hypoglycemic agents for 
their diabetes, randomized to LDC + GRASPA. 
The IDMC also reviewed safety and tolerance of GRASPA when 60 patients had been enrolled, 
at the end of recruitment and when 60 PFS events had been observed. 
Additional information is provided in the IDMC Charter and the minutes of the IDMC meetings. 
3.2. 
Randomization Methodology 
The patients will be randomly and sequentially allocated to either one of the two treatments A or 
B, and the treatment allocation will be stratified by Eastern Cooperative Oncology Group 
(ECOG) performance status (PS=0 or 1 versus PS=2). This will ensure balance between the 
performance groups, which was been identified as a risk factor for early death. 
Randomization 1:2 will be performed using Interactive Web Response Services (IWRS).  
Randomization group will be confirmed to investigator by e-mail, specifying the treatment arm 
assigned, namely A or B, as follows: 
 A: Low-dose cytarabine 
 B: Low-dose cytarabine + GRASPA 
Randomization will continue until 123 patients are recruited and receive study treatment. 
3.3. 
Stopping Rules and Unblinding 
An interim analysis was originally planned to be performed when half of the 123 expected PFS 
events had occurred (i.e. 60). The study could have been stopped at this point for futility.  
However, this interim analysis was not undertaken.


 
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3.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
 
Table 1: Schedule of Assessments  
 
TREATMENT COURSE – 28 days cycle (+/- 3 days)
Day
D – 28 
max.
1
2
3
4
5
6
7
8
9
10
11
13
18
23
27
Visit
Inclusion
1/2/3 
…
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent
X
Demographics
X
Inclusion/exclusion criteria
X
Medical history
X
AML history/ assessment (a)
X
X*
Clinical assessment (b)
X
Quality of life survey
X
Randomization
X
Low-dose cytarabine
X
X
X
X
X
X
X
X
X
X
GRASPA
P
X
IAST (c)
X
PK- PD (only for GRASPA receiving 
patients) (d)
 
 
 
 
 
 
 
 
 
 
 
X
X
X
 
X
Immunogenicity (only before GRASPA 
administration)
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
 
Biology (e)
X
X (f)
X
X
X
X
X
X
Patient diary distribution and/or 
review
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Bone marrow aspiration and extramedullary assessment may take place in the 4 weeks prior to randomization, for baseline status; samples for biomarkers 
assessments should be sent within max. 2 days after collection; 


 
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(b) including occurrence of AE/SAE; concomitant treatment; 
(c) Irregular Antibodies Screening Test only for patients receiving GRASPA; 
(d) See PK-PD assessments table 5 
(e) hematology (CBC) ; biochemistry ; coagulation parameters; serology tests only at inclusion; pregnancy test at inclusion and end of treatment, if applicable 
(f) for the first course = if biochemistry/hematology tests are available within 7 days, it is not necessary to repeat them; for coagulation tests – results should not 
be older than 3 days; for subsequent courses = to be performed within max. 3 days before next treatment course start;  
P : prescription of GRASPA; 
*: before the next treatment course 
 
 
 
Table 2: Calendar of Study PK/PD Assessments  
 
 
Table 3: Calendar of Study Assessments – Follow-Up 
 
 
 
 
 
 


 
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*: a phone call, at minimum, will be performed at 4 months (+/- 1 week) after end of study treatment, for safety assessment 
Patient will have to attend visit every 28 days (+/- 3 days), at the start of each cycle, for a duration up to 24 months. Assessments required are 
provided in Tables 1 and 2. 
When study treatment is stopped (see required conditions in section 8.9), the visits will take place every 3 months until 24-months study duration.  


 
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3.5. 
Efficacy, Pharmacokinetic, and Safety Variables 
3.5.1. 
Efficacy Variables 
The primary objective of this study is to evaluate the efficacy and tolerability of GRASPA when 
combined with LDAC. The primary endpoint is overall survival (OS), defined as the time 
elapsed between randomization and death for any cause. Patients not known to have this event 
are censored on the date they were last examined. 
Secondary efficacy endpoints include the following: 
1) Complete remission (CR), Complete remission with incomplete recovery (neutrophil or 
platelet regeneration, CRi), Partial remission (PR)  
2) Progression-free survival (PFS) defined as the time elapsed between randomization and 
resistant disease or relapse or death from any cause  
3) Relapse Free Survival defined only for patients who achieved CR or CRi as the time 
elapsed between date of CR/CRi and date of disease relapse or death from any cause   
4) Percentage of patients who need transfusions (red blood cells and/or platelets), number 
of transfusions by patient 
5) Patient quality of life evaluated using the EORTC QLQ-C30 version 3 scale 
6) Number of hospitalizations (except scheduled protocol visit) required during the study 
 
3.5.2. 
Pharmacokinetic Variables 
Blood samples for determination of GRASPA pharmacokinetics were to be collected as outlined 
in the protocol.  Pharmacokinetic parameters to be determined include minimum plasma 
concentration (Cmin), maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax), the distribution rate constant (λzl), distribution half-life (dist t1/2), elimination 
rate constant (λz2), terminal elimination half-life (elim t1/2), area under the concentration versus 
time curve (AUC), clearance (Cl/F), and volume of distribution () (Vd/F). 
Pharmacokinetic and pharmacodynamic endpoints include the following:  
1) Plasma concentrations of asparagine, aspartate, glutamine, glutamate 
2) Whole Blood L-asparaginase activity 
3) Immunogenicity by measuring titer of anti-L-asparaginase antibodies  
4) Biomarker cytogenetic testing (optional)  
5) Measurement of the following parameters on harvested bone marrow tumor cells 
(optional): 
a. Asparagine synthetase protein expression  
b. Asparagine synthetase mRNA expression  


 
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c. In vitro sensitivity to L-asparaginase 
 
3.5.3. 
Safety Variables 
All subjects who received at least one dose of investigational products will be included in the 
safety analyses. Safety data will be summarized using actual treatment received, regardless of 
randomized treatment.  
Safety and tolerability will be assessed in terms of AEs, SAEs, laboratory data and vital signs 
which will be collected for all subjects. AEs will be coded according to the Medical dictionary 
for regulatory activities (MedDRA) version 15.1 or higher. The intensity of AEs will be graded 
according to the NCI-CTCAE (version 4.0).  
AEs, AE leading to study treatment discontinuation, AE related to study treatment, and SAEs will 
be listed individually by subject, and summarized by System Organ Class (SOC) and Preferred 
Term (PT) by treatment group. Summary of AEs with NCI-CTCAE grade 3 or 4 and most frequent 
PT will also be provided. 
Specific attention will be given to NCI-CTCAE Grade 3 or 4 of pancreatic toxicity, Grade 3 or 4 
of hepatotoxicity, allergic reactions or coagulation disorders, known to be potentially related to 
L-asparaginase as well as to hypoproteinemia and hyperglycemia/diabetes events. 
Specific safety endpoints will include the following: 
1) Safety of GRASPA in combination with low-dose cytarabine, with specific attention to :  
a. Grade 3 or 4 of pancreatic toxicity  
b. Grade 3 or 4 of hepatic toxicity, allergic reaction or coagulation event  
c. Grade 3 or 4 of hypoproteinemia or hyperglycemia/diabetes  
d. All other non-hematologic Grade 4 toxicities 
 


 
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4. 
SUBJECT POPULATIONS 
4.1. 
Population Definitions 
The intent-to-treat (ITT) population will comprise all randomized patients in the groups to 
which they were randomly assigned, regardless of their adherence with the entry criteria, 
regardless of the treatment they actually received, and regardless of subsequent withdrawal from 
treatment or deviation from protocol. 
The per-protocol (PP) population will comprise all patients from the ITT population without 
any major protocol deviation that have received trial product and have completed at least one 
course of treatment. 
All data analysed on the ITT or PP populations will be summarized using randomized treatment. 
The safety population will comprise all patients that have received at least one administration of 
trial products. 
All data analysed on the safety population will be summarized using actual treatment received. 
The responsibility for defining the study populations and excluding patients from the analysis will 
be a joint decision by the sponsor, trial statistician, investigator and trial monitor. The patients to 
be excluded and the reasons for their exclusion must be documented and signed by those 
responsible prior to database release. The documentation must be stored together with the 
remaining trial documentation.  
4.2. 
Protocol Violations 
Major protocol violations are defined as violations liable to prevent or change the interpretation 
of the results of the study or may impact patient safety, affect the integrity of study data and/or 
affect patient’s willingness to participate in the study.  
The list of protocol violations will be drafted by ICTA PM and sent to sponsor for approval. The 
list will contain possible protocol violations (according to inclusion/exclusion criteria, disallowed 
treatments, minimum treatment exposure, and calendar of visits...), and significant violations 
which require immediate information to the Sponsor will be identified.  This list may be updated 
in the course of the Data Management process, and will be finalized during the data review 
meeting before database lock. 
During the data review, the impact of each violation (Minor/major) on the primary endpoint will 
be discussed and thus, the list of patients to be excluded from the population sets will be defined. 
Patients who met protocol violation as detailed in the previous list will be listed and the number 
of such patient will be summarized.  


 
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5. 
STATISTICAL METHODS 
5.1. 
Sample Size Justification 
The sample size calculation is based on the original primary efficacy endpoint (PFS). We assumed 
75% improvement in median PFS in the GRASPA plus LDAC group (treatment) compared to 
median PFS in the LDAC group (control). This corresponded to a median PFS of 2 months for 
the null hypothesis and a median of 3.5 months for the alternative hypothesis. An assumption of 
24 months of accrual time and whole study duration of 48 months was used. No dropout rate was 
taken into consideration. 
With a two-sided 5% level significance test and a power of 80%, taking into account the 
unbalanced group size (1 : 2), a total of 117 patients should be enrolled in order to observe 117 
PFS events. 
The study was designed based on the initial primary endpoint using group sequential 
methodology, allowing for interim analysis for futility. In order to account for this, the sample 
size was increased from 117 to 123 patients (41 in the LDAC group and 82 in the GRASPA plus 
LDAC group).  
However, the sponsor amended the study, and the primary endpoint was changed from PFS to 
OS. It is acknowledged that the study is not powered to detect a statistically significant difference 
in OS; rather this is a proof of concept signal seeking study. In light of this, the one-sided 
significance level will be 0.025.  
A decision as to whether GRASPA appears to be a promising drug in this indication will be based 
on the numerical values for the hazard ratio for OS. A hazard ratio of ≤0.80 will indicate a 20% 
numerical reduction in the death rate on average over time in the GRASPA group compared to 
control. 
5.2. 
General Statistical Methods and Data Handling 
5.2.1. 
General Methods 
All outputs will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic 
and safety parameters.  For categorical variables, summary tabulations of the number and 
percentage within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the mean, median, standard deviation, minimum and 
maximum values will be presented.  Time to event data will be summarized using Kaplan-Meier 
methodology with median time to event and associated 2-sided 95% confidence intervals, as well 
as percent of censored observations.   


 
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Formal statistical hypothesis testing to be performed on the primary efficacy endpoint will be 
conducted at the 1-sided, 0.025 level of significance. Secondary efficacy endpoints will be 
conducted at the 2-sided, 0.05 level of significance.  Summary statistics will be presented, as well 
as confidence intervals on selected parameters, as described in the sections below. 
Any patient not known to have had an event (death/progression) at the time of analysis will be 
censored based on the last recorded date on which the patient was known to be event-free.  
For numeric secondary endpoints (e.g. quality of life scores) the analysis of these endpoints will 
be based on observed data. For repeated measures analyses using mixed models, all available data 
will be included in the analysis, and missing data will not be imputed. 
5.2.2. 
Computing Environment 
All statistical analyses will be performed using Statistical Analysis Systems (SAS®) release 9.2 
or higher, unless indicated otherwise. All computer programs will be developed and validated 
according to ICTA PM (CRO) standard operating procedures. 
Medical History and adverse events will be coding using MedDRA version 15.1 or higher.  The 
intensity of AEs will be graded according to the NCI-CTCAE (version 4.0).  Concomitant 
medications will be coded using World Health Organization (WHO) Drug Dictionary, version 
March 2013.  
5.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
5.2.4. 
Adjustments for Covariates 
No formal statistical analysis that adjusts for possible covariate effects is planned. 
5.2.5. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a single primary efficacy endpoint. 
5.2.6. 
Subpopulations 
Analyses (estimated treatment effects and 95% confidence intervals) will be undertaken in 
relation to OS, PFS and objective response according to the following subgroups and presented 
in Forest Plots: 
 Gender (male/female) 
 ECOG PS (0 versus 1 versus 2) 
 Age (< 70 / ≥ 70) 
 Karyotype (Intermediate risk / High risk) 
 Baseline bone marrow blasts, % (< 20% / ≥ 20% to ≤30%/ >30%) 
 LDH levels at baseline (normal/elevated/unknown) 


 
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 FAB (French-American-British) Classification of AML (M1/2 vs. M4/5 vs. M0/6/7)  
Other subgroups may be investigated in exploratory analyses. 
5.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who withdrew from the study were not to be replaced. 
5.2.8. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points.  All data 
recorded on the CRF will be included in data listings that will accompany the clinical study report.   
5.2.9. 
Visit Windows 
Assessments are taken at specific study days in relation to the first day of LDAC (Study Day 1).  
LDAC is administered each day following and including Day 1, for 10 consecutive days (D1-
D10). Patients in the treatment group are also administered GRASPA at Day 11. This will occur 
each course, which is 28 days +/- 3 days.  
Biological assessments will be performed (if applicable) at D1, D5, D9, D13, D18, D23 and 
D27 during each course (+/- 2 days). The quality of life questionnaire and information about 
both hospitalizations and transfusion needs will be completed at each visit. 
Follow-up visits will occur at the end of study treatment every 3 months +/- 2 weeks (i.e. M3, 
M6, M12,…). At minimum, a phone call will be performed every 4 months +/- 1 week after end 
of treatment for safety assessments. 
5.3. 
Interim Analyses 
This study was designed with a group sequential design to provide an interim analysis for futility. 
This futility evaluation was removed from consideration prior to its’ scheduled occurrence and 
did not take place. 
5.4. 
Subject Disposition 
A tabulation of subject disposition will be tabulated, including the number screened, the number 
dosed with each treatment, the number in each subject population for analysis, the number that 
withdrew prior to completing the study, and reasons for withdrawal. The number in each risk 
group (PS=0 or 1 versus PS=2) will be tabulated.   
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
5.5. 
Demographic and Baseline Characteristics 
Baseline, demographic and medical history information will be summarized using descriptive 
statistics.  No formal statistical comparisons will be performed.  


 
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Demographic and baseline data will be provided in data listings. 
5.6. 
Efficacy Evaluation 
All efficacy analyses will be performed on the ITT population. Analyses on the primary efficacy 
endpoint will be repeated on the PP population. 
Primary Endpoint Definition and Analysis 
The primary endpoint, OS, will be defined as the time elapsed between date of randomization 
and date of death (or censoring) from any cause. Any patient not known to have died at the time 
of analysis will be censored based on the last recorded date on which the patient was known to 
be alive. 
The primary objective of the trial is to estimate whether GRASPA plus LDAC is more promising 
than LDAC alone with respect to OS in subjects from 65 to 85 years old with newly diagnosed 
AML unfit for intensive chemotherapy. 
Overall survival will be summarized by treatment group for the ITT population. Summaries will 
include the number of patients who died during the study, the number of patients who didn’t die 
during the study (censored) with the date of censoring equal to the date that the patient was last 
known to be alive. Median time-to-event will be estimated from a Kaplan-Meier analysis, with 
associated survival curves produced. The p-value for this analysis will be provided from the 
stratified log-rank test, with stratification variable of type of ECOG performance status (0 or 1 
versus 2) and will compare the overall survival curves between the two treatment groups. In 
addition, the hazard ratio and its associated 95% CI will be estimated from a stratified Cox 
proportional hazards model using the same strata as the Kaplan-Meier analysis (ECOG status) 
and censoring rules. Forest plots for the OS hazard ratios for the subgroups detailed in Section 
4.2.6 will also be produced.  
OS event rates at Months 12 and 24 will be summarized by treatment group for the ITT 
population. Summaries will include the event rate for each treatment group from the Kaplan-
Meier analysis, using the estimated proportions at Month 12 and 24. A 95% CI for the difference 
in event rates between the treatment groups will also be provided.  
5.6.1. 
Sensitivity Analyses for the Primary Endpoint 
The analyses described in Section 4.6 will also be repeated on the PP population and separately 
for patients recruited before and after the protocol amendment to assess sensitivity of results to 
protocol compliance and amendment. 
A further sensitivity analysis will be undertaken based on a stratified Cox Model, stratified for PS 
(0 or 1 versus 2), and including age (< 70 / ≥ 70) and Karyotype (Intermediate risk / High risk) as 
covariates.  


 
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5.6.2. 
Secondary Endpoint Definitions and Analyses 
Secondary endpoints will be assessed on both the ITT and PP populations. 
5.6.2.1. Complete Remission (CR), Complete Remission with Incomplete Recovery (neutrophil 
or platelet recovery, CRi, CRp), Partial Remission (PR) 
Definitions for CR, CRi, and PR can be found in Table 4 below. This information will be 
collected in the section “AML-disease evaluation.”  Responses are entered by the site in 
accordance with various criteria. Exploratory analyses may include imputed responses (not site 
defined) based on the data available per the criteria in Table 4 for the derivation of response.  
 
 


 
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Table 4: Definitions of CR, CRi, PR, Relapse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percentages of patients with CR, CR or Cri, and PR will be calculated and presented by 
treatment group. All other subjects will be considered non-responders for determining the 
denominator. This objective response rate data (i.e. CR, CRi or PR) will be analyzed based on a 
logistic regression model with both treatment and PS included in the model. The treatment 
effect will be summarized with an adjusted Odds Ratio (OR) and 95% confidence interval. 
Percentage of patients with objective response will be calculated and associated exact 95% CIs 
will be presented by treatment group.  
5.6.2.2. Progression-Free Survival (PFS) 
PFS was originally defined as death due to progression in the protocol. However, to be consistent 
with regulatory guidance, which considers death from any cause in its definition, this endpoint 
was modified to be time elapsed between randomization and disease progression or death from 
any cause. Patients not known to have any of these events will be censored on the date they were 
last known to be event-free. 
Category  
Definition according to protocol 
V4 to V6 
Definition according to 
protocol V7 
Morphologic 
leukemia-free state 
Bone marrow blasts < 5% 
No extramedullary disease 
Complete remission 
(CR) 
Morphologic CR
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count > 1.0 × 109/L 
(1000/μL); platelet count > 100 × 109/L (100 000/μL); patient 
independent of transfusions 
Cytogenetic CR 
Cytogenetic normal (in those with previously abnormal cytogenetics) 
Molecular CR 
Molecular studies negative 
CR with incomplete 
recovery (CRi) 
All CR criteria except for residual neutropenia (< 1.0 × 109/L [1000/μL]) 
OR thrombocytopenia (< 100 × 109/L [100 000/μL]).  patient 
independent of transfusions 
Partial remission 
(PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5% to 25% And normalization of blood counts 
Relapse following CR
Bone marrow blasts ≥ 5%; OR reappearance of blasts in the blood OR 
Development of extramedullary disease 


 
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Progressive disease (PD) will be defined according to the section “AML-DISEASE 
EVALUATION” in the e-CRF as any of the following 
 At least a 25% increase of BMBC compared with baseline (defined in the section 
“AML history / BM evaluation at baseline”, Bone Marrow Aspirate - Analyte - 
Blast)  
 At least a 50% increase of PBBC compared with baseline 
 Presence of extramedullary disease 
Potential PD events presented by the patients will be reviewed and approved before database 
lock. 
The methods for the analysis of PFS will be the same as those for OS. Specifically, PFS will be 
analyzed at the time of final analysis using a stratified log-rank test (stratified by PS) and 
displayed using Kaplan-Meier curves. Furthermore, a Cox model will also be used to test the 
effect of treatment and will include terms for prognostic factors (PS, age and karyoptypic 
group). 
 
5.6.2.3. Relapse Free Survival (RFS) 
Relapse free survival is defined for patients who have achieved CR or CRi, as time elapsed between date 
of CR or CRi and date of disease relapse or death from any cause. Patients not known to have any 
of these events will be censored on the date they were last known to be event-free. 
Specifically, RFS will be analyzed at the time of final analysis using a stratified log-rank test 
(stratified by PS) and displayed using Kaplan-Meier curves. Furthermore, a Cox model will also 
be used to assess the effect of treatment and will include terms for prognostic factors (PS, age 
and karyotipic group). P-values for these analyses however will not be quoted as these are not 
randomised comparisons. 
 
5.6.2.4. Transfusions 
For collection of information regarding transfusions, the following variables will be collected at 
each visit:  
 Transfusions (Yes/No) 
If yes, 
o mean number of transfusions 
o mean weekly number of transfusions 
o mean number of units transfused 
o at least 1 transfusion of RBC (Yes/No) 


 
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o at least 1 transfusion of platelets (Yes/No) 
o at least 1 transfusion of other (Yes/No) and specifications 
 
Any transfusion occurring after a PD will not be taken into account. 
 
The number of transfusions will be grouped by quarter, up to an event (PD/death) and overall, 
by treatment group, using descriptive statistics. The mean number of transfusions of RBC and/or 
platelets required during the study, along with a corresponding 95% CI, will be calculated.  
 
5.6.2.5. Quality of Life 
Quality of life (QoL) will be defined by raw scores obtained from the QoL questionnaire (EORTC 
QLQ-C30), which is to be completed by all participants at each visit. Raw score at each visit, 
absolute and relative change from baseline score will be described in each treatment group for the 
5 items of the functional scale, the QoL, the three symptom scales and the six single items. 
EORTC QoL scores will be compared across time in each treatment group using a mixed model 
for repeated measures data. 
The event to be considered in further analyses is QoL deterioration, defined as a decrease in QoL 
score from baseline without any return to a better state during the study. A 10% decrease in total 
QoL score from baseline will be considered the primary threshold of interest. Other thresholds 
may be considered as exploratory analyses. Of note, death will also be considered as a QoL 
deterioration. 
 
5.6.2.6. Hospitalizations 
For collection of information regarding hospitalizations, the following variables will be collected 
at each visit:  
 Hospitalization (Yes/No) 
If yes, 
o mean number of hospitalizations 
o mean weekly number of hospitalizations 
o reasons for hospitalization 
o mean duration of hospitalization (days) 
 
The duration of hospitalization will be defined in days as the following:  
 If hospitalization lasts more than 24 hours, the duration=End Date - Beginning Date + 1 
 If hospitalization lasts less than 24 hours, the duration=1 day 
 
Any hospitalization occurring after a PD will not be taken into account. 


 
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The number of hospitalizations will be grouped by quarter, up to an event (PD/death) and 
overall, by treatment group, using descriptive statistics. The mean number of hospitalizations 
occurring during the study, along with a corresponding 95% CI, will be calculated. 
 
Additionally, a special focus will be taken on hospitalization lasting more than 24 hours, and all 
previous variables will be described for hospitalizations lasting more than 24 hours. 
5.6.3. 
Exploratory Endpoints 
Bone marrow biopsy/aspirate will be collected at study entry and analyzed for biomarker analysis 
of potentially relevant biomarkers, utilizing proteomic and transcriptomic techniques. 
Assessments could be repeated on further bone marrow aspirate, if possible. This data will be for 
exploratory purposes. 
The following assays will be performed:  
 Mononuclear cells from bone marrow of AML patients will be assessed for Asparagine 
synthetase (ASNS) expression by two different methods: real-time qRT-PCR for the 
quantification of ASNS mRNA and westernblot for the quantification of ASNS. 
 Mutational analyses and detection of gene amplification of relevant oncogenes; e.g. FLT3, 
NPM1, IDH, or KIT. 
 Dependent upon tissue availability, immunohistochemistry (IHC), gene expression 
profiling and transcriptomic profiling may be performed.  
 Other biomarkers deemed relevant that may emerge with new scientific data. 
Cells isolated from bone marrow by ficoll will be also cultured in presence of L-asparaginase. In-
vitro sensitivity to L-asparaginase will be assessed at ERYTECH Pharma by measuring the 
cytotoxicity using a colorimetric assay. 
ARN and proteic extraction obtained from samples will be frozen at ERYTECH Pharma in order 
to perform other analyses allowing a better knowledge of mechanism of action, or new drug 
development. 
ASNS mRNA expression at baseline will be summarized by treatment group, and select efficacy 
endpoints will be plotted against ASNS mRNA expression. 
 
 
 
 
 


 
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5.7. 
Pharmacokinetic Evaluations 
Pharmacokinetic, pharmacodynamic and immunogenicity parameters will only be assessed on the 
subgroup of subjects having received GRASPA. Samples of amino acids (asparagine, aspartate, 
glutamine and glutamate) and whole blood asparaginase  will be taken on Days 11 and 18 of the 
first two cycles for all patients, on Days 11 and 18 of the remaining cycles for patients included 
before protocol amendment and on Days 11, 13, 18 and 27 of the first two cycles for patients 
included after the protocol amendment. Summary of absolute values over time and summary of 
change from baseline values over time will be presented separately for patients recruited before 
and after the protocol amendment.  Prior to analysis, the concentration data will be combined with 
concentration data collected in previous clinical studies. The model building will be conducted 
using NONMEM (Icon Development Solutions, Ellicott City, MD, USA, 2009) and reported 
separately. 
Regarding PK/PD analyses, as only 2 measurements of total blood asparaginase will be performed 
(D11 - 5 minutes before administration and D18), no accurate pharmacokinetic curve will be 
available for encapsulated asparaginase. Only those pharmacokinetic measurements which can be 
calculate using two timepoints will be presented. 
5.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population.   
5.8.1. 
Adverse Events 
Safety and tolerability will be assessed in terms of AEs, SAEs, laboratory data and vital signs, 
which will be collected for all subjects. The AE term (Investigator term) will be assigned to the 
lowest level term (LLT), and a preferred term (PT) will be classified by a high level term 
(HLT), a high level group term (HLGT) and a system organ class (SOC) according to the 
Medical Dictionary for Regulatory Activities (MedDRA) thesaurus, Version 15.1 or higher 
depending on the latest version available during the study. The intensity of AEs will be graded 
according to the NCI-CTCAE (version 4.0). 
An overview of the number of patients with AEs and the corresponding number of AEs will be 
presented through tables and listings: 
 Total AE count 
 Any AE 
 Any treatment-related AE (Cytarabine and/or GRASPA®) 
 Any AE of CTCAE grade ≥ 3 
 Any AE of CTCAE grade = 4 
 Any treatment-related (Cytarabine and/or GRASPA®) AE of CTCAE grade ≥3 
 Any severe treatment-related (Cytarabine and/or GRASPA®) AE 
 Any AE with outcome of death 
 Any serious AE 


 
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 Any treatment-related (Cytarabine and/or GRASPA®) serious AE 
 Any AE leading to permanent discontinuation 
 Any treatment-related (Cytarabine and/or GRASPA®) AE leading to permanent 
discontinuation (Action taken=Withdrawn) 
 Any AE leading to temporary discontinuation 
 Any treatment-related (Cytarabine and/or GRASPA®) AE leading to temporary 
discontinuation (Action taken=Reduced) 
 
An AE will be considered as “treatment-related” if the relationship to study treatment is ticked 
“possible,” “probable” or “certain/definite”. 
For subject counts, subjects are included only once, even if they experienced multiple events in 
that category. 
All the following summaries will be displayed by treatment groups on the safety population: 
 All AE by System Organ Class (SOC) term, Preferred Term (PT) 
 AE Experienced by 5% of Subjects by SOC term and PT 
 Treatment-related (Cytarabine and/or GRASPA®) AE by SOC term and PT 
 AE of CTCAE grade ≥ 3 by SOC term and PT 
 AE of CTCAE grade = 4 by SOC term and PT 
 Treatment-related (Cytarabine and/or GRASPA®) AE of CTCAE grade ≥3 by SOC term 
and PT 
 Severe treatment-related (Cytarabine and/or GRASPA®) AE by SOC term and PT 
 AE with outcome of death 
 Serious AE 
 Treatment-related (Cytarabine and/or GRASPA®) serious AE 
 AE leading to permanent discontinuation 
 AE leading to temporary discontinuation 
Serious AE, AE with outcome of death and AE leading to permanent or temporary 
discontinuation will also be described on an individual basis: treatment group, patient's code, 
sex and age, investigator's reported term, preferred term, date of onset, NCI-CTCAE Criteria 
Grading, intensity, outcome, seriousness, suspected relationship regarding Cytarabine and 
GRASPA®, action taken, corrective therapy. 
A special focus will be put on diabetogenic and pancreatic adverse events based on the 
following table: 
 
 


 
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GRASPA + LDAC 
LDAC 
Total 
 
n(%) 
n(%) 
n(%) 
Number of patients with xxx adverse events 
xx (x.x%) 
xx (x.x%) 
xx (x.x%) 
PT1
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
PT2
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Number of events 
xx 
xx 
xx 
Events characteristics, n 
 
 
 
Serious
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Cytarabine-related
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
GRASPA®-related
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Permanent discontinuation of Cytarabine
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Permanent discontinuation of GRASPA
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Fatal
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Number of occurences, n 
 
 
 
One
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Two or more
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Maximum toxicity grade, n 
 
 
 
Grade 1
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Grade 2
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Grade 3
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Grade 4
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Outcome, n 
 
 
 
Resolved
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Not resolved
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Fatal
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Action taken with cytarabine, n 
 
 
 
Dose not changed
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Temporarily interrupted
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Permanently discontinued
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Not applicable
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Action taken with GRASPA®, n 
 
 
 
Dose not changed
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Temporarily interrupted
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Permanently discontinued
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Not applicable
x   (x.x%) 
x   (x.x%) 
x   (x.x%) 
Diabetogenic effects will comprise diabetes mellitus, glucose and lipid increase. Pancreatic 
events will comprise clinical pancreatitis and asymptomatic (biochemical) pancreatitis. 


 
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5.8.2. 
Laboratory Data 
5.8.2.1. Haematology, Coagulation, Biochemistry tests 
Biological parameters will be described at inclusion, D1, D5, D9, D13, D18 and D23 of each 
course of chemotherapy. The concerned biological parameters are the followings: 
 Haematology 
o Haemoglobin (g/dL) 
o Hematocrit (%) 
o Erythrocytes (T/L) 
o Leukocytes (G/L) 
o Neutrophils (G/L) 
o Blasts (%) 
o Platelets (G/L) 
 Blood coagulation 
o Activated Partial Thromboplastin Time (aPTT) (sec) 
o Prothrombin time (%) 
o Fibrinogen (g/L) 
o Antithrombin III (%) 
o INR 
 Blood biochemistry 
o Albumin (g/L) 
o Plasma Bicarbonate (mmol/L) 
o Creatinine clearance (mL/min) 
o Serum Creatinine 
o Glycaemia (mmol/L) 
o Alkaline Phosphatase (U/L) 
o AST (U/L) 
o ALT (U/L) 
o Cholesterol (mmol/L) 
o LDH (U/L) 
o Gamma-GT (U/L) 
o Bilirubin (µmol/L) 
o Triglycerides (g/L) 
o Sodium (mmol/L) 
o Potassium (mmol/L) 
o Calcium (mmol/L) 
 Pancreas 
o Lipase (U/L) 
o Amylase (U/L) 


 
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Raw results as well as absolute and relative change from baseline will be described at each 
timepoint between treatment groups. 
Absolute change in the biological parameter between visit Vi and baseline will be calculated 
according to the formula: biological parameter at Vi – biological parameter at baseline 
Relative change in biological parameter between visit Vi and baseline will be calculated 
according to the formula: biological parameter at Vi – biological parameter at baseline x 100 
                            
 
 
biological parameter at baseline 
All laboratory data will be provided in data listings.  A subset listing will be presented for all 
clinically significant abnormal laboratory values. Data will be summarized by treatment group 
and patients with laboratory values of NCI-CTCAE grade 3 or 4 will be identified. 
5.8.2.2. Amino-acids and total blood asparaginase 
This procedure is applicable to patients under GRASPA® treatment only. 
Amino acids will be described at D11 and D18 of the first two cycles of chemotherapy on all 
patients, at D11 and D18 of every remaining cycle for patients included before the protocol 
amendment and at D13 and D27 of the first two cycles for patients included after the protocol 
amendment: 
 asparagine 
 aspartate 
 glutamine 
 glutamate 
Total blood asparaginase will be described at D11 and D18 of the first two cycles of 
chemotherapy on all patients, at D11 and D18 of every remaining cycle for patients included 
before the protocol amendment and at D13 and D27 of the first two cycles for patients included 
after the protocol amendment: 
 Plasmatic asparaginase 
 Total asparaginase 
 Encapsulated asparaginase 
 Free asparaginase 
 
Encapsulated asparaginase is defined as: Total asparaginase - Plasmatic asparaginase.   
 
Free asparaginase is defined as: Plasmatic asparaginase / Total asparaginase 
For lab values reported in the format BLLQ (Below Lower Limit of Quantification), the value 
of limitation should be used for the purpose of including this data in the calculation of summary 
statistics: 


 
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Parameters 
Lower limit of quantification 
Asparagine 
0.519 µmol/L* 
Aspartate 
0.987 µmol/L* 
Glutamine 
49.802 µmol/L* 
Glutamate 
10.716 µmol/L* 
Plasmatic asparaginase 
2.5 U/L* 
Total asparaginase 
75 U/L * 
* These data will depend of the central laboratory, and will be confirmed before analyses. 
Raw results as well as absolute and relative change from D11 will be described at each time 
point between treatment groups, and presented separately for patients recruited before and after 
the protocol amendment. 
Absolute change in biological parameter between D18 and D11 will be calculated according to 
the formula: Biological parameter at D18 – Biological parameter at D11 
Relative change in biological parameter between D18 and D11 will be calculated according to 
the formula:  
Biological parameter at D18 – Biological parameter at D11 x 100 
Biological parameter at D11 
5.8.3. 
Vital Signs and Physical Examinations 
Raw results as well as absolute and relative change from baseline for weight, ECG, heart rate, 
systolic and diastolic blood pressure will be described at each visit between treatment groups. 
Absolute change in vital signs between visit Vi and baseline will be calculated according to the 
formula: Vital signs at Vi – Vital signs at baseline 
Relative change in vital signs between visit Vi and baseline will be calculated according to the 
formula:  
Vital signs at Vi – Vital signs at baseline x 100 
Vital signs at baseline 


 
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By-subject listings of vital sign measurements will be presented in data listings and patients 
with vital sign values of NCI-CTCAE grade 3 or 4 will be identified. 
5.8.3.1. Physical Examinations 
Physical examination results at each time point will be summarized; shifts between baseline and 
a subsequent study visit in physical examination findings to will also be presented.  All physical 
examination findings will be presented in a data listing. 
5.8.4. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary. Results will be 
tabulated by Anatomic Therapeutic Class (ATC) and preferred term. 
The use of concomitant medications will be included in by-subject data listing. 
Previous medications are defined as medications reported with a stop date prior or equal to the 
date of inclusion. In case of partial/missing stop date the following rules will be applied: 
 If only the day is missing: month and year of stop date will be used to determine 
whether the medication is prior or concomitant 
 If day and month are missing: the year of stop date will be used to determine 
whether the medication is prior or concomitant 
 If the stop date is missing the medication will be considered as prior and 
concomitant 
All other medications reported will be considered as concomitant. Previous and concomitant 
medications will be described in each treatment group according to their therapeutic class 
(ATC) and preferred term (PT) (WHO Drug Dictionary, version of March 2013). 
The previous and concomitant medications will be summarized by treatment group in the ITT 
population.: 
 The number and percentage of patients presenting at least one previous medication 
will be described in each treatment group.  
o The previous medication will then be presented per ATC and PT in a frequency 
table in each treatment group. 
 The number and percentage of patients presenting at least one concomitant medication 
will be described in each treatment group.  
o The concomitant medication will then be presented per ATC and PT in a 
frequency table, in each treatment group. 
The medications given for type II diabetes will be presented. 
 


 
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6. 
CHANGES TO PLANNED ANALYSES 
Initially, this study was designed with Progression Free Survival as its primary endpoint.  
However, the protocol definition of PFS only considered death due to progression. It was 
recognised that this was not in line with regulatory guidance where death from any cause is 
included in the endpoint and the definition of PFS was therefore modified. Based on 
recommendations from the AML Advisory Board (meeting conducted on 24th January 2017) the 
primary endpoint was changed from PFS to overall survival. 
A planned interim analysis for futility was not conducted. 


 
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7. 
REFERENCES 


 
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8. 
CLINICAL STUDY REPORT APPENDICES 
8.1. 
Statistical Tables, Figures, and Listings to be Generated 
 
Table/Figure 
Number 
Output Title 
Analysis Set 
 
Patient Information 
 
14.1.1.1 
Overall Patients Disposition  
All Patients 
14.1.1.2 
Patients Disposition by Investigator Centre  
All Patients 
 
Protocol Deviations 
 
14.1.2.1 
Summary of Deviations Related to Inclusion/Exclusion Criteria 
ITT 
14.1.2.2 
Summary of Major Protocol Deviations – Reasons for Exclusion 
From Per Protocol Population 
ITT 
14.1.2.3 
Listing of Patients Randomized but not Treated 
ITT 
 
Demographic Data and Baseline Characteristics 
 
14.1.3.1 
Patient Demographics and Baseline Characteristics 
ITT 
14.1.3.2 
Disease Characteristics and AML Cancer History 
ITT 
 
Prior Related Therapies 
 
 
Medical History Related to Other Diseases 
 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.1.4.1 
Summary of Medical History – Previous Condition  
ITT 
14.1.4.2 
Summary of Medical History – Ongoing Condition  
ITT 
 
Prior and Concomitant Medications
 
14.1.5.1 
Summary of Prior Medications  
ITT 
14.1.5.2 
Summary of Concomitant Medications  
ITT 
 
Treatment Compliance and Exposure 
 
14.1.6.1 
Summary of Study Duration  
Safety 
 
Treatment Exposure  
 
14.1.6.2.1 
Summary of Exposure to GRASPA and Low Dose Cytarabine and 
Dose Intensity  
Safety 
14.1.6.2.2 
Compliance, Dose Reductions and Interruptions of GRASPA and 
Low Dose Cytarabine 
Safety 
14.1.6.2.3 
Listing of Patients with at Least One Dose Reduction or Interruption 
of GRASPA and Low Dose Cytarabine 
Safety 
 
Efficacy Data 
 
14.2.1.1.1.1 
Summary of Overall Survival by Treatment Group  
ITT 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.2.1.1.1.2 
Summary of Overall Survival by Treatment Group  
PP 
14.2.1.1.2.1 
Overall Survival by Treatment Group – Kaplan Meier Curves  
ITT 
14.2.1.1.2.2 
Overall Survival by Treatment Group – Kaplan Meier Curves 
PP 
14.2.1.1.3.1 
Summary of Overall Survival by Treatment Group – Cox PH Model 
with Prognostic Factors  
ITT 
14.2.1.1.3.2 
Summary of Overall Survival by Treatment Group – Cox PH Model 
with Prognostic Factors  
PP 
14.2.1.1.4.1 
Forest Plot of OS Hazard Ratios – Subgroup Analyses 
ITT 
14.2.1.1.4.2 
Forest Plot of OS Hazard Ratios – Subgroup Analyses 
PP 
14.2.1.2.1.1 
Summary of Disease Response and Duration of Response by 
Treatment Group 
ITT 
14.2.1.2.1.2 
Summary of Disease Response and Duration of Response by 
Treatment Group – Subgroup Analyses 
ITT 
14.2.1.3.1.1 
Summary of Progression Free Survival by Treatment Group  
ITT 
14.2.1.3.1.2 
Summary of Progression Free Survival by Treatment Group  
PP 
14.2.1.3.2.1 
Progression Free Survival by Treatment Group – Kaplan Meier 
Curves  
ITT 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.2.1.3.2.2 
Progression Free Survival by Treatment Group – Kaplan Meier 
Curves  
PP 
14.2.1.3.3.1 
Summary of Progression Free Survival by Treatment Group – Cox 
PH Model with Prognostic Factors 
ITT 
14.2.1.3.3.2 
Summary of Progression Free Survival by Treatment Group – Cox 
PH Model with Prognostic Factors 
PP 
14.2.1.3.4.1 
Forest Plot of Progression Free Survival Odds Ratios – Subgroup 
Analyses 
ITT 
14.2.1.3.4.2 
Forest Plot of Progression Free Survival Odds Ratios – Subgroup 
Analyses 
PP 
14.2.1.4.1 
Summary of Relapse Free Survival by Treatment Group 
ITT 
14.2.1.4.2 
Relapse Free Survival by Treatment Group – Kaplan Meier Curves  
ITT 
14.2.1.5 
Summary of Transfusion Needs by Treatment Group 
ITT 
14.2.1.6.1 
Summary of Biomarkers 
ITT 
Figure 14.2.1.6.2 
Biomarkers Over Time – Spaghetti Plots  
ITT 
 
PK and PD Parameters 
 
14.2.9.1 
PK and PD Parameters – Plasma and Blood – Summary Statistics 
Over Time 
Safety 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.2.9.2 
PK and PD Parameters – Plasma and Blood – Patients with 
Asparagine Depletion  
Safety 
14.2.9.3 
PK and PD Parameters – Immunogenicity  
Safety 
14.2.9.4 
Summary of Biomarker Cytogenetic Testing 
Safety 
14.2.9.5 
Summary of Bone Marrow Tumor Cell Parameters 
Safety 
 
Quality of Life Questionnaires
 
14.2.10 
QLQ-C30 Absolute and Changes From Baseline  
ITT 
 
Number of Hospitalizations 
 
14.2.11 
Summary of Hospitalizations by Treatment Group  
ITT 
 
Safety Data 
 
 
Adverse Events 
 
14.3.1.1.1 
Summary Analysis of Incidence of Treatment Emergent Adverse 
Events  
Safety 
14.3.1.1.2 
Summary 
Analysis 
of 
Incidence 
of 
Treatment-
Related Treatment Emergent Adverse Events 
Safety 
14.3.1.1.3 
Summary Safety Analysis of GRASPA in combination with low-
dose cytarabine 
ITT 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.3.1.2.1 
Incidence of Treatment Emergent Adverse Events by Preferred Term
Safety 
14.3.1.2.2 
Incidence of Treatment Related Treatment Emergent Adverse Events 
by Preferred Term 
Safety 
14.3.1.2.3 
Incidence of Treatment Emergent Adverse Events with Toxicity 
Grade of 3 or 4 by Preferred Term  
Safety 
14.3.1.2.4 
Incidence of Treatment Related Treatment Emergent Adverse Events 
with Toxicity Grade of 3 or 4 by Preferred Term 
Safety 
14.3.1.2.5 
Incidence of Treatment Emergent Serious Adverse Events by 
Preferred Term 
Safety 
14.3.1.2.6 
Incidence of Treatment Related Treatment Emergent Serious 
Adverse Events by Preferred Term 
Safety 
14.3.1.2.7 
Incidence of Treatment Emergent Adverse Events of Special Interest 
by Preferred Term 
Safety 
14.3.1.2.8 
Incidence of Treatment Emergent Adverse Events of Special Interest 
with Toxicity Grade of 3 or 4 by Preferred Term  
Safety 
14.3.1.2.9 
Incidence of Treatment Emergent Adverse Events Occurring in at 
least 5% of Patients in either Treatment Group by MedDRA 
Preferred Term  
Safety 
14.3.1.3 
Listing of Treatment Emergent Adverse Events Leading to Either 
GRASPA or Chemotherapy Withdrawal 
Safety 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
 
Deaths
 
14.3.2.1 
Deaths and Deaths within 28 Days After Last IMP Administration  
Safety 
14.3.2.2 
Listing of All Deaths  
Safety 
 
Clinical Laboratory Data
 
 
Biochemistry 
 
14.3.3.1.1 
Biochemistry – Summary of Shift From Baseline to Worst Post-
Baseline Results  
 
14.3.3.1.2 
Biochemistry – Summary Statistics for Clinically Significant 
Parameters  by Treatment Group and Time  
 
 
Hematology
 
14.3.3.2.1 
Hematology – Summary of Shift From Baseline to Worst Post-
Baseline Results  
Safety 
14.3.3.2.2 
Hematology – Summary Statistics for Clinically Significant 
Parameters  by Treatment Group and Time  
Safety 
 
Coagulation
 
14.3.3.3.1 
Coagulation – Summary of  Shift From Baseline to Worst Post-
Baseline Results  
Safety 


 
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Table/Figure 
Number 
Output Title 
Analysis Set 
14.3.3.3.2 
Coagulation – Summary Statistics for Clinically Significant 
Parameters by Treatment Group and Time  
Safety 
 
Other Safety Parameters
 
 
Vital Signs Data
 
14.3.4.1.1 
Vital Signs – Descriptive Statistics for Change From Baseline  
Safety 
14.3.4.1.2 
Vital Signs – Listing of Clinically Significant Values  
Safety 
14.3.4.2 
ECOG Performance Status – Shift From Baseline to Worst Post-
Baseline Value  
Safety 
 
 
 
8.2. 
Data Listings to be Generated 
 
Subject Data Listings 
 
 
Subjects Disposition 
 
16.2.1.1 
Patient Disposition and Analysis Sets 
ITT 
16.2.1.2 
Subject Visit Dates 
ITT 


 
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Protocol Deviations
 
16.2.2.1 
Deviations Relating to Inclusion/Exclusion Criteria 
All Patients 
16.2.2.2 
Other Protocol Deviations 
ITT 
 
Demographic Data and Baseline Characteristics
 
16.2.4.1 
Demographic Data  
ITT 
16.2.4.2 
Baseline Characteristics 
ITT 
16.2.4.3 
Medical and Surgical History  
ITT 
16.2.4.3.1 
Medical History Related to Primary Disease Condition  
ITT 
16.2.4.3.2 
Medical History Related to Other Disease 
ITT 
16.2.4.3.3 
Physical Examination 
ITT 
 
Previous and Concomitant Medications
 
16.2.4.4.1 
Prior Medications 
ITT 
16.2.4.4.2 
Concomitant Medications  
ITT 
 
Compliance and/or Drug Concentration Data
 
 
Drug Exposure  
 
16.2.5.1.1 
GRASPA Administration  
Safety 


 
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16.2.5.1.2 
Cytarabine Administration 
Safety 
 
Efficacy Data 
 
16.2.6.1 
Tumour Lesions Measurements  
ITT 
16.2.6.2 
Tumour Assessment Responses – Investigator and Central Readings 
ITT 
16.2.6.3 
PFS and Overall Survival – Time-to-Event Variables 
ITT 
16.2.6.4 
PK and PD Parameters 
Safety 
16.2.6.5 
Biomarker Parameters 
Safety 
16.2.6.6 
Immunogenicity Parameters 
Safety 
16.2.6.7 
Quality of Life – QLQ-C30 
ITT 
 
Adverse Event Listings 
 
16.2.7.1 
Treatment Emergent Adverse Events  
Safety 
 
Clinical Laboratory Data  
 
16.2.8.1 
Biochemistry Data (SI Units)  
Safety 
16.2.8.2 
Hematology Data (SI Units) 
Safety 
16.2.8.3 
Coagulation Data (SI Units) 
Safety 


 
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Other Safety Parameters 
 
16.2.9 
Vital Signs Parameters and Weight Assessments  
Safety