A Phase 2 Clinical Study of SHP674 in Patients With Newly Diagnosed, Untreated Acute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Sponsor: Institut de Recherches Internationales Servier

Official Title: A Phase 2 Clinical Study of SHP674 in Patients with Newly 
Diagnosed, Untreated Acute Lymphoblastic Leukemia 
NCT Number: NCT04067518 
Document Date: Protocol Version 1.5: 22 January 2021 

 
 
Protocol Number: SHP674-201 
 
 
 
 
 
 
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Protocol 
 
A Phase 2 Clinical Study of SHP674 in Patients with Newly 
Diagnosed, Untreated Acute Lymphoblastic Leukemia 
 
Protocol No.: 
SHP674-201 
(Referred 
to 
internally 
at 
Servier 
as 
CL1-95014-001) 
Edition: 
1.5 
Date: 
22 January, 2021 
 
 
Investigational product 
(test drug): 
SHP674 (Referred to internally at Servier as S095014) 
Phase of the study: 
2 
 
 
 
 
 
 
Sponsor: 
Institut de Recherches Internationales Servier (IRIS) 
50 Rue Carnot 92284 Suresnes, France 
In-country caretaker 
Kyowa Kirin Co., Ltd. 
1-9-2, Otemachi, Chiyoda-ku, Tokyo, Japan 
 
 
Confidentiality Statement 
The information contained in the present document is the property of IRIS, the Sponsor, and Kyowa Kirin Co., Ltd., the in-country caretaker, 
and is only provided to those who are involved in the study such as the investigators and the subinvestigators (including clinical research 
coordinators and other staff), the directors of investigative sites, the investigational product managers, the study administrative office, and the 
Institutional Review Boards (IRBs). Therefore, it is understood that this information will not be disclosed or leaked to any third party not 
involved in the study. It is also understood that this information will not be duplicated, cited, or published without authorization from IRIS and 
Kyowa Kirin Co., Ltd.

 
 
Protocol Number: SHP674-201 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
Abbreviations 
Expanded Form 
6-MP 
6-Mercaptopurine 
ADA 
Anti-drug antibody 
ALL 
Acute lymphoblastic leukemia 
Ara-C 
Cytarabine 
BMA 
Bone marrow aspiration 
CNS 
Central nervous system 
CPA 
Cyclophosphamide 
CRT 
Cranial radiotherapy 
CSI 
Craniospinal irradiation 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cy 
Cytoplasmic 
DEX 
Dexamethasone 
DIC 
Disseminated intravascular coagulation 
DNR 
Daunorubicin 
FCM 
Flow cytometry 
FDP 
Fibrin/Fibrinogen Degradation Products 
G-CSF 
Granulocyte colony-stimulating factor 
HR 
High risk 
IFO 
Ifosfamide 
IR 
Intermediate risk 
LV 
Leucovorin 
MRD 
Minimal residual disease 
MTX 
Methotrexate 
NCC 
Nucleated cells 
NUDT15 
Nudix Hydrolase 15 
PD 
Pharmacodynamics 
PEG 
Polyethylene glycol 
PGR 
Prednisolone-good responder 
PK 
Pharmacokinetics/pharmacokinetic 
PPR 
Prednisolone-poor responder 
PS 
Performance status 
PSL 
Prednisolone 
RT-PCR 
Reverse transcriptase-polymerase chain reaction 
SD 
Standard deviation 
SR 
Standard risk 
TEAE 
Treatment-emergent adverse event  
THP 
Pirarubicin hydrochloride 
TIT 
Triple intrathecal therapy 
VCR 
Vincristine 
VDS 
Vindesine 
VP-16 
Etoposide 

 
 
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Definition of Terms 
Term 
Definition and Explanation 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
LLT 
Lowest level term in MedDRA 
MedDRA 
ICH Medical Dictionary for Regulatory Activities 
PT 
Preferred term in MedDRA 
SOC 
System organ class in MedDRA 
Pharmaceuticals and Medical 
Devices Act 
Japanese law to ensure the quality, efficacy, and safety of pharmaceuticals, 
quasi-drugs, cosmetics, and medical devices. 
AUC 
Area under the plasma asparaginase activity-time curve 
AUC0-25d 
Area under the plasma asparaginase activity-time curve from time 0 to 25 days 
after administration 
AUC0-inf 
Area under the plasma asparaginase activity-time curve from time 0 to infinity 
AUC0-t 
Area under the plasma asparaginase activity-time curve from time 0 to t 
BFM 
Berlin-Frankfurt-Münster 
BLA 
Biological License Application 
CL 
Clearance; CL=Dose/AUC0-inf 
Cmax 
Maximum observed plasma asparaginase activity in plasma 
COG 
Children's Oncology Group 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good Clinical Practice 
HBc antibody 
Hepatitis B core antibody 
HBs antigen 
Hepatitis B surface antigen 
HBs antibody 
Hepatitis B surface antibody 
HIV antigen 
Human immunodeficiency virus antigen 
IUPAC 
International Union of Pure and Applied Chemistry 
IRB 
Institutional Review Board 
IU 
International unit 
JPLSG 
Japanese Pediatric Leukemia/Lymphoma Study Group 
t1/2 
Biological half-life 
tmax 
Time to peak plasma asparaginase activity 
Vss 
Volume of distribution at steady state 
 
List of Parameters (Hematology, Chemistry, Urinalysis, Vital Signs, ECG, and Genetic 
Testing) 
Parameter 
Abbreviation 
Display Name on Case Report Form 
Red blood cell count  
RBC 
Erythrocytes 
White blood cell count 
WBC 
Leukocytes 
Hematocrit 
Ht 
Hematocrit 
Hemoglobin concentration 
Hb 
Hemoglobin 
Platelet count 
PLT 
Platelets 
Basophil count 
Baso 
Basophils 
Eosinophil count 
Eosino 
Eosinophils 
Neutrophil count 
Neutro 
Neutrophils 
Lymphoblast count 
− 
Lymphoblasts 
Monocyte count 
Mono 
Monocytes 
Lymphocyte count 
Lymph 
Lymphocytes 
C-reactive protein 
CRP 
C-reactive protein 

 
 
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Gamma-glutamyltransferase 
γ-GTP 
Gamma Glutamyl Transferase 
Aspartate aminotransferase 
AST 
Aspartate Aminotransferase 
Amylase 
AMY 
Amylase  
Alanine aminotransferase 
ALT 
Alanine Aminotransferase 
Alkaline phosphatase 
ALP 
Alkaline Phosphatase 
Albumin 
ALB 
Albumin 
Potassium 
K 
Potassium 
Calcium 
Ca 
Calcium 
Creatinine 
Cr 
Creatinine 
Chloride 
Cl 
Chloride 
Blood urea nitrogen 
BUN 
Urea Nitrogen 
Blood glucose 
Glu 
Glucose 
Total cholesterol 
T-Cho 
Cholesterol 
Total bilirubin 
T-Bil 
Total bilirubin 
Total protein 
TP 
Protein 
Triglyceride 
TG 
Triglycerides 
Direct bilirubin 
D-Bil 
Direct bilirubin 
Sodium 
Na 
Sodium 
Lactate dehydrogenase 
LDH 
Lactate Dehydrogenase 
Uric acid 
UA 
Urate 
Corrected serum calcium 
Corrected serum 
Ca 
Calcium Corrected 
Lipase 
− 
Lipase 
Phosphate 
P 
Phosphate 
Urine occult blood 
− 
Occult Blood 
Urine urobilinogen 
− 
Urobilinogen 
Urine ketone bodies 
− 
Ketone Bodies 
Urine protein 
− 
Protein 
Urine glucose 
− 
Glucose 
Percutaneous arterial oxygen saturation 
SpO2 
Percutaneous Arterial Oxygen Saturation 
Diastolic blood pressure 
− 
Diastolic Blood Pressure 
Systolic blood pressure 
− 
Systolic Blood Pressure 
Eastern 
Cooperative 
Oncology 
Group 
Performance Status 
ECOG PS 
Eastern Cooperative Oncology Group 
Performance Status 
Height 
− 
Height 
Temperature 
− 
Temperature 
Weight 
− 
Weight 
Pulse rate 
− 
Pulse Rate 
D-dimer 
− 
D-dimer 
Antithrombin activity 
− 
Antithrombin Activity 
Activated partial thromboplastin time 
APTT 
Activated Partial Thromboplastin Time 
Fibrinogen 
− 
Fibrinogen 
Fibrin/fibrinogen degradation products 
FDP 
Fibrin/Fibrinogen Degradation Products 
Protein S 
− 
Protein S 
Prothrombin time-international normalized ratio 
Prothrombin 
time -INR 
Prothrombin Time-International 
Normalized Ratio 
Immunoglobulin A 
IgA 
Immunoglobulin A 
Immunoglobulin G 
IgG 
Immunoglobulin G 
Immunoglobulin M 
IgM 
Immunoglobulin M 

 
 
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HBs antigen test 
− 
HBs antigen test 
HBs antibody test 
− 
HBs antibody test 
HBc antibody test 
 
HBc antibody test 
HCV antibody test 
− 
HCV antibody test 
HIV antibody test 
− 
HIV antibody test 
HBV DNA test 
− 
HBV DNA test 
Time from the beginning of the P wave to the 
beginning 
of 
the 
QRS 
complex 
on 
an 
electrocardiogram 
PR interval 
PR Interval 
Time from the beginning of the Q wave to the end 
of the S wave on an electrocardiogram 
QRS duration 
QRS Duration 
Time from the beginning of the Q wave to the end 
of the T wave on an electrocardiogram 
QT interval 
QT Interval 
QT interval corrected for heart rate using the 
Bazett formula or QT interval corrected for heart 
rate using the Fridericia formula 
QTc interval 
(QTcB, QTcF) 
QTcB Interval, QTcF Interval 
Heart rate 
− 
Heart Rate 
Computed tomography 
CT 
Computed Tomography 
Magnetic resonance imaging 
MRI 
Magnetic Resonance Imaging 
Positron emission tomography 
PET 
Positron Emission Tomography 
Positron Emission Tomography- Computed 
Tomography 
PET-CT 
Positron 
Emission 
Tomography- 
Computed Tomography 
Bone marrow lymphoblasts 
− 
Blasts/Nucleated cells 
Nucleated cells 
− 
Nucleated cells 
Pregnancy test 
− 
Pregnancy Test 
NUDT15 codon 139 polymorphism analysis 
NUDT15 
Nudix Hydrolase 15 
Study participation period 
The study participation period for each subject in this study is defined as the period from the day of 
informed consent to the day of the last assessment prescribed in the protocol. After the end of the study 
participation period, subjects will be followed for survival as specified in Section 8.24. 
Time points for investigational product administration, observations, and tests 
The date of starting prednisolone administration in the pre-treatment phase (IP) is defined as Day 1. 
Days of each treatment phase or block are defined in the protocol. The week when the pre-treatment 
phase is started is defined as Week 1. Subsequently, the week that is Y weeks after the start of the 
pre-treatment phase will be regarded as Week Y. The week preceding the start week of the 
pre-treatment phase is defined as Week 0.  
Subject identification code 
The investigator or subinvestigator will assign subject identification codes (SIDs) to all subjects who 
give informed consent at the investigative site according to the following rule: 
SID:  
 
 
 
 
 

 
 
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ex.) The SID of the first subject (Part 1) who provides informed consent at XX Hospital 
(investigative site code:
) in Japan is
 

 
 
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PROTOCOL SYNOPSIS 
I Study Title 
A Phase 2 Clinical Study of SHP674 in Patients with Newly Diagnosed, Untreated Acute 
Lymphoblastic Leukemia 
II 
Study Objectives and Endpoints 
Study Objectives 
Part 1 
• Primary objective 
– To assess the tolerability and safety of a single dose of SHP674 in subjects with newly diagnosed, 
untreated acute lymphoblastic leukemia (ALL) in the tolerability assessment period. 
• Secondary objectives 
– To assess the percentage of subjects with newly diagnosed, untreated ALL who have a plasma 
asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first dose of SHP674. 
– To assess the safety of SHP674. 
– To assess the PK of SHP674. 
– To assess the immunogenicity of SHP674. 
– To assess the survival rate at 1 year after the start of study treatment. 
– To assess the event-free survival rate at 1 year after the start of study treatment. 
 
 
 
 
Part 2 
• Primary objective 
– To assess the percentage of subjects with newly diagnosed, untreated ALL who have a plasma 
asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first dose of SHP674. 
• Secondary objectives 
– To assess the safety of SHP674 
– To assess the PK of SHP674. 
– To assess the immunogenicity of SHP674. 
– To assess the survival rate at 1 year after the start of study treatment. 
– To assess the event-free survival rate at 1 year after the start of study treatment. 
 
 
 
 
 

 
 
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Endpoints 
Part 1  
• Primary endpoint 
– Incidence and nature of treatment-emergent adverse events (TEAEs) and SHP674-related TEAEs 
that occur or worsen during the tolerability assessment period. 
• Secondary endpoints 
– Safety 
• Incidence and nature of treatment-emergent adverse events (TEAEs) and drug-related TEAEs 
• Laboratory values 
• Vital signs 
– PK 
• PK parameters 
– Immunogenicity 
• ADA (anti-SHP674 antibody) and anti-PEG antibody 
– Efficacy 
• Achievement of a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the 
first dose of SHP674. 
• Survival rate at 1 year after the start of study treatment 
• Event-free survival rate at 1 year after the start of study treatment 
  
 
 
Part 2  
• Primary endpoint 
– Achievement of a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first 
dose of SHP674. 
• Secondary endpoints 
– Safety 
• Incidence and nature of treatment-emergent adverse events (TEAEs) and drug-related TEAEs 
• Laboratory values 
• Vital signs 
– PK 
• PK parameters 
– Immunogenicity 
• ADA (anti-SHP674 antibody) and anti-PEG antibody 
– Efficacy 
• Plasma asparaginase activity 
• Survival rate at 1 year after the start of study treatment 
• Event-free survival rate at 1 year after the start of study treatment 
  

 
 
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III Study Design 
This is a multicenter, non-randomized, open-label, Phase 2 clinical study of SHP674 in Japanese 
subjects with newly diagnosed, untreated ALL. The study consists of Part 1 and Part 2.  
In this study, the date of starting prednisolone administration in the pre-treatment phase (IP) is defined as 
Day 1. Days of each treatment phase or block are defined in the protocol. The week when the pre-treatment 
phase is started is defined as Week 1. The week preceding the start week of the pre-treatment phase is 
defined as Week 0. The week that is Y weeks after the start of the pre-treatment period will be regarded as 
Week Y. As a general rule, subjects will be hospitalized during remission induction therapy (IA2/IA4). The 
dosing schedule of each drug including SHP674 is outlined in Table 7-1 to Table 7-3. 
Part 1 
Part 1 is comprised of a screening period and a subsequent tolerability assessment period (from the 
pre-treatment phase through remission induction therapy [Day 1 to Day 37]; for at least 25 days after the 
first dose of SHP674) and a treatment period (from early consolidation therapy to the end-of-study 
assessment). Subjects categorized as SR or IR will receive a total of 3 doses of SHP674 and those 
categorized as HR will receive a total of 8 doses of SHP674 during the tolerability assessment period and 
the treatment period. The outline of the study design in Part 1 is shown in the figure below. The tolerability 
assessment period consists of a pre-treatment phase (IP) and remission induction therapy (IA2/IA4) 
according to the regimen used in Study ALL-B12. The treatment period consists of early consolidation 
therapy (IB/IB+L), consolidation therapy (M2/M5/HR3, HR2, HR1), re-induction therapy (III/III+L), and 
interim maintenance therapy (IM), which are also based on the regimen used in Study ALL-B12. Subjects 
who complete the tolerability assessment period will move to the treatment period and continue to receive 
SHP674.  
Subjects will undergo screening after giving informed consent, and eligible subjects will be enrolled 
within 21 days after giving informed consent and within 14 days after screening. Subjects will start 
treatment within 7 days after enrollment. Only subjects who are able to give assent or informed consent 
will be enrolled in Part 1. 
Part 1 will enroll 3 to 6 subjects who give informed assent or written informed consent to assess 
tolerability. The tolerability assessment will be based on the number of subjects who experience 
intolerable toxicity during the tolerability assessment period (the details of the assessment method are 
described in Section 7.5.4). 
Safety data of part 1 will be reviewed by an internal safety committee (composed of the sponsor and 
study investigators) that will determine if the dose investigated in part 1 was well tolerated and Part 2 can 
be initiated with this dose. 

 
 
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Outline of Study Design in Part 1 
 
Part 2 
Part 2 is comprised of a screening period and a subsequent treatment period (from the pre-treatment 
phase to the end-of-study assessment). Subjects categorized as SR or IR will receive 3 doses of SHP674 
and those categorized as HR will receive 8 doses of SHP674 during the treatment period. The outline of the 
study design in Part 2 is shown in the figure below. The treatment period consists of a pre-treatment phase 
(IP), remission induction therapy (IA2/IA4), early consolidation therapy (IB/IB+L), consolidation therapy 
(M2/M5/[HR3/HR2/HR1]), re-induction therapy (III/III+L), and interim maintenance therapy (IM) 
according to the regimen used in Study ALL-B12. 
Subjects will undergo screening after giving informed consent, and eligible subjects will be enrolled 
within 21 days after giving informed consent and within 14 days after screening. Subjects will start 
treatment within 7 days after enrollment. 
Part 2 will target to enroll 22 subjects to evaluate the efficacy, safety, and pharmacokinetics of SHP674 
at the dose shown to be tolerated in Part 1. 

 
 
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Outline of Study Design in Part 2 
 
IV Target Disease 
ALL 
V 
Inclusion Criteria 
Subjects who are enrolled in the study must meet all of the following criteria: 
1) 
For Part 1, personally provided informed assent or written informed consent. If informed assent is 
obtained from a subject, written informed consent should be obtained from a legally acceptable 
representative. For Part 2, written informed consent provided by the subject and/or a legally 
acceptable representative. Written or verbal assent should be obtained from the subject as far as 
possible even if written informed consent is obtained from a legally acceptable representative; 
2) Age 1 to ≤21 years at the time of informed consent; 
3) Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2; 
4) Newly diagnosed, untreated precursor B-cell ALL (see Attachment 5 to the protocol 
[supplement]); 
5) 
No prior therapy for malignant tumor such as chemotherapy and radiation therapy before signing 
the informed consent; 
6) The following laboratory criteria are met at the time of screening; 
• AST and ALT ≤10 × age-specific upper limit of normal (ULN) 
• D-Bil <1.5 mg/dL 
• Serum creatinine ≤1.5 × age-specific ULN 
• Corrected serum calcium ≤11.5 mg/dL 

 
 
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• Left ventricular ejection fraction ≥63% 
• SpO2 ≥94% 
• QT interval corrected by the Fridericia formula (QTcF = QT/PR1/3) <0.45 seconds 
7) 
Life expectancy of at least 6 months from the date of enrollment; 
8) 
Women of childbearing potential and fertile men must agree to use highly effective contraceptive 
methods* from the time of informed consent to at least 6 months after the last dose of SHP674 (for 
women) or from the start of SHP674 administration to at least 6 months after the last dose of 
SHP674 (for men). Women of childbearing potential must have a negative serum or urinary 
pregnancy test result at screening test.  
* Note:  
• A woman of childbearing potential is defined as a woman who has experienced her first 
menstruation, has not undergone hysterectomy, bilateral tubal ligation, or bilateral ovariectomy 
and is not postmenopausal. Postmenopausal status is defined as amenorrhea of ≥12 consecutive 
months with no specific causes. 
 
• Since there is a potential for an indirect interaction between SHP674 and oral contraceptives, 
the concomitant use of SHP674 and oral contraceptives is not recommended. Another, non-oral 
contraceptive method should be used in women of childbearing potential. 
VI Exclusion Criteria 
Subjects must be excluded from participating in this study if they meet any of the following criteria: 
1) Down syndrome; 
2) Mature B-cell ALL (e.g., Burkitt’s ALL); 
3) Currently active infection; 
4) Poorly controlled concurrent illness; 
5) Preexisting known coagulopathy (e.g., hemophilia and known protein S deficiency); 
6) History of pancreatitis; 
7) Continuous use of corticosteroids (transient use for transfusion reactions and topical or local use 
for the treatment of diseases other than the primary disease will be allowed); 
8) Positive for HBs antigen, HCV antibody, or HIV antibody. Subjects who are negative for HBs 
antigen but positive for HBc antibody and/or HBs antibody will undergo an HBV DNA test and 
will be excluded from the study if they are positive for HBV DNA (≥20 IU/mL [1.3 LogIU/mL]); 
9) Prior treatment or possible prior treatment with an L-asparaginase preparation; 
10) History of sensitivity to polyethylene glycol (PEG) or PEG-based drugs; 
11) Current symptoms or signs of CNS involvement (e.g., cranial nerve symptoms such as facial palsy), 
with CNS disease detected on CT or MRI; 
12) Pregnant (or planning to become pregnant in near future) or breastfeeding women (breastfeeding 
women will be excluded from the study even if they stop their breastfeeding); 
13) History of previous malignancy, other concurrent malignancy, or secondary ALL; or 
14) Other inadequacy determined by the investigator or subinvestigator. 
VII Target Sample Size 
Part 1 = 3 to 6 evaluable subjects 
Part 2 = 22 subjects 

 
 
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VIII Investigational Products 
Test drug 
Company code: SHP674 
Nonproprietary name: Pegaspargase 
 
Backbone Therapy drugs provided by the Sponsor for investigational use 
Predonine® Tablets 5 mg 
Company code: PSL-SER-PO-T 
Non-proprietary name: Prednisolone 
Prednisolone Powder 1% 
Company code: PSL-SER-PO-P 
Non-proprietary name: Prednisolone 
Predonine® 50 mg (water-soluble) 
Company code: PSL-SER 
Non-proprietary name: Prednisolone sodium succinate 
Endoxan® 500 mg (for Injection) 
Company code: CPA-SER 
Non-proprietary name: Cyclophosphamide hydrate 
Leukerin® Powder 10% 
Company code: 6-MP-SER 
Non-proprietary name: Mercaptopurine hydrate 
Lastet® Inj.100 mg/5 mL 
Company code: VP-16-SER 
Non-proprietary name: Etoposide 
Ifomide® 1 g (for injection) 
Company code: IFO-SER 
Non-proprietary name: Ifosfamide 
Decadron® Tablets 0.5 mg/4 mg 
Company code: DEX-SER-PO 
Non-proprietary name: Dexamethasone 
Decadron® Phosphate Injection 6.6 mg 
Company code: DEX-SER-IV 
Non-proprietary name: Dexamethasone sodium phosphate  
Methotrexate® Tablets 2.5 mg 
Company code: MTX-SER 
Non-proprietary name: Methotrexate 
Methotrexate® Injection 1000 mg 
Company code: HD-MTX-SER 
Non-proprietary name: Methotrexate 
X 
Planned Study Period 
May, 2019 to December, 2022 

 
 
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A snapshot of data will be taken for analysis of all available endpoints after all subjects completed 
remission induction therapy. The clinical study report (CSR) will be based on the data from the period of 
remission induction phase. Additional safety, PK and survival final analysis of all secondary 
 
 endpoints will be performed after all subjects complete the study (365 [±7] days after the first 
dose of SHP674 or at the time all subjects complete the study) and submitted as an addendum to the CSR. 

 
 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 2 
PROTOCOL SYNOPSIS ........................................................................................................ 7 
Table of Contents .................................................................................................................. 15 
1 
INTRODUCTION ............................................................................................................. 21 
1.1 
Background .................................................................................................................................. 21 
1.2 
Positioning of L-asparaginase Preparations in the Treatment of ALL ......................................... 22 
1.3 
SHP674......................................................................................................................................... 22 
1.3.1 
Development Status of SHP674 in the United States and Europe ............................................ 22 
1.4 
Nonclinical Study Results ............................................................................................................ 23 
1.5 
Clinical Study Results .................................................................................................................. 24 
1.5.1 
Outline of Foreign Clinical Studies .......................................................................................... 24 
1.5.1.1 
Study AALL07P4 ................................................................................................................. 24 
1.5.1.2 
Study DFCI 11-001 .............................................................................................................. 25 
1.5.1.3 
Study CCG-1962 .................................................................................................................. 25 
1.5.2 
Efficacy of SHP674 in Foreign Clinical Studies ...................................................................... 26 
1.5.3 
Safety of SHP674 in Foreign Clinical Studies ......................................................................... 26 
1.6 
Risks and Benefits ........................................................................................................................ 27 
1.6.1 
Risks ......................................................................................................................................... 27 
1.6.2 
Benefits ..................................................................................................................................... 27 
1.7 
Background to the Study Plan ...................................................................................................... 28 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 29 
2.1 
Study Objectives........................................................................................................................... 29 
2.1.1 
Primary Objective ..................................................................................................................... 29 
2.1.2 
Secondary Objectives ............................................................................................................... 29 
29 
2.2 
Endpoints ...................................................................................................................................... 29 
2.2.1 
Primary Endpoints .................................................................................................................... 29 
2.2.2 
Rationale for the Primary Endpoint .......................................................................................... 30 
2.2.3 
Secondary Endpoints ................................................................................................................ 30 
31 
3 
STUDY DESIGN .............................................................................................................. 31 
3.1 
Study Design ................................................................................................................................ 31 
3.1.1 
Part 1 ........................................................................................................................................ 31 
3.1.2 
Part 2 ........................................................................................................................................ 32 
3.1.3 
Risk Classification .................................................................................................................... 35 
3.1.3.1 
Change of Risk Category...................................................................................................... 35 
3.1.4 
Criteria for Evaluation of Organ Involvement ......................................................................... 36 

 
 
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3.1.4.1 
Central Nervous System (CNS) Involvement ...................................................................... 36 
3.1.5 
Rationale for Study Design ...................................................................................................... 36 
3.2 
Enrollment of Subjects ................................................................................................................. 37 
3.3 
Target Sample Size ....................................................................................................................... 37 
3.4 
Planned Study Period ................................................................................................................... 37 
4 
SUBJECT ELIGIBILITY CRITERIA .............................................................................. 38 
4.1 
Target Disease .............................................................................................................................. 38 
4.1.1 
Diagnosis of ALL ..................................................................................................................... 38 
4.2 
Inclusion Criteria .......................................................................................................................... 38 
4.3 
Exclusion Criteria ......................................................................................................................... 39 
5 
STOPPING RULES AND PROCEDURES ..................................................................... 40 
5.1 
Subject Withdrawal ...................................................................................................................... 40 
5.1.1 
Withdrawal from the Study ...................................................................................................... 40 
5.1.2 
Treatment Discontinuation ....................................................................................................... 41 
5.2 
Definition of Relapsed Disease .................................................................................................... 42 
5.2.1 
Extramedullary Relapse............................................................................................................ 42 
5.3 
Premature Termination or Suspension of the Study at the Investigative Site .............................. 42 
5.4 
Premature Termination or Suspension of the Entire Study .......................................................... 43 
6 
Investigational Product ...................................................................................................... 44 
6.1 
Test Drug and Backbone Therapy Drugs Provided by the Sponsor for Investigational Use ........ 44 
6.1.1 
Test Drug .................................................................................................................................. 44 
6.1.2 
Backbone Therapy Drugs Provided by the Sponsor for Investigational Use ........................... 44 
6.2 
Packaging and Labeling ............................................................................................................... 47 
6.2.1 
Package Presentation ................................................................................................................ 47 
6.2.2 
Labeling .................................................................................................................................... 47 
6.3 
Storage Conditions ....................................................................................................................... 48 
6.4 
Dispensing, Storage, Management, and Return of Investigational Product ................................. 48 
7 
TREATMENT PLAN AND CONCOMITANT TREATMENTS .................................... 49 
7.1 
Dose, Dosing Regimen, and Treatment Duration of SHP674 ...................................................... 62 
7.1.1 
Dose and Dosing Regimen of SHP674..................................................................................... 62 
7.1.1.1 
Formula for Calculation of Body Surface Area (BSA) ........................................................ 62 
7.1.2 
Rationale for Dose and Dosing Regimen of SHP674 ............................................................... 63 
7.2 
Concomitant Medications and Therapies ..................................................................................... 63 
7.2.1 
Backbone Therapy Drugs Used in This Study ......................................................................... 63 
7.2.1.1 
Doses of Backbone Therapy Drugs Used in This Study ...................................................... 64 
7.2.2 
Outline of Each Treatment Phase ............................................................................................. 64 
7.2.2.1 
Pre-treatment Phase (IP) ....................................................................................................... 64 
7.2.2.2 
Remission Induction Therapy (IA2/IA4) ............................................................................... 65 
7.2.2.3 
Early Consolidation Therapy (IB/IB+L) ................................................................................ 67 
7.2.2.4 
Consolidation Therapy (M2/M5/HR3→HR2→HR1) .......................................................... 69 

 
 
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7.2.2.5 
Re-induction Therapy (III/III+L) ......................................................................................... 76 
7.2.2.6 
Interim Maintenance Therapy (IM) ...................................................................................... 79 
7.2.3 
Criteria for Changes in Treatment with Each Backbone Therapy Drug ................................... 81 
7.2.4 
Criteria for Changes in Treatment by Symptom ...................................................................... 86 
7.2.5 
Prohibited Concomitant Therapies ........................................................................................... 87 
7.2.5.1 
Prohibited Concomitant Therapies throughout the Study .................................................... 87 
7.2.5.2 
Temporarily Prohibited Concomitant Therapies .................................................................. 87 
7.2.6 
Restricted Concomitant Medications........................................................................................ 88 
7.3 
Criteria for Starting Administration in Each Treatment Phase ..................................................... 88 
7.3.1 
Criteria for Starting Pre-treatment Phase (IP) ........................................................................... 88 
7.3.2 
Criteria for Starting Remission Induction Therapy (IA2/IA4) ................................................... 88 
7.3.3 
Criteria for Starting Early Consolidation Therapy (IB/IB+L) .................................................... 88 
7.3.4 
Criteria for Starting Consolidation Therapy (M2/M5/HR3→HR2→HR1).............................. 89 
7.3.4.1 
Criteria for Starting M2 and M5 ........................................................................................... 89 
7.3.4.2 
Criteria for Starting HR3, HR2, and HR1 ............................................................................ 89 
7.3.5 
Criteria for Starting Re-induction Therapy (III/III+L) ............................................................. 89 
7.3.6 
Interim Maintenance Therapy (IM) .......................................................................................... 90 
7.4 
Points to Note and Criteria for Changes in Treatment in Each Phase .......................................... 90 
7.4.1 
Points to Note and Criteria for Changes in Treatment during the Pre-treatment Phase (IP) ..... 90 
7.4.2 
Points to Note and Criteria for Changes in Treatment during Remission Induction Therapy 
(IA2/IA4) .................................................................................................................................... 90 
7.4.2.1 
Points to Note and Criteria for Changes in Treatment during IA2 in All the Groups and 
IA4 in the IR Group............................................................................................................... 90 
7.4.2.2 
Points to Note and Criteria for Changes in Treatment during IA4 in the HR Group ............ 91 
7.4.3 
Points to Note and Criteria for Changes in Treatment during Early Consolidation Therapy 
(IB/IB+L) ................................................................................................................................... 91 
7.4.4 
Points to Note and Criteria for Changes in Treatment during Consolidation Therapy 
(M2/M5) ................................................................................................................................... 91 
7.4.5 
Points to Note and Criteria for Changes in Treatment during Re-induction Therapy 
(III/III+L) ................................................................................................................................. 92 
7.4.6 
Points to Note and Criteria for Changes in Treatment during Interim Maintenance Therapy 
(IM) .......................................................................................................................................... 92 
7.5 
Tolerability Assessment in Part 1 ................................................................................................. 93 
7.5.1 
Tolerability Assessment Period ................................................................................................ 93 
7.5.2 
Definition of Intolerable Toxicity ............................................................................................ 93 
7.5.3 
Expected Toxicity ..................................................................................................................... 94 
7.5.4 
Procedure for Tolerability Assessment..................................................................................... 96 
7.5.5 
Decision on Whether to Move to Part 2 ................................................................................... 96 
8 
STUDY PROCEDURES AND SCHEDULE ................................................................... 97 
8.1 
Screening .................................................................................................................................... 105 
8.2 
Subject Demographics ................................................................................................................ 105 

 
 
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8.3 
Disease Assessment and Risk Classification .............................................................................. 106 
8.3.1 
NCI Classification .................................................................................................................. 106 
8.3.2 
Identification of Chimeric Gene Analysis Results ................................................................. 106 
8.3.3 
Identification of Chromosome Analysis Results .................................................................... 106 
8.3.4 
Assessment of Response to PSL ............................................................................................. 106 
8.3.4.1 
Definition of Response to PSL ........................................................................................... 106 
8.3.5 
Identification of Bone Marrow Examination Results ............................................................. 106 
8.4 
Symptoms and Findings ............................................................................................................. 106 
8.5 
Height, Weight ........................................................................................................................... 107 
8.6 
Vital Signs and ECOG PS .......................................................................................................... 107 
8.7 
Percutaneous Arterial Oxygen Saturation (SpO2) ...................................................................... 107 
8.8 
Hematology ................................................................................................................................ 107 
8.9 
Chemistry ................................................................................................................................... 107 
8.10 
Coagulation Test......................................................................................................................... 107 
8.11 
Immunoserological Test ............................................................................................................. 108 
8.12 
Viral Test .................................................................................................................................... 108 
8.13 
Urinalysis ................................................................................................................................... 108 
8.14 
CT, MRI, and PET ..................................................................................................................... 108 
8.15 
Twelve-lead Resting Electrocardiography ................................................................................. 108 
8.16 
Echocardiography ....................................................................................................................... 109 
8.17 
Pregnancy Test ........................................................................................................................... 109 
8.18 
Bone Marrow Examination ........................................................................................................ 109 
8.18.1 
Bone Marrow Aspiration during Remission Induction Therapy: Points to Note for BMA2 .. 110 
8.18.2 
Bone Marrow Aspiration after the End of Remission Induction Therapy: Points to Note for 
BMA3 ..................................................................................................................................... 110 
8.18.3 
Bone Marrow Aspiration after the End of Early Consolidation Therapy: Points to Note at 
BMA4 ..................................................................................................................................... 110 
8.19 
Cerebrospinal Fluid Examination ............................................................................................... 110 
8.20 
Blood MTX Concentration ......................................................................................................... 111 
111 
111 
8.21.2 
Evaluation of CNS Involvement ............................................................................................ 112 
8.21.3 
Evaluation of Extramedullary Disease ................................................................................... 112 
8.22 
Plasma Asparaginase Activity and Anti-Drug Antibodies ......................................................... 114 
8.22.1 
Plasma Asparaginase Activity ................................................................................................ 114 
8.22.2 
Anti-Drug Antibodies ............................................................................................................. 114 
8.24 
Survival Follow-up ..................................................................................................................... 116 
8.25 
Genetic Testing........................................................................................................................... 116 
8.25.1 
Test Item ................................................................................................................................. 116 
8.25.2 
Purpose of Testing and Relation to the Study ........................................................................ 116 
8.25.3 
Target Population, Time of Testing, Handling of Samples Collected .................................... 116 
8.25.4 
Genomic Analysis Method ..................................................................................................... 116 

 
 
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8.25.5 
Anonymization of Samples .................................................................................................... 117 
8.25.6 
Procedure for Obtaining Informed Consent ........................................................................... 117 
8.25.7 
Actions to Be Taken in the Case of Consent Withdrawal ...................................................... 117 
8.25.8 
Disclosure of Genotype to Subjects ....................................................................................... 117 
8.25.9 
Other Points to Note ............................................................................................................... 117 
9 
Adverse Events ................................................................................................................ 118 
9.1 
Definition of Adverse Events ..................................................................................................... 118 
9.2 
Assessment Items ....................................................................................................................... 118 
9.2.1 
Severity Assessment ............................................................................................................... 119 
9.2.2 
Assessment of Causal Relationship with Study Treatment .................................................... 120 
9.2.3 
Definition of Serious Adverse Events .................................................................................... 120 
9.2.4 
Other Significant Adverse Events .......................................................................................... 121 
9.3 
Actions to Be Taken for Adverse Events ................................................................................... 121 
9.3.1 
Treatment of Subjects ............................................................................................................. 121 
9.3.2 
Emergency Safety Measures .................................................................................................. 121 
9.3.3 
Reporting to Parties Involved ................................................................................................. 121 
9.3.3.1 
Serious Adverse Event ....................................................................................................... 121 
9.3.3.2 
Non-Serious Adverse Events .............................................................................................. 122 
10 MANAGEMENT OF SUBJECTS .................................................................................. 123 
10.1 
Notification to Other Departments or Hospitals ......................................................................... 123 
10.2 
Instructions to Subjects .............................................................................................................. 123 
10.2.1 
Contraception ......................................................................................................................... 123 
11 Data Management ........................................................................................................... 124 
11.1 
Source Documents ...................................................................................................................... 124 
11.2 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS......................................................... 124 
11.3 
eCRF........................................................................................................................................... 124 
11.4 
Items That Allow Handling of eCRF Entries as Source Documents (Source Data) .................. 125 
11.5 
QUALITY CONTROL AND QUALITY ASSURANCE OF THE STUDY ............................ 125 
12 STATISTICAL ANALYSIS ........................................................................................... 126 
12.1 
Statistical Methods ..................................................................................................................... 126 
12.1.1 
Primary Endpoint ................................................................................................................... 126 
12.1.2 
Secondary Endpoints .............................................................................................................. 126 
12.1.2.1 
Safety .................................................................................................................................. 126 
12.1.2.2 
PK ....................................................................................................................................... 127 
12.1.2.3 
Immunogenicity .................................................................................................................. 127 
12.1.2.4 
Efficacy .............................................................................................................................. 127 
128 
12.2 
Target Sample Size ..................................................................................................................... 128 
12.2.1 
Rationale for Target Sample Size ........................................................................................... 128 
12.3 
Criteria for Premature Termination of the Entire Study ............................................................. 128 

 
 
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12.4 
Handling of Missing, Unused, and Abnormal Data ................................................................... 128 
12.5 
Development of Statistical Analysis Plan and Procedure for Reporting Deviations from the 
Original Statistical Analysis Plan ............................................................................................... 128 
12.6 
Selection of Subjects to be Included in Analyses ....................................................................... 129 
12.6.1 
All Enrolled Set ...................................................................................................................... 129 
12.6.2 
Safety Analysis Set ................................................................................................................. 129 
12.6.3 
Full Analysis Set (FAS) ......................................................................................................... 129 
12.6.4 
Immunogenicity Analysis Set ................................................................................................. 129 
12.6.5 
PK Analysis Set ...................................................................................................................... 129 
12.7 
Data Cut Off ............................................................................................................................... 129 
13 ETHICAL CONSIDERATIONS .................................................................................... 130 
13.1 
Compliance with GCP and the Protocol ..................................................................................... 130 
13.2 
IRB ............................................................................................................................................. 130 
13.2.1 
Review of the Propriety of Conducting the Study .................................................................. 130 
13.2.2 
Follow-up Review .................................................................................................................. 130 
13.3 
Selection of Subjects to be Enrolled in the Study and Assurance of Their Safety ..................... 130 
13.4 
Protection of Subjects’ Personal Information and Privacy ......................................................... 131 
13.5 
Informed Consent ....................................................................................................................... 131 
13.5.1 
Informed Consent (Assent) for Subjects (Pediatric Patients) ................................................. 131 
13.5.2 
Points to Note regarding Section 13.5 and Section 13.5.1 ..................................................... 132 
13.5.3 
Information for Subjects/Informed Consent Form ................................................................. 132 
13.6 
Audit and Inspection .................................................................................................................. 133 
13.7 
Expenses Related to the Study ................................................................................................... 134 
13.8 
Expenses for Reducing the Burden to Subjects Resulting from Participation in the Study ....... 134 
13.9 
Compensation for Health Injury ................................................................................................. 134 
13.10 
Publication Policy....................................................................................................................... 134 
14 PROTOCOL 
COMPLIANCE, 
DEVIATIONS 
OR 
CHANGES, 
AND 
AMENDMENTS ............................................................................................................. 135 
14.1 
Compliance with the Protocol .................................................................................................... 135 
14.2 
Deviations from or Changes to the Protocol .............................................................................. 135 
14.3 
Protocol Amendments ................................................................................................................ 135 
15 STUDY COMPLETION ................................................................................................. 135 
16 RECORD KEEPING ....................................................................................................... 136 
16.1 
Retention of Source Documents Related to Plasma Asparaginase Activity ............................... 136 
16.2 
Retentions of Source Documents Related to Laboratory and Other Tests ................................. 136 
16.3 
Biological Sample Archiving ..................................................................................................... 137 
17 STUDY ADMINISTRATIVE STRUCTURE ................................................................ 137 
18 MAIN RESPONSIBILITIES OF THE INVESTIGATOR ............................................. 137 
19 REFRENCES .................................................................................................................. 138 

 
 
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1 INTRODUCTION 
1.1 
Background 
Leukemia is the most common pediatric malignancy. Acute lymphoblastic leukemia (ALL) is the most 
common type (46.6%) of acute leukemia in childhood.1,2 About 500 children are newly diagnosed with 
ALL each year in Japan.2 When looking at the proportion of patients by age group, approximately 40% of 
all patients newly diagnosed with pediatric ALL are 1 to 4 years of age, approximately 30% are 5 to 9 years, 
and approximately 20% are 10 to 14 years. The proportion of patients newly diagnosed with ALL is low at 
15 to 19 years, accounting for approximately 4% of all patients newly diagnosed with ALL.2 According to 
the immunological classification, precursor B-cell ALL accounts for 85.6% of all pediatric ALL. The 
male-to-female ratio is 1.34:1; the proportion of male children is slightly larger than that of female 
children.3 
Previously, ALL and malignant lymphoma were considered to be derived from bone marrow and lymph 
nodes, respectively. ALL was diagnosed in the presence of bone marrow infiltration with lymphoblasts, 
and lymphoblastic lymphoma (LBL) was diagnosed in the absence of bone marrow infiltration. However, 
according to the WHO classification published from 2008 onwards, lymphoid tumors are broadly divided 
into B-cell type and T-cell and natural killer-cell (T/NK-cell) type, and ALL and LBL are classified as 
being derived from precursor B cells and precursor T cells, the most immature type of B and T cells.4 
ALL and LBL are biologically the same disease, but in general, ALL is diagnosed when extensive tumor 
cell infiltration is noted in peripheral blood and the percentage of blasts in bone marrow is ≥25%, and LBL 
is diagnosed when the percentage of blasts is <25%. Thus, in this study, ALL is to be diagnosed when the 
percentage of lymphoid tumor cells in bone marrow is ≥25%.5 
In Japan, stratified treatment according to risk groups is recommended for patients with pediatric ALL.6 
Required tests depend on the age of patients. Treatment is stratified based on the presence or absence of 
rearrangement of the MLL gene for patients <1 year and based on the combination of response to 
prednisolone (circulating lymphoblast count 8 days after 7-day administration of prednisolone), 
immunological classification, age, and white blood cell count for patients ≥1 year. Treatment requires the 
reassessment of risks based on information such as the proportion of bone marrow lymphoblasts and the 
presence or absence of minimal residual disease after chemotherapy in the course of the treatment. If the 
proportion of lymphoblasts is ≤1%, minimal residual disease is difficult to detect by microscopy, but can 
be detected by flow cytometry or polymerase chain reaction. Treatment strategy is recommended to be 
determined by assessing response to treatment based on the quantitative measurement of minimal residual 
disease. Remission induction therapy for patients with pediatric ALL was established in 1970’s.7 As it is 
now, triple combination therapy with prednisolone or dexamethasone, vincristine, and L-asparaginase 
provides long-term remission in approximately 80% of patients. In addition, intrathecal injection of 
methotrexate is essential to prevent the onset of central nervous system leukemia.8 In high risk patients, 
quadruple combination therapy with the above 3 drugs plus an anthracycline has shown a trend toward 
further improvement in treatment results.9 The Practical Guideline for Pediatric Leukemia and Lymphoma 
(2016 version)6 recommends that post-remission consolidation therapy be started immediately after the 
end of remission induction therapy. The Practical Guidelines for Hematological Malignancies, 2018 
recommend that adult patients up to about 30 years of age receive treatment per pediatric protocol.5 

 
 
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The worldwide standard treatments for pediatric ALL include the treatment backbones established by 
the Children’s Oncology Group (COG) and the Berlin-Frankfurt-Münster (BFM) group. In Japan, there is 
little experience with the COG backbone, and treatment based on the BFM backbone described above has 
been adopted. 
1.2 
Positioning of L-asparaginase Preparations in the Treatment of ALL 
The mechanism of action of L-asparaginase is considered to be a selective killing effect on leukemia 
cells exerted by depleting asparagine in blood. Lymphoblastic leukemia cells cannot produce asparagine 
by themselves because of low expression of asparagine synthetase; extracellular asparagine is essential for 
the survival of leukemia cells. L-asparaginase exerts an antitumor effect by hydrolyzing blood asparagine 
into aspartic acid and ammonia and thereby depleting asparagine in blood. On the other hand, normal cells, 
having ability to synthesize asparagine, are unlikely to be affected by the depletion of blood asparagine. 
Treatment for patients with acute ALL consists of remission induction therapy, early consolidation 
therapy, central nervous system preventive therapy, consolidation therapy, and maintenance therapy, all of 
which are combination therapies with antitumor drugs. L-asparaginase is incorporated into combination 
therapy and plays an important role as a key drug for the treatment of patients with ALL, since it causes 
relatively mild myelosuppression and has no cross-resistance with other anticancer drugs. However, 
L-asparaginase is a protein derived from Escherichia coli, and some patients have a difficulty in the 
continued use of the drug due to allergic reactions such as anaphylactic shock, which prevents the patients 
from completing treatment. Many of the patients with ALL who are allergic to L-asparaginase have a 
difficulty in continuing treatment and cannot receive chemotherapy of adequate intensity, and this leads to 
worsening of prognosis in these patients. 
1.3 
SHP674 
SHP674 (international non-proprietary name: pegaspargase) was developed by chemical modification 
of native L-asparaginase with polyethylene glycol (PEG) and is expected to play an important role in Japan 
as a first-line treatment for ALL. Due to the pegylation the half-life of SHP674 becomes longer than that of 
native L-asparaginase. It has been shown that one dose of SHP674 maintains plasma asparaginase activity 
levels exceeding the lowest effective plasma asparaginase activity (0.1 IU/mL) for 2 to 3 weeks, depleting 
asparagine for a long time.10,11 Therefore, SHP674 is expected to considerably decrease the number of 
doses in remission induction therapy and consolidation therapy, reducing the burden for patients and 
health care workers. Additionally the chemical modification with PEG may reduce the immunogenicity of 
native L-asparaginase.  
 SHP674 can also be administered to patients who are allergic to native L-asparaginase such as 
Leunase®. In addition, randomized comparative studies in patients with untreated ALL that were 
conducted outside Japan showed that SHP674 had a similar safety profile to native L-asparaginase and that 
there were no differences in efficacy between SHP674 and native L-asparaginase.10  
 
1.3.1 
Development Status of SHP674 in the United States and Europe 
In the United States, SHP674 was approved for marketing in February 1994 as a second-line drug for the 
treatment of ALL after the onset of hypersensitivity to native L-asparaginase. After that, SHP674 was 
approved as the first-line drug for the treatment of ALL in 2006.10,12-15 

 
 
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SHP674 liquid formulation had been authorized by centralized review procedure in 28 countries in the 
EU and 3 countries in the European Economic Area (EEA) in first line treatment of ALL on 14 January, 
2016. The lyophilized formulation of SHP674 was shown to exert pharmacokinetic/pharmacodynamic 
actions similar to those of the liquid formulation of SHP674 in October 2017 based on the analysis 
recommended by the Committee for Medical Products for Human Use (CHMP) of the European 
Medicines Agency (EMA) and the demonstration of comparability performed through comprehensive 
analytical and nonclinical comparability assessments. Accordingly, the additional dosage form 
(lyophilized formulation) was approved for SHP674 by centralized review procedure in 28 countries in the 
EU and 3 countries in the EEA on December 8, 2017. 
1.4 
Nonclinical Study Results 
Depletion of asparagine by L-asparaginase causes cytotoxicity of lymphoblastic tumor cells, pancreatic 
cancer cell lines, and ovarian cancer cell lines. Treatment of diseased animals with SHP674 extends 
survival independent of route of administration. 
Pegylation has been proven to reduce drug clearance and degradation and development of anti-drug 
antibodies. Pegylation extends the half-life of enzyme activity, resulting in a lower dosage schedule with 
longer administration intervals. 
The pharmacokinetics of SHP674 were linear over the dose range tested. The clearance and the 
distribution volume of SHP674 were small as expected for a protein with a high molecular weight. The 
volume of distribution was equivalent to blood volumes in all the species, indicating that SHP674 is not 
distributed outside the systemic circulation. SHP674 did not cross the blood barrier in monkey, and there is 
a low potential to cross the placental barrier. 
There is very limited information about the metabolism and elimination of SHP674. Available study 
data suggest that SHP674 is cleared by mechanisms other than urinary excretion. Possible mechanisms for 
its elimination include proteolysis and removal from plasma by the reticuloendothelial system or 
mononuclear phagocyte system. Metabolism mediated by the liver and excretion through the bile also 
cannot be excluded. 
The main findings in single-dose and/or repeat-dose toxicology studies in mice, rats, and dogs were 
decreased body weight, slight decrease in spleen weight, sporadic fatty infiltration of hepatocytes without 
cell necrosis or incidence on the liver functions. No effects on circulating lymphocytes were observed. 
Little information is available on the genotoxicity or clastogenicity of SHP674. Available data from 
Ames tests suggest SHP674 is not genotoxic. L-asparaginase did not induce karyotype abnormalities in 
pregnant rabbits and in their progeny. 
Classical reproductive studies have not been performed with SHP674. Nevertheless, results obtained in 
vivo or in vitro studies in rats or rabbits gave some evidence of embryotoxic/teratogenic potency of 
L-asparaginase. No juvenile animal toxicology studies have been performed. 
The lyophilization process had no impact on the nonclinical pharmacokinetics, pharmacodynamics, or 
anti-drug antibody development of the drug and consequently, the safety and effectiveness of the drug 
product. 
Taken together, SHP674 exerted a selective killing effect on leukemia cells by depleting asparagine, 
leaving healthy cells relatively unharmed, and prolonged survival of diseased animals. The toxicology 
studies demonstrate that SHP674 is well tolerated and does not have toxic effects (other than 

 
 
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embryotoxicity) at clinically relevant doses. These data support the use of SHP674 for the treatment of 
ALL. 
1.5 
Clinical Study Results 
1.5.1 
Outline of Foreign Clinical Studies 
The outline of the 3 major clinical studies of SHP674 conducted outside Japan (Studies AALL07P4, 
DFCI 11-011, and CCG-1962) is described below. 
In Study AALL07P4, 163 subjects with high risk ALL received investigational product (SHP674, 54 
subjects; 2100 IU/m2 EZN-2285 [recently approved in the United States that has an SC linker, which is 
novel and different from the SS linker used in SHP674, at the binding site of L-asparagine and PEG], 68 
subjects; 2500 IU/m2 EZN-2285, 41 subjects). The primary objective of the study was to assess the 
pharmacokinetic comparability of SHP674 versus EZN-2285 intravenously administered during remission 
induction therapy and consolidation therapy to patients with high risk ALL receiving an augmented BFM 
treatment regimen. 
In Study DFCI 11-001, 237 subjects with previously untreated ALL or malignant lymphoma (ALL, 228 
subjects; malignant lymphoma, 9 subjects) received investigational product (SHP674, 119 subjects; 
2500 IU/m2 EZN-2285, 118 subjects). The primary objectives of the study were (1) to assess toxicity 
following the administration of SHP674 or EZN-2285 and (2) to determine and compare serum asparagine 
activity levels following the administration of SHP674 and EZN-2285. 
In Study CCG-1962, of 118 subjects with newly diagnosed, untreated ALL, 59 received SHP674 and 59 
received Elspar® (native L-asparaginase preparation). The primary objectives of the study were (1) to 
compare the safety of SHP674 with that of Elspar® and (2) to determine whether the incidence of high-titer 
anti-drug antibodies (ADA) (ADA ratio [ratio of ADA titer relative to the negative control titer] ≥2.5) in 
children treated with SHP674 was decreased by ≥50% compared to Elspar®. 
Data on SHP674 and Elspar® obtained from the 3 studies AALL07P4, DFCI 11-011, and CCG-1962 are 
described in the following sections. 
1.5.1.1 
Study AALL07P4 
Subjects enrolled in the study received IV doses of SHP674 2500 IU/m2 for at least 1 hour on Day 4 of 
remission induction therapy (the start day of remission induction therapy was regarded as Day 1) and Day 
15 (the start day of consolidation therapy was regarded as Day 1) and Day 43 of consolidation therapy. 
Plasma asparaginase activity was assessed on Days 4 (pre-dose, 5 minutes post-dose, 4 hours post-dose), 5, 
6, 8, 15, 22, and 29 of remission induction therapy and on Days 15 (pre-dose, 5 minutes post-dose, 4 hours 
post-dose), 16, 17, 22, 29, 36, and 43 of consolidation therapy. As a result, the percentage of subjects with 
a plasma asparaginase activity of ≥0.1 IU/mL on Days 22 and 29 (18 and 25 days after the administration 
of SHP674) of remission induction therapy was 95.3% and 29.5%, respectively. The median plasma 
half-life of SHP674 was 4.4 days. The median plasma asparagine concentration remained below the lower 
limit of quantification of the assay (0.05 μg/mL) until Day 29 of remission induction therapy. 
Samples for immunogenicity assessment were collected on Day 4 (pre-dose) and Day 29 of remission 
induction therapy; Day 15 (pre-dose) and Day 43 of consolidation therapy; Day 2 (pre-dose) and Day 22 of 
the first and second interim maintenance therapy (the second therapy was received only by subjects 
categorized as slow early responders); Day 4 (pre-dose) and Day 43 of the first and second late 

 
 
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consolidation therapy (the second therapy was received only by subjects categorized as slow early 
responders); and Day 1 of Cycles 1 and 2 of maintenance therapy. After the administration of SHP674, 
ADA was detected in 5 of 50 subjects (10%) and 6 of 26 subjects (23.1%), respectively, but no neutralizing 
activity was observed in any of the subjects. 
1.5.1.2 
Study DFCI 11-001 
Subjects enrolled in the study received IV doses of SHP674 2500 IU/m2 on Day 7 of remission induction 
therapy and subsequently every 2 weeks from Day 1 of central nervous system preventive therapy (Day 8 
of the first consolidation therapy for subjects categorized in the very high-risk group). The serum 
asparaginase activity reached a maximum level at the first measurement point after the start of 
administration of SHP674 (5 to 10 minutes post-dose) and decreased thereafter. The percentage of subjects 
who had a serum asparaginase activity of ≥0.1 IU/mL 18 days after the first dose of SHP674 (Day 7 of 
remission induction therapy) was 93.5%. Following repeated doses of SHP674 every 2 weeks after 
remission induction therapy, the trough serum asparaginase activity increased to plateau. Among subjects 
who had evaluable pharmacokinetic data at 1 or more time points after remission induction therapy, the 
percentage of subjects with a trough serum asparaginase activity of ≥0.1 IU/mL was 99.0%. 
Samples for ADA measurement were collected on Day 7 (pre-dose) and Day 32 of remission induction 
therapy, Day 8 (pre-dose) of the first consolidation therapy (only for subjects categorized in the very 
high-risk group), and before the administration of SHP674 in central nervous system preventive therapy 
and the second consolidation therapy. After the administration of SHP674, anti-asparaginase antibodies 
and anti-PEG antibodies were detected in 10 of 54 subjects (18.5%) and 11 of 66 subjects (16.7%), 
respectively, but no neutralizing activity was observed in any of the subjects. 
1.5.1.3 
Study CCG-1962 
Subjects enrolled in the study received a single intramuscular (IM) dose of SHP674 2500 IU/m2 on Day 
3 of remission induction therapy and the first and second delayed intensification therapy; or IM doses of 
Elspar® (native L-asparaginase) 2500 IU/m2 (9 doses in remission induction therapy and 6 doses each in 
the first and second late consolidation therapies). Serum asparaginase activity was assessed before dosing 
and on Days 7, 14, 21, 28 of remission induction therapy and on Days 0, 7, 14, 21, and 28 of the first and 
second late consolidation therapy. In the remission induction therapy phase, the serum asparaginase 
activity following the administration of SHP674 reached a peak on Day 5, with a mean value of 1.0 IU/mL. 
The elimination half-life from the IM injection site was 5.8 days. The percentage of subjects with a serum 
asparaginase activity of ≥0.1 IU/mL on Day 21 of the first and second late consolidation therapy was 91% 
and 93%, respectively. Serum asparagine concentrations rapidly decreased until 4 days after the first dose 
of SHP674 and remained at low levels until approximately 3 weeks after the first dose. The elimination of 
Elspar® after the first dose in the remission induction therapy phase was assessed with data from 1 subject 
who provided multiple samples. The serum asparaginase activity reached a peak (2.0 IU/mL) 4 hours after 
the IM injection of Elspar®. The elimination half-life was 1.1 days. The percentage of subjects with a 
serum asparaginase activity of ≥0.1 IU/mL on Day 21 of the first and second late consolidation therapies 
was 25% and 28%, respectively. 
In addition, samples for the assessment of the production of ADA were collected at the same time points 
as for serum asparaginase activity. As a result of the assessment, the percentage of subjects with high-titer 

 
 
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ADA during the first late consolidation therapy was 15% (7 of 46 subjects) in the Elspar® group and 6% (3 
of 49 subjects) in the SHP674 group. The percentage of subjects with high-titer ADA during the second 
late consolidation therapy was 2% (1 of 44 subjects) in the Elspar® group and 11% (5 of 45 subjects) in the 
SHP674 group. The asparaginase activity at the time point when the highest titer was reported was 
assessed to determine the effects of high-titer antibodies in both groups. As a result, although the number 
of subjects was small, an asparaginase activity of ≥0.1 IU/mL was maintained in more subjects in the 
SHP674 group than in the Elspar® group in the presence of high-titer ADA. 
1.5.2 
Efficacy of SHP674 in Foreign Clinical Studies 
In Study AALL07P4, the presence or absence of minimal residual disease, complete remission (CR) rate, 
event-free survival rate, and disease-free survival rate and overall survival rate after CR were assessed at 
the end of remission induction therapy (Day 29). In the SHP674 group, 74.1% of the subjects (40 of 54 
subjects) were negative for minimal residual disease, and the CR rate was 92.6% (50 of 54 subjects). At 
4 years, the event-free survival rate was 81.8%, the disease-free survival rate was 85.5%, and the overall 
survival rate was ≥90%. 
In Study DFCI 11-001, the presence or absence of minimal residual disease, CR rate, disease-free 
survival rate, and overall survival rate were assessed at the end of remission induction therapy (Day 32). In 
the SHP674 group, 87.9% of the subjects (80 of 91 subjects) had low end-induction MRD (defined as 
<0.001 by PCR), and the CR rate was 95.7% (110 of 115 subjects). At 1 year, the event-free survival rate 
was 98.0%, the disease-free survival rate was 98.9%, and the overall survival rate was 100%. 
Part of the efficacy assessments conducted in Study CCG-1962 is described in Section 1.5.1.3. 
Lymphoblasts were depleted more rapidly in the SHP674 group than in the Elspar® group from Day 7 to 
Day 14 of remission induction therapy. The event-free survival rates at 3, 5, and 7 years were 83%, 78%, 
and 75% in the SHP674 group and 79%, 73%, and 66% in the Elspar® group. 
1.5.3 
Safety of SHP674 in Foreign Clinical Studies 
In Study AALL07P4, TEAEs were reported in 48 of 52 subjects (92.3%) and drug-related TEAEs were 
reported in 44 subjects of 52 subjects (84.6%) in the SHP674 group. Grade 3 or 4 TEAEs and drug-related 
TEAEs were reported in 90.4% (47 of 52 subjects) and 76.9% (40 of 52 subjects) of the subjects, 
respectively. 
The drug-related TEAEs that were reported with high incidence (≥15%) in subjects in the SHP674 
group were hyperglycaemia (42.3%), blood bilirubin increased (42.3%), neutrophil count decreased 
(32.7%), alanine aminotransferase increased (19.2%), anaphylactic reaction (19.2%), white blood cell 
count decreased (19.2%), activated partial thromboplastin time prolonged (17.3%), and febrile neutropenia 
(15.4%). 
The Grade 3 or 4 drug-related TEAEs that were reported with high incidence (≥15%) in subjects in the 
SHP674 group were neutrophil count decreased (32.7%), anaphylactic reaction (19.2%), white blood cell 
count decreased (19.2%), alanine aminotransferase increased (17.3%), hyperglycaemia (15.4%), and 
febrile neutropenia (15.4%). 
The overall safety profile observed in Study AALL07P4 was consistent with the profiles of other 
asparaginase preparations. 

 
 
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In Study DFCI 11-01, TEAEs and drug-related TEAEs were reported in all of the 119 subjects in the 
SHP674 group. Grade 3 or 4 TEAEs and drug-related TEAEs were reported in 114 subjects (95.8%) and 
104 subjects (87.4%), respectively. The drug-related TEAEs that were reported with high incidence 
(≥15.0%) in subjects in the SHP674 group were hypoalbuminaemia (80.7%), alanine aminotransferase 
increased (52.1%), aspartate aminotransferase increased (39.5%), hypertriglyceridaemia (36.1%), blood 
fibrinogen decreased (25.2%), blood bilirubin increased (23.5%), lipase increased (23.5%), 
hyperglycaemia (21.8%), amylase increased (16.8%), hypoglycaemia (16.8%), pancreatitis (16.8%), and 
febrile neutropenia (15.1%). 
The Grade 3 or 4 drug-related TEAEs that were reported in ≥5% of the subjects in the SHP674 group 
with high incidence (≥15%) were alanine aminotransferase increased (35.3%), hypertriglyceridaemia 
(30.0%), hypoalbuminaemia (26.1%), lipase increased (20.2%), aspartate aminotransferase increased 
(19.3%), hyperglycaemia (17.6%), blood fibrinogen decreased (17.6%), and febrile neutropenia (15.1%). 
The TEAEs reported in Study DFCI 11-01 were consistent with those specific to asparaginase 
preparations. 
In Study CCG-1962, data on Grade 3 or 4 nonhematologic toxicity were collected. The incidence and 
types of Grade 3 or 4 TEAEs that were reported during the period of treatment with asparaginase 
(remission induction therapy, first and second late consolidation therapy) were similar in both groups and 
similar to those observed with other treatment protocols for low-risk and standard-risk ALL. 
1.6 
Risks and Benefits 
1.6.1 
Risks 
Risks of SHP674 include attenuation or loss of drug efficacy due to anti-SHP674 antibody development 
and the potential for hypersensitivity, which are typical of all foreign proteins (L-asparaginase enzymes). 
Other risks include toxicities associated with the impairment of protein synthesis (e.g., pancreatic-, 
hepatic-, and coagulation-related abnormalities), glucose intolerance, CNS toxicity, myelosuppression, 
hyperammonemia, and toxicities caused by concomitant drugs (including other anticancer agents). 
1.6.2 
Benefits 
The purpose of asparaginase therapy in ALL is to deplete circulating asparagine amino acid, which ALL 
cells are unable to synthesize constitutively. This concept has been well established in ALL treatment, and 
asparaginase is a standard and key component of ALL therapy. 
Pegylated asparaginase has advantages over native L-asparaginase. First, the pharmacokinetics of 
pegylated asparaginase are more favorable than those of native L-asparaginase (longer half-life with 
correspondingly less frequent drug administrations). Pegylated asparaginase is thus expected to reduce the 
burden for patients and health care workers, requiring a lower number of doses. 
SHP674 is able to deplete plasma asparagine even in the presence of antibodies to native L-asparaginase. 
In addition, SHP674 is less immunogenic because of pegylation and can be used in patients who have 
become hypersensitive to native L-asparaginase (the second-line population) to deplete plasma asparagine. 
Inability to complete planned asparaginase therapy due to hypersensitivity is known to correlate with poor 
outcome. SHP674 can be continuously administered to patients who are hypersensitive to native 
L-asparaginase and constitute a major contribution to the care of these patients. 

 
 
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Data from previous studies have shown SHP674 has a similar safety profile to native L-asparaginase. 
More recent studies DFCI 11-001 and AALL07P4 provided more updated data and information regarding 
the safety and efficacy profiles for SHP674.  SHP674 is able to deplete plasma asparagine in patients who 
are naïve to asparaginase therapy or who are continuing asparaginase therapy and in whom there is no 
evidence of allergy or the development of antibodies to SHP674 (the first-line population) and widely used 
as the first-line drug in clinical practice in Europe and the United States. Thus, SHP674 is intended to be 
the first-line treatment for ALL in Japan, which could also be used for patients with hypersensitivity to 
native L-asparaginase.12 
1.7 
Background to the Study Plan 
SHP674 has been approved in foreign countries, but the development of the drug has not been started in 
Japan. As mentioned in Section 1.6.2, there are patients who have a difficulty in continuing the use of the 
native L-asparaginase Leunase® because of allergic reactions such as anaphylactic shock, which prevents 
the patients from completing treatment. In addition, the blood half-life of Leunase® is as short as 
1.24±0.17 days, and the drug needs to be administered daily or every other day. 
SHP674 has immunogenicity reduced by pegylation and can be administered to patients who are allergic 
to Leunase®. SHP674 is expected to play an important role as an alternative drug for patients who have 
allergic reactions to Leunase® in Japan. In addition, SHP674 has a blood half-life prolonged by pegylation 
(5.73±3.24 days), which allows administration every 14 days. Thus, SHP674 is expected to reduce the 
burden for patients and health care workers as it requires considerably lower number of doses during 
remission induction therapy and consolidation therapy. 
With the above background, the Phase 2 clinical study consisting of Part 1 (Dose Confirmation) to 
evaluate the tolerability of SHP674 in Japanese patients and Part 2 to evaluate the efficacy of SHP674 has 
been designed to obtain the marketing approval of SHP674 in Japan. 

 
 
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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
Part 1 
– To assess the tolerability and safety of a single dose of SHP674 in subjects with newly diagnosed, 
untreated acute lymphoblastic leukemia (ALL) in the tolerability assessment period. 
Part 2 
– To assess the percentage of subjects with newly diagnosed, untreated ALL who have a plasma 
asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first dose of SHP674. 
2.1.2 
Secondary Objectives 
Part 1 
– To assess the percentage of subjects with newly diagnosed, untreated ALL who have a plasma 
asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first dose of SHP674. 
– To assess the safety of SHP674. 
– To assess the PK of SHP674. 
– To assess the immunogenicity of SHP674. 
– To assess the survival rate at 1 year after the start of study treatment. 
– To assess the event-free survival rate at 1 year after the start of study treatment. 
Part 2 
– To assess the safety of SHP674. 
– To assess the PK of SHP674. 
– To assess the immunogenicity of SHP674. 
– To assess the survival rate at 1 year after the start of study treatment. 
– To assess the event-free survival rate at 1 year after the start of study treatment. 
 
 
 
 
 
 
 
 
 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
Part 1 
– Incidence and nature of treatment-emergent adverse events (TEAEs) and SHP674-related TEAEs 

 
 
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that occur or worsen during the tolerability assessment period. 
Part 2 
– Achievement of a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first 
dose of SHP674. 
2.2.2 
Rationale for the Primary Endpoint 
Part 1 
– The current dose of SHP674 has been confirmed in multiple clinical studies overseas. Based on the 
characteristics of the drug (i.e., large protein), ethnic factors (genetic polymorphisms etc.) are not 
expected to affect the dose of the drug in the Japanese patients. Part 1 of the study is intended to 
confirm the tolerability of the established dose in the Japanese population. TEAEs and 
SHP674-related TEAEs have been selected as the primary endpoint to assess the tolerability and 
safety of SHP674 in Japanese patients. 
Part 2 
– Plasma or serum asparaginase activity is an effective surrogate endpoint for clinical efficacy, and a 
plasma or serum asparaginase activity of ≥0.1 IU/mL is the threshold for securing sustained 
asparagine depletion.16 In the foreign clinical studies, achievement of a plasma asparaginase 
activity of ≥0.1 IU/mL after the administration of SHP674 was used as an endpoint. The dosing 
interval of SHP674 stated in the package insert in Europe is 14 days. Thus, the percentage of 
subjects who have a plasma asparaginase activity of ≥0.1 IU/mL 14 days after the administration of 
SHP674 has been selected as the primary endpoint of the present study to demonstrate the efficacy 
of SHP674 similar to that shown in the foreign studies. 
2.2.3 
Secondary Endpoints 
Part 1 
– Safety 
• Incidence and nature of treatment-emergent adverse events (TEAEs) and drug-related TEAEs 
• Laboratory values 
• Vital signs 
– PK 
• PK parameters 
– Immunogenicity 
• ADA (anti-SHP674 antibody) and anti-PEG antibody 
– Efficacy 
• Achievement of a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first 
dose of SHP674. 
• Survival rate at 1 year after the start of study treatment 
• Event-free survival rate at 1 year after the start of study treatment 
Part 2 
– Safety 
• Incidence and nature of TEAEs and drug-related TEAEs 
• Laboratory values 

 
 
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• Vital signs 
– PK 
• PK parameters 
– Immunogenicity 
• ADA (anti-SHP674 antibody) and anti-PEG antibody 
– Efficacy 
• Plasma asparaginase activity 
• Survival rate at 1 year after the start of study treatment 
• Event-free survival rate at 1 year after the start of study treatment 
 
  
 
 
 
 
 
 
3 STUDY DESIGN 
3.1 
Study Design 
This is a multicenter, non-randomized, open-label, Phase 2 clinical study of SHP674 in Japanese 
subjects with newly diagnosed, untreated ALL. The study consists of Part 1 and Part 2. 
In this study, the date of starting prednisolone administration in the pre-treatment phase (IP) is defined as 
Day 1. Days of each treatment phase or block are defined in the protocol. The week when the pre-treatment 
phase is started is defined as Week 1. The week preceding the start week of the pre-treatment phase is 
defined as Week 0. The week that is Y weeks after the start of the pre-treatment period will be regarded as 
Week Y. As a general rule, subjects will be hospitalized during remission induction therapy (IA2/IA4). The 
dosing schedule of each drug including SHP674 is outlined in Table 7-1 to Table 7-3. 
3.1.1 
Part 1 
Part 1 is comprised of a screening period and a subsequent tolerability assessment period (from the 
pre-treatment phase through remission induction therapy [Day 1 to Day 37]; for at least 25 days after the 
first dose of SHP674) and a treatment period (from early consolidation therapy to the end-of-study 
assessment). Subjects categorized as SR or IR will receive total 3 doses of SHP674 and those categorized 
as HR will receive total 8 doses of SHP674 during the tolerability assessment period and the treatment 
period. The outline of the study design in Part 1 is shown in Figure 3.1-1. The tolerability assessment 
period consists of a pre-treatment phase (IP) and remission induction therapy (IA2/IA4) according to the 
regimen used in Study ALL-B12.17 The treatment period consists of early consolidation therapy (IB/IB+L), 
consolidation therapy (M2/M5/HR3, HR2, HR1), re-induction therapy (III/III+L), and interim 
maintenance therapy (IM), which are also based on the regimen used in Study ALL-B12. Subjects who 

 
 
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complete the tolerability assessment period will move to the treatment period and continue to receive 
SHP674. The outline of each treatment phase is shown in Figure 3.1-3.   
Subjects will undergo screening after giving informed consent, and eligible subjects will be enrolled 
within 21 days after giving informed consent and within 14 days after screening. Subjects will start 
treatment within 7 days after enrollment. Only subjects who are able to give assent or informed consent 
will be enrolled in Part 1. 
Part 1 will enroll 3 to 6 subjects to assess tolerability. The tolerability assessment will be based on the 
number of subjects who experience intolerable toxicity during the tolerability assessment period (the 
details of the assessment procedure are described in Section 7.5.4).  
Safety data of Part 1 will be reviewed by an internal safety committee (composed of the Sponsor and 
study investigators) that will determine if the dose investigated in Part 1 was well tolerated and Part 2 can 
be initiated with this dose. 
Figure 3.1-1 Outline of Study Design in Part 1 
 
3.1.2 
Part 2 
Part 2 is comprised of a screening period and a subsequent treatment period (from the pre-treatment 
phase to the end-of-study assessment). Subjects categorized as SR or IR will receive 3 doses of SHP674 
and those categorized as HR will receive 8 doses of SHP674 during the treatment period. The outline of the 
study design in Part 2 is shown in Figure 3.1-2. The treatment period consists of a pre-treatment phase (IP), 
remission induction therapy (IA2/IA4), early consolidation therapy (IB/IB+L), consolidation therapy 
(M2/M5/HR3, HR2, HR1), re-induction therapy (III/III+L), and interim maintenance therapy (IM) 

 
 
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according to the regimen used in Study ALL-B12. The outline of each treatment phase is shown in Figure 
3.1-3. 
Subjects will undergo screening after giving informed consent, and eligible subjects will be enrolled 
within 21 days after giving informed consent and within 14 days after screening. Subjects will start 
treatment within 7 days after enrollment. 
Part 2 will target to enroll 22 subjects to evaluate the efficacy, safety, and pharmacokinetics of SHP674 
at the dose shown to be tolerated in Part 1. 
Figure 3.1-2 
Outline of Study Design in Part 2 
 

 
 
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Figure 3.1-3 
Outline of Each Treatment Phase 
 

 
 
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3.1.3 
Risk Classification 
Subjects who are newly diagnosed with ALL will be stratified into the SR, IR, or HR group according to 
the risk classification criteria based on the comprehensive assessment from the pre-treatment phase 
through remission induction therapy. The ALL risk classification used in this study is presented in Table 
3.1.3-1. The NCI classification is presented in Table 3.1.3-2. 
Table 3.1.3-1 Criteria for Risk Classification 
SR 
Subject meets all of the following criteria: 
・Not categorized as HR according to this classification. 
・Prednisolone-good responder (PGR)a) 
・Categorized as SR per NCI classification (NCI-SR). 
・ M1 or M2 marrow b) at bone marrow examination on Day 15 of remission induction 
therapy (BMA2). 
IR 
Subject meets any of the following criteria: 
・Categorized as other than HR according to this classification, PGR, and HR per NCI 
classification (NCI-HR). 
・Categorized as PGR and NCI-SR; and M3 marrowb) at bone marrow examination on Day 
15 of remission induction therapy (BMA2). 
HR 
Subject meets one or more of the following criteria: 
・CNS-3c) on Day 1 of the pre-treatment phase. 
・Categorized as a prednisolone-poor responder (PPR)a) on Day 8 of remission induction 
therapy. 
・Categorized as PGR and NCI-HR; and M3 marrowb) on Day 15 of remission induction 
therapy (BMA2). 
・Assessed as having refractory disease at BMA3. 
・ KMT2A-AFF1 (MLL-AF4) fusion gene-positive (to be determined before the start of 
treatment on Day 22 of remission induction therapy). 
・Hypodiploid (≤44 chromosomes) (to be determined before the start of treatment on Day 
22 of remission induction therapy) 
SR, standard risk; IR, intermediate risk; HR, high risk 
a: See Section 8.3.4. 
b: Bone marrow status is categorized as follows according to the percentage of blasts in bone marrow: 
∙ M1 marrow: <5% 
∙ M2 marrow: 5% to ≤25% 
∙ M3 marrow: >25% 
c: See Section 3.1.4.1.1. In this study, subjects with CNS-3 status meet the withdrawal criterion. 
Table 3.1.3-2 Criteria for NCI Classification 
 
 
Circulating White Blood Cell Counta) 
 
 
<50000/μL 
≥50000/μL 
Age 
1 to ≤9 years 
SR 
HR 
<1 year, ≥10 years 
HR 
HR 
a Categorized based on the maximum value obtained at the investigative site before the start of treatment. 
3.1.3.1 
Change of Risk Category 
A subject’s risk category needs to be changed in the following cases: 
• If a subject is considered a prednisolone poor responder (PPR) on Day 8 of remission 
induction therapy, the subject’s risk category will be changed to HR. 
• If a subject is assessed as having M3 marrow at bone marrow examination on Day 15 of 
remission induction therapy (BMA2), the subject’s risk category will be changed to the next 
higher level (from SR to IR, from IR to HR). 

 
 
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• If a subject is shown to be KMT2A-AFF1 (MLL-AF4) fusion gene-positive or hypodiploid 
(≤44 chromosomes) before the start of treatment on Day 22 of remission induction therapy, 
the subject’s risk category will be changed to HR. 
• If a subject is assessed as having refractory disease at BMA3, the subject’s risk category will 
be changed to HR. 
3.1.4 
Criteria for Evaluation of Organ Involvement 
3.1.4.1 
Central Nervous System (CNS) Involvement 
3.1.4.1.1 
Classification of CNS Status (NCCN Guidelines18) 
• CNS-1: No lymphoblasts in cerebrospinal fluid (CSF) regardless of white blood cell count. 
• CNS-2: WBC <5/μL in CSF with presence of lymphoblasts. 
• CNS-3: WBC ≥5/μL in CSF with presence of lymphoblasts. 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and WBC 
≥5/μL in CSF with blasts, then compare the CSF WBC/RBC ratio to the blood WBC/RBC ratio. If the CSF 
ratio is at least 2-fold greater than the blood ratio, then the classification is CNS-3; if not, then it is CNS-2. 
3.1.4.1.2 
Test for Determination of CNS Status 
When determining the presence or absence of CNS involvement at the initial visit, the first cerebrospinal 
fluid examination must be performed simultaneously with the first intrathecal injection to prevent the 
invasion of the marrow cavity by blasts associated with lumbar puncture. The presence or absence of blasts 
must be determined only with Cytospin samples. Not only white blood cell count but also red blood cell 
count should be calculated when determining the number of cells in the cerebrospinal fluid. Search for 
findings such as tumor lesions by brain tomography (MRI or CT) is also essential before the start of 
treatment. 
3.1.5 
Rationale for Study Design 
The position of L-asparaginase preparations in the treatment of ALL has been established based on 
treatment results obtained in and outside Japan. Data on SHP674 has been obtained from multiple clinical 
studies outside of Japan and were found to be comparable to native L-asparaginase, this study will be 
conducted as a multicenter, non-randomized, open-label, single arm Phase 2 clinical study.  
The current dose of SHP674 has been confirmed in multiple clinical studies overseas. Based on the 
characteristics of the drug (i.e., large protein), ethnic factors (genetic polymorphisms etc) are not expected 
to affect the dose of the drug in the Japanese patients. Part 1 of the study is intended to confirm the 
tolerability of the established dose in the Japanese population. TEAEs and SHP674-related TEAEs have 
been selected as the primary endpoint to assess the tolerability and safety of SHP674 in Japanese patients. 
The tolerability assessment period is defined as the period until the end of remission induction therapy to 
assess tolerability at least for a period corresponding to approximately 5 half-lives of SHP674 
(approximately 25 days). Due to potential increased risk of hypersensitivity when switching from SHP674 
to native L-asparaginase patients treated in Part 1 of the study will continue to receive SHP674 for all 
subsequent treatment phases where asparaginase administration is required. 
The study will be further continued as Part 2 after the tolerability of SHP674 is established in Part 1. 

 
 
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3.2 
Enrollment of Subjects 
The investigator or subinvestigator will enroll subjects according to the procedure described below. 
1) 
If the potential subject is an adult, the investigator or subinvestigator will fully explain the nature of 
the study to the potential subject and obtain his or her written informed consent for participation in 
the study. If the potential subject is a child, the investigator or subinvestigator will fully explain the 
nature of the study to the potential subject and his or her legally acceptable representative and obtain 
written informed consent for participation in the study from the legally acceptable representative. In 
addition, the investigator or subinvestigator will obtain adequate oral or written assent from the 
potential subject as far as possible. 
2) 
The investigator or subinvestigator will assess the subject for all the inclusion and exclusion criteria 
to determine eligibility. If the subject is considered eligible, the investigator or subinvestigator will 
enter relevant information on the subject into an interactive web response system (IWRS) according 
to the written procedure developed elsewhere. Study treatment will be started within 7 days after 
enrollment. Subjects enrolled once cannot be re-enrolled. If the subject is ineligible for enrollment, 
the investigator or subinvestigator will enter SID, date of obtaining informed assent or consent, sex, 
and the reason for ineligibility into the eCRF. 
3.3 
Target Sample Size 
Part 1 = 3 to 6 evaluable subjects 
Part 2 = 22 subjects 
3.4 
Planned Study Period 
May 2019 to December, 2022 
 A snapshot of data will be taken for analysis of all available endpoints after all subjects completed 
remission induction therapy. The clinical study report (CSR) will be based on the data from the period of 
remission induction phase. Additional safety, PK and survival final analysis of all secondary 
 
 endpoints will be performed after all subjects complete the study (365 [±7] days after the first 
dose of SHP674 or at the time all subjects complete the study) and submitted as an addendum to the CSR.  

 
 
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4 SUBJECT ELIGIBILITY CRITERIA 
4.1 
Target Disease 
ALL 
4.1.1 
Diagnosis of ALL 
ALL is defined as a condition in which lymphoblasts account for at least 25% of all nucleated cells in 
bone marrow.  
B-ALL is defined as ALL that meets the immunological criteria for diagnosis based on immunological 
marker findings (see Attachment 5 to the protocol [supplement]), according to the WHO Classification 
2017. 
4.2 
Inclusion Criteria 
Subjects enrolled in the study must meet all of the following criteria: 
1) 
For Part 1, personally provided informed assent or written informed consent. If informed assent is 
obtained from a subject, written informed consent should be obtained from a legally acceptable 
representative. For Part 2, written informed consent provided by the subject and/or a legally 
acceptable representative. Written or verbal assent should be obtained from the subject as far as 
possible even if written informed consent is obtained from a legally acceptable representative; 
2) 
Age 1 to ≤21 years at the time of informed consent; 
3) 
Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2; 
4) 
Newly diagnosed, untreated precursor B-cell ALL (see Attachment 5 to the protocol [supplement]); 
5) 
No prior therapy for malignant tumor such as chemotherapy and radiation therapy before signing the 
informed consent; 
6) 
The following laboratory criteria are met at the time of screening: 
• AST and ALT ≤10 × age-specific upper limit of normal (ULN) 
• D-Bil <1.5 mg/dL 
• Serum creatinine ≤1.5 × age-specific ULN 
• Corrected serum calcium ≤11.5 mg/dL 
• Left ventricular ejection fraction ≥63% 
• SpO2 ≥94% 
• QT interval corrected by the Fridericia formula (QTcF = QT/PR1/3) <0.45 seconds 
7) 
Life expectancy of at least 6 months from the date of enrollment; 
8) 
Women of childbearing potential and fertile men must agree to use highly effective contraceptive 
methods from the time of informed consent to at least 6 months after the last dose of SHP674 (for 
women) or from the start of SHP674 administration to at least 6 months after the last dose of SHP674 
(for men). Women of childbearing potential must have a negative serum or urinary pregnancy test 
result at screening test. 
Note:  
• A woman of childbearing potential is defined as a woman who has experienced her first 
menstruation, has not undergone hysterectomy, bilateral tubal ligation, or bilateral ovariectomy 

 
 
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and is not postmenopausal. Postmenopausal status is defined as amenorrhea of ≥12 consecutive 
months with no specific causes 
• Since there is a potential for an indirect interaction between SHP674 and oral contraceptives, 
the concomitant use of SHP674 and oral contraceptives is not recommended. Another, non-oral 
contraceptive method should be used in women of childbearing potential. 
 
4.3 
Exclusion Criteria 
Subjects must be excluded from participating in this study if they meet any of the following criteria: 
1) 
Down syndrome; 
2) 
Mature B-cell ALL (e.g., Burkitt’s ALL); 
3) 
Currently active infection; 
4) 
Poorly controlled concurrent illness; 
5) 
Preexisting known coagulopathy (e.g., hemophilia and known protein S deficiency); 
6) 
History of pancreatitis; 
7) 
Continuous use of corticosteroids (transient use for transfusion reactions and topical or local use for 
the treatment of diseases other than the primary disease will be allowed); 
8) 
Positive for HBs antigen, HCV antibody, or HIV antibody. Subjects who are negative for HBs 
antigen but positive for HBc antibody and/or HBs antibody will undergo an HBV DNA test and will 
be excluded from the study if they are positive for HBV DNA (≥20 IU/mL [1.3 LogIU/mL]); 
9) 
Prior treatment or possible prior treatment with an L-asparaginase preparation; 
10) 
History of sensitivity to polyethylene glycol (PEG) or PEG-based drugs; 
11) 
Current symptoms or signs of CNS involvement (e.g., cranial nerve symptoms such as facial palsy), 
with CNS disease detected on CT or MRI; 
12) 
Pregnant (or planning to become pregnant in near future) or breastfeeding women (breastfeeding 
women will be excluded from the study even if they stop their breastfeeding); 
13) 
History of previous malignancy, other concurrent malignancy, or secondary ALL; or 
14) 
Other inadequacy determined by the investigator or subinvestigator. 
 

 
 
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5 STOPPING RULES AND PROCEDURES 
5.1 
Subject Withdrawal 
The investigator or subinvestigator will take appropriate actions for subjects who are withdrawn from 
the study or treatment in the case of safety issues such as occurrence of an AE. The investigator or 
subinvestigator will also ensure the safety of withdrawn subjects and conduct an early termination (ET) 
assessment 30 (+7) days after the last dose of investigational product.  If the subject’s next therapy starts 30 
(+7) days after the last dose of investigational product or earlier, the ET assessment may be conducted 
within 7 days of the start date of the next therapy. Adverse event information should be collected until 30 
(+7) days after the last dose of investigational product. 
 
Subjects who do not return to the investigative site without completing the scheduled assessments after 
the start of study treatment will be followed up as long as possible, with due consideration of the subject’s 
human rights, to assess safety. The investigator or subinvestigator will make best efforts to keep subjects 
participating in the study unless there is a medical contraindication or significant deviation from the 
protocol. However, if the investigator or subinvestigator determines that discontinuation of study 
treatment is the best interest of the subject, or if the subject decides to withdraw his or her consent, the 
investigator or subinvestigator will make best efforts to complete sufficient observation and report the 
results as far as possible. 
The investigator or subinvestigator will identify the date of early termination and the reason for early 
termination and enter the information into the electronic case report form (eCRF). 
5.1.1 
Withdrawal from the Study 
Subjects will be withdrawn from the study if any of the following situations occurs. Withdrawn subjects 
will not undergo survival follow-up specified in Section 8.24 after withdrawal from the study. 
1) 
The subject is found not to meet the eligibility criteria after the start of the study prior to 
administration of SHP674 unless the investigator indicate that the participation of the subjects is 
beneficial and the Sponsor approved the continuation of the subject participation. 
2) 
The subject (or his or her legally acceptable representative) wishes to withdraw consent from the 
study. 
3) 
The subject cannot undergo necessary observations and examinations for a personal reason before 
the administration of SHP674 in remission induction therapy. 
4) 
The investigator or subinvestigator determines that the subject should discontinue study treatment 
because of an AE before the administration of SHP674 in remission induction therapy. 
5) 
A new malignancy is detected in the subject before the administration of SHP674 in remission 
induction therapy. 
6) 
The subject is found to have MYC translocation-positive ALL before the administration of SHP674 
in remission induction therapy. 
7) 
The subject is found to have Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL 
before the administration of SHP674 in remission induction therapy. 
8) 
The subject cannot receive SHP674 in remission induction therapy. 

 
 
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9) 
Central nervous system (CNS) involvement status classified as CNS-3 according to the NCCN 
guidelines at the time of first MTX IT during the pre-treatment phase (see Attachment 6 to the 
protocol [supplement]). 
10) 
The total dosage of PSL received by the subject in the pre-treatment phase (IP) is <210 mg/m2; or the 
subject has a circulating white blood cell count of ≥100000/μL and a circulating blast count that is 
≥1.5-fold that on Day 1 during the period from Day 4 to Day 7, requiring the earlier start of remission 
induction therapy (including VCR administration on Day 8). 
11) 
The subject requires a treatment for the primary disease that is not specified in the protocol including 
hematopoietic stem cell transplantation before the administration of SHP674 in remission induction 
therapy (subjects for whom hematopoietic stem cell transplantation is indicated must be withdrawn 
from the study before pre-treatment for transplantation). 
12) 
The investigator or subinvestigator determines that the subject should be withdrawn from the study 
for a reason other than above before the administration of SHP674 in remission induction therapy. 
13) 
The Sponsor determines that the study (the entire study or the study at the investigative site) should 
be terminated. 
5.1.2 
Treatment Discontinuation 
The protocol-specified treatment will be discontinued if a subject meets any of the criteria below. 
Subjects treated with SHP674 will be followed for survival as specified in Section 8.24 after treatment 
discontinuation. 
1) 
The subject is found not to meet the eligibility criteria after the administration of SHP674 in 
remission induction therapy unless the investigator indicate that the participation of the subjects is 
beneficial and the Sponsor approved the continuation of the subject participation. 
2) 
The investigator or subinvestigator determines that the subject should discontinue study treatment 
because of an AE after the administration of SHP674 in remission induction therapy. 
3) 
The subject has relapse of the primary disease (see Section 5.2). 
4) 
A new malignancy is detected in the subject after the administration of SHP674 in remission 
induction therapy. 
5) 
The subject has no remission at bone marrow examination during early consolidation therapy 
(BMA4). 
6) 
After receiving the prescribed treatment with SHP674 in remission induction therapy, the subject 
becomes unable to undergo necessary observations and examinations for a personal reason. 
7) 
The subject is found to have MYC translocation-positive ALL after the administration of SHP674 in 
remission induction therapy. 
8) 
The subject is found to have Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL 
after the administration of SHP674 in remission induction therapy. 
9) 
The subject cannot receive SHP674 in any of the treatment phases after remission induction therapy. 
10) 
The administration of VCR, DNR, SHP674, or TIT (for subjects with CNS-2 status) is postponed for 
≥15 consecutive days during remission induction therapy (IA2/IA4). 
11) 
Early consolidation therapy (IB/IB+L) is interrupted for ≥28 days. 
12) 
Re-induction therapy (III/III+L) is interrupted for ≥28 days. 
13) 
The subject cannot start or complete treatment within the periods specified below:  

 
 
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• Early consolidation therapy (IB/IB+L) cannot be completed within 18 weeks after the start of 
remission induction therapy (IA2/IA4). 
• Consolidation therapy (M2/M5/HR3, HR2, HR1) cannot be completed within 14 weeks after 
the start of each consolidation therapy. 
• Re-induction therapy (III/III+L) cannot be completed within 16 weeks after the start of each 
re-induction therapy. 
• The next treatment phase cannot be started within 6 weeks from the day after the completion 
of drug treatment in early consolidation therapy (IB/IB+L).  
• Re-induction therapy (III/III+L) cannot be started within 6 weeks from the day after the 
completion of drug treatment in consolidation therapy (M2/M5/HR3, HR2, HR1). 
• There is an interval of ≥8 weeks between treatment phases in cases other than those listed 
above. 
14) 
The subject requires a treatment for the primary disease that is not specified in the protocol including 
hematopoietic stem cell transplantation after the administration of SHP674 in remission induction 
therapy (subjects for whom hematopoietic stem cell transplantation is indicated must be withdrawn 
from the study before pre-treatment for transplantation). 
15) 
The subject experiences Grade 3 pancreatitis, hypersensitivity reaction, or thrombosis after the 
administration of SHP674.  
16) 
The subject experiences the intolerable toxicity that is specified in Section 7.5.2 in Part 1 and does 
not or is not expected to recover by Day 37 of remission induction therapy. 
17) 
The investigator or subinvestigator determines that the subject should be withdrawn from the study 
for a reason other than above after the administration of SHP674 in remission induction therapy. 
5.2 
Definition of Relapsed Disease 
 
 
 
5.2.1 
Extramedullary Relapse 
1) 
CNS relapse: Development of CNS-3 status or clinical signs of CNS leukemia such as facial nerve 
palsy, brain/eye involvement, or hypothalamic syndrome
 
2) 
Other organs: Recurrence of mediastinal enlargement 
 At least one of the 
previously observed lesions is positive on post-treatment PET for subjects who had a positive result 
on previous PET. 
5.3 
Premature Termination or Suspension of the Study at the Investigative Site 
If the investigator prematurely terminates or suspends the study at his or her site for concerns over the 
safety of investigational product or for any other reason, the investigator will promptly notify the director 
of the investigative site in writing, with a detailed written explanation. The director of the investigative site 
will promptly notify the Sponsor or in-country caretaker and the IRB in writing of the premature 
termination or suspension and the reason for the decision. 
Any of the following circumstances will also result in the premature termination of the study at the 
investigative site. In such an event, appropriate steps will be taken in a similar manner to the above. 

 
 
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1) 
The director of the investigative site requests that the protocol be revised based on the IRB’s 
recommendation, but the Sponsor cannot accept it. 
2) 
The IRB consulted by the director of the investigative site concludes that the study should not be 
continued, and the director of the investigative site orders that the study be terminated. 
3) 
The investigative site has major or continuous violations of GCP, the protocol, or the clinical study 
agreement. 
5.4 
Premature Termination or Suspension of the Entire Study 
If the entire study is prematurely terminated or suspended, the Sponsor will promptly inform all 
investigative site directors and the regulatory authority with a detailed explanation of the reason. Upon 
receipt of the notification, the director of the investigative site will promptly inform the investigator and 
the IRB of the termination or suspension in writing, with a description of the reason. If the study is 
prematurely terminated or suspended, the investigator will promptly notify subjects of the termination or 
suspension and take necessary measures such as providing appropriate medical care. 

 
 
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6 Investigational Product 
6.1 
Test Drug and Backbone Therapy Drugs Provided by the Sponsor for 
Investigational Use 
6.1.1 
Test Drug 
Company code: SHP674 
Nonproprietary name: Pegaspargase 
Molecular weight: 280000 to 300000 
Strength and formulation: 
A vial containing 3570 IU active ingredient. SHP674 is a white to off-white lyophilized powder and 
supplied as a sterile, single-use vial.  
Drug reconciliation method: 
The drug is dissolved in 5.2 mL sterile water for injection to make 750 IU/mL of solution. The 
composition of lyophilized SHP674 after dissolution is shown in Table 6.1.1-1. 
Table 6.1.1-1 Composition of Lyophilized SHP674 
Ingredient 
Amount per mL (after dissolution) 
Function 
SHP674 drug substance 
750 IU 
Active ingredient 
Disodium hydrogen phosphate 
0.56 mg 
Buffer agent 
Sodium dihydrogenphosphate 
2.58 mg 
Buffer agent 
Sodium chloride 
3.94 mg 
Isotonic fluid 
Sucrose 
42 mg 
Stabilizer 
Sodium hydroxide 
Trace amount 
pH adjustment 
Hydrochloric acid 
Trace amount 
pH adjustment 
6.1.2 
Backbone Therapy Drugs Provided by the Sponsor for Investigational Use 
1) Predonine® Tablets 5 mg 
Company code: PSL-SER-PO-T 
Non-proprietary name: Prednisolone 
Chemical name: 11β, 17, 21-Trihydroxypregna-1, 4-diene-3, 20-dione (IUPAC) 
Molecular formula: C21H2O5 
Molecular weight: 360.44 
Strength and formulation: 
Light orange tablets each containing 5 mg prednisolone. 
2) Prednisolone Powder 1% 
Company code: PSL-SER-PO-P 
Non-proprietary name: Prednisolone 
Chemical name: 11β, 17, 21-Trihydroxypregna-1, 4-diene-3, 20-dione (IUPAC) 
Molecular formula: C21H2O5 
Molecular weight: 360.44 

 
 
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Strength and formulation: 
Vials of 100 g power containing 10 mg prednisolone per gram.  
3) Predonine® 50 mg (Water-soluble) 
Company code: PSL-SER 
Non-proprietary name: Prednisolone sodium succinate 
Chemical name: Monosodium 11β, 17, 21-trihydroxypregna-1, 4-diene-3, 20-dione 21-succinate 
(IUPAC) 
Molecular formula: C25H31O8 
Molecular weight: 482.50 
Strength and formulation: 
An ampule containing 50 mg prednisolone. The drug is supplied as a lyophilized, sterile, single-use 
ampule. 
Drug reconciliation method: 
The ampule contents are dissolved in 1 to 5 mL water for injection or isotonic sodium chloride 
solution to prepare solution. 
Procedure for triple intrathecal therapy (TIT): 
Dissolve MTX in distilled water for injection to a concentration of 2.5 mg/mL. Dissolve PSL in 
distilled water for injection to a concentration of 10 mg/mL. Take the necessary amount of Ara-C in 
a syringe. Administer MTX, Ara-C, and PSL in one syringe. 
4) Endoxan® 500 mg (for Injection) 
Company code: CPA-SER 
Non-proprietary name: Cyclophosphamide hydrate 
Chemical name: N,N-Bis(2-chloroethyl)-3,4,5,6-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 
2-oxide monohydrate (IUPAC) 
Molecular formula: C7H15Cl2N2O2P∙H2O 
Molecular weight: 279.10 
Strength and formulation: 
A vial containing 500 mg cyclophosphamide. The drug is supplied as a sterile, single-use vial. 
Drug reconciliation method: 
Five milliliters of isotonic sodium chloride solution or water for injection are added per 100 mg of 
cyclophosphamide (as anhydride) to dissolve. Water for injection should not be used for one-shot 
administration such as intravenous injection because the solution becomes hypotonic. 
5) Leukerin® Powder 10% 
Company code: 6-MP-SER 
Non-proprietary name: Mercaptopurine hydrate 
Chemical name: 1,7-Dihydro-6H-purine-6-thione monohydrate (IUPAC) 
Molecular formula: C5H4N4S∙H2O 
Molecular weight: 170.19 
Strength and formulation: 
Bottle of 25 g of power containing 100 mg mercaptopurine hydrate per gram. 

 
 
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6) Lastet® Inj. 100 mg/5 mL 
Company code: VP-16-SER 
Non-proprietary name: Etoposide 
Chemical name: (5R,5aR,8aR,9S)-9-{[4,6-O-(1R)-Ethylideneβ-D-glucopyranosyl]oxy}-5- 
(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d] 
[1,3]dioxol-6(5aH)-one 
Molecular formula: C29H3O13 
Molecular weight: 588.5 
Strength and formulation: 
A vial (5 mL) containing 100 mg etoposide. The drug is supplied as a sterile, single-use vial. 
 
7) Ifomide® 1 g (for Injection) 
Company code: IFO-SER 
Non-proprietary name: Ifosfamide 
Chemical name: (±)-3-(2-Chloroethyl)-2-[(2-chloroetyl)amino] tetrahydro-2H-1,3 2-oxazaphosphorine 
2-oxide (IUPAC) 
Molecular formula: C7H15Cl2N2O2P 
Molecular weight: 261.09 
Strength and formulation: 
A vial containing 1 g ifosfamide. The drug is supplied as a sterile, single-use vial. 
Drug reconciliation method: 
One gram (1 bottle) of ifosfamide is dissolved in 25 mL isotonic sodium chloride solution or water 
for injection. 
8) Decadron® Tablets 0.5 mg/4 mg 
Company code: DEX-SER-PO 
Non-proprietary name: Dexamethasone 
Chemical name: 9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione (IUPAC) 
Molecular formula: C22H29FO5 
Molecular weight: 392.46 
Strength and formulation: 
White or light red tablets each containing 0.5 mg or 4 mg dexamethasone. 
9) Decadron® Phosphate Injection 6.6 mg 
Company code: DEX-SER-IV 
Non-proprietary name: Dexamethasone sodium phosphate 
Chemical name: 9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione 
21-(disodium phosphate) (IUPAC) 
Molecular formula: C22H28FNa2O8P 
Molecular weight: 516.40 
Strength and formulation: 
A vial (2 mL) containing 6.6 mg dexamethasone. The drug is supplied as a sterile, single-use vial. 

 
 
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10) Methotrexate® Tablets 2.5 mg 
Company code: MTX-SER 
Non-proprietary name: Methotrexate 
Chemical name: N-{4-[(2,4-Diaminopteridin-6-ylmethyl)(methyl)amino]benzoyl}-L-glutamic acid 
(IUPAC) 
Molecular formula: C20H22N8O5 
Molecular weight: 454.44 
Strength and formulation: 
Light yellow-brown tablets each containing 2.5 mg methotrexate. 
11) Methotrexate® Injection 1000 mg 
Company code: HD-MTX-SER 
Non-proprietary name: Methotrexate 
Chemical name: N-{4-[(2,4-Diaminopteridin-6-ylmethyl)(methyl)amino]benzoyl}-L-glutamic acid 
(IUPAC) 
Molecular formula: C20H22N8O5 
Molecular weight: 454.44 
Strength and formulation: 
A vial (10 mL or 40 mL) containing 1000 mg methotrexate. The drug is supplied as a sterile, 
single-use vial. 
6.2 
Packaging and Labeling 
6.2.1 
Package Presentation 
SHP674: 1 vial/box 
Predonine® Tablets 5 mg: 100 tablets/box 
Prednisolone Powder 1%: 1 vial/box 
Predonine® 50 mg (water-soluble): 5 ampules/box 
Endoxan® 500 mg (for injection): 1 vial/box 
Leukerin® Powder 10%: 1 vial/box 
Lastet® Inj.100 mg/5 mL: 1 vial/box 
Ifomide® 1 g (for injection): 10 vials/box 
Decadron® Tablets 0.5 mg/4 mg: 100 tablets/box 
Decadron® Phosphate Injection 6.6 mg: 10 vials/box 
Methotrexate® Tablets 2.5 mg: 100 tablets/box 
Methotrexate® Injection 1000 mg: 1 vial/box 
6.2.2 
Labeling 
All labels for the test drug and the backbone therapy drugs provided by the Sponsor for investigational 
use will contain the following information: 
Label for outer box: Statement that the drug is for investigational use, name and country name of the 
Sponsor, name and address of the in-country caretaker, company code, lot number, 
investigational product number, and storage directions  

 
 
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Label for syringe, ampule or vial: a statement to the effect that the drug is for investigational use, name 
of the Sponsor and the in-country caretaker, company code, lot number, and 
investigational product number 
6.3 
Storage Conditions 
SHP674: At 2°C to 8°C. 
Predonine® Tablets 5 mg: At room temperature. 
Prednisolone Powder 1%: At room temperature. 
Predonine® 50 mg (water-soluble): At room temperature, protected from light. 
Endoxan® 500 mg (for injection): At 2°C to 8°C. 
Leukerin® Powder 10%: At room temperature. 
Lastet® Inj.100 mg/5 mL: At room temperature. 
Ifomide® 1 g (for injection): At room temperature. 
Decadron® Tablets 0.5 mg/4 mg: At room temperature. 
Decadron® Phosphate Injection 6.6 mg: Store in a cold place, protected from light. Avoid freezing. 
Methotrexate® Tablets 2.5 mg: At room temperature, protected from light. 
Methotrexate® Injection 1000 mg: The 10-mL preparation should be stored at 15°C to 25°C, protected 
from light. The 40-mL preparation should be stored at room 
temperature, protected from light. 
6.4 
Dispensing, Storage, Management, and Return of Investigational Product 
The Sponsor or the in-country caretaker will dispense investigational product to each investigative site 
through a contractor for transportation selected by the Sponsor or the in-country caretaker after concluding 
a clinical study agreement with the investigative site. The details of investigational product dispensing will 
be described in the study pharmacy manual provided to each site prior to the site initiation. Each site will 
be trained regarding these procedures during the site initiation visit and later on as required. The Sponsor 
will develop a written procedure for the management of investigational product and submit it to the 
investigative site. 
The investigational product manager at each investigative site will properly store and manage 
investigational product according to the written procedure and will document the use of investigational 
product, including inventory, return, and destruction. The investigational product manager will properly 
check the number of unused and used supplies of the investigational product (including empty vials and 
boxes) against the investigational product management record. The investigational product manager will 
return investigational product to the Sponsor or the in-country caretaker after the end of the study or at the 
time of re-dispensing of investigational product accompanied by batch switch. 
The investigational product manager will submit a copy of the investigational product management 
record to the Sponsor or the in-country caretaker after finalizing the records of use of investigational 
product. 

 
 
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7 TREATMENT PLAN AND CONCOMITANT TREATMENTS 
The outline of the treatment schedule is shown in Table 7-1 to Table 7-3. 

 
 
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Table 7-1 Treatment Schedule for SR 
 
* If a subject cannot receive intrathecal MTX on Day 1 for a reason such as that the subject’s initial visit falls on a weekend, the administration of MTX can be postponed until up to Day 4. 
** IA2 will be from Day 8 (Week 2) to the end of PSL administration on Day 37 (Week 6). 
***TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
Each symbol represents the day of each drug administration. 
 

 
 
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Table 7-1 Treatment Schedule for SR (Continued) 
 
 
Table 7-1 Treatment Schedule for SR (Continued) 
 
 
 

 
 
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Table 7-1 Treatment Schedule for SR (Continued) 
 
 
 
Table 7-1 Treatment Schedule for SR (Continued) 
 
 
 

 
 
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Table 7-1 Treatment Schedule for SR (Continued) 
 

 
 
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Table 7-2 Treatment Schedule for IR 
 
* If a subject cannot receive intrathecal MTX on Day 1 for a reason such as that the subject’s initial visit falls on a weekend, the administration of MTX can be postponed until up to Day 4. 
** IA4 will be from Day 8 (Week 2) to the end of PSL administration on Day 37 (Week 6). 
*** TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend or holiday. 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
 
Each symbol represents the day of each drug administration. 

 
 
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Table 7-2 Treatment Schedule for IR (Continued) 
 
 
Table 7-2 Treatment Schedule for IR (Continued) 
 
 

 
 
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Table 7-2 Treatment Schedule for IR (Continued) 
 
 
Table 7-2 Treatment Schedule for IR (Continued) 
 
 

 
 
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Table 7-2 Treatment Schedule for IR (Continued) 
 
 
 

 
 
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Table 7-3 Treatment Schedule for HR 
 
* If a subject cannot receive intrathecal MTX on Day 1 for a reason such as that the subject’s initial visit falls on a weekend, the administration of MTX can be postponed until up to Day 4. 
** IA4 will be from Day 8 (Week 2) to the end of PSL administration on Day 37 (Week 6). 
*** TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend or holiday. 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
 
Each symbol represents the day of each drug administration. 
 

 
 
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Table 7-3 Treatment Schedule for HR (Continued) 
 
 
Table 7-3 Treatment Schedule for HR (Continued) 
 

 
 
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Table 7-3 Treatment Schedule for HR (Continued) 
 
 
Table 7-3 Treatment Schedule for HR (Continued) 
 

 
 
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Table 7-3 Treatment Schedule for HR (Continued) 
 
 

 
 
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7.1 
Dose, Dosing Regimen, and Treatment Duration of SHP674 
7.1.1 
Dose and Dosing Regimen of SHP674 
Subjects will receive a single IV dose of SHP674 at the following time points specified for each risk 
category: 
SR: Total 3 doses 
Remission induction therapy (IA2), Day 12; re-induction therapy (III)*, Day 2 
*Re-induction therapy (III) will be conducted twice. 
IR: Total 3 doses 
Remission induction therapy (IA4), Day 12; re-induction therapy (III)*, Day 2 
*Re-induction therapy (III) will be conducted twice. 
HR: Total 8 doses 
Remission induction therapy (IA4), Day 12; early consolidation therapy (IB+L), Day 38; 
consolidation therapy (HR3), Day 6; consolidation therapy (HR2), Day 6;  
consolidation therapy (HR1), Day 7; re-induction therapy (III+L)*, Day 2  
*Re-induction therapy (III+L) will be conducted 3 times. 
For the outline of the treatment schedule, see Table 7-1, Table 7-2, and Table 7-3. 
 
The dose of SHP674 will be determined as below according to the body surface area (BSA) of each 
subject. No dose increase or reduction will be conducted. 
• BSA ≥0.6 m2: 2500 IU/m2 
• BSA <0.6 m2: 82.5 IU/kg 
When SHP674 is used, the following information should be entered into the eCRF: 
• Date and time of administration 
• Dose administered 
7.1.1.1 
Formula for Calculation of Body Surface Area (BSA) 
The BSA will be calculated based on the height and weight measured on the start day of each treatment 
phase (including Day 8 of remission induction therapy [IA2/IA4] and Day 36 of early consolidation therapy 
[IB/IB+L]), according to the following formula. Height and weight measured within 7 days (3 days for 
Pre-treatment Phase Day 1) before the prescribed day will be acceptable. 
BSA = √(Height [cm] ×  Weight [kg]/3600) 
When fitted to the above formula, height and weight will be rounded according to the following rules. If 
the measuring instrument of weight displays values up to one decimal place, the displayed value will be 
used for the calculation. 
Height: Rounded to the nearest integer (for example, 123.1 cm → 123 cm) 
Weight: Rounded to one decimal place (for example, 30.15 kg → 30.2 cm) 
The resulting value will be rounded to two decimal places to obtain the BSA (example 1: 1.234 m2 → 
1.23 m2, example 2: 0.968 m2 → 0.97 m2). 

 
 
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7.1.2 
Rationale for Dose and Dosing Regimen of SHP674 
Treatment in this study will be based on the regimen used in Study ALL-B12.17 Native L-asparaginase 
in the treatment regimen of Study ALL-B12 will be replaced by SHP674; SHP674 will be administered on 
the day of the first dose of native L-asparaginase in each treatment phase. SHP674 is recommended to be 
administered at least 12 hours after vincristine administration because of potential drug-drug interactions. 
Thus, if vincristine administration is scheduled on the same day as SHP674, the administration of SHP674 
will be postponed by 1 day (see Investigator’s Brochure for SHP674).  
It is considered that there are generally no ethnic differences in the PK of SHP674, since it is a protein 
product and not affected by polymorphic drug-metabolizing enzymes. There are no data comparing the 
pharmacokinetics of SHP674 in Japanese subjects with those in foreign subjects; however, a population 
pharmacokinetic analysis was conducted on data from 144 subjects (Asian subjects, 9; non-Asian subjects, 
135 subjects) who were enrolled in Study AALL07P4, DFCI 11-001, or CCG-1962 and received SHP674. 
As a result, there was no difference in the pharmacokinetic profile of SHP674 between Asian subjects and 
non-Asian subjects. On the basis of the results mentioned above, the dose of SHP674 in this study will be 
the same as that in Europe. 
7.2 
Concomitant Medications and Therapies 
The following information will be entered into the eCRF if any drug or therapy other than SHP674 or 
the backbone therapy drugs specified in Section 7.2.1 was received by a subject during the period from the 
day of informed consent to the day of the end-of-study or early termination assessment or 30 days after the 
last dose of investigational product, whichever comes later: 
• Name of drug (non-proprietary name) or therapy 
• Start date and end date of treatment 
• Route of administration 
• Reason for use 
As a general rule, non-proprietary name should be provided as the name of drug, but brand name is 
acceptable for combination products. 
7.2.1 
Backbone Therapy Drugs Used in This Study 
The drugs for combination chemotherapy other than SHP674 will be administered according to the 
regimens used in Study ALL-B12. The backbone therapy drugs used in this study are as listed below. For 
the drugs provided by the Sponsor for investigational use, see Section 6.1. 
Ifosfamide (IFO)    
Brand name: Ifomide® 
Cyclophosphamide (CPA) 
Brand name: Endoxan® 
Methotrexate (MTX)  
Brand name: Methotrexate® 
Cytarabine (Ara-C)   
Brand name: Cylocide®, Cylocide®N 
Mercaptopurine hydrate (6-MP) 
Brand name: Leukerin® 
Etoposide (VP-16)   
Brand name: Lastet® 
Daunorubicin (DNR)  
Brand name: Daunomycin® 
Pirarubicin hydrochloride (THP) 
Brand name: Therarubicin®, Pinorubin® 
Vincristine (VCR)   
Brand name: Oncovin ® 
Vindesine (VDS)   
Brand name: Fildesin® 

 
 
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Dexamethasone (DEX) 
Brand name: Decadron ® 
Prednisolone (PSL)   
Brand name: Predonine®, Prednisolone Powder 1% 
Calcium Folinate (LV) 
Brand name: Leucovorin® 
 
When any of the backbone therapy drugs listed in this section is used, the following information should 
be entered into the eCRF: 
• Date and time of administration or duration of administration 
• Dose* 
• Route of administration 
• Reason for change in treatment 
* If a dose of a powder drug is not completely taken, 50% of the scheduled dose will be entered into the 
eCRF as the amount taken, regardless of the actual amount of the remaining powder. 
7.2.1.1 
Doses of Backbone Therapy Drugs Used in This Study 
For the formula for calculation of BSA, see Section 7.1.1.1. The BSA will be calculated based on the 
height and weight measured on the start day of each treatment phase (including Day 8 of remission 
induction therapy [IA2/IA4]) and Day 36 of early consolidation therapy [IB/IB+L]), according to the formula 
provided in Section 7.1.1.1. Height and weight are allowed to be measured within 7 days (3 days for 
Pre-treatment Phase Day 1) before the prescribed day. 
If a subject’s body weight exceeds 30% of the ideal body weight,19 the dose will be calculated using the 
value that is 1.3-fold the ideal body weight of the subject. The ideal body weight in subjects ≥18 years will 
be calculated according to the formula “height (m) × height (m) × 22.” If the subject’s body weight exceeds 
30% of the ideal body weight, the dose will be calculated using the value that is 1.3-fold the ideal body 
weight of the subject. Note that these rules are not applied to SHP674. 
The dose of backbone therapy drugs other than VCR will be calculated to two significant figures. The 
dose of VCR will be rounded off to two decimal places if the calculated dose is <1 mg and will be rounded 
up to two significant figures if the calculated dose is ≥1 mg. This rule does not apply to SHP674. For 
backbone therapy drugs with age-based dosage rules, the dose will be determined by age at the start date of 
each treatment phase. 
7.2.2 
Outline of Each Treatment Phase 
As a general rule, statements in this section should be followed regarding the dose and dosing regimen 
of each backbone therapy drug. 
7.2.2.1 
Pre-treatment Phase (IP) 
Before determining the risk category, all subjects will receive an intrathecal dose of methotrexate 
(MTX) alone and start treatment with oral (or IV) prednisolone (PSL) on Day 1 of the pre-treatment phase. 
PSL will be administered divided into 3 doses per day. If a subject cannot receive intrathecal MTX (MTX 
IT) on Day 1 for a reason such as that the subject’s initial visit falls on a weekend, the administration of 
MTX can be postponed until up to Day 4. The dose of MTX will be 8 mg for subjects 1 to <2 years, 10 mg 
for subjects 2 to <3 years, and 12 mg for subjects ≥3 years. The oral (or IV) administration of PSL will be 
started at 15 mg/m2/day. The dose will then be titrated to 30 mg/m2/day on Day 2 and 60 mg/m2/day by 
Day 4 or 5. PSL will be administered for 7 days. The total dosage of PSL for 7 days will be ≥210 mg/m2. 

 
 
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Points to note and criteria for changes in treatment must be followed during the pre-treatment phase (see 
Section 7.4.1). 
Table 7.2.2.1-1 Dosing Schedule for IP 
 
* If a subject cannot receive intrathecal MTX on Day 1 for a reason such as that the subject’s initial visit falls on a weekend, the administration 
of MTX can be postponed until up to Day 4. 
# To be provided by the Sponsor as an investigational product. 
 
Table 7.2.2.1-2 Route of Administration, Dose, and Days of Administration of Drugs Used in 
IP 
Drug 
Administration 
PSL# 
Day 1 to Day7 (ascending dose) 
Day 1, 15 mg/m2; Day 2, 30 mg/m2; The dose will be increased to 60 mg/m2 by Day 4 or Day 5. 
Oral or IV administration in 3 doses per day 
MTX IT 
Day 1 (*If a subject cannot receive intrathecal MTX on Day 1 for a reason such as that the subject’s 
initial visit falls on a weekend, the administration of MTX can be postponed until up to Day 4. The 
dose of MTX will be 8 mg for subjects 1 to <2 years, 10 mg for subjects 2 to <3 years, and 12 mg 
for subjects ≥3 years.) 
# To be provided by the Sponsor as an investigational product. 
7.2.2.2 
Remission Induction Therapy (IA2/IA4) 
7.2.2.2.1 
IA2 
IA2 is remission induction therapy for SR. Vincristine (VCR) will be administered intravenously at 
1.5 mg/m2 (maximum 2 mg) on Days 8, 15, 22, and 29. PSL will be administered orally (or intravenously) 
at 60 mg/m2/day from Day 8 to Day 28, divided into 3 doses per day. The dose of PSL will be decreased by 
half every 3 days from Day 29, and the administration of PSL will be completed on Day 37. Day 36 and 
Day 37 of IA2 will overlap with early consolidation therapy. Daunorubicin (DNR) will be administered 
intravenously for 60±15 minutes at 30 mg/m2 on Days 8 and 15. In addition, MTX, cytarabine (Ara-C), 
and PSL will be administered intrathecally on Days 12 and 33 (triple intrathecal therapy [TIT]). Subjects 
with CNS-2 status will receive additional doses of TIT on Days 18 and 27. The doses of MTX, Ara-C, and 
PSL will be determined according to Table 7.2.2.2.1-1. SHP674 will be administered intravenously for 
90±30 minutes at 2500 IU/m2 (if body surface area is ≥0.6 m2) or at 82.5 IU/kg (if body surface area is <0.6 
m2) on Day 12. Note that the risk category of subjects may be changed in remission induction therapy (see 
Section 3.1.3.1). 
Table 7.2.2.2.1-1 Doses of Drugs for TIT 
Age 
1 to <2 years 
2 to <3 years 
≥3 years 
MTX (mg) 
8 
10 
12 
Ara-C (mg) 
20 
26 
30 
PSL (mg) 
6 
8 
10 

 
 
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Table 7.2.2.2.1-2 Dosing Schedule for IA2 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product.  
Table 7.2.2.4.3.1-3 Route of Administration, Dose, and Days of Administration of Drugs 
Used in IA2 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
PSL# 
PO or IV in 3 doses 
60 mg/m2 
Day 8 to Day 28 
PSL# 
PO or IV in 3 doses 
30→15→7.5 mg/m2 
Day 29 to Day 37 (dose tapering for 9 days) 
VCR 
IV 
1.5 mg/m2 (up to 2 mg) 
Days  8, 15, 22, and 29 
DNR 
IV (60±15 minutes) 
30 mg/m2 
Day 8, 15  
SHP674# 
IV (90±30 minutes) 
BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m²: 82.5 IU/kg 
Day 12 
TIT*: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1 
Days 12 and 33; subjects with CNS-2 will 
receive additional doses on Days 18 and 
27. 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
7.2.2.2.2 
IA4 
IA4 is remission induction therapy for IR and HR. VCR will be administered intravenously at 1.5 mg/m2 
(maximum 2 mg) on Days 8, 15, 22, and 29. PSL will be administered orally (or intravenously) at 
60 mg/m2/day from Day 8 to Day 28, divided into 3 doses per day. The dose of PSL will be decreased by 
half every 3 days from Day 29, and the administration of PSL will be completed on Day 37. Day 36 and 
Day 37 of IA4 will overlap with early consolidation therapy. DNR will be administered intravenously for 
60±15 minutes at 30 mg/m2 on Days 8, 15, 22 and 29. In addition, MTX, Ara-C, and PSL will be 
administered intrathecally on Days 12 and 33 (TIT). Subjects with CNS-2 status will receive additional 
doses of TIT on Days 18 and 27. The doses of MTX, Ara-C, and PSL will be determined according to 
Table 7.2.2.2.1-1. TIT is allowed to be performed within 3 days of the prescribed dose if there is a social 
reason such as that the prescribed day falls on a weekend or holiday. SHP674 will be administered 
intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is ≥0.6 m2) or at 82.5 IU/kg (if body 
surface area is <0.6 m2) on Day 12. Note that the risk category of subjects may be changed in IA4 (see 
Section 3.1.3.1). 

 
 
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Table 7.2.2.2.2-1 Dosing Schedule for IA4 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product.  
Table 7.2.2.2.2-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IA4 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
PSL# 
PO or IV in 3 doses 
60 mg/m2 
Day 8 to Day 28 
PSL# 
PO or IV in 3 doses 
30→15→7.5 mg/m2 
Day 29 to Day 37 (dose tapering for 9 days) 
VCR 
IV 
1.5 mg/m2 (up to 2 mg) 
Days 8, 15, 22, 29 
DNR 
IV (60±15 minutes) 30 mg/m2 
Days 8, 15, 22, 29 
SHP674# 
IV (90±30 minutes) BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m²: 82.5 IU/kg 
Day 12 
TIT*: MTX, 
Ara-C, PSL#  IT 
See Table 7.2.2.2.1-1 
Days 12 and 33; subjects with CNS-2 will 
receive additional doses on Days 18 and 
27. 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.3 
Early Consolidation Therapy (IB/IB+L) 
7.2.2.3.1 
IB 
IB is early consolidation therapy for SR and IR. Cyclophosphamide (CPA) will be administered 
intravenously for 60±15 minutes at 1000 mg/m2 on Days 36 and 64. The criteria for starting treatment with 
CPA must be followed on Day 64 (see Section 0). 6-Mercaptopurine (6-MP) will be administered orally at 
60 mg/m2 once daily at bedtime from Day 36 to Day 63. Ara-C will be administered intravenously by rapid 
injection or for ≤15 minutes once daily on Days 38 to 41, Days 45 to 48, Days 52 to 55, and Days 59 to 62. 
The criteria for starting treatment with Ara-C must be followed (see Section 0). In addition, Ara-C, MTX, 
and PSL will be administered intrathecally on Days 45 and 59 (TIT). The dose will be determined 
according to Table 7.2.2.2.1-1. TIT is allowed to be performed within 3 days of the prescribed day if there 
is a social reason such as that the prescribed day falls on a weekend or holiday. Points to note and criteria 
for changes in treatment must be followed during early consolidation therapy (see Section 7.4.3). 

 
 
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Table 7.2.2.3.1-1 Dosing Schedule for IB 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product.  
Table 7.2.2.3.1-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IB 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
CPA# 
IV (60±15 minutes) 1000 mg/m2 
Days 36 and 64 
Ara-C 
IV (by rapid 
injection or for ≤15 
minutes) 
75 mg/m2 
Day 38 to Day 41, Day 45 to Day 48, Day 52 to 
Day 55, Day 59 to Day 62 
6-MP# 
PO in one dose at 
bedtime 
60 mg/m2 
(The dose will be 
adjusted according to the 
results of NUDT15 codon 
139 polymorphism 
analysis. See Section 
7.2.3-(7).) 
Day 36 to Day 63 
TIT*: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Day 45 and Day 59 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
7.2.2.3.2 
IB+L 
IB+L is early consolidation therapy for HR. CPA will be administered intravenously for 60±15 minutes 
at 1000 mg/m2 on Days 36 and 64. The criteria for starting treatment with CPA must be followed on Day 
64 (see Section 7.2.3). 6-MP will be administered orally at 60 mg/m2 once daily at bedtime from Day 36 
to Day 63. Ara-C will be administered intravenously by rapid injection or for ≤15 minutes once daily on 
Days 38 to 41, Days 45 to 48, Days 52 to 55, and Days 59 to 62. The criteria for starting treatment with 
Ara-C must be followed (see Section 7.2.3). In addition, MTX, Ara-C, and PSL will be administered 
intrathecally on Days 45 and 59 (TIT). The dose will be determined according to Table 7.2.2.2.1-1. TIT is 
allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the 
prescribed day falls on a weekend or holiday. 
SHP674 will be administered intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is 
≥0.6 m2) or at 82.5 IU/kg (if body surface area is <0.6 m2) on Day 38. Points to note and criteria for 
changes in treatment must be followed during early consolidation therapy (see Section 7.4.3). 

 
 
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Table 7.2.2.3.2-1 Dosing Schedule for IB+L 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product.  
Table 7.2.2.3.2-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IB+L 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
CPA# 
IV (60±15 minutes) 
1000 mg/m2 
Days 36 and 64 
Ara-C 
IV (by rapid 
injection or for 
≤15 minutes) 
75 mg/m2 
Day 38 to Day 41, Day 45 to Day 48, Day 
52 to Day 55, Day 59 to Day 62 
6-MP# 
PO in one dose at 
bedtime 
60 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. See 
Section 7.2.3-(7).) 
Day 36 to Day 63 
SHP674# 
IV (90±30 minutes) BSA ≥0.6 m2: 2500 IU/m² 
BSA <0.6 m2: 82.5 IU/kg 
Day 38 
TIT*: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Days 45 and 59 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.4 
Consolidation Therapy (M2/M5/HR3→HR2→HR1) 
7.2.2.4.1 
M2 
M2 is consolidation therapy for SR. The start day of 6-MP administration will be regarded as Day 1. 
High-dose methotrexate (HD-MTX) will be administered on Days 8, 22, 36, and 50 (total 4 doses). The 
following are the details of HD-MTX administration. 
HD-MTX will be administered intravenously at 2 g/m2, 10% (0.2 g/m2) of which will be administered 
for 0.5 hours, and the remaining 90% (1.8 g/m2) will be administered for 23.5 hours (total 24±2 hours). 
Leucovorin (LV) rescue will be performed after HD-MTX administration. The details of the LV rescue 
regimen and points to note for HD-MTX administration are described in Dosing Criteria and Points to 
Note for HD-MTX Administration. 6-MP will be administered orally at 25 mg/m2 once daily at bedtime 
from Day 1 to Day 56. In addition, MTX, Ara-C, and PSL will be administered intrathecally during 
HD-MTX administration on Days 8, 22, 36, and 50 (TIT). The intrathecal administration of these drugs 
should be performed at least 30 minutes after the start of HD-MTX but before the end of HD-MTX. The 
doses of the intrathecal drugs will be determined according to Table 7.2.2.2.1-1. Points to note and criteria 
for changes in treatment must be followed during consolidation therapy (see Section 7.4.4). 

 
 
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Table 7.2.2.4.1-1 Dosing Schedule for M2 
 
 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
Table 7.2.2.4.1-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in M2 
Drug 
Route of Administration 
Dose 
Days of Administration 
6-MP# 
PO in one dose at bedtime 
25 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. See 
Section 7.2.3-(7).) 
Day 1 to Day 56 
HD-MTX# 
IV (24±2 hours) 
For each of 4 doses, administer 
10% for 0.5 hours and the 
remaining 90% for 23.5 hours 
by intravenous infusion. 
2 g/m2 
Days 8, 22, 36, and 50 
LV rescue 
IV  
15 mg/m2 
42, 48, and 54 hours after the 
start of MTX administration 
(see “Detailed procedure for 
LV rescue” in Section 7.2.3) 
TIT: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Days 8, 22, 36, and 50 
Complete administration at 
least 30 minutes after the start 
of HD-MTX administration 
but before the end of HD-MTX 
administration 
# To be provided by the Sponsor as an investigational product. 
7.2.2.4.2 
M5 
M5 is consolidation therapy for IR. The start day of 6-MP administration will be regarded as Day 1. 
HD-MTX will be administered on Days 8, 22, 36, and 50 (total 4 doses). The following are the details of 
HD-MTX administration. 
HD-MTX will be administered intravenously at 5 g/m2, 10% (0.5 g/m2) of which will be administered 
for 0.5 hours, and the remaining 90% (4.5 g/m2) will be administered for 23.5 hours (total 24±2 hours). LV 
rescue will be performed after HD-MTX administration. The details of the LV rescue regimen and points 
to note for HD-MTX administration are described in Dosing Criteria and Points to Note for HD-MTX 
Administration. 6-MP will be administered orally at 25 mg/m2 once daily at bedtime from Day 1 to Day 
56. In addition, MTX, Ara-C, and PSL will be administered intrathecally during HD-MTX administration 
on Days 8, 22, 36, and 50 (TIT). The intrathecal administration of these drugs should be performed at least 
30 minutes after the start of HD-MTX but before the end of HD-MTX. The doses of the intrathecal drugs 

 
 
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are determined according to Table 7.2.2.2.1-1. Points to note and criteria for changes in treatment must be 
followed during consolidation therapy (see Section 7.4.4). 
Table 7.2.2.4.2-1 Dosing Schedule for M5 
 
 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
Table 7.2.2.4.2-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in M5 
Drug 
Route of Administration 
Dose 
Days of Administration 
6-MP# 
PO in one dose at bedtime 
25 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. See 
Section 7.2.3-(7).) 
Day 1 to Day 56 
HD-MTX# 
IV (24±2 hours) 
For each of 4 doses, administer 
10% for 0.5 hours and the 
remaining 90% for 23.5 hours 
by intravenous infusion. 
5 g/m2 
Days 8, 22, 36, and 50 
LV rescue 
IV  
15 mg/m2 
42, 48, and 54 hours after the 
start of MTX administration 
(see “Detailed procedure for 
LV rescue” in Section 7.2.3) 
TIT: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Days 8, 22, 36, and 50 
Complete administration at 
least 30 minutes after the start 
of HD-MTX administration 
but before the end of HD-MTX 
administration 
# To be provided by the Sponsor as an investigational product. 
7.2.2.4.3 
HR3, HR2, and HR1 
HR3, HR2, and HR1 are blocks of consolidation therapy for HR. Subjects will receive HR3, HR2, and 
HR1 sequentially in this order. 
7.2.2.4.3.1 
HR3 
The start day of the administration of DEX or HD-Ara-C, whichever is administered first, will be 
regarded as Day 1. Dexamethasone (DEX) will be administered orally (or intravenously) at 20 mg/m2/day 
divided into 3 doses per day from Day 1 to Day 5. Ara-C will be administered intravenously a total of 4 

 
 
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times every 12 hours from Day 1 to Day 2 (high-dose [HD] Ara-C). The dose of Ara-C will be 2000 
mg/m2; the total dose administered will be 8000 mg/m2. Ara-C will be administered intravenously for 
180±15 minutes per dose. Etoposide (VP-16) will be administered intravenously a total of 5 times every 12 
hours from Day 3 to Day 5 (the administration of the first dose on Day 3 is recommended to be started in 
the afternoon). VP-16 will be administered intravenously for 60±15 minutes at 100 mg/m2. In addition, 
MTX, Ara-C, and PSL will be administered intrathecally on Day 5 (TIT). The doses of the intrathecal 
drugs are determined according to Table 7.2.2.2.1-1. TIT is allowed to be performed within 3 days of the 
prescribed day if there is a social reason such as that the prescribed day falls on a weekend or holiday. 
SHP674 will be administered intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is 
≥0.6 m2) or at 82.5 IU/kg (if body surface area is <0.6 m2) on Day 6. 
Table 7.2.2.4.3.1-1 
Dosing Schedule for HR3 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 

 
 
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Table 7.2.2.4.3.1-2 
Route of Administration, Dose, and Days of Administration of Drugs 
Used in HR3 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
DEX# 
PO or IV in 3 doses 
20 mg/m2 
Day 1 to Day 5 
HD-Ara-C 
IV (180±15 
minutes) 
2000 mg/m2 
Day 1 to Day 2 
4 doses every 12 hours 
VP-16# 
IV (60±15 minutes) 100 mg/m2 
Day 3 to Day 5 
5 (2+2+1) doses every 12 hours 
(first dose on Day 3 is 
recommended to be started in the 
afternoon) 
SHP674# 
IV (90±30 minutes) BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m²: 82.5 IU/kg 
Day 6 
TIT*: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Day 5 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.4.3.2 
HR2 
The start day of the administration of DEX, VDS, HD-MTX, or TIT, whichever is administered first, 
will be regarded as Day 1. DEX will be administered orally (or intravenously) at 20 mg/m2/day divided 
into 3 doses per day from Day 1 to Day 5. Vindesine (VDS) will be administered intravenously at 3 mg/m2 
(maximum 5 mg) on Days 1 and 6. HD-MTX will be administered on Day 1. The following are the details 
of HD-MTX administration. 
HD-MTX will be administered intravenously at 5 g/m2, 10% (0.5 g/m2) of which will be administered 
for 0.5 hours, and the remaining 90% (4.5 g/m2) will be administered for 23.5 hours (total 24±2 hours). 
LV rescue will be performed after HD-MTX administration. The details of the LV rescue regimen and 
points to note for HD-MTX administration are described in Dosing Criteria and Points to Note for 
HD-MTX Administration. Ifosfamide (IFO) will be administered intravenously a total of 5 times every 
12 hours from Day 2 to Day 4. The dose of IFO will be 800 mg/m2; the total dose administered will be 
4 g/m2. IFO will be administered intravenously for 60±15 minutes per dose. DNR will be administered 
intravenously for 24±2 hours at 30 mg/m2 on Day 5. In addition, MTX, Ara-C, and PSL will be 
administered intrathecally on Day 1 (TIT). Subjects with CNS-2 status will receive an additional dose of 
TIT on Day 5). The doses of the intrathecal drugs are determined according to Table 7.2.2.2.1-1. SHP674 
will be administered intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is ≥0.6 m2) or at 
82.5 IU/kg (if body surface area is <0.6 m2) on Day 6. 

 
 
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Table 7.2.2.4.3.2-1 
Dosing Schedule for HR2 
 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
Table 7.2.2.4.3.2-2 Route of Administration, Dose, and Days of Administration of Drugs 
Used in HR2 
Dose 
Route of Administration 
Dose 
Days of Administration 
DEX# 
PO or IV in 3 doses 
20 mg/m2 
Day 1 to Day 5 
VDS 
IV 
3 mg/m2 (up to 5 mg) 
Days 1 and 6 
DNR 
IV (24±2 hours) 
30 mg/m2 
Day 5 
HD-MTX# 
IV (24±2 hours) 
Administer 10% of the dose 
for 0.5 hours and the 
remaining 90% for 23.5 
hours by intravenous 
infusion. 
5 g/m2 
Day 1 
LV rescue 
IV  
15 mg/m2 
42, 48, 54 hours after the start 
of MTX administration (see 
“Detailed procedure for LV 
rescue” in Section 7.2.3) 
IFO*,# 
IV (60±15 minutes) 
800 mg/m2 
Administer 5 doses of IFO 
every 12 hours from Day 2 to 
Day 4, using mesna 
concomitantly. 
SHP674# 
IV (90±30 minutes) 
BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m2: 82.5 IU/kg 
Day 6 
TIT: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Day 1 
Subjects with CNS-2 will 
receive an additional dose on 
Day 5. 
* When administering IFO, supportive care should be considered based on the following procedure used in the regimen of Study ALL-B12 
IFO:  
For prevention of hemorrhagic cystitis, adequate diuresis should be maintained with 3000 mL/m2 per day of fluid replacement and a diuretic 
drug such as Lasix®. It is also recommended that mesna (Uromitexan®) be administered intravenously at a dose of 160 mg/m2 immediately 
before IFO administration and 4 and 8 hours after the start of IFO administration. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.4.3.3 
HR1 
The start day of the administration of DEX, HD-MTX, VCR or TIT, whichever is administered first, 
will be regarded as Day 1. DEX will be administered orally (or intravenously) at 20 mg/m2/day divided 
into 3 doses per day from Day 1 to Day 5. VCR will be administered intravenously at 1.5 mg/m2 

 
 
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(maximum 2 mg) on Days 1 and 6. HD-MTX will be administered on Day 1. The following are the details 
of HD-MTX administration. 
HD-MTX will be administered intravenously at 5 g/m2, 10% (0.5 g/m2) of which will be administered 
for 0.5 hours, and the remaining 90% (4.5 g/m2) will be administered for 23.5 hours (total 24±2 hours). LV 
rescue will be performed after HD-MTX administration. The details of the LV rescue regimen and points 
to note in administering HD-MTX are described in Dosing Criteria and Points to Note for HD-MTX 
Administration. Ara-C will be administered intravenously twice every 12 hours on Day 5. The dose of 
Ara-C will be 2000 mg/m2; the total dose administered will be 4000 mg/m2. Ara-C will be administered 
intravenously for 180±15 minutes per dose. 
CPA will be administered intravenously a total of 5 times every 12 hours from Day 2 to Day 4 (the 
administration of the first dose on Day 2 is recommended to be started in the afternoon). The dose of CPA 
will be 200 mg/m2; the total dose administered will be 1 g/m2. CPA will be administered intravenously for 
60±15 minutes per dose. In addition, MTX, Ara-C, and PSL will be administered intrathecally on Day 1 
(TIT). The doses of the intrathecal drugs are determined according to Table 7.2.2.2.1-1. SHP674 will be 
administered intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is ≥0.6 m2) or at 82.5 
IU/kg (if body surface area is <0.6 m2) on Day 7. 
Table 7.2.2.4.3.3-1 
Dosing Schedule for HR1 
 
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 

 
 
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Table 7.2.2.4.3.3-2 Route of Administration, Dose, and Days of Administration of Drugs 
Used in HR1 
Drug 
Route of Administration 
Dose 
Days of Administration 
DEX# 
PO or IV in 3 doses 
20 mg/m2 
Day 1 to Day 5 
VCR 
IV 
1.5 mg/m2 (up to 2 mg) 
Days 1 and 6 
HD-MTX# 
IV (24±2 hours) 
Administer 10% of the dose 
for 0.5 hours and the 
remaining 90% for 23.5 hours 
by intravenous infusion. 
5 g/m2 
Day 1 
LV rescue 
IV 
15 mg/m2 
42, 48, and 54 hours after the 
start of MTX administration 
HD-Ara-C 
IV (180±15 minutes) 
2000 mg/m2 
Day 5: Administer 2 doses 
every 12 hours 
CPA# 
IV (60±15 minutes) 
200 mg/m2 
Day 2 to Day 4 (first dose on 
Day 2 is recommended to be 
administered in the 
afternoon) 
SHP674# 
IV (90±30 minutes) 
BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m²: 82.5 IU/kg 
Day 7 
TIT: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1 
Day 1 
# To be provided by the Sponsor as an investigational product. 
7.2.2.5 
Re-induction Therapy (III/III+L) 
7.2.2.5.1 
III 
The start day of the administration of DEX, VCR, or THP, whichever is administered first, will be 
regarded as Day 1. III is re-induction therapy for SR and IR. Treatment with DEX will be started on Day 1. 
The criteria for starting treatment with DEX must be followed not only before the start of III, but also on 
Day 15 of III (see Section 7.3.5). For subjects <10 years, DEX will be administered orally (or 
intravenously) at 10 mg/m2/day divided into 3 doses per day from Day 1 to Day 14. Subsequently, the dose 
of DEX will be decreased to 5 mg/m2 per day from Day 15 to Day 17, 2.5 mg/m2 per day from Day 18 to 
Day 20, and 1.25 mg/m2 per day from Day 21 to Day 23 (administration will be completed on Day 23). For 
subjects ≥10 years, DEX will be administered orally (or intravenously) at 10 mg/m2/day from Day 1 to 
Day 7 and from Day 15 to Day 21. VCR will be administered intravenously at 1.5 mg/m2 (maximum 2 mg) 
on Days 1 and 8. Pirarubicin hydrochloride (THP) will be administered intravenously for 60±15 minutes at 
25 mg/m2 on Days 1 and 8. CPA will be administered intravenously at 500 mg/m2 for 60±15 minutes on 
Day 15. Ara-C will be administered intravenously by rapid injection or for ≤15 minutes once daily at 75 
mg/m2 from Day 17 to Day 20 and from Day 24 to Day 27. 6-MP will be administered orally at 60 mg/m2 
at bedtime from Day 15 to Day 28. The criteria for changes in treatment must be followed when starting 
treatment with Ara-C (see Section 7.4.5). In addition, MTX, Ara-C, and PSL will be administered 
intrathecally on Days 17 and 24 (TIT). Subjects with CNS-2 will receive an additional dose of TIT on Day 
1. The doses of the intrathecal drugs are determined according to Table 7.2.2.1-1. TIT is allowed to be 
performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls 
on a weekend or holiday. SHP674 will be administered intravenously for 90±30 minutes at 2500 IU/m2 (if 
body surface area is ≥0.6 m2) or at 82.5 IU/kg (if body surface area is <0.6 m2) on Day 2. Points to note and 
criteria for changes in treatment must be followed during re-induction therapy (see Section 7.4.5). 

 
 
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Table 7.2.2.5.1-1 Dosing Schedule for III 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 
Table 7.2.2.5.1-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in III 
Dose 
Route of 
Administration 
Dose 
Days of Administration 
DEX# for subjects 
<10 years 
PO or IV in 3 doses 
10 mg/m2 
Day 1 to Day 14 
DEX# for subjects 
<10 years 
PO or IV in 3 doses 
5→2.5→1.25 mg/m2 
Day 15 to Day 23 (dose tapered 
for 9 days) 
DEX# for subjects 
≥10 years 
PO or IV in 3 doses 
10 mg/m2 
Day 1 to Day 7, Day 15 to Day 21 
VCR 
IV 
1.5 mg/m2 (up to 2 mg) 
Day 1 and 8 
THP 
IV (60±15 minutes) 
25 mg/m2 
Day 1 and 8 
SHP674# 
IV (90±30 minutes) 
BSA ≥0.6 m²: 2500 IU/m² 
BSA <0.6 m2: 82.5 IU/kg 
Day 2 
CPA# 
IV (60±15 minutes) 
500 mg/m² 
Day 15 
Ara-C 
IV (by rapid injection 
or for ≤15 minutes) 
75 mg/m2 
Day 17 to Day 20, Day 24 to Day 
27 
6-MP# 
PO in one dose at 
bedtime 
60 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. See 
Section 7.2.3-(7).) 
Day 15 to Day 28 
TIT*: MTX, Ara-C, 
PSL# 
IT 
See Table 7.2.2.2.1-1 
Days 17 and 24; subjects with 
CNS-2 will receive an additional 
dose on Day 1. 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.5.2 
III+L 
The start day of the administration of DEX, VCR, or THP, whichever is administered first, will be 
regarded as Day 1. III+L is re-induction therapy for HR. Note that criteria for starting treatment must be 
followed not only before the start of III+L, but also on Day 15 of III+L (see Section 7.3.5). Treatment with 
DEX will be started on Day 1. For subjects <10 years, DEX will be administered orally (or intravenously) 
at 10 mg/m2/day divided into 3 doses per day from Day 1 to Day 14. Subsequently, the dose of DEX will 
be decreased to 5 mg/m2 per day from Day 15 to Day 17, 2.5 mg/m2 per day from Day 18 to Day 20, and 

 
 
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1.25 mg/m2 per day from Day 21 to Day 23 (administration will be completed on Day 23).The dose of 
DEX will be decreased by half every 3 days from Day 15 and decreased to 1.25 mg/m2/day on Day 21. 
Treatment with DEX will be completed on Day 23. For subjects ≥10 years, DEX will be administered 
orally (or intravenously) at 10 mg/m2/day from Day 1 to Day 7 and from Day 15 to Day 21. VCR will be 
administered intravenously at 1.5 mg/m2 (maximum 2 mg) on Days 1 and 8. Pirarubicin hydrochloride 
(THP) will be administered intravenously for 60±15 minutes at 25 mg/m2 on Days 1 and 8. CPA will be 
administered intravenously at 500 mg/m2 for 60±15 minutes on Day 15. Ara-C will be administered 
intravenously by rapid injection or for ≤15 minutes once daily at 75 mg/m2 from Day 17 to Day 20 and 
from Day 24 to Day 27. 6-MP will be administered orally at 60 mg/m2 at bedtime from Day 15 to Day 28. 
The criteria for changes in treatment must be followed when starting treatment with Ara-C (see Section 
7.4.5). In addition, MTX, Ara-C, and PSL will be administered intrathecally on Days 17 and 24 (TIT). 
Subjects with CNS-2 status will receive an additional dose of TIT on Day 1). The doses of the intrathecal 
drugs are determined according to Table 7.2.2.2.1-1. TIT is allowed to be performed within 3 days of the 
prescribed day if there is a social reason such as that the prescribed day falls on a weekend or holiday. 
SHP674 will be administered intravenously for 90±30 minutes at 2500 IU/m2 (if body surface area is ≥0.6 
m2) or at 82.5 IU/kg (if body surface area is <0.6 m2) on Day 2. Points to note and criteria for changes in 
treatment must be followed during re-induction therapy (see Section 7.4.5). 
Table 7.2.2.5.2-1 Dosing Schedule for III+L 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 

 
 
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Table 7.2.2.5.2-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in III+L 
Drug 
Route of Administration 
Dose 
Days of Administration 
DEX# for subjects 
<10 years 
PO or IV in 3 doses 
10 mg/m2 
Day 1 to Day 14 
DEX# for subjects 
<10 years 
PO or IV in 3 doses 
5→2.5→1.25 mg/m2 
Day 15 to Day 23 (dose tapering for 
9 days) 
DEX# for subjects 
≥10 years 
PO or IV in 3 doses 
10 mg/m2 
Day 1 to Day 7, Day 15 to Day 21 
VCR 
IV 
1.5 mg/m2 (up to 2.0 
mg) 
Days 1 and 8 
THP 
IV (60±15 minutes) 
25 mg/m2 
Days 1 and 8 
SHP674# 
IV (90±30 minutes) 
BSA ≥0.6 m²: 2500 
IU/m² 
BSA <0.6 m²: 82.5 
IU/kg 
Day 2 
CPA# 
IV (60±15 minutes) 
500 mg/m² 
Day 15 
Ara-C 
IV (by rapid injection or for 
≤15 minutes) 
75 mg/m2 
Day 17 to Day 20, Day 24 to Day 27 
6-MP# 
PO in one dose at bedtime 
60 mg/m2 
(The dose will be 
adjusted according to 
the results of 
NUDT15 codon 139 
polymorphism 
analysis. See Section 
7.2.3-(7).) 
Day 15 to Day 28 
TIT*: MTX, Ara-C, 
PSL# 
IT 
See Table 7.2.2.2.1-1 
Subjects with CNS-2 will receive an 
additional dose on Day 1. 
Days 17 and 24 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.6 
Interim Maintenance Therapy (IM) 
A 10-week interim maintenance therapy (IM) will be performed in all of the subjects categorized as SR, 
IR, and HR, but the regimen will vary between the risk categories. IM will be performed once for 10 weeks 
in the SR and IR groups, whereas the 10-week IM will be divided in 2 periods (5 weeks × 2) in the HR 
group. 
7.2.2.6.1 
IM for SR 
The start day of the administration of 6-MP or MTX, whichever is administered first, will be regarded as 
Day 1. MTX will be administered orally at 20 mg/m2 on Days 1, 8, 15, 22, 29, 36, 43, and 50. 6-MP will be 
administered orally at 50 mg/m2 once daily at bedtime from Day 1 to Day 56. 

 
 
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Table 7.2.2.6.1-1 Dosing Schedule for IM (SR) 
 
 
# To be provided by the Sponsor as an investigational product. 
Table 7.2.2.6.1-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IM for SR Subjects 
Drug 
Route of Administration 
Dose 
Days of Administration 
6-MP# 
PO in one dose at bedtime 
50 mg/m2 
(The dose will be 
adjusted according to 
the results of NUDT15 
codon 139 
polymorphism 
analysis. See Section 
7.2.3-(7).) 
Day 1 to Day 56 
MTX# 
PO in one dose 
20 mg/m2/week 
Days 1, 8, 15, 22, 29, 36, 43, and 50 
# To be provided by the Sponsor as an investigational product. 
7.2.2.6.2 
IM for IR 
The start day of the administration of 6-MP, MTX, or TIT, whichever is administered first, will be 
regarded as Day 1. MTX will be administered orally at 20 mg/m2 on Days 1, 8, 15, 22, 29, 36, 43, and 50. 
6-MP will be administered orally at 50 mg/m2 once daily at bedtime from Day 1 to Day 56. In addition, 
MTX, Ara-C, and PSL will be administered intrathecally on Days 1 and 29 (TIT). The doses of the 
intrathecal drugs are determined according to Table 7.2.2.2.1-1. TIT is allowed to be performed within 3 
days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend or 
holiday. 
Table 7.2.2.6.2-1 Dosing Schedule for IM (IR) 
 
 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday.  
# To be provided by the Sponsor as an investigational product. 
## Only PSL will be provided by the Sponsor as an investigational product. 

 
 
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Table 7.2.2.6.2-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IM for IR Subjects 
Drug 
Route of 
Administration 
Dose 
Days of Administration 
6-MP# 
PO in one dose at 
bedtime 
50 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. See 
Section 7.2.3-(7).) 
Day 1 to Day 56 
MTX# 
PO in one dose 
20 mg/m2/week 
Days 1, 8, 15, 22, 29, 36, 43, and 50 
TIT*: MTX, 
Ara-C, PSL# 
IT 
See Table 7.2.2.2.1-1. 
Days 1 and 29 
* TIT is allowed to be performed within 3 days of the prescribed day if there is a social reason such as that the prescribed day falls on a weekend 
or holiday. 
# To be provided by the Sponsor as an investigational product. 
7.2.2.6.3 
IM for HR 
The start day of 6-MP or MTX administration will be regarded as Day 1. MTX will be administered 
orally at 20 mg/m2 on Days 1, 8, 15, and 22. 6-MP will be administered orally at 50 mg/m2 once daily at 
bedtime from Day 1 to Day 28. 
Table 7.2.2.6.3-1 Dosing Schedule for IM (HR) 
 
# To be provided by the Sponsor as an investigational product. 
Table 7.2.2.6.3-2 Route of Administration, Dose, and Days of Administration of Drugs Used 
in IM for HR Subjects 
Drug 
Route of Administration 
Dose 
Days of Administration 
6-MP# 
PO in one dose at bedtime 
50 mg/m2 
(The dose will be adjusted 
according to the results of 
NUDT15 codon 139 
polymorphism analysis. 
See Section 7.2.3-(7).) 
Day 1 to Day 28 
MTX# 
PO in one dose 
20 mg/m2/week 
Days 1, 8, 15, and 22 
# To be provided by the Sponsor as an investigational product. 
7.2.3 
Criteria for Changes in Treatment with Each Backbone Therapy Drug 
If it is difficult to determine whether a subject should be withdrawn from the study, the investigator 
should consult with the Sponsor or the in-country caretaker. The definitions of terms used are provided 
below. 
Dose reduction: To reduce the dose of a specific drug during treatment. 
Specific-drug discontinuation: To stop administration of a specific drug or a treatment phase/block 
without resuming thereafter. 
Interruption: To temporarily stop administration of a specific drug or the whole treatment phase/block in 
the course of treatment. Interruption is classified into the following categories 1) to 4): 

 
 
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1) 
Drug interruption: To temporarily stop administration of a part of the drugs included in a 
treatment phase/block, while the treatment phase/block itself is continued as prescribed (the 
administration of the interrupted drug will be resumed if required conditions are met). The term 
“drug interruption” is used for individual drugs. 
2) 
Postponement: To postpone the prescribed start of the next whole treatment phase/block. The 
term “postponement” is used for individual treatment phases/blocks. As a result of 
postponement, the interval between treatment phases/blocks will be prolonged. 
3) 
Treatment interruption: To temporarily stop administration of all drugs included in a treatment 
phase/block after the start of the treatment phase (the interrupted treatment will be resumed if 
required conditions are met). 
4) 
Skip: To proceed to the next schedule without administering some or all of the drugs included in 
a treatment phase/block. 
1) CPA 
Criteria for Starting Second (Day 64) Treatment with CPA in Early Consolidation Therapy 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. 
Skip and Dose Reduction 
The administration of CPA will be skipped until Grade 3 or higher hemorrhagic cystitis symptoms 
accompanied by hematuria improve, resumed at half (1/2) of the original dose in the next phase if the 
hemorrhagic cystitis symptoms improve to Grade 1, and continued at the original dose (1/1)  thereafter 
unless the symptoms worsen. 
2) MTX 
Dosing Criteria and Points to Note for HD-MTX Administration 
Dosing Criteria for HD-MTX 
The following criteria will be applied in addition to the criteria for starting treatment and the criteria 
for changes in treatment for each treatment phase: 
1) Renal function: Serum creatinine does not exceed the age-specific ULN. 
2) Liver function: D-Bil <1.5 mg/dL. For the second and subsequent doses, if AST or ALT is elevated 
after the previous administration, the subject must be judged by the investigator or subinvestigator 
that he or she can receive treatment. 
3) There is no fluid retention such as pleural effusion and ascites, as judged by the investigator or 
subinvestigator based on clinical symptoms, test results, and other information. 
Points to Note for HD-MTX Administration 
1) Blood MTX concentrations will be measured at 24, 42, 48, and 66 hours post-dose. Additional 
measurement may be performed at other time points if the physician considers it necessary. 
2) If any of the following symptoms is observed during the administration of HD-MTX, delayed 
excretion of MTX is suspected: acute diarrhea after the start of MTX administration, severe vomiting, 
and an evident increase in serum creatinine compared with the previous level. If severe hepatic 
disorder or acute renal failure (oliguric or nonoliguric) is noted in chemistry or blood coagulation test 
results, the administration of MTX will be skipped at the discretion of the investigator or 

 
 
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subinvestigator after recording the amount of MTX administered into the subject’s body until that 
time. 
3) Detailed procedure for LV rescue: If no abnormal blood MTX levels are observed, only 3 doses of 
15 mg/m2 LV will be administered 42, 48, and 54 hours after the start of MTX administration. At the 
investigative sites where the rapid measurement of the concentration at 54 hours is impossible, the 
administration of LV can be continued until the next blood MTX concentration obtained after the 
measurement at 48 hours becomes ≤0.25 μmoL/L (essential time point: 66 hours). Specifically, at 
such investigative sites, LV will be administered at the same dose 60 and 66 hours after the start of 
MTX administration subsequent to administration at 42, 48, and 54 hours. Whether the 
administration of LV can be stopped will be determined based on measurement at 66 hours. The 
details are presented in Table 7.2.3-1. 
4) When administering HD-MTX, supportive care should be considered based on the following 
procedure used in the regimen of Study ALL-B12 and the “Precautions” section of the package insert 
for Methotrexate® Injection 1000 mg: 
a) 
Start fluid replacement at 3000 mL/m2 per day not later than 3 hours before HD-MTX 
administration. Continue the fluid replacement until blood MTX concentration becomes 
≤0.25 μmoL/L. If blood MTX concentration is above the upper limit of reference range, 
increase the amount of fluid replacement to 4500 mL/m2 per day until the concentration 
decreases to the reference range. In this case, start fluid replacement at 4500 mL/m2 per day at 
the next HD-MTX administration and thereafter. 
b) 
Maintain diuresis so that fluid balance is <+400 mL/m2/12 hour. Administer 7 doses of 
acetazolamide (<5 years, 125 mg; ≥5 years, 250 mg) orally or intravenously every 6 hours from 
12 hours before MTX administration. Fluid balance, urine pH, and other parameters should be 
assessed as appropriate to increase or decrease the dose of acetazolamide as needed. 
c) 
Mix 500 mL of maintenance fluid and 20 mL (16 to 20 mEq) of sodium bicarbonate (7% or 
8.4%). Administer the solution until blood MTX concentration decreases to ≤0.25 μmoL/L. 
Make the best effort to keep urine pH at ≥7.0. 
Table 7.2.3-1 Criteria for Blood MTX Concentrations and LV Rescue 
Time of Blood MTX 
Concentration Measurement (hr) 
MTXhr Reference Value 
(μmol/L) 
Rescue Time Point 
(hr) 
Intravenous LV 
24 
TXhr  ≤150 
 
 
36 
TXhr ≤3.0 
 
 
42 
TXhr ≤1.0 
42 
15 mg/m2 
48 
TXhr ≤0.4 
48 
15 mg/m2 
54 
TXhr ≤0.25 
54 
15 mg/m2 
66 
TXhr ≤0.25 
 
 
Measures to Be Taken in Case of Abnormal Blood MTX Concentrations 
• 
If the blood concentration at 24 hours is >150 μmoL/L, LV rescue (30 mg/m2) will be started at 
36 hours. In this case, the concentration at 42 hours should be obtained as soon as possible to 
immediately adjust the dose of LV since a further dose increase may be required. 
• 
The rapid measurement at 36 hours (optional time point) is strongly recommended for subjects 
with a blood concentration of >150 μmoL/L at 24 hours, diuretic failure, or increased creatinine. 

 
 
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For other subjects, the blood concentration may be measured simultaneously with a sample at 42 
hours after being collected as scheduled to check the data retrospectively (in this case, there will be 
no change in LV rescue for an abnormal level at 36 hours). 
• 
If the blood concentration at 36 hours is >3 μmoL/L, LV rescue should be started immediately at 
30 mg/m2. In this case, the concentration at 42 hours should be obtained as soon as possible to 
immediately adjust the dose of LV since a further dose increase may be required. 
• 
If the blood concentration at 42 hours is >1 μmoL/L but ≤5 μmoL/L, LV rescue will be continued 
according to Table 7.2.3-2 (even in this case, the blood concentration 66 hours after the start of 
MTX administration must be obtained to appropriately change the further schedule of LV 
administration). The dose of LV can be changed at the time when the blood concentration is 
determined (an additional dose may be administered before the next regular rescue time point). 
• 
If the blood concentration at 42 hours is >5 μmoL/L, LV rescue will be continued according to the 
following formula until the concentration decreases to ≤5 μmoL/L. The dose of LV will be 
calculated based on the latest measurement: LV dose (mg) = MTX (μmoL/L) × weight (kg) (dose 
per 6 hours). 
• 
If the blood concentration at 48 hours is >0.4 μmoL/L but ≤1 μmoL/L, it is not necessary to 
increase the dose of LV. The duration of treatment continuation will be determined based on the 
subsequent measurements. The action to be taken in the case of a blood concentration of 
>1 μmoL/L will be the same as at 42 hours. 
• 
LV administration can be stopped at 3 doses without measurement at 54 hours only if a blood 
concentration of ≤0.25 μmoL/L is achieved at 48 hours. Even in this case, it is essential to measure 
the concentration at 66 hours. If the concentration again exceeds 0.25 μmoL/L, LV rescue should 
be re-started (15 mg/m2). 
• 
If the blood concentration at 54 hours is confirmed to be ≤0.25 μmoL/L, LV rescue will be stopped 
at 3 doses. If this criterion is not met (and ≤1.0 μmoL/L), LV will be administered at 15 mg/m2 
every 6 hours until the blood concentration decreases to ≤0.25 μmoL/L. The action to be taken in 
the case of a blood concentration of >1.0 μmoL/L will be the same as at 42 hours. 
• 
For the investigative sites where the rapid measurement at 54 hours is impossible, LV will be 
administered at 60 and 66 hours additionally. LV rescue will be stopped if the blood concentration 
at 66 hours (essential time point) is ≤0.25 μmoL/L. If the blood concentration is >0.25 μmoL/L, LV 
will be administered at 15 mg/m2 every 6 hours until the concentration becomes ≤0.25 μmoL/L. 
For details, see Dosing Criteria and Points to Note for HD-MTX Administration. 

 
 
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Table 7.2.3-2 Blood MTX Concentrations at 42 Hours, 48 Hours, and Subsequent Time 
Points and Dose of LV 
MTX (μmol/L) 
0.25< C ≤1.0 
1.0< C ≤2.0 
2.0< C ≤3.0 
3.0< C ≤4.0 
4.0< C ≤5.0 
5.0< C 
LV (mg/m2) 
15 
30 
45 
60 
75 
See belowa 
Route of 
administration 
IV 
IV 
IV 
IV 
IV 
IVa 
Dosing interval 
Every 6 hours 
Every 6 hours 
Every 6 hours 
Every 6 hours 
Every 6 hours 
Every 6 hours 
a: Dose of LV (mg) = MTX (μmoL/L) × MTX (μmoL/L) × body weight (kg). 
 
Specific-drug discontinuation and Skip 
Further treatment with MTX will be discontinued if a subject has leukoencephalopathy accompanied by 
neurologic symptoms or if any findings associated with Grade 3 or higher (CTCAE ver 5.0) 
leukoencephalopathy are noted on images. For further information, see Dosing Criteria and Points to 
Note for HD-MTX administration. 
3) Ara-C 
Criteria for Starting Treatment Phase for 4-Day Repeated Administration of Ara-C (Ara-C 
Treatment Phase) in Early Consolidation Therapy and Points to Note 
1) Each Ara-C treatment phase should be started when white blood cell count is ≥500/μL. 
2) Ara-C treatment phase should not be interrupted as far as possible (however, the treatment phase 
should be interrupted if neutrophil count is 0/μL). 
3) If it is necessary to interrupt the Ara-C treatment phase, the administration of all other drugs that are 
included in Section 7 (Treatment Plan and Concomitant Treatments) should also be interrupted. 
Specific-drug discontinuation 
Ara-C will be discontinued if any of the following symptoms are noted: 
Serious Ara-C syndrome: Symptoms such as high fever, skin erythema, and joint pain that are difficult 
to treat or prevent. 
Grade 3 or higher CNS symptoms: Convulsion, serious consciousness disorder (coma, in particular), 
etc. 
4) VCR 
Skip and Dose Reduction 
The administration of VCR will be skipped until Grade 3 or higher peripheral motor or sensory 
neuropathy improves, resumed at half of the original dose if the peripheral motor or sensory neuropathy 
improves to Grade 1, and continued at the same dose thereafter unless the symptom worsens. The dose of 
VCR will be reduced to half of the original dose when D-Bil is ≥1.5 mg/dL. The administration of VCR 
will be skipped when D-Bil is ≥2 mg/dL. 
5) DEX 
Determination of Treatment Strategy According to the Subject’s Symptoms 
Steroids will not be reduced or discontinued even if osteonecrosis is diagnosed, regardless of whether it 
is asymptomatic or symptomatic. 
Switch to Injection 
As with oral DEX, injectable DEX will be administered divided into 3 doses per day. 

 
 
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6) PSL 
Determination of Treatment Strategy According to the Subject’s Symptoms 
1) 
Steroids will not be reduced or discontinued even if osteonecrosis is diagnosed, regardless of whether 
it is asymptomatic or symptomatic. 
2) 
PSL will not be discontinued in TIT for subjects who are diagnosed with osteonecrosis, regardless of 
whether it is asymptomatic or symptomatic. 
Switch to Injection 
As with oral DEX, injectable DEX will be administered divided into 3 doses per day. 
7) 6-MP 
Determination of Treatment Strategy According to the Results of NUDT15 Codon 139 
Polymorphism Analysis and the Subject’s Symptoms 
Arg/Arg type: 
Treatment with 6-MP will be started at a usual dose. The dose of 6-MP will not be adjusted unless the 
criteria for dose changes specified in other sections (Sections 7.2.4 and 7.4.6) of the protocol are met. 
Cys/Cys type: 
As a general rule, treatment with 6-MP will be started at 1/10 of the usual dose. If it is difficult to 
continue treatment at 1/10 of the usual dose because of a TEAE that is related to 6-MP, the dose should 
be decreased appropriately at the discretion of the investigator or subinvestigator. If no TEAEs or other 
safety concerns related to 6-MP are observed at 1/10 of the usual dose or the observed TEAE or other 
safety concerns related to 6-MP are mild and if the investigator or subinvestigator determines that dose 
increase for the subject is possible, the dose of 6-MP can be increased to levels not exceeding the usual 
dose. This will not apply if the dose is adjusted according to Section 7.4.6. 
Homozygous genotype other than Arg/Arg and Cys/Cys or heterozygous genotype: 
As a general rule, treatment with 6-MP will be started at the usual dose. If it is difficult to continue 
treatment at the usual dose because of a TEAE related to 6-MP, the dose should be decreased 
appropriately at the discretion of the investigator or subinvestigator. If the TEAE related to 6-MP is 
relieved after dose reduction and if the investigator or subinvestigator determines that dose increase for 
the subject is possible, the dose of 6-MP can be increased to levels not exceeding the usual dose. This 
will not apply if the dose is adjusted according to Section 7.4.6. 
7.2.4 
Criteria for Changes in Treatment by Symptom 
1) 
Renal toxicity 
Treatment will be interrupted if Grade 4 renal dysfunction is observed during the treatment. The 
treatment will be resumed when the symptom is improved to Grade 2 or lower. The criteria for starting 
treatment with HD-MTX are specified separately. (See Dosing Criteria and Points to Note for 
HD-MTX Administration). 
2) 
Cardiotoxicity 
If left ventricular fractional shortening (FS) is <0.28 (corresponding to an ejection fraction [EF] of 0.63) 
on ultrasonography, the administration of DNR, THP, and CPA will be skipped until FS increases to 
≥0.28. 
3) 
Hepatotoxicity 

 
 
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If AST or ALT increases to ≥20-fold the age-specific ULN (Grade 4) during treatment, the treatment 
will be temporarily interrupted, and the administration of a liver protection drug will be started. If D-Bil is 
≥1.5 mg/dL, treatment will be interrupted. As a general rule, treatment will be resumed when increased 
AST or ALT is improved to Grade 2 or lower (≤5-fold the age-specific reference level) and D-Bil 
decreases to <1.5 mg/dL. However, for AST and ALT levels, treatment can be resumed when the increased 
level decreases to ≤10-fold the age-specific ULN. In the treatment phases/blocks in which 6-MP is likely 
to be associated with hepatic dysfunction, 6-MP can be administered at half of the prescribed dose until 
AST or ALT decreases to ≤10-fold the age-specific ULN. 
4) 
Hyperglycemia 
• 
Sustained fasting blood glucose level ≥250 mg/dL and negative (−) urinary ketones: Steroids will 
be administered at half of the prescribed dose. 
• 
Sustained fasting blood glucose level ≥250 mg/dL and positive (+) urinary ketones: Steroids will 
be interrupted. After improvement of blood glucose levels and ketoacidosis, the administration of 
steroids will be resumed at half of the prescribed dose. 
5) 
Hypertriglyceridemia 
• 
Any increase in blood triglyceride levels will be managed by the investigator or subinvestigator 
according to their clinical judgment and established medical/institutional guidelines. In case of 
severe asymptomatic hypertriglyceridemia (i.e., TG levels of >1000 mg/dL and no association with 
acute pancreatitis), as first line therapy, dietary intervention followed by fibrates or other treatment 
of investigator’s or subinvestigator’s choice, including plasmapheresis, may be considered . 
• 
Administration of SHP674 will be left to the discretion of the investigator or subinvestigator. For 
SHP674 administration in early consolidation therapy (IB+L) for HR, see item 2) of Section 7.4.3. 
7.2.5 
Prohibited Concomitant Therapies 
7.2.5.1 
Prohibited Concomitant Therapies throughout the Study 
Any of the following therapies must not be conducted during the study as long as no relapse occurs: 
1) 
Treatment with anticancer agents and anticancer therapies (e.g., chemotherapy, hormone therapy, 
immunotherapy, radiation therapy, exchange transfusion, leukapheresis) that are not prescribed in 
the protocol. 
2) 
Systemic corticosteroid therapy for the treatment of cancer that is not prescribed in the protocol. 
3) 
Hematopoietic stem cell transplantation 
4) 
Treatment with pegylated preparations 
5) 
Treatment with live vaccines (until 3 months after the end of treatment in Study SHP674-201). 
7.2.5.2 
Temporarily Prohibited Concomitant Therapies 
As a general rule, trimethoprim-sulfamethoxazole combination should be stopped from 6 days before 
the start of HD-MTX administration. 
As a general rule, trimethoprim-sulfamethoxazole combination and nonsteroidal antiinflammatory 
drugs should not be administered during the administration of MTX and until blood MTX concentration 
decreases to ≤0.25 μmol/L, since these drugs may cause delayed excretion of MTX.  

 
 
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7.2.6 
Restricted Concomitant Medications 
Concomitant medications that are not prescribed in the protocol should be used taking account of 
drug-drug interactions based on the Investigator’s Brochure for SHP674 (see Sections 6.4 and 6.6), 
package insert for each medication, and institutional standards. The following is an example: 
The use of antibiotics for infections should be avoided as far as possible during the administration of 
MTX or until blood MTX concentration decreases to ≤0.25 μmol/L, since the antibiotics may cause 
delayed excretion of MTX. The use of drugs that lead to acidic urine pH (furosemide, ethacrynic acid, 
thiazide diuretics) should also be avoided. 
Note that a decrease in serum protein levels due to SHP674 may increase the toxicity of protein-binding 
drugs. It should also be noted that SHP674 may prevent metabolism and clearance of concomitant 
medications because of its actions on protein synthesis and liver function, or when coadministered with 
other chemotherapeutic agents that are known to interact with CYP enzymes. 
7.3 
Criteria for Starting Administration in Each Treatment Phase 
Subjects will be assessed for the starting criteria before the start of treatment in each phase and on Day 
15 of re-induction therapy (III, III+L). 
The starting criteria for each treatment phase are described below. 
7.3.1 
Criteria for Starting Pre-treatment Phase (IP) 
Subjects enrolled will start fluid therapy. After adequate diuresis (recommendation: ≥50 mL/m2/hour) is 
obtained, as judged by the investigator or subinvestigator, subjects will start treatment in the pre-treatment 
phase. 
7.3.2 
Criteria for Starting Remission Induction Therapy (IA2/IA4) 
Subjects must meet all of the following criteria 1) to 3): 
1) 
On or after Day 8 of study treatment. 
2) 
No serious infections, concurrent diseases, or adverse events. Exceptionally, subjects can receive 
treatment if the concurrent disease is attributable to leukemia and expected to be relieved with 
anticancer agents. 
3) 
If a subject has a severe infectious complication, or if treatment with anticancer agents is considered 
inappropriate for a subject, the administration of VCR, DNR, SHP674, and triple intrathecal therapy 
(TIT) (for subjects with CNS-2 status) can be postponed by up to 14 consecutive days during the 
treatment phase. However, the administration of PSL in the pre-treatment phase will be continued 
during the postponed period. 
7.3.3 
Criteria for Starting Early Consolidation Therapy (IB/IB+L) 
Subjects must meet all of the following criteria 1) to 3): 
1) 
On or after Day 36 of study treatment. 
2) 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. These laboratory values must be obtained 
at least 48 hours after the last dose of G-CSF and at least 3 days after the last platelet transfusion. 
However, subjects who do not meet the above criteria for 7 days after the end of administration of the 
last drug in remission induction therapy (IA2/IA4) will undergo a bone marrow examination (BMA3 
must be conducted at least once within 7 days after the end of administration on Day 33, before the 

 
 
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start of early consolidation therapy [IB/IB+L]). Subjects with ≥5% blasts will start early consolidation 
therapy once white blood cell count increases to ≥1000/μL. Subjects with <5% blasts will start early 
consolidation therapy once neutrophil count increases to ≥500/μL and platelet count increases to 
≥50000/μL. If it is difficult to determine whether the subject can start the next therapy 7 days after the 
end of administration on Day 33 (for example, the presence of blasts is suspected but not evident 
because of hypocellular bone marrow), an additional bone marrow examination will be performed at 
the time when white blood cell count increases to around 1000/μL to immediately start early 
consolidation therapy. 
3) 
No serious infections, concurrent diseases, or adverse events. 
7.3.4 
Criteria for Starting Consolidation Therapy (M2/M5/HR3→HR2→HR1) 
7.3.4.1 
Criteria for Starting M2 and M5 
Subjects must meet all of the following criteria 1) to 5): 
1) 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. These laboratory values must be obtained 
at least 48 hours after the last administration of G-CSF and at least 3 days after the last platelet 
transfusion. Subjects must meet this criterion also before the start of each HD-MTX administration. 
2) 
No serious infections, concurrent diseases, or adverse events. 
3) 
Renal function: Serum creatinine not exceeding the age-specific ULN. 
4) 
Liver function: D-Bil <1.5 mg/dL and AST or ALT ≤5 × age-specific ULN. For the second and 
subsequent doses, if AST or ALT is elevated after the previous administration, the subject can 
receive treatment only when the investigator or subinvestigator judges that AST or ALT tends to 
decrease and the subject has no problems receiving treatment. 
5) 
No fluid retention, including pleural effusion and ascites, as judged by the investigator or 
subinvestigator based on clinical symptoms, test results, and other information. 
7.3.4.2 
Criteria for Starting HR3, HR2, and HR1 
Subjects must meet both of the following criteria 1) and 2): 
1) 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. These laboratory values must be obtained 
at least 48 hours after the last dose of G-CSF and at least 3 days after the last platelet transfusion. 
2) 
No serious infections, concurrent diseases, or adverse events. 
7.3.5 
Criteria for Starting Re-induction Therapy (III/III+L) 
Subjects must meet all of the following criteria 1) to 3). Subjects are required to meet criteria 1) and 2) 
when they start treatment from Day 15 onwards. However, even if a subject does not meet criteria 1) or 2) 
to start treatment from Day 15 onwards, DEX administration from Day 15 will be conducted as scheduled, 
whereas the administration of drugs other than DEX will be started after confirming that the subject meets 
the criteria for starting treatment. 
1) 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. These laboratory values must be obtained 
at least 48 hours after the last dose of G-CSF and at least 3 days after the last platelet transfusion. 
2) 
No serious infections, concurrent diseases, or adverse events. 
3) 
Subject has completed the washout period after the last dose in the preceding treatment phase (for 
2 weeks after HD-MTX [M2/M5] and for 2 weeks for SR and IR and 1 weeks for HR after interim 

 
 
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maintenance therapy). If 6-MP is interrupted for myelosuppression or other reasons during treatment 
with HD-MTX and 6-MP alone is administered additionally after MTX, the washout period will be 
“2 weeks after the last dose of HD-MTX and 1 week after the last dose of 6-MP.” 
7.3.6 
Interim Maintenance Therapy (IM) 
Subjects must meet both of the following criteria 1) and 2): 
1) 
Neutrophil count ≥500/μL and platelet count ≥50000/μL. These laboratory values must be obtained 
at least 48 hours after the last dose of G-CSF and at least 3 days after the last platelet transfusion. 
2) 
No serious infections, concurrent diseases, or adverse events. 
7.4 
Points to Note and Criteria for Changes in Treatment in Each Phase 
7.4.1 
Points to Note and Criteria for Changes in Treatment during the Pre-treatment 
Phase (IP) 
1) 
For subjects having a large tumor burden in the body due to significant organomegaly or other 
conditions, the initial dose of PSL will be 0.2 to 0.5 mg/kg/day. The dose should be increased under 
monitoring of the subjects’ symptoms, since these subjects frequently experience tumor lysis 
syndrome. Even in that case, the dose should be increased so that the total dosage from Day 1 to Day 
7 will be ≥210 mg/m². If a total dosage of ≥210 mg/m² cannot be secured for a subject, the subject 
will be withdrawn from the study (see Section 5.1.1). 
2) 
In the pre-treatment phase, if a subject has a white blood cell count of ≥100000/μL from Day 4 to 
Day 7 and the circulating blast count increased ≥1.5-fold that on Day 1, requiring earlier start of 
remission induction therapy including the administration of VCR on Day 8, the subject will be 
withdrawn from the study (see Section 5.1.1). 
3) 
Subjects who have CNS-3 status at the cerebrospinal fluid examination on Day 1 will be withdrawn 
from the study (see Section 5.1.1). 
4) 
Circulating leukemic cell count (lymphoblast count) will be assessed on Day 8, and the subject’s risk 
category will be changed according to the following rules (see Section 3.1.3.1). 
• PGRs will be moved to SR or IR. 
− White blood cell count <50000/μL at the initial visit and age 1 to ≤9 years → SR 
− White blood cell count <50000/μL at the initial visit and age ≥10 years → IR 
− White blood cell count ≥50000/μL at the initial visit (regardless of age) → IR 
• PPRs will be moved to HR. 
7.4.2 
Points to Note and Criteria for Changes in Treatment during Remission 
Induction Therapy (IA2/IA4) 
7.4.2.1 
Points to Note and Criteria for Changes in Treatment during IA2 in All the 
Groups and IA4 in the IR Group 
1) 
Circulating leukemic cell count (lymphoblast count) will be assessed on Day 8 (see Section 3.1.3.1). 
PPRs will be moved to the HR group. 
2) 
Bone marrow will be assessed on Day 15 (BMA2). If Day 15 falls on a national holiday or a weekend, 
BMA2 can be performed ±1 day of Day 15. If BMA2 is performed on Day 16, the administration of 

 
 
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VCR and DNR on Day 15 should also be shifted to Day 16. VCR and DNR should be administered 
after the completion of BMA2). 
3) 
Subjects will be moved to the HR group upon detection of any of the following factors before the 
start of treatment on Day 22: 
• KMT2A-AFF1 (MLL-AF4) fusion gene abnormality 
• Hypodiploid (≤44 chromosomes) 
4) 
A bone marrow examination (BMA3) will be performed within 7 days from Day 33. 
7.4.2.2 
Points to Note and Criteria for Changes in Treatment during IA4 in the HR 
Group 
A bone marrow examination (BMA3) will be performed within 7 days from Day 33. 
7.4.3 
Points to Note and Criteria for Changes in Treatment during Early 
Consolidation Therapy (IB/IB+L) 
1) 
Treatment will be interrupted when neutrophil count is 0/μL and will be resumed when neutrophil 
count is ≥200/μL. Treatment will not be interrupted based on white blood cell count. Treatment will 
be discontinued if it is interrupted for ≥28 consecutive days. 
2) 
In the case of elevated blood triglyceride levels, administration of SHP674 will be left to the 
discretion of the investigator or subinvestigator according to item 5) of Section 7.2.4. If SHP674 
administration on Day 38 is postponed, it may still take place at any time by Day 59 of early 
consolidation therapy (IB+L), provided blood triglyceride levels have sufficiently subsided, 
according to the determination by the investigator or subinvestigator that resuming SHP674 
administration is safe. However, this does not apply to the case where the Ara-C treatment phase 
must be interrupted (see Section 7.2.2.3). 
7.4.4 
Points to Note and Criteria for Changes in Treatment during Consolidation 
Therapy (M2/M5) 
1) 
If a subject does not meet starting criterion 1) for the second and subsequent administrations of 
HD-MTX (see Dosing Criteria and Points to Note for HD-MTX Administration), 6-MP will be 
interrupted, and the administration of 2 g/m2 (M2) or 5 g/m2 (M5) HD-MTX will be started when 
criterion 1) is fulfilled. If the subject meets starting criterion 1) for the next HD-MTX administration 
after receiving HD-MTX with interrupted 6-MP, the administration of 6-MP will be resumed at the 
time of starting the next administration of HD-MTX. If the subject does not meet criterion 1) again 
after receiving HD-MTX without 6-MP, the subsequent dose of HD-MTX will be decreased to 
1 g/m2 (M2) or 2 g/m2 (M5). If the subject again experiences a similar adverse event, further 
treatment with HD-MTX will be discontinued. The remaining doses of 6-MP after the fourth 
administration of HD-MTX will be administered. The period of the additional administration of 
6-MP after the end of treatment with HD-MTX will be a maximum of 2 weeks. 
2) 
If a subject experiences extensive oral mucosal disorders (CTCAE ver 5.0 Grade 4) after the 
administration of HD-MTX, the subsequent dose of HD-MTX will be decreased to 1 g/m2 (M2) or 
2 g/m2 (M5). If the subject again experiences a similar adverse event, HD-MTX will then be 
administered at 1 g/m2 (M2) or 2 g/m2 (M5) for 6 hours. If the subject still experiences a similar 
adverse event, further treatment with HD-MTX will be discontinued. 

 
 
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3) 
If a subject experiences complications such as severe and extensive skin rash, encephalopathy, or 
renal failure caused by HD-MTX, further treatment with HD-MTX will be discontinued. 
7.4.5 
Points to Note and Criteria for Changes in Treatment during Re-induction 
Therapy (III/III+L) 
1) 
Ara-C treatment block will be started when white blood cell count is ≥500/μL. 
2) 
Treatment should be interrupted when neutrophil count is 0/μL and should be resumed when 
neutrophil count is ≥200/μL. Treatment will not be interrupted based on white blood cell count. 
3) 
Treatment will be discontinued if it is interrupted for ≥28 days. 
7.4.6 
Points to Note and Criteria for Changes in Treatment during Interim 
Maintenance Therapy (IM) 
Treatment in interim maintenance therapy (IM) is allowed to be changed at the discretion of the 
investigator or subinvestigator according to the following criteria for changes in treatment. The results of 
NUDT15 codon 139 polymorphism analysis must be considered when determining the starting dose of 
6-MP (see Section 7.2.3 7)). 
1) 
Adjustment of Doses of MTX and 6-MP 
The dose will be adjusted to maintain a peripheral white blood cell count of 2000 to 3000/μL and 
a peripheral lymphocyte count of ≥300/μL. The criteria for adjustment are as follows: 
• Treatment will be initiated at the starting dose. The dose will be adjusted as below based on 
peripheral blood findings 2 weeks after the start of treatment. 
• The dose will continue to be adjusted after the first remeasurement of peripheral counts. For 
this purpose, the peripheral counts will be remeasured as needed after the first remeasurement. 
• White blood cell count ≥3000/μL: The dose of 6-MP will be increased by 25%, without 
changing the dose of MTX, and the white blood cell count will be remeasured 2 weeks after 
increasing the dose of 6-MP. If the white blood cell count is still ≥3000/μL, the dose of MTX 
will be increased by 25%, without changing the dose of 6-MP, and the white blood cell count 
will be remeasured 2 weeks after increasing the dose of MTX. If the white blood cell count 
still remains ≥3000/μL, the dose of 6-MP will be increased by 25%, and the white blood cell 
count will be remeasured 2 weeks after increasing the dose of 6-MP. However, if the absolute 
lymphocyte count is ≤300/μL, which increases the risk of infections, the dose reduction 
criteria based on lymphocyte counts must be prioritized even when the white blood cell count 
is ≥3000/μL. 
• White blood cell count 2000 to <3000/μL: No dose change. 
• White blood cell count 1500 to <2000/μL: The dose of 6-MP will be reduced by 25%, without 
changing the dose of MTX. The white blood cell count will be remeasured 2 weeks after 
reducing the dose of 6-MP. 
• White blood cell count <1500/μL: Both 6-MP and MTX will be interrupted for  2 weeks. The 
white blood cell count will be remeasured after the 2-week dose interruption. 
• Lymphocyte count <300/μL: The dose of 6-MP will be reduced by 50%, without changing the 
dose of MTX. The lymphocyte count will be remeasured 2 weeks after reducing the dose of 
6-MP. 

 
 
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• If the white blood cell count or lymphocyte count does not improve at the remeasurement 2 
weeks after dose increase or reduction, the dose may be adjusted at the discretion of the 
investigator or subinvestigator. 
2) 
Adjustment in the Case of Dose Interruption during Interim Maintenance Therapy (IM) 
If MTX or 6-MP is interrupted because of myelosuppression or any other adverse event and the 
treatment is resumed within 6 days of interruption, the duration of maintenance therapy will 
remain unchanged, without administering the scheduled doses that were not administered during 
interruption. If the drug is interrupted for 7 or more days, the duration of maintenance therapy will 
be extended on a weekly basis to administer the scheduled doses that were not administered 
during interruption. 
7.5 
Tolerability Assessment in Part 1 
Tolerability assessment in Part 1 will be based on the number of subjects who experience intolerable 
toxicity during the tolerability assessment period (from the pre-treatment phase through remission 
induction therapy [Day 1 to Day 37*]; for at least 25 days after the first dose of SHP674). Any intolerable 
toxicity will be followed until Day 37* and will not be considered “intolerable” if the toxicity recovers to 
Grade 2 or lower. If the intolerable toxicity does not recover to Grade 2 or lower by Day 37*, treatment 
will be discontinued. 
* Tolerability assessment should be continued until Day 37. If the assessment cannot be conducted on 
Day 37, it may take place within +1 day of Day 37 but before the administration of Ara-C (for HR, Ara-C 
and SHP674). 
7.5.1 
Tolerability Assessment Period 
The tolerability assessment period is defined as the period from the pre-treatment phase through 
remission induction therapy (Day 1 to Day 37; for at least 25 days after the first dose of SHP674). If the 
tolerability assessment cannot be conducted on Day 37, it may take place within +1 day of Day 37 but 
before the administration of Ara-C (for HR, Ara-C and SHP674). 
7.5.2 
Definition of Intolerable Toxicity 
Intolerable toxicity is defined as the following toxicity that is observed during the tolerability 
assessment period. A TEAE for which a causal relationship to SHP674 is evidently ruled out will not be 
considered toxicity. 
Grade 3 or higher toxicity (that does not improve to Grade 2 or lower by Day 37), with the exception of 
adverse drug reactions stated in the package inserts for PSL, DNR, VCR, L-asparaginase, MTX, Ara-C, 
CPA, and 6-MP (examples are presented in 7.5.3 Expected Toxicity), will be considered intolerable. Any 
expected toxicity that is more severe than usual and judged by the physician to be intolerable will also be 
regarded as intolerable toxicity. An SHP674-related TEAE that leads to interruption of early consolidation 
therapy for ≥28 days will also be regarded as intolerable toxicity if confirmed by the internal safety 
committee  (composed of the Sponsor and study investigators) taking into consideration the expectedness 
and severity of the event according to section 7.5.5. The investigator or subinvestigator will report the 
occurrence of intolerable toxicity to the Sponsor or the in-country caretaker in an Intolerable Toxicity 
Report form (Attachment 7 to the protocol [supplement]) immediately after the end of Day 37. 

 
 
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7.5.3 
Expected Toxicity 
SOC (Internationally Agreed Order) 
Expected Toxicity 
Infections and infestations 
Viral infection, infection, bacterial infection, opportunistic infection, 
sepsis, pneumonia, cystitis 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) 
Lymphoma, acute leukaemia, myelodysplastic syndrome, secondary 
malignancy 
Blood and lymphatic system disorders 
Lymphadenopathy, coagulopathy, hypercoagulation, blood disorder, 
haematotoxicity, thrombocytopenia, eosinophilia, bone marrow 
failure, aplastic anaemia, haemorrhagic diathesis, erythropenia, 
increased tendency to bruise, leukopenia, leukocytosis, pancytopenia, 
anaemia, agranulocytosis, granulocytopenia 
Immune system disorder 
Anaphylactic shock, anaphylactic reaction, hypersensitivity, 
hypogammaglobulinaemia, immunosuppression 
Endocrine disorder 
Cushingoid, inappropriate antidiuretic hormone secretion, 
hyperthyroidism, secondary adrenocortical insufficiency, 
adrenocortical insufficiency, endocrine pancreatic disorder 
Metabolism and nutrition disorders 
Hyperammonaemia, hyperkalaemia, hyperphosphataemia, 
hyperglycaemia, hyperlipidaemia, hyperuricaemia, tumour lysis 
syndrome, decreased appetite, increased appetite, polydipsia, glucose 
tolerance impaired, metabolic acidosis, hypokalaemia, alkalosis 
hypokalaemic, hypocalcaemia, hyponatraemia, blood hyposmosis, 
hypoproteinaemia, electrolyte imbalance, diabetes mellitus 
Mental disorder 
Depression, irritability, confusional state, disorientation, nervousness, 
mental disorder, mental status changes, euphoric mood, anxiety, 
insomnia, depressive symptom 
Nervous system disorder 
Depressed level of consciousness, loss of consciousness, altered state 
of consciousness, ataxia, posterior reversible encephalopathy 
syndrome, hypoaesthesia, nystagmus, hypotonia, somnolence, 
language disorder, epidural lipomatosis, hypertensive 
encephalopathy, coma, paraesthesia, autonomic neuropathy, 
myasthenia gravis, cerebellar ataxia, nervous system disorder, 
neuralgia, neurotoxicity, intracranial pressure increased, headache, 
widespread structural disorder of the brain, cerebral infarction, 
cerebral haemorrhage, encephalopathy, cranial nerve disorder, 
leukoencephalopathy, hyporeflexia, dizziness, balance disorder, 
paralysis, neuropathy peripheral, peripheral motor neuropathy, 
peripheral sensory neuropathy, dysgeusia, seizure, peroneal nerve 
palsy 
Eye disorders 
Blindness transient, exophthalmos, ocular hyperaemia, ocular 
hypertension, optic atrophy, dysmetropsia, visual acuity reduced, 
cataract subcapsular, diplopia, metamorphopsia, vision blurred, 
retinal disorder, retinal pigment epitheliopathy, retinal detachment, 
chorioretinopathy, glaucoma 
Ear and labyrinth disorders 
Vertigo, deafness 
Cardiac disorders 
Angina pectoris, cardiac tamponade, myocardial ischaemia, 
myocardial infarction, myocardial damage, cardiotoxicity, pericardial 
effusion, cardiac failure, pericarditis, palpitations, tachycardia 
Angiopathy 
Shock, orthostatic hypotension, vasculitis, angiopathy, vascular pain, 
thrombosis, thrombophlebitis, hypertension, haemorrhage, 
gastrointestinal haemorrhage, phlebitis, flushing, hypotension, 
aneurysm 
Respiratory, thoracic and mediastinal 
disorders 
Cough, interstitial lung disease, pneumomediastinum, acute 
respiratory distress syndrome, pleural effusion, dyspnoea, respiratory 
failure, oropharyngeal pain, pulmonary haemorrhage, pulmonary 
fibrosis, nasal discomfort, wheezing asthma 

 
 
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SOC (Internationally Agreed Order) 
Expected Toxicity 
Gastrointestinal disorder 
Ileus, eructation, melaena, nausea, gastrointestinal disorder, 
gastrointestinal ulcer, diarrhoea, necrotising colitis, pancreatitis acute, 
mouth ulceration, lip swelling, stomatitis, neutropenic colitis, 
pancreatitis relapsing, enterocolitis haemorrhagic, gastrointestinal 
motility disorder, gastrointestinal disorder, gastrointestinal 
perforation, peptic ulcer, dyspepsia, abdominal pain upper, glossitis, 
enterocolitis, intestinal paralysis, pneumatosis intestinalis, abdominal 
pain, abdominal distension, constipation, ileus paralytic, vomiting, 
insulitis, pancreatitis 
Hepatobiliary disorders 
Jaundice, hepatic necrosis, hepatic function abnormal, hepatic 
cirrhosis, liver disorder, hepatic vein occlusion, hepatic fibrosis, 
hepatic failure, hepatitis fulminant, hepatic steatosis 
Skin and subcutaneous tissue disorders 
Acne, pruritus, nodular rash, angioedema, photosensitivity reaction, 
erythema, purpura, panniculitis, lipohypertrophy, pigmentation 
disorder, hyperhidrosis, hypertrichosis, alopecia, toxic epidermal 
necrolysis, naildeformity, nail discolouration, rash, ecchymosis, 
dermatitis, skin depigmentation, skin fragility, skin striae, skin ulcer, 
oculomucocutaneous syndrome, skin exfoliation, skin thinning, 
urticaria 
Musculoskeletal and connective tissue 
disorders 
Myopathy, rhabdomyolysis, arthralgia, muscle atrophy, muscle 
disorder, myalgia, muscle spasms, nuchal rigidity, osteonecrosis, 
osteoporosis, back pain, convulsion 
Renal and urinary disorders 
Nephrotic syndrome, acute kidney injury, scleroderma renal crisis, 
haematuria, azotaemia, hypersthenuria, cystitis haemorrhagic, renal 
impairment, nephropathy, renal disorder, renal tubular necrosis, renal 
failure, polyuria, protein urine, urinary retention, calculus urinary, 
dysuria, oliguria, bladder disorder 
Reproductive system and breast disorders Menstrual disorder, gonadopathy, amenorrhoea, azoospermia, ovarian 
failure 
General disorders and administration site 
conditions 
Influenza like illness, chills, chest discomfort, malaise, thirst, 
induration, impaired healing, injection site reaction, developmental 
delay, pyrexia, fatigue, discomfort, oedema, gait disturbance, 
asthenia, withdrawal syndrome, feeling cold, pain 
Investigations 
Gamma-glutamyltransferase increased, aspartate aminotransferase 
increased, amylase increased, alanine aminotransferase increased, 
antithrombin iii decreased, plasminogen decreased, protein c 
decreased, prothrombin level decreased, liver function test abnormal, 
intraocular pressure increased, megaloblasts increased, blood pressure 
increased, blood pressure decreased, platelet count decreased, blood 
alkaline phosphatase increased, blood albumin decreased, blood 
creatinine increased, blood creatine phosphokinase increased, blood 
cholinesterase decreased, blood sodium decreased, blood fibrinogen 
decreased, blood glucose increased, myoglobin blood increased, 
blood lactate dehydrogenase increased, blood uric acid increased, 
blood urea increased, eosinophil count increased, bone density 
decreased, ECG signs of myocardial ischaemia, electrocardiogram 
abnormal, spermatozoa progressive motility abnormal, sperm 
concentration abnormal, red blood cell count decreased, weight 
decreased, weight increased, nitrogen balance negative, urine sodium 
increased, myoglobin urine present, white blood cell count decreased, 
white blood cell count increased, reticulocyte count decreased, 
pancreatic enzymes increased 
Injury, poisoning and procedural 
complications 
Fat embolism, tendon rupture 
 

 
 
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7.5.4 
Procedure for Tolerability Assessment 
The Sponsor or in-country caretaker and the medical officer will assess tolerability in 3 subjects who 
receive SHP674. The second and third subjects will start the pre-treatment phase at least 72 hours after the 
preceding subject receives SHP674 on Day 12 of remission induction therapy. Tolerability issues will be 
considered not present if 0 of the 3 subjects experience intolerable toxicity (see Section 7.5.2). If 0 of 3 
subjects experience intolerable toxicity tolerability issues will be considered not present, the dose will be 
confirmed and the study will move to Part 2. If 1 of the 3 subjects experiences intolerable toxicity, 
additional 3 subjects will be enrolled in the study. Tolerability issues will be considered not present if 1 of 
the 6 subjects experiences intolerable toxicity. If ≥2 of the 3 subjects or ≥2 of the 6 subjects experience 
intolerable toxicity, the Sponsor or in-country caretaker and the medical officer will discuss the necessity 
of dose reduction, and the Sponsor will make a final decision whether to reduce the dose of SHP674. 
In the case that tolerability cannot be assessed adequately, for example, if a subject enrolled does not 
start treatment with SHP674 for any reason or if a subject is withdrawn from the study during the 
tolerability assessment period for a reason other than a tolerability issue, enrollment of an additional 
subject will be considered. 
Figure 7.5.4-1 Outline of Tolerability Assessment Procedure 
 
7.5.5 
Decision on Whether to Move to Part 2 
Safety data of Part 1 will be reviewed by an internal safety committee that will determine if the dose 
investigated in Part 1 was well tolerated and Part 2 can be initiated with this dose. 
 

 
 
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8 STUDY PROCEDURES AND SCHEDULE 
The schedule for study procedures during the period from informed consent through remission 
induction therapy, which is common to SR, IR, and HR, is presented in Table 8-1. The schedule for early 
consolidation therapy and subsequent therapies is presented in Table 8-2 (SR and IR) and Table 8-3 (HR). 
Table 8-1 Schedule for Study Procedures from Informed Consent through Remission 
Induction Therapy (Common to SR, IR, and HR) 
 
a) If treatment is postponed, the relevant test schedule will also be postponed. 
b) As a general rule, subjects will be hospitalized during remission induction therapy. 
c) Laboratory results obtained within 4 days before the start of treatment in each phase may be used to assess subjects for the criteria for starting 
treatment related to hematology or chemistry. 
d) To be performed before the start of the administration of SHP674 or the backbone therapy drugs that are listed in Section 7.2.1 (7.2.1
Backbone Therapy Drugs Used in This Study). 
e) The test or examination is allowed to be performed within 4 days before the prescribed day, except for that at screening and on IP Day 1. 
f) Height and weight are allowed to be measured within 7 days before the prescribed day, except for those at screening and on IP Day 1. 
g) Informed consent must be obtained not later than 21 days before enrollment. 
h) Screening must be performed not later than 14 days before enrollment. 
i) Treatment in the pre-treatment phase will be started within 7 days after enrollment. If screening is performed within 3 days before Day 1, the 
duplicate test items scheduled for Day 1 pre-dose may be omitted, except for symptoms and findings and vital signs,.  
j) Cerebrospinal fluid examination will be performed simultaneously with MTX-IT on IP Day 1. However, it can be postponed until up to Day 
4, if a subject cannot receive MTX IT on Day 1 for a reason such as that the subject’s initial visit falls on a weekend. 
k) Oral administration (or IV administration at the same dose) of PSL will be started on IP Day 1. A subject who has a circulating leukemic cell 
count (lymphoblast count) of <1000/μL on Day 8 is defined as a prednisolone good responder (PGR). A subject who has a circulating 
leukemic cell count (lymphoblast count) of ≥1000/μL on Day 8 is defined as a prednisolone poor responder (PPR). Circulating leukemic cell 
count will be calculated by multiplying circulating white blood cell count (/μL) measured on the same day by the percentage of leukemic cells 
(%). Results of smear microscopy at each investigative site will be used to determine the response to PSL. A total dosage of PSL of 
≥210 mg/m2 is required to determine the response to PSL. The test required for the determination of PSL response should be performed 

 
 
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before the start of administration of the investigational product or backbone therapy drugs listed in Section 7.2.1 (Backbone Therapy Drugs 
Used in This Study). 
l) Risk category will be determined before administration on IA2/IA4 Day 22 based on the result of the bone marrow examination (BMA2) 
performed on IA2/IA4 Day 15.  
m) On Day 15 of IA2/IA4, VCR and DNR should be administered after the completion of BMA2. If Day 15 of IA2/IA4 falls on a national holiday 
or a weekend, BMA2 can be performed ±1 day of Day 15. If BMA2 is performed on Day 16, the administration of VCR and DNR scheduled 
for Day 15 of IA2/ IA4 should also be shifted to Day 16.  
n) Whether to categorize a subject as HR will be determined based on the results of chimeric gene analysis and chromosome analysis. The 
determination should be completed before the start of administration of the investigational product or backbone therapy drugs listed in 
Section 7.2.1 (Backbone Therapy Drugs Used in This Study). 
o) Risk category will be determined based on the results of BMA3. 
p) As a general rule, PET will be performed in the fasting state. 
q) To be performed within 7 days after the end of administration on Day 33 of IA2/IA4. 
r) To be performed from Day 33 of IA2/IA4 to before the start of early consolidation therapy (IB/IB+L). If the day of TIT is changed for a social 
reason such as that the prescribed day falls on a weekend or holiday, the day of bone marrow examination may also be changed accordingly. 
 

 
 
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Table 8-2 Schedule for Study Procedures in Early Consolidation Therapy and Subsequent Therapies (SR/IR) 
 
 

 
 
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Table 8-2 Schedule for Study Procedures in Early Consolidation Therapy and Subsequent Therapies (SR/IR) (Continued) 
 

 
 
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a) If treatment is postponed, the relevant test schedule will also be postponed. 
b) Laboratory results obtained within 4 days before the start of treatment in each phase may be used to assess subjects for the starting criteria related to hematology or chemistry.  
c) To be performed before the start of the administration of SHP674 or the backbone therapy drugs that are listed in Section 7.2.1 (Backbone Therapy Drugs Used in This Study) 
d) Height and weight are allowed to be measured within 7 days before the prescribed day, except for those at treatment completion, treatment discontinuation, or study discontinuation. 
e) Laboratory tests are allowed to be performed within 4 days before the prescribed day, except for those at treatment completion, treatment discontinuation, or study discontinuation. 
f) If the subject is negative for HBs antigen and positive for HBc antibody or HBs antibody at screening, HBV DNA will be measured to confirm that the result is negative. HBV DNA measurement other than that at 
screening will not be required for subjects with a documented history of HBV vaccination. 
g) As a general rule, PET should be performed in the fasting state. 
 
i) To be performed during the period from Day 59 of IB/ IB+L to before the start of consolidation therapy (M2/M5/HR3). If the day of TIT is changed for a social reason such as that the prescribed day falls on a weekend or 
holiday, the day of bone marrow examination may also be changed accordingly. 
j) To be performed 24 hours after the administration of MTX. 
k) To be performed 42 and 48 hours after the administration of MTX. Measurement at 36 hours is optional. 
l) To be performed 66 hours after the administration of MTX. Measurement at 54 hours is optional. 
m) Tests and assessments on M2/M5 Day 57, M2/M5 Day 64, III Day 29, IM Day 57, and IM Day 64 can be omitted if the investigator or subinvestigator considers unnecessary. If not omitted, these tests and assessments 
are allowed to be performed within 4 days before the prescribed day. 
n) The assessment is allowed to be performed within 4 days before the prescribe day. 
o) To be performed 30 (+7) days after the last dose of investigational product. 
p) If the subject’s next therapy starts 30 (+7) days after the last dose of investigational product or earlier, the assessment may be performed during the period from 7 days before the start date of the next therapy to before 
the start of the next therapy. 

 
 
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Table 8-3 Schedule for Study Procedures in Early Consolidation Therapy and Subsequent Therapies (HR) 

 
 
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Table 8-3 Schedule for Study Procedures in Early Consolidation Therapy and Subsequent Therapies (HR) (Continued) 
 

 
 
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a) If treatment is postponed, the relevant rest schedule will also be postponed. 
b) Laboratory results obtained within 4 days before the prescribed day may be used to assess subjects for the starting criteria related to hematology or chemistry. 
c) To be performed before the start of the administration of SHP674 or the backbone therapy drugs that are listed in Section 7.2.1 (Backbone Therapy Drugs Used in This Study). 
d) Height and weight are allowed to be measured within 7 days before the prescribed day, except for those at treatment completion, treatment discontinuation, or study discontinuation. 
e) Laboratory tests are allowed to be performed within 4 days before the prescribed day, except for those at treatment completion, treatment discontinuation, or study discontinuation. 
f) If the subject is negative for HBs antigen and positive for HBc antibody or HBs antibody, HBV DNA will be measured to confirm that the result is negative. HBV DNA measurement other than that at screening will not 
be required for subjects with a documented history of HBV vaccination. 
g) When SHP674 administration is resumed after interruption, the same tests as scheduled for Day 38 (except urinalysis) should be performed before administration. If SHP674 is administered on Day 43, 50, or 57, the tests 
scheduled for that day may be substituted for the tests before administration. 
h) As a general rule, PET should be performed in the fasting state. 
 
j) To be performed during the period from Day 59 of IB/ IB+L to before the start of consolidation therapy (M2/M5/HR3). If the day of TIT is changed for a social reason such as that the prescribed day falls on a weekend or 
holiday, the day of bone marrow examination may also be changed accordingly. 
k) Tests and assessments can be omitted if the investigator or subinvestigator considers unnecessary. If not omitted, these tests and assessments are allowed to be performed within 4 days before the prescribed day. 
l) To be performed 24 hours after the administration of MTX. 
m) To be performed 42 and 48 hours after the administration of MTX. Measurement at 36 hours is optional. 
n) To be performed 66 hours after the administration of MTX. Measurement at 54 hours is optional. 
o) Tests and assessments on IM Day 29 can be omitted if the investigator or subinvestigator considers unnecessary. If not omitted, these tests and assessments are allowed to be performed within 4 days before the prescribed 
day. 
p) The assessment is allowed to be performed within 4 days before the prescribed day. 
q) To be performed 30 (+7) days after the last dose of investigational product. 
r) If the subject’s next therapy starts 30 (+7) days after the last dose of investigational product or earlier, the assessment may be performed during the period from 7 days before the start date of the next therapy to before the 
start of the next therapy. 
 

 
 
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8.1 
Screening 
Subjects will undergo screening after giving informed consent. Screening test items are presented in 
Table 8.1-1. Screening tests should be conducted within 14 days before enrollment. For subjects who have 
undergone screening within 3 days before Day 1, duplicated test items can be omitted on Day 1 pre-dose. 
Test results obtained before informed consent but within 14 days before enrollment (within 28 days 
before enrollment for imaging examinations) can be used as screening test results after getting consent 
from the subject (or the subject’s legally acceptable representative).  
Table 8.1-1 Screening Test Items 
Demographics 
Date of written informed consent, sex, date of birth, race, concurrent diseases,  medical 
history, time of diagnosis of the primary disease, genetic analysis results related to the 
primary disease, chromosome analysis results related to the primary disease, date of 
enrollment, assessment for the inclusion and exclusion criteria 
Disease assessment 
Risk classification 
Physiological 
examination 
Height, weight, vital signs (blood pressure, pulse rate, temperature, percutaneous 
arterial oxygen saturation [SpO2]), ECOG PS 
Hematology 
RBC, Hb, Ht, WBC, Baso, Eosino, Lymph, Mono, Neutro, lymphoblast count, PLT 
Chemistry 
AST, ALT, T-Bil, D-Bil, ALP, LDH, γ-GTP, Cr, BUN, TP, Alb, UA, Glu, T-Cho, TG, 
AMY, lipase, CRP, Na, K, Cl, P, Ca 
Coagulation test 
Prothrombin time-INR, APTT, fibrinogen, protein S activity, antithrombin activity, 
D-dimer, FDP 
Immunoserological test 
IgG, IgA, IgM 
Viral test 
HIV antibody, HBs antigen, HBs antibody, HBc antibody, HBV DNA*, HCV antibody 
Urinalysis 
Qualitative urinalysis (protein, glucose, ketone bodies, urobilinogen, occult blood) 
Imaging examination 
Echocardiography, 12-lead resting ECG, MRI*, PET*, CT 
Other tests 
Pregnancy test* 
Genetic testing 
Nudix hydrolase 15 (NUDT15) codon 139 polymorphism analysis 
* To be performed as necessary. (See Section 8.12 for HBV DNA, Section 8.14 for MRI and PET, and Section 8.17 for pregnancy test.) 
8.2 
Subject Demographics 
The following information will be entered into the eCRF: 
• 
Date of written informed consent 
• 
Sex 
• 
Date of birth 
• 
Race 
• 
Concurrent diseases 
• 
Medical history 
• 
Time of diagnosis of the primary disease 
• 
Genetic analysis results related to the primary disease (KMT2A-AFF1 [MLL-AF4])  
• 
Chromosome analysis results related to the primary disease (hypodiploid) 
• 
Date of enrollment 
• 
Eligibility based on the inclusion and exclusion criteria 
Time point: Screening. Genetic analysis and Chromosome analysis results related to the primary disease 
should be obtained before risk determination (see Section 3.1.3.1). 

 
 
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8.3 
Disease Assessment and Risk Classification 
The following assessments will be performed to determine the risk category after the start of study 
treatment. The results of the assessments will be entered into the eCRF. 
8.3.1 
NCI Classification 
Assessment item: NCI classification 
Time points: Screening 
8.3.2 
Identification of Chimeric Gene Analysis Results 
Assessment item: KMT2A-AFF1 (MLL-AF4) 
Time points: Before Day 22 of IA2/IA4 
8.3.3 
Identification of Chromosome Analysis Results 
Assessment item: Hypodiploid 
Time points: Before Day 22 of IA2/IA4 
8.3.4 
Assessment of Response to PSL 
Assessment item: Circulating lymphoblast count 
Time points: IA2/IA4 Day 8 
8.3.4.1 
Definition of Response to PSL 
MTX alone will be administered intrathecally on the first day of the pre-treatment phase (Day 1), and 
oral administration (or IV administration at the same dose) of PSL will be started on the same day. A 
subject who has a circulating leukemic cell count (lymphoblast count) of <1000/μL on Day 8 is defined as 
a prednisolone good responder (PGR). A subject who has a circulating leukemic cell count (lymphoblast 
count) of ≥1000/μL on Day 8 is defined as a prednisolone poor responder (PPR). Circulating leukemic cell 
count will be calculated by multiplying circulating white blood cell count (/μL) measured on the same day 
by the percentage of leukemic cells (%). Results of smear microscopy at each investigative site will be 
used to determine the response to PSL. A total dosage of PSL of ≥210 mg/m2 is required to determine the 
response to PSL. The test required for the determination of PSL response should be performed before the 
start of administration of the investigational product or backbone therapy drugs listed in Section 7.2.1 
(Backbone Therapy Drugs Used in This Study). 
8.3.5 
Identification of Bone Marrow Examination Results 
Assessment items: BMA2, BMA3 
Time points: BMA2, IA2/IA4 Day15; BMA3, within 7 days from IA2/IA4 Day33 
Points to note regarding bone marrow aspiration are provided in Section 8.18. 
8.4 
Symptoms and Findings 
Assessment items: Changes in symptoms and findings after the start of study treatment, the presence or 
absence of new symptoms and findings. 
Time points: Screening; once a week from Day 1 of each treatment phase; before SHP674 
administration; at the time of treatment completion, treatment discontinuation, or study 
discontinuation 

 
 
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8.5 
Height, Weight 
Test items: Measurement of height and weight 
Time points: Screening; Ip Day 1; IA2/IA4 Day 8; IB/IB+L Day 36; Day 1 of each treatment phase after 
consolidation therapy; at the time of treatment completion, treatment discontinuation, or 
study discontinuation 
8.6 
Vital Signs and ECOG PS 
Test items: Temperature (°C), blood pressure (mm Hg), pulse rate (beat/minute), ECOG PS 
Axillary temperature will be measured. As a general rule, blood pressure (systolic and diastolic) and 
pulse rate will be measured at rest in the sitting position. Subjects’ performance status will be recorded 
according to the ECOG PS (see Attachment 4 to the protocol [supplement]). 
Time points: Screening; once a week from Day 1 of each treatment phase; before SHP674 
administration; at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.7 
Percutaneous Arterial Oxygen Saturation (SpO2) 
Test item: SpO2 
Time points: Screening and at treatment completion, treatment discontinuation, or study discontinuation 
8.8 
Hematology 
Test items: RBC, Hb, Ht, WBC, Baso, Eosino, Lymph, Mono, Neutro, lymphoblast count, PLT 
Time points: Screening; once a week from Day 1 of each treatment phase; before SHP674 
administration; at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.9 
Chemistry 
As a general rule, chemistry will be performed in the fasting state (at least 2 hours after a meal). 
Test items: AST, ALT, T-Bil, D-Bil, ALP, LDH, γ-GTP, Cr, BUN, TP, Alb, UA, Glu, T-Cho, TG, 
amylase, lipase, CRP, Na, K, Cl, P, Ca, corrected Ca* 
* Corrected Ca will be calculated according to the following formulas based on the observed Ca and 
albumin levels: 
• If albumin level is <4.0 g/dL: 
Corrected Ca = Observed Ca level (mg/dL) − albumin level (g/dL) + 4.0 
• If albumin level is ≥4.0 g/dL: 
Corrected Ca = Observed Ca level (mg/dL) 
Time points: Screening; once a week from Day 1 of each treatment phase; before SHP674 
administration; at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.10 Coagulation Test 
Test items: Prothrombin time-INR, APTT, fibrinogen, protein S activity*, antithrombin activity, 
D-dimer, FDP 
* Protein S activity will be measured only at screening. 

 
 
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Time points: Screening; once a week from Day 1 of each treatment phase; before SHP674 
administration; at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.11 Immunoserological Test 
Test items: IgG, IgA, IgM 
Time points: Screening; start day of each treatment phase (including IA2/IA4 Day 8 and IB/IB+L Day 36); 
at the time of treatment completion, treatment discontinuation, or study discontinuation 
8.12 Viral Test 
Test items: HIV antibody, HBs antigen, HBs antibody, HBc antibody, HCV antibody, HBV DNA* 
Time point: Screening 
* If the subject is negative for HBs antigen and positive for HBs antibody or HBc antibody at screening, 
HBV DNA will be measured to confirm that the result is negative (<20 IU/mL [1.3 LogIU/mL]). 
Subsequently, HBV DNA will be measured for the subject on the start day of each treatment phase**, 
except for the pre-treatment phase and remission induction therapy, and at the time of treatment 
completion, treatment discontinuation, or study discontinuation to confirm that the result is negative. 
If the subject has a documented history of HBV vaccination, HBV DNA measurement will not be 
required, except for at screening. 
** To be measured only on Day 1 of HR3 in consolidation therapy for HR. 
8.13 Urinalysis 
Test items: Qualitative urinalysis (protein, glucose, ketone bodies, urobilinogen, occult blood) 
Time points: Screening; once a week from Day 1 of remission induction therapy; before SHP674 
administration; Day 1 of each treatment phase after early consolidation therapy; at the time 
of treatment completion, treatment discontinuation, or study discontinuation 
8.14 CT, MRI, and PET 
As a general rule, PET should be performed in the fasting state. 
Detailed conditions for image assessment will be specified in a written procedure developed elsewhere. 
Test item: CT, MRI, PET 
Time point:
8.15 Twelve-lead Resting Electrocardiography 
Test items: Heart rate, PR interval, QRS duration, QT interval, QTc intervals (QTcF, QTcB) 
*The QTc intervals (QTcF, QTcB) will be automatically calculated on the electronic case report form 
according to the following formulas: 
QTcF (msec) = QT interval/(60/heart rate)1/3 
QTcB (msec) = QT interval/(60/heart rate)1/2 
Standard 12-lead ECG will be performed at rest in the decubitus position to determine the presence or 
absence of findings. If there are any findings, whether they are clinically significant or not will be 
determined, and the interpretation of clinical significance and the nature of the findings will be entered into 
the eCRF. During remission induction therapy, the ECG will be recorded before SHP674 administration, 

 
 
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immediately after SHP674 administration, and 11 days after the end of SHP674 administration using 
measurement equipment available at the investigative site 3 consecutive times at 1- to 2-minute intervals, 
after approximately 5-minute rest in the decubitus position. Drug concentration measurement that is 
scheduled for the same time point as ECG recording must be performed after ECG. ECG recording 
immediately after SHP674 administration and 11 days after the end of SHP674 administration should be 
performed before the start of administration of investigational product or the backbone therapy drugs listed 
in Section 7.2.1 (Backbone Therapy Drugs Used in This Study) on the same day. 
Time points: Screening; remission induction therapy (see Table 8.15-1); Day 1 of each treatment phase 
after early consolidation therapy; at the time of treatment completion, treatment 
discontinuation, or study discontinuation 
Table 8.15-1 ECG Measurement Schedule in Remission Induction Therapy (SR/IR/HR) 
Time Points 
Allowance 
Remission induction therapy (IA2/IA4) 
Before SHP674 administration 
One day to 15 minutes before 
administration, and before drug 
concentration measurement 
Immediately after the end of 
SHP674 administration 
From the last dose of SHP674 to  
before drug concentration 
measurement 
11 days after the end of SHP674 
administration 
±1 day and before drug 
concentration measurement 
8.16 Echocardiography 
Test item: LVEF 
Time point: Screening, at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.17 Pregnancy Test 
The presence or absence of menstruation, menstrual cycle, surgical history, and other relevant 
information will be obtained through interview. Women of childbearing potential (a woman of 
childbearing potential is defined as a woman who has experienced her first menstruation, has not 
undergone hysterectomy, bilateral tubal ligation, or bilateral ovariectomy and is not postmenopausal. 
Postmenopausal status is defined as amenorrhea of ≥12 consecutive months with no specific causes) will 
undergo a pregnancy test. 
Test item: Serum or urine hCG 
Time point: Screening, at the time of treatment completion, treatment discontinuation, or study 
discontinuation 
8.18 Bone Marrow Examination 
Test items: NCC, proportion of lymphoblasts 
Time points:  
BMA2: ±1 day from IA2/IA4 Day 15 
BMA3: Within 7 days after the end of administration on Day 33 of IA2/IA4 
BMA4: From IB/ IB+L Day 65 to before the start of consolidation therapy (M2/M5/HR3) 

 
 
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8.18.1 Bone Marrow Aspiration during Remission Induction Therapy: Points to Note 
for BMA2 
On Day 15 of IA2/IA4, VCR and DNR should be administered after the completion of BMA2. If Day 15 
of IA2/IA4 falls on a national holiday or a weekend, BMA2 can be performed ±1 day of Day 15. However, 
if BMA2 is performed on Day 16 of IA2/IA4, the administration of VCR and DNR on Day 15 should also 
be shifted to Day 16.. 
8.18.2 Bone Marrow Aspiration after the End of Remission Induction Therapy: Points 
to Note for BMA3 
Bone marrow aspiration at the end of remission induction therapy (IA2/IA4) should not necessarily be 
performed on Day 33 of IA2/IA4, since a certain level of bone marrow recovery is required to perform the 
aspiration. It can be performed later than Day 33 if bone marrow recovery appears to be delayed. On the 
other hand, the criteria for starting early consolidation therapy (IB/IB+L) is “neutrophil count ≥500/μL and 
platelet count ≥50000/μL.” Both of the above criteria are based on the conditions that the subject is not 
receiving G-CSF or received the last dose of G-CSF at least 48 hours before and that the subject received 
the last platelet transfusion at least 3 days before. It is necessary to perform bone marrow aspiration at an 
appropriate time focusing on minimizing the transition period from remission induction therapy (IA2/IA4) 
to early consolidation therapy (IB/IB+L) as much as possible. Therefore, there may be some subjects who 
meet the criteria for starting early consolidation therapy (IB/IB+L) 
 
 
 Subjects who do not meet the criteria for starting early consolidation therapy (IB/IB+L) for 
7 days after the end of remission induction therapy (IB/IB+L) will undergo a bone marrow examination. 
Subjects with ≥5% blasts will start early consolidation therapy once white blood cell count increases to 
≥1000/μL. Subjects with <5% blasts will start early consolidation therapy once neutrophil count increases 
to ≥500/μL and platelet count increases to ≥50000/μL. Thus, all subjects must undergo bone marrow 
aspiration at least once within 7 days after the end of administration on Day 33 of IA2/IA4. If it is difficult to 
determine whether the subject can start the next therapy 7 days after the end of administration on Day 33 of 
IA2/IA4 (for example, the presence of blasts is suspected but not evident because of hypocellular bone 
marrow), an additional bone marrow examination will be performed when white blood cell count has 
increased to around 1000/μL to immediately start early consolidation therapy.  
8.18.3 Bone Marrow Aspiration after the End of Early Consolidation Therapy: Points 
to Note at BMA4 
All subjects will be assessed for remission by bone marrow aspiration (BMA4) at the end of early 
consolidation therapy (IB/IB+L).  Remission should be assessed under the conditions that the subject is not 
receiving G-CSF or received the last dose of G-CSF at least 48 hours before the assessment and that the 
subject received the last platelet transfusion at least 3 days before the assessment. 
 
 
 
8.19 Cerebrospinal Fluid Examination 
Test items: Cell counts (WBC and RBC), lymphoblast count, CNS status 

 
 
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Time points: Ip Day 1 (the examination is to be performed simultaneously with MTX IT. However, it 
can be postponed until up to Day 4, if a subject cannot receive MTX IT for a reason such as 
that the subject’s initial visit falls on a weekend), from Day 33* of IA2/IA4 to before the 
start of early consolidation therapy (IB/IB+L), from IB/IB+L Day 59* to before the start of 
consolidation therapy (M2/M5/HR3). 
* If the day of TIT is changed for a social reason such as that the prescribed day falls on a 
weekend or holiday, the day of cerebrospinal fluid examination may also be changed 
accordingly. 
8.20 Blood MTX Concentration 
Test item: Blood MTX concentration 
Time points: As specified below for each risk category. 
SR and IR: M2 Days 9, 10, 11, 23, 24, 25, 37, 38, 39, 51, 52, and 53 
HR: HR2 Days 2, 3, and 4; HR1 Days 2, 3, and 4 

 
 
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8.21.2 Evaluation of CNS Involvement 
CNS remission is defined as achievement of CNS-1 status in a subject with CNS-2 status. CNS relapse 
is defined as new development of CNS-3 status or clinical signs of CNS leukemia such as facial nerve 
palsy, brain/eye involvement, or hypothalamic syndrome. 
8.21.3 Evaluation of Extramedullary Disease  
Extramedullary disease will be evaluated by contrast-enhanced CT (neck, chest, abdominal, or pelvic). 
PET, biopsy, and other tests will be performed if a false-positive result is suspected on CT and the 
investigator or subinvestigator judges it necessary. The response criteria presented in Table 8.21.3-1 will 
be used for evaluation. 

 
 
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Table 8.21.3-1 Response Criteria for Mediastinal Disease18 
PR 
>50% decrease in the sum of the products of the greatest perpendicular diameters (SPD) of the 
mediastinal enlargement. At least one of the previously observed lesions is positive on 
post-treatment PET for subjects who had a positive result on previous PET. 
PD 
>25% increase in the SPD of the mediastinal enlargement. At least one of the previously 
observed lesions is positive on post-treatment PET for subjects who had a positive result on 
previous PET. 
No response 
(NR) 
Failure to qualify for PR or PD. 

 
 
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8.22 Plasma Asparaginase Activity and Anti-Drug Antibodies 
8.22.1 Plasma Asparaginase Activity 
Test items: Plasma asparaginase activity 
Time points: As shown in Table 8.22.1-1 below. 
Table 8.22.1-1 Time Points for Measurement of Plasma Asparaginase Activity (SR/IR/HR) 
Time Points 
Allowance 
Remission induction therapy (IA2/IA4) 
Before the start of SHP674 administration 
One day before administration to 
15 minutes before administration 
5 minutes after the end of SHP674 
administration 
−2 to 10 minutes 
4 hours after the end of SHP674 
administration 
±10 minutes 
24 hours after the end of SHP674 
administration 
±1 hour 
48 hours after the end of SHP674 
administration 
±2 hours 
4 days after the end of SHP674 
administration 
±4 hours 
11 days after the end of SHP674 
administration 
±1 day 
14 days after the end of SHP674 
administration 
±1 day 
18 days after the end of SHP674 
administration 
±2 days 
25 days after the end of SHP674 
administration 
±2 days 
Re-induction therapy-1 (III/III+L) 
Re-induction therapy-2 (III/III+L) 
Before the start of SHP674 administration 
One day before administration to 
15 minutes before administration 
11 days after the end of SHP674 
administration 
±1 day 
14 days after the end of SHP674 
administration 
±1 day 
25 days after the end of SHP674 
administration 
±2 days 
Treatment completion, treatment 
discontinuation, or study 
discontinuation 
At treatment completion, treatment 
discontinuation, or study discontinuation 
30 (+7) days after the last dose of 
investigational product or from 7 
days before the start date of next 
therapy to before the start of the next 
therapy, whichever is earlier. 
 
Asparaginase activity will be determined using a coupled enzymatic activity assay, validated according 
to current regulatory guidelines. 
8.22.2 Anti-Drug Antibodies 
Test items: Presence or absence of the production of ADA 
Time points: As shown in Table 8.22.2-1 below. 

 
 
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Table 8.22.2-1 Time Points for Immunogenicity Measurements (SR/IR/HR) 
Time Points 
Allowance 
Remission induction therapy (IA2/IA4) 
Before the start of SHP674 administration 
One day before administration to 
15 minutes before administration 
25 days after the end of SHP674 
administration 
±2 days 
Re-induction therapy-1 (III/III+L) 
Before the start of SHP674 administration 
One day before administration to 
15 minutes before administration 
Re-induction therapy-2 (III/III+L) 
Before the start of SHP674 administration 
One day before administration to 
15 minutes before administration 
Treatment 
completion, 
treatment 
discontinuation, 
or 
study 
discontinuation 
At treatment completion, treatment 
discontinuation, or study discontinuation 
30 (+7) days after the last dose of 
investigational product or from 7 
days before the start date of next 
therapy to before the start of the next 
therapy, whichever is earlier. 
 
Immunogenicity assessments will include the detection of binding antibodies against the study drug 
(SHP674) as well as those antibodies that bind to PEG in samples taken during the study.  
 This evaluation will be based on qualitative enzyme-linked immunosorbent assays (ELISA) using 
SHP674 as coating antigen. All positive samples will be further confirmed by competitive ELISA for the 
presence of binding antibodies against SHP674. Samples, confirmed positive, will then be assayed for 
antibodies against PEG. For all these assays, antibody status (negative or positive) will be reported.  
 The antibody positive samples will be further diluted and tested, and the highest sample dilution with a 
positive result will be reported as the anti-drug antibody titer.  
 In the absence of a validated neutralizing antibody assay, the neutralizing potential of anti-drug 
antibodies in positive samples will be evaluated based on the concomitant results of the asparaginase 
activity assay. 
 All assays are validated with respect to cut-point, precision, linearity, short-term stability, freeze-thaw 
stability and drug interference. 
Figure 8.22.2-1 Flow of Immunogenicity Measurements 
 

 
 
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8.23 Number and Volume of Blood Sampling 
The number of blood sampling for tests specified for this study is at least 52. The volume of blood 
sampling will be maximum 25.4 mL per day (the volume can be determined by each investigative site 
according to the body constitution of each subject) for hematology, chemistry, coagulation test, 
immunoserological test, and viral test; and maximum 2.5 mL per sampling for the assessments of plasma 
asparaginase activity and the production of ADA. However, the number and volume of blood sampling 
may increase if retests are required. For subjects with a body weight of <5.5 kg, the time points and volume 
of blood sampling for the assessments of plasma asparaginase activity and ADA production will be 
determined in consultation with the Sponsor.  
8.24 Survival Follow-up 
The investigator or subinvestigator will follow subjects for survival at the following time point: 
Investigation items: Date of death, cause of death, causal relationship between death and investigational 
product, information on post-study treatment, presence or absence of relapse, date 
of relapse, presence or absence and date of occurrence of second malignancy 
(including myelodysplastic syndrome), date of last survival update 
Time point: 365 (±7) days after the start of SHP674 administration in remission induction therapy. 
8.25 Genetic Testing 
8.25.1 Test Item 
NUDT15 codon 139 polymorphism analysis 
8.25.2 Purpose of Testing and Relation to the Study 
NUDT15 is an enzyme involved in the metabolism of thiopurine drugs such as 6-MP that are used for 
the treatment of ALL. Patients who have the Cys/Cys homozygous genotype of the NUDT15 codon 139 
have been reported to experience serious adverse reactions (e.g., severe leukopenia and alopecia 
universalis) early after the start of treatment with thiopurine drugs such as 6-MP, because the enzyme 
activity of NUDT15 is significantly reduced in these patients.20 In consideration of the safety of subjects, 
the NUDT15 codon 139 polymorphism analysis will be conducted in this study to adjust the dose of 6-MP 
according to the genotype determined. 
8.25.3 Target Population, Time of Testing, Handling of Samples Collected 
Peripheral blood (2.0 mL) will be collected at screening from all subjects who provide consent to 
participate in the study. Since this testing has already been listed on the national health insurance coverage 
list in Japan, blood will be collected according to the procedure of each investigative site or laboratory and 
immediately tested. The Sponsor or in-country caretaker will not store blood samples collected from 
subjects or DNA samples extracted from subjects’ blood; these samples will be discarded as soon as the 
testing is completed, according to the procedure of each investigative site or laboratory. 
8.25.4 Genomic Analysis Method 
DNA will be extracted from blood collected. The NUDT15 codon 139 genotype will be determined by 
the real-time PCR method. 

 
 
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8.25.5 Anonymization of Samples 
To protect subjects’ privacy, samples will be anonymized according to the procedure of each 
investigative site and laboratory.  
8.25.6 Procedure for Obtaining Informed Consent 
An explanation about the NUDT15 codon 139 polymorphism analysis will be provided and consent for 
the analysis will be obtained, simultaneously at the time of informed consent discussion for the study. 
Since this testing will be conducted in all subjects who participate in the study, subjects who do not give 
consent for the testing cannot participate in the study. 
8.25.7 Actions to Be Taken in the Case of Consent Withdrawal 
If a subject or legally acceptable representative withdraws consent for the testing, the investigative site 
will promptly notify it to the Sponsor and take appropriate actions to discard the blood samples or 
extracted DNA samples of the subject. If the results of the NUDT15 codon 139 polymorphism analysis 
cannot be obtained from a subject because of consent withdrawal, or if a subject or legally acceptable 
representative withdraws consent for the use of analysis results after they are obtained, the subject will be 
withdrawn from the study according to Section 5.1.1 Withdrawal from the Study or Section 5.1.2 
Treatment Discontinuation. 
8.25.8 Disclosure of Genotype to Subjects 
As a general rule, information on the NUDT15 codon 139 genotype will be disclosed by the investigator 
or subinvestigator to the subject or legally acceptable representative (if the subject’s legally acceptable 
representative has given informed consent to participate in the study). The results of the NUDT15 codon 
139 polymorphism analysis will be documented on medical records and other relevant documents and 
retained. 
8.25.9 Other Points to Note 
If the genotype determined by the NUDT15 codon 139 polymorphism analysis is Cys/Cys or 
heterozygous, the dose of 6-MP should be changed according to Section 7.2.3 Criteria for Changes in 
Treatment with Each Backbone Therapy Drug. 
If it takes time to obtain the results of the analysis, the subject can be enrolled with no data at screening. 
In that case, the data must be obtained before the first dose of 6-MP. 

 
 
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9 Adverse Events 
9.1 
Definition of Adverse Events 
An adverse event (AE) is herein defined as any untoward medical occurrence in a subject after signing 
informed consent. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease, whether or not it is related to the investigational product. 
Worsening during the study of a symptom or disease already present when the subject entered the study 
(increase in frequency and/or intensity) also constitutes an adverse event. A treatment-emergent adverse 
event (TEAE) is defined as any untoward medical occurrence in a subject who received an investigational 
product which occurs during the period from Day 1 of the pre-treatment phase to 30 (+7) days after the last 
dose of investigational product, or until the start of a new therapy, whichever occurs first. A drug-related 
TEAE is defined as an AE for which a causal relationship to investigational product is assessed as “related.” 
The worsening of the primary disease (including concurrent conditions) or PS needs not to be regarded as 
a AE. 
Results of laboratory tests will be checked against the reference range at the investigative site for any 
deviations (abnormal test results). Any abnormal test results will be compared with those obtained before 
the start of study treatment to determine whether or not such a change is clinically significant (abnormal 
change). 
When any abnormal changes in signs, symptoms, or laboratory data associated with a disease 
(diagnosis) are reported, the underlying disease or diagnosis will be recorded as AEs. However, any 
individual atypical or extremely severe signs or symptoms of the disease will be regarded as independent 
AEs, separately from the diagnosis. 
Adverse events will be collected from the time of signing the informed consent to 30 (+7) days after the 
last dose of investigational product. In the screening period, any event that the investigator considers 
associated with a procedure, change or withdrawal of previous/concomitant treatment relating to the 
conditions of the protocol, or a product other than the test drug, taken as part of the protocol will be 
recorded as adverse events; all others may be recorded as past medical history.  
  
Note: Serious AEs that are deemed by the investigator to be related to investigational product or to study 
procedures or conduct may be reported irrespective of the time of onset after the end of the study. 
9.2 
Assessment Items 
The following information will be recorded on the eCRF. 
AEs will be followed up until the subject recovers to the baseline status or until the investigator or 
subinvestigator judges that no further follow-up is necessary, based on symptoms, findings, and laboratory 
data, among other conditions. Information collected during the period from informed consent to 30 (+7) 
days after the last dose of investigational product, will be entered into the eCRF. Any actions taken during 
follow-up with respect to the AE will be recorded on the eCRF. 
1) 
Reported term for the adverse event 
2) 
Start date of adverse event 
3) 
Severity (standard toxicity grade): As described in Section 9.2.1. 

 
 
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4) 
Seriousness (serious event) 
• Serious (Yes): AEs defined in Section 9.2.3. 
• Non-serious (No): AEs other than those defined in Section 9.2.3. 
5) 
Action taken for SHP674 or other investigational products 
• Dose not changed 
• Dose reduced 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 
6) 
Other action taken 
• None 
• Other drug taken/Other therapy provided 
• Other 
7) 
Outcome of adverse event 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fetal 
• Unknown 
8) 
End date of adverse event 
9) 
Relationship to SHP674 or other investigational products 
A causal relationship to investigational product will be determined according to the following 2 
categories (see Section 9.2.2). 
• Related 
• Not related 
9.2.1 
Severity Assessment 
The severity of all AEs will be determined according to CTCAE version 5.0, and the worst grade will be 
recorded: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) (preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening (Severe); 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
(bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden). 
Grade 4: Life-threatening; urgent intervention indicated. 
Grade 5: Death related to a AE (fatal) 

 
 
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9.2.2 
Assessment of Causal Relationship with Study Treatment 
A causal relationship with study treatment is categorized as either of the following: 
Related: There is a reasonable causal relationship between study treatment and an AE. 
Not related: There is no reasonable causal relationship between study treatment and an AE. 
 
Whether there is a “reasonable causal relationship” or not should be determined comprehensively by 
considering the following points: 
• 
Recurrence of the event after rechallenge: The AE occurs again when the administration of the 
investigational product is resumed after dosing or drug interruption. 
• 
No doubt: An evident causal relationship has been established. 
• 
Reasonable time of onset: Time to the onset of the AE is reasonable to explain the causal 
relationship. 
• 
Disappearance of the event after stopping administration: The AE improves or recovers after 
dosing interruption, discontinuation, or dose reduction. 
• 
No confounding risk factors: There are no other possible risk factors, and the occurrence of the 
AE can be predicted based on the pharmacological property of the investigational product. 
• 
Exposure and duration of exposure are explainable in view of the causal relationship: There is 
no contradiction between the onset of the AE and actual dose and duration of administration of 
the investigational product in view of the known mechanism of the investigational product. 
• 
Medical history is accurate enough to support the causal relationship: The subject has never 
experienced the AE before the start of study treatment. 
• 
A causal relationship can be evidently determined: A causal relationship can be evidently 
determined based on information such as results of tests specially performed, the subject’s 
background, and clinical symptoms. 
• 
No other reasonable factors: The onset of the AE cannot be reasonably explained by other 
factors such as the subject’s underlying condition, other medications, or environmental factors. 
On the other hand, no “reasonable causal relationship” between the AE and the investigational product 
is considered to be present in the following circumstances: 
• 
The AE does not meet any of the above conditions. 
• 
There is a rationale such as exposure or reasonable time course, but the AE does not resolve 
after discontinuation of the investigational product (if discontinued). 
• 
The AE may meet any of the above conditions, but there are other possible causes of the AE. 
9.2.3 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is any event defined as below. Hospitalization for screening and 
pre-planned hospitalization are not regarded as SAEs. The worsening of the primary disease (including 
concurrent conditions) or PS needs not to be regarded as an AE even if the conditions specified below are 
met. 
1) 
Death; 
2) 
Life-threatening; 
• 
An event in which the subject was at risk of death at the time of the event; not one which 
hypothetically might have caused death if it were more severe. 

 
 
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3) 
Hospitalization or prolongation of existing hospitalization; 
4) 
Persistent or significant disability/incapacity (as per reporter's opinion); 
• 
For example seriously disrupts the ability of the subject to lead a normal life, leads to a 
persistent or permanent significant change, deterioration, injury or perturbation of the subject’s 
body functions or structure, physical activity and/or quality of life. 
5) 
Congenital anomaly or birth defect; or 
6) 
Other clinically critical conditions 
• 
Any event that might not be immediately life-threatening or result in death or hospitalization, 
but might jeopardize the subject or might require intervention to prevent one of these outcomes. 
The investigator should exercise his/her scientific and medical judgement to decide whether or 
not such an event requires expedited reporting to the Sponsor. 
9.2.4 
Other Significant Adverse Events 
Other significant AEs are defined as follows: 
• 
Any non-serious AEs that lead to discontinuation of investigational product administration. 
• 
Investigational/non-investigational drug overdose.  Must notify the Sponsor immediately after 
learning of the event. 
• 
Pregnancy: Stop the study treatment immediately upon learning of the event and notify the 
sponsor immediately. 
9.3 
Actions to Be Taken for Adverse Events 
9.3.1 
Treatment of Subjects 
If an AE occurs, the investigator or subinvestigator will take appropriate actions such as providing 
adequate medical care and withdrawal from the study as needed to ensure the safety of the subject. 
9.3.2 
Emergency Safety Measures 
The investigator or subinvestigator will have a responsibility for ensuring the safety of subjects 
throughout the study procedures. An emergency safety measure is a deviation from or change to the 
protocol that needs to be conducted by the investigator or subinvestigator without prior approval by the 
IEC/IRB to avoid immediate hazards to a subject. 
The investigator or subinvestigator may take appropriate emergency safety measures to protect subjects 
from immediate hazards to health or safety. However, the investigator or subinvestigator must report 
the measures to the Sponsor or the in-country caretaker immediately after taking such measures. 
Any AEs that lead to emergency safety measures must be reported to the parties involved according to the 
reporting procedure described in Section 9.3.3. 
9.3.3 
Reporting to Parties Involved 
9.3.3.1 
Serious Adverse Event 
1) 
If a serious AE occurs, regardless of whether it is related to the investigational product or not, the 
investigator or subinvestigator will immediately (within 24 hours of first awareness of the event) 
notify the Emergency Safety Information Center or the Sponsor or in-country caretaker in person, or 

 
 
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by phone, e-mail, or fax (Serious Adverse Event Report Form [Attachment 3 to the protocol 
[supplement] or a form prescribed by the investigative site should be used). 
2) 
Within 7 days after receipt of the notice, the investigator will submit a detailed written report using 
the Serious Adverse Event Report Form (Detailed Report) to the Sponsor or in-country caretaker and 
the director of the investigative site. Serious and unexpected drug-related AEs should be identified 
when reporting to the director of the investigative site. 
3) 
The investigator will provide additional information as requested by the Sponsor or in-country 
caretaker, the director of the investigative site, or the IRB. 
4) 
The director of the investigative site will consult with the IRB whether to continue the study at the 
site. 
Emergency Contact 
Emergency Safety Information Center 
BELLSYSTEM24, Inc. 
Tel:
 Fax:
Reception hours:24 hours a day, every day of the year 
9.3.3.2 
Non-Serious Adverse Events 
If a noteworthy AE occurs, the investigator or subinvestigator will promptly provide the Sponsor or the 
in-country caretaker with a description of the event and the action taken. Any other AEs will be reported to 
the Sponsor or the in-country caretaker at appropriate times. 

 
 
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10 MANAGEMENT OF SUBJECTS 
10.1 Notification to Other Departments or Hospitals 
Before the start of study treatment, the investigator or subinvestigator will ask the subject if he or she is 
scheduled to receive medical care or medications at any other department or hospital. If the subject is 
receiving medical care or medications at other department or hospital, the investigator or subinvestigator 
will notify the treating physician that the subject will participate in the study. The investigator or 
subinvestigator will identify the name of any medication the subject has received other than those 
prescribed by the investigator or subinvestigator as well as how it has been used. 
If the subject newly receives medical care or medications at any other department or hospital during the 
study, the investigator or subinvestigator will take similar actions to the above. 
10.2 Instructions to Subjects 
The investigator, subinvestigator, or clinical research coordinator provided the following instructions to 
subjects (or their guardians). 
10.2.1 Contraception 
The investigator or subinvestigator will instruct subjects to use effective contraception from the day of 
informed consent to 6 months after the last dose of SHP674 for women of child-bearing potential and from 
the date of the first dose of SHP674 to 6 months after the last dose of SHP674 for fertile men. Effective 
contraception is defined as using any two of the following methods: condom, intrauterine contraceptive 
device, and diaphragm; or avoiding sexual intercourse. The concomitant use of SHP674 and oral 
contraceptives is not recommended since there is a potential for an indirect interaction between them. The 
investigator or subinvestigator will thoroughly explain the risks in pregnancy and the effective 
contraceptive methods to subjects. 
Subjects will be instructed to report immediately to the investigator or subinvestigator if a female 
subject or a partner of a male subject becomes pregnant during the above period. If a female subject 
becomes pregnant, the investigator or subinvestigator will immediately take appropriate measures such as 
withdrawing the subject from the study or treatment to ensure safety and will follow up until further 
observation is considered unnecessary. If a partner of a male subject becomes pregnant, necessary actions 
such as follow-up will be taken after obtaining voluntary written informed consent (the informed consent 
form will be developed elsewhere) from the partner. 

 
 
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11 Data Management 
11.1 Source Documents 
Subjects’ data will be obtained from source documents in which the data are originally recorded. Source 
documents include, but are not limited to, medical records (medical information, previous medications, 
and concomitant medications are entered in the eCRF based on medical records), clinical and office charts, 
test and pharmacy dispensing records, diaries, microfiches, X-rays, and correspondence. 
All source documents will be handled as confidential information and stored securely. In study-specific 
documents other than signed written informed assent or consent, subjects will be identified not by name 
but by a subject identifier or code. 
11.2 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
By agreeing with this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this study in accordance with all applicable rules, and regulations for privacy protection, 
including applicable provisions of the Personal Information Protection Law and their implementing 
regulations. During monitoring and auditing by the Sponsor or the in-country caretaker, the IRB/IEC’s 
review, and inspections by domestic and foreign regulatory authorities, the investigator and the 
investigative site should allow them direct access to (and copying of, if required) all study-related records 
including source documents. 
11.3 eCRF 
In this study, an electronic data capture (EDC) system will be used for data collection. The EDC system 
provides each investigative site with the functions of data entry in the eCRF, checking the input data, and 
responding to inquiries from the Sponsor or the in-country caretaker on the input data, besides the function 
of electronic signature. The entered data will be encrypted and transferred to the EDC server via the 
Internet. This EDC system is designed to meet requirements and guidelines of regulatory agencies. 
The investigator will fill out an eCRF for each subject and after ascertaining all data to be accurate and 
complete, append his or her electronic signature through the EDC system. If an eCRF is filled out by a 
subinvestigator or clinical research coordinator, the investigator will check the accuracy and completeness 
of data prior to appending his or her electronic signature. The Guide for Changes or Corrections to the 
Electronic Case Report Form provided by the Sponsor or the in-country caretaker will be followed. 
In this study, the subject data stored in the EDC server will be handled as the original eCRF. If the eCRF 
data are relocated to a non-rewritable medium (e.g., DVD), the eCRF in the medium will be handled as the 
original. If the eCRF data are relocated to an electronic document management system, the eCRF in the 
system will be handled as the original. A predefined written procedure will be followed when relocating 
the data to a non-rewritable medium or the electronic document management system. 
The Sponsor or the in-country caretaker will provide a copy of the eCRF and a copy of change or 
correction history to the investigative site. 
By agreeing with this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this study in accordance with all applicable rules and regulations for privacy protection. 

 
 
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The investigator, subinvestigator, or clinical research coordinator will change or correct entries in the 
eCRF according to the Guide for Changes or Corrections to the Electronic Case Report Form provided by 
the Sponsor or the in-country caretaker. The change or correction history to the eCRF is automatically 
recorded on the EDC system. 
11.4 Items That Allow Handling of eCRF Entries as Source Documents (Source Data) 
The following data may be directly entered into the eCRF and used as source document (source data). In 
the case that the same information is included in a medical record, the information in the medical record 
will be handled as source document (source data). 
1) 
AE term, severity, seriousness, action taken, date of outcome identification, causal relationship to 
investigational product, and comments 
2) 
Reason for use of a concomitant medication or therapy 
3) 
Date of early termination, time of early termination (only during hospitalization), reason for the early 
termination, action taken, and course of the subject’s condition after early termination 
4) 
Special notes in particular other than those above and comments from the investigator or 
subinvestigator 
11.5 QUALITY CONTROL AND QUALITY ASSURANCE OF THE STUDY 
The Sponsor or the in-country caretaker will verify, through monitoring and auditing, that the study, 
data generation, recording, and reporting are being conducted in compliance with the protocol and the 
Standards for the Implementation of Clinical Trials on Pharmaceutical Products (GCP Ordinance; 
Ministry of Health and Welfare Ordinance No. 28; 27 March, 1997). 
The management and quality assurance of data will be conducted according to the standard operating 
procedures for clinical studies and auditing of the Sponsor or the in-country caretaker. 
The monitor will check and ensure that the study is being conducted in compliance with ICH E6 
Guidelines, the protocol, and written procedures for this study and that the entries of the eCRF are 
consistent with the source document. Detailed procedures will be given in a monitoring plan document 
developed elsewhere or an alternative written procedure. 
 

 
 
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12 STATISTICAL ANALYSIS 
12.1 Statistical Methods 
Efficacy, safety, PK and immunogenicity endpoints to be analyzed and the relevant analysis methods 
are specified below. 
All analyses will be performed separately for Part 1 and Part 2 of study. Analysis of safety, PK, and 
immunogenicity will be performed by combining data from Part 1 and Part 2 (for subjects receiving the 
same dose in Part 1 as in Part 2) in addition to analyses performed separately for Part 1 and Part 2. 
Unless otherwise specified, categorical data will be summarized using frequencies and percentages, and 
continuous data will be summarized using descriptive statistics. The descriptive statistics will be the 
number of subjects, mean, standard deviation, minimum, median, and maximum. 
12.1.1 Primary Endpoint 
Part 1 
The frequencies of all TEAEs and SHP674-related TEAEs that occur or worsen during the tolerability 
assessment period will be summarized by nature of events, based on the MedDRA PTs and SOCs. A list of 
the intolerable toxicities that are observed during the tolerability assessment period will be created. 
Part 2 
The percentage of subjects who have a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) 
after the first dose of SHP674 and the corresponding 95% confidence interval will be calculated. 
12.1.2 Secondary Endpoints 
12.1.2.1 Safety 
The frequencies of all TEAEs and SHP674-related TEAEs that occur or worsen after the start of study 
treatment will be summarized by nature of events based on the MedDRA PTs and SOCs. 
All adverse events will be analyzed as follows: 
*Or until switch to next therapy 
**Applicable if concomitant investigational products are administered after completion of SHP674 treatment or any SAE related to SHP674 or 
study procedure that occurs outside of defined period end for SHP674 Treatment period 
Descriptive statistics of laboratory parameters and continuous variables of vital signs will be calculated 
for each time point. Shift tables for qualitative urinalysis results and 12-lead ECG data at baseline and at 
each time point after the start of administration will be created. 
Definition 
Period 
Period start 
Period End 
AE type 
AE 
Pre-treatment period 
Screening 
Day 1 
Pre-treatment AEs 
TEAE 
Pre SHP674 treatment 
period 
Day 1 
Day 12 (prior to first dose of 
SHP674)* 
Pre SHP674 TEAEs 
SHP674 treatment 
period 
Day 12 (first dose of 
SHP674) 
+30 days post last SHP674 
dose* 
SHP674 TEAEs 
Post SHP674 
treatment period** 
+30 days post last SHP674 
dose 
+30 (+7) days  post last dose 
of concomitant 
investigational product* 
Post SHP674 TEAEs 
AE 
Post treatment 
period 
Start day of next 
therapy 
+30 days  post last dose of 
SHP674/concomitant 
investigational product 
Post treatment 
AEs 

 
 
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12.1.2.2 PK 
The PK parameters shown in the table below will be computed from individual plasma asparaginase 
activity by noncompartmental analysis using an appropriate validated PK software. 
Cmax 
Maximum observed plasma asparaginase activity 
Tmax  
Time to maximum plasma asparaginase activity  
T1/2 
Elimination half-life.  
AUC0-t 
Area under the plasma asparaginase activity-time curve from time zero to the time of the last 
quantifiable concentration (Ct) 
AUC0-inf 
Area under the plasma asparaginase activity-time curve from time zero to infinity.  
CL 
Clearance 
Vss 
Volume of distribution at steady-state 
Descriptive statistics of plasma asparaginase activity and PK parameters (mean, SD, median and [min, 
max]) will be performed. Plasma asparaginase activity over time will be plotted. This will be performed by 
a pharmacokineticist. 
12.1.2.3 Immunogenicity 
Immunogenicity assessments will include the detection of binding antibodies against the study drug 
(SHP674) as well as those antibodies that bind to PEG in samples taken during the study.  
Considering the low number of subjects and the anticipated low rate of seroconversion, results will be 
reported as follows:  
• 
Pre-existing anti-drug or anti-PEG antibodies: Number of samples confirmed positive at 
baseline versus total number of baseline samples. If the predose sample at induction is missing, 
the baseline sample status will be considered negative.  
• 
Seroconversion upon treatment: Number of samples converted from negative at baseline to 
positive after treatment. 
If a confirmed positive sample at baseline has titer increase after treatment by more than 4-fold then it 
will be included within the seroconverters. 
• 
Persistence of anti-drug or anti-PEG antibodies will be evaluated based on consecutive results 
after treatment. 
 On a case by case approach, the impact of anti-drug and anti-PEG antibodies positive status will be 
investigated: 
• 
on the pharmacokinetics through the temporal association of antibodies with the loss of 
asparaginase activity. 
• 
on the safety through the potential relationships with treatment–emergent hypersensitivity and 
anaphylactic reactions. 
12.1.2.4 Efficacy 
The percentage of subjects with a plasma asparaginase activity of ≥0.1 IU/mL or <0.1 IU/mL at each 
time point will be calculated. 
The overall survival rate and the event-free survival rate (EFS) at 1 year after the start of study treatment 
will be calculated. Event-free survival is defined as time from the first dose of SHP674 to the date of 
induction failure, documented relapse, diagnosis of a second malignant neoplasm (including 
myelodysplastic syndrome), or death from any cause, whichever comes first. In the absence of a 
documented EFS event as defined above, EFS is to be censored on the date of last evaluation.  

 
 
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12.2 Target Sample Size 
Part 1: 3 to 6 evaluable subjects 
Part 2: 22 subjects 
12.2.1 Rationale for Target Sample Size 
Leukemia is the most common pediatric malignancy. ALL is the most common type (46.6%) of acute 
leukemia in childhood,1,2 and 500 children are newly diagnosed with ALL each year in Japan.2 
Precursor B-cell ALL, which is the target disease of this study, accounts for 85.6% of all pediatric ALL. 
Therefore, the number of patients in the target population of this study is estimated to be approximately 
428 per year. The target sample size for Part 2 of the study has been set at 22, based on the estimated 
number of subjects who meet the eligibility criteria in the protocol, study feasibility, information on 
subject accrual provided by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), limited 
number of investigative sites, and the rate of informed consent. 
The appropriateness of setting the target sample size at 22 was determined based on the percentage of 
subjects who achieve a plasma asparaginase activity of ≥0.1 IU/mL 14 days (336 hours) after the first dose 
of SHP674, which is the expected level in this study, and the corresponding 95% confidence interval. The 
percentages of subjects with a plasma asparaginase activity of 0.1 IU/mL and the corresponding exact 95% 
confidence intervals in clinical studies of SHP674 conducted outside Japan were 100.0% (50/50 subjects) 
(95% CI: 92.9%, 100.0%) in Study AALL07P4, 93.8% (45/48 subjects) (95% CI: 82.8%, 98.7%) in Study 
CCG-1962, and 98.2% (111/113 subjects) (95% CI: 92.9%, 100.0%) in Study DFCI 11-001. On the basis 
of these results, the percentage of subjects achieving a plasma asparaginase activity of ≥0.1 IU/mL 14 days 
(336 hours) after the first dose of SHP674, the expected level in this study, was estimated to be around 90%. 
If the expected percentage is 90.9% (20/22 subjects) in this study, a target sample size of 22 would provide 
an exact 95% confidence interval of 70.8% to 98.9%. 
Since this is the first study of SHP674 in Japanese patients, 3 to 6 subjects will be enrolled in Part 1 of 
the study for tolerability assessment, separately from the above 22 subjects. 
12.3 Criteria for Premature Termination of the Entire Study 
No criteria for premature termination of the study based on a statistical rationale will be specified. 
12.4 Handling of Missing, Unused, and Abnormal Data 
If any of the data described in Section 12.1 are missing, the missing data will not be imputed by a 
specific statistical method unless otherwise specified. 
12.5 Development of Statistical Analysis Plan and Procedure for Reporting Deviations 
from the Original Statistical Analysis Plan 
 The statistical analysis plan (SAP) will be prepared prior to first patient enrolled and any subsequent 
amendments will be documented, with final amendments completed prior to CRF database lock at the end 
of remission induction therapy. 

 
 
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12.6 Selection of Subjects to be Included in Analyses 
The following sets are defined as analysis sets.  
12.6.1 All Enrolled Set 
The all Enrolled set will consist of all patients who have provided informed consent in the study. 
12.6.2 Safety Analysis Set 
The safety analysis set is defined as the set of all subjects who have received at least one dose of SHP674  
in Part 1 or Part 2 of study. The safety endpoints will be analyzed in the safety analysis set. 
All safety analyses will be performed separately for Part 1 and Part 2 of study as well as for the 
combination of Parts 1 and 2 resulting in all patients dosed in the study. 
Descriptive analyses on efficacy endpoints in the Part 1 will be based on the safety analysis set . 
12.6.3  Full Analysis Set (FAS) 
The full analysis set (FAS) is defined as a set of all subjects who are enrolled and receive SHP674 in Part 
2 of study. All efficacy analyses (including primary analysis) in Part 2 will be based on the Full Analysis 
Set.  
12.6.4 Immunogenicity Analysis Set 
The immunogenicity analysis set is defined as the set of all subjects who have received at least one dose 
of SHP674  in Part 1 or Part 2 of study and have at least one evaluable post-dose sample. In the case of 
immunogenicity if the pre-dose sample is missing it will be considered negative. 
All immunogenicity analyses will be performed separately for Part 1 and Part 2 of study as well as for 
the combination of Parts 1 and 2 resulting in all patients dosed in the study. 
12.6.5 PK Analysis Set 
The PK analysis set is defined as all subjects enrolled in Part 1 or Part 2 who have received first dose of 
SHP674 at remission induction therapy and are evaluable for non-compartmental analysis. The PK 
analysis set will include only the subjects who had sufficient samples collected to provide interpretable PK 
results with no deviations that might have affected the PK interpretation. 
12.7 Data Cut Off 
A snapshot of  data will be taken for analysis of all available endpoints after all subjects completed 
remission induction therapy. The primary analysis of the study will be performed after all patients 
complete remission induction therapy. The clinical study report (CSR) will be based off of the data from 
the period of remission induction phase.  
 Data from subsequent treatment periods in the study will be part of the final analysis that will be 
performed at the time of completion of study, which will occur 365 (±7) days after the first dose of 
SHP674 in the last subject or at the time when all subjects complete the study.  

 
 
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13 ETHICAL CONSIDERATIONS 
13.1 Compliance with GCP and the Protocol 
This study will be conducted based on the principles described in the Declaration of Helsinki and in 
compliance with the Pharmaceuticals and Medical Devices Act, “Standards for the Implementation of 
Clinical Trials on Pharmaceutical Products” (Ministry of Health and Welfare Ordinance No. 28; 27 March, 
1997) and the partial revision of the Ordinance, the Personal Data Protection Law, “Guidelines on 
Genomic Sampling and Management of Genomic Data” (Notification No. 0118-1 of the Pharmaceutical 
Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, 
Labour and Welfare; 18 January, 2018), “Studies Utilizing Pharmacogenomics” (Notification No. 
0930007 of the Evaluation and Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry 
of Health and Welfare; 30 September, 2008), “Ethical Guidelines for Medical and Health Research 
Involving Human Subjects” (Ministry of Education, Culture, Sports, Science and Technology, Ministry of 
Health, Labour and Welfare, and Ministry of Economy, Trade and Industry; 25 November, 2014 [partial 
revision]), and “Points to Consider in Collecting Genomic Samples in Clinical Studies for Drug 
Development” (Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association; April 
2018). 
13.2 IRB 
13.2.1 Review of the Propriety of Conducting the Study 
This study will not be initiated without review and approval of the protocol, informed consent form, and 
appropriateness of conducting the study from the viewpoint of ethical, scientific, and medical 
appropriateness by the IRB consulted by the director of each investigative site. 
13.2.2 Follow-up Review 
The investigator will submit a brief summary of the actual status of the study in writing to the director of 
the investigative site for review at least once a year or upon request from the IRB. 
13.3 Selection of Subjects to be Enrolled in the Study and Assurance of Their Safety 
In order to protect the human rights of subjects, the investigator or subinvestigator must carefully 
examine the appropriateness of participating in the study for each subject. For example, individuals who 
may be put at a disadvantage in the case of refusal to participate (socially vulnerable people) should not be 
enrolled in the study. 
The investigator or subinvestigator will determine whether each subject is eligible for enrollment based 
on the inclusion and exclusion criteria to ensure that the study will not include any subjects whose safety 
cannot be ensured. 
Throughout the study, the investigator or subinvestigator will keep track of subjects’ conditions by 
ensuring emergency contact or any other method and will collect and share safety information that may be 
relevant to investigational product. If a AE occurs, the investigator or subinvestigator will ensure the safety 
of the subject by taking such measures as providing appropriate treatment to the subject and if necessary, 
discontinuing investigational product. 

 
 
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13.4 Protection of Subjects’ Personal Information and Privacy 
In filling out the eCRF, the investigator or subinvestigator will identify each subject with his or her 
subject identification code to ensure that the subject’s personal information is properly protected. 
Individuals who belong to the units of the Sponsor or the in-country caretaker that are involved in the 
study must not disclose, without a valid reason, confidential information on a subject to which they have 
access in the performance of their duties. 
13.5 Informed Consent 
The investigator or subinvestigator will fully explain the nature of the study to each potential subject  (or 
his or her legally acceptable representative) before their participation in the study in a language 
understandable for them, based on the Information for Subjects/Informed Consent Form (ICF) provided 
elsewhere. A legally acceptable representative of a subject <20 years must be a person in parental authority 
or a guardian of a minor. The subject (or his or her legally acceptable representative) will be given 
sufficient time to decide whether or not to participate in the study, and the investigator or subinvestigator 
will obtain written consent (using the ICF developed elsewhere) from the subject (or his or her legally 
acceptable representative) on a voluntary basis before the screening examinations. 
The ICF will be personally signed and dated by the subject and then by the investigator or 
subinvestigator who has conducted the informed consent discussion. 
If the clinical research coordinator gives supplemental explanation, he or she will also sign and date the 
informed consent form. If the subject is unable to sign because of handwriting difficulties, oral consent will 
be obtained from the subject and written consent will be obtained from the subject’s legally acceptable 
representative. In such a case, the following will be recorded in informed consent: date of written consent 
by the subject’s legally acceptable representative, his/her relationship to the subject, reason for the 
subject’s legally acceptable representative giving written consent (handwriting difficulties), and date of 
oral consent by the subject. 
13.5.1 Informed Consent (Assent) for Subjects (Pediatric Patients) 
Before enrollment in the study, the investigator or subinvestigator will explain a candidate pediatric 
subject the nature of the study to the extent that he or she can understand, based on the Information for 
Subjects/ICF (for Assent) developed elsewhere. In addition to this, the clinical research coordinator may 
also give a supplemental explanation regarding the study. Pediatric patients who have the ability to provide 
assent will be given sufficient time to consider whether to participate in the study. After that, the 
investigator or subinvestigator will obtain assent (consent given by a pediatric subject, which is not legally 
required) for participation in the study from the candidate subject on a voluntary basis before the start of 
screening. 
If oral assent is obtained from the subject, obtainment of oral assent will be recorded on the informed 
consent form (ICF) signed by the subject’s legally acceptable representative. 
If written assent is obtained from the subject, the ICF will be personally signed and dated by the 
investigator or subinvestigator who has conducted the informed consent discussion and by the subject. If 
the clinical research coordinator gives supplemental explanation, he or she will also sign and date the ICF. 

 
 
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13.5.2 Points to Note regarding Section 13.5 and Section 13.5.1 
The investigator or subinvestigator will provide the subject (or the subject’s legally acceptable 
representative) with a copy of the ICF for the subject’s records and the Information for Subjects. The 
investigator or subinvestigator will retain the original ICF for storage at the investigative site according to 
the policy of each institution. 
The Information for Subjects/ICF must include information required by the GCP guidelines and the 
applicable laws and regulations. 
Whenever any new information that may influence the subject’s willingness to continue participation in 
the study becomes available, the investigator or subinvestigator will promptly update the subject to 
confirm his or her willingness to continue in the study, and enter the details of the explanation given, date 
of the explanation, name of the person who indicated the subject’s decision, and a description of the 
subject’s decision in the medical records. 
If the investigator determines that the Information for Subjects/ICF needs to be updated to include the 
explanation given to subjects, the investigator will promptly revise it and gain the IRB/IEC’s approval. 
Subsequently, the investigator or subinvestigator will conduct the informed consent discussion again using 
the new Information for Subjects/ICF and obtain written consent to continue in the study from the subjects 
(or their legally acceptable representative) through the same procedure as for the initial consent If possible, 
informed assent should also be obtained from the subject in person. 
If a subject who was a minor (<20 years) at the time of informed consent (assent) comes of age (20 
years) during the study, first-person informed consent must be newly obtained from the subject. 
13.5.3 Information for Subjects/Informed Consent Form 
The written information provided to subjects and the ICF should include explanation of the following: 
1) 
That the study involves research; 
2) 
Study objectives 
3) 
Name, title, and contact information of the investigator; 
4) 
Study method; 
5) 
Expected beneficial effects of investigational product on the subject’s mental and physical health 
(when there is no such benefit to the subject, the subject should be made aware of this) and expected 
hazards or inconveniences to the subject; 
6) 
The alternative procedure(s) or course(s) of treatment; 
7) 
The expected duration of the subject’s participation in the study; 
8) 
That the subject is allowed to withdraw from the study at any time; 
9) 
That the subject may refuse or withdraw from the study without penalty or loss of benefits to which 
the subject is otherwise entitled; 
10) 
That the monitors, the auditors, the IRB of the investigative site, and other relevant parties will be 
granted direct access to the source documents, without violating the confidentiality of the subject; 
11) 
That the subject’s identity will remain confidential; 
12) 
Contact information of the person(s) at the investigative site to contact in the event of study-related 
health injury; 
13) 
That necessary treatment will be provided to the subject in the event of study-related health injury; 
14) 
The compensation available to the subject in the event of study-related injury; 

 
 
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15) 
The types of the IRBs that will investigate and review the propriety of the study and others, issues to 
be investigated and reviewed at each IRB, and other matters related to the IRBs involved in the study; 
16) 
The anticipated expenses, if any, to the subject for participating in the study; and 
17) 
Other relevant information related to the study. 
 
Neither of the following should be included in the Information for Subjects/ICF: 
1) 
Words and phrases that expressly or impliedly, make potential subjects waive their rights; and 
2) 
Words and phrases that expressly or impliedly, discharge the Sponsor, investigative site, investigator, 
or subinvestigator from any liability that they may have, or reduce such liability. 
The explanation about the genetic testing (NUDT15 codon 139 polymorphism analysis in this study) 
should include the following information: 
1) 
Purpose of the testing; 
2) 
Relation of the testing to the study; 
3) 
Subjects targeted; 
4) 
That the NUDT15 codon 139 polymorphism analysis is essential for this study and subjects who do 
not give consent for the testing cannot participate in the study; 
5) 
Time and method of the NUDT15 codon 139 polymorphism analysis; 
6) 
Time of and procedures for storage and disposal of samples for the NUDT15 codon 139 
polymorphism analysis; 
7) 
Measures taken to protect personal information; 
8) 
Benefits, disadvantages, and burdens associated with the subject’s giving consent for the testing; 
9) 
Withdrawal of consent: 
• That the subject is allowed to withdraw his or her consent at any time. 
• That the samples collected from the subject will be discarded immediately after consent 
withdrawal but data obtained before consent withdrawal will not be discarded. 
• That the subject will be withdrawn from the study if he or she withdraws consent for the 
testing. 
10) 
That the monitors, the auditors, the IRB of the investigative site, and regulatory authorities will be 
granted direct access to source documents including analysis results; 
11) 
Publication of analysis results; and 
12) 
Rights arising from obtaining the analysis results. 
 
13.6 Audit and Inspection 
The Sponsor or in-country caretaker or regulatory authorities can inspect the investigative site according 
to the ICH E6 Guidelines. The Sponsor or the in-country caretaker will verify, through monitoring and 
auditing, that the study, data generation, recording, and reporting are being conducted in compliance with 
the protocol and ICH E6-GCP. The Quality Assurance Unit of the Sponsor or the in-country caretaker, 
which is independent of the Clinical Development Department, will be responsible for inspecting the 
study. 
The investigator must accept that regulatory authorities may conduct an inspection to verify compliance 
of the study with GCP. 

 
 
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The management and quality assurance of data will be conducted according to the standard operating 
procedures (SOPs) for clinical studies and auditing of the Sponsor or the in-country caretaker. 
13.7 Expenses Related to the Study 
The details of the expenses for all examinations and imaging tests conducted during the study treatment 
period and the medication or injection of pharmaceutical products with the indication similar to that 
expected for the test drug will be specified in the clinical study agreement. 
13.8 Expenses for Reducing the Burden to Subjects Resulting from Participation in 
the Study 
In order to reduce the burden to subjects resulting from participation in the study, the Sponsor or the 
in-country caretaker will bear the compensation or reimbursements for incurred expenses to the subjects 
through the relevant investigative sites, in accordance with the applicable rules of each investigative site. 
13.9 Compensation for Health Injury 
In the event of any study-related disease or health injury in a subject, appropriate therapeutic measures 
will be taken in accordance with the clauses on compensation in the Information for Subjects/ICF or the 
Clinical Trial Agreement. An information leaflet containing essential information about the compensation 
will be attached to the Information for Subjects/ICF. 
Basic Policy on Compensation for Health Injury 
1) 
In the event of any study-related health injury in a subject, the investigator or subinvestigator will 
take necessary measures, including appropriate treatment. 
2) 
If any study-related health injury occurs to a subject and if any dispute with the subject and others 
arises or may arise, the investigative site should immediately notify the Sponsor or the in-country 
caretaker, and the two (or three) parties will cooperate to settle the dispute. 
3) 
If liability for damages arises out of a study-related health injury, the Sponsor will reimburse the 
investigative site for all of the compensation and settlement expenses incurred by it, unless the 
investigative site is responsible for the health injury. 
4) 
If compensation liability arises out of a study-related health injury in a subject, the Sponsor will incur 
the compensation liability. For medical expenses required for treatment, the Sponsor will 
compensate for the subject’s out-of-pocket medical expenses, excluding benefits paid by health 
insurance or other sources. 
5) 
The compensation liability described above will be incurred according to the compensation rules 
specified by the Sponsor or the in-country caretaker. 
13.10 Publication Policy 
The investigator or subinvestigator must obtain prior agreement from the Sponsor before publishing 
data derived from this study in an academic conference, journal, or other media. The detailed publication 
policy of the Sponsor is described in the clinical study agreement. 

 
 
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14 PROTOCOL COMPLIANCE, DEVIATIONS OR CHANGES, AND 
AMENDMENTS 
14.1 Compliance with the Protocol 
The investigator or subinvestigator will comply with the protocol on which the investigator and the 
Sponsor or in-country caretaker have agreed and which has been approved in writing by the IRB consulted 
by the director of the investigative site. 
14.2 Deviations from or Changes to the Protocol 
The investigator or subinvestigator must not deviate from or make changes to the protocol unless 
obtaining the prior written agreement of the Sponsor or the in-country caretaker and the written approval of 
the IRB based on its prior review. In the event of a deviation from or change to the protocol, the 
investigator or subinvestigator will make a record of all of the relevant actions regardless of the reason. 
For medical reasons such as the need to eliminate immediate hazards to the subject, the investigator or 
subinvestigator may deviate from or make changes to the protocol without the prior written agreement of 
the Sponsor or the in-country caretaker or the prior written approval of the IRB. In such a case, the 
investigator should immediately submit a document describing the nature of and reason for the deviation 
or change to the Sponsor or in-country caretaker and the director of the investigative site. The investigator 
will also submit the document to the IRB via the director of the investigative site for its approval, and in 
addition, will obtain the written consent of the director of the investigative site and the written agreement 
of the Sponsor or the in-country caretaker. 
The investigator should submit, as soon as possible, a description of the deviation or change, the reason, 
and if appropriate, a proposed amendment to the protocol to the Sponsor or in-country caretaker, the 
director of the investigative site, and the IRB (via the director of the investigative site) for their approval. 
The written consent of the director of the investigative site and the written agreement of the Sponsor or the 
in-country caretaker should also be obtained. 
14.3 Protocol Amendments 
When the Sponsor amends the protocol, the Sponsor or the in-country caretaker will fully inform each 
investigator using the amended version of the protocol or a written description of the amendment to obtain 
their agreement. The investigator will conduct the study according to the amended protocol after receiving 
the written approval of the IRB based on its prior review. However, this does not apply to amendments that 
only involve administrative issues (e.g., changes in affiliation, job title, address, and telephone number). 
15 STUDY COMPLETION 
Upon completion of the protocol-specified dosing and observations of all subjects at the investigative 
site, the investigator will report the study completion and outlined study results to the director of the 
investigative site in writing. 
The director of the investigative site will immediately notify the IRB and the Sponsor or in-country 
caretaker of study completion in writing and at the same time, report the outlined study results based on the 
report provided by the investigator. 

 
 
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16 RECORD KEEPING 
The investigative site, IRB, and the Sponsor or in-country caretaker will retain records related to the 
study and subjects’ medical records until either of the following dates whichever comes later. Further 
handling of the records will be discussed between the study director and the Sponsor or in-country 
caretaker. 
• 
The date of the marketing authorization granted for SHP674 (or, in the case of development 
discontinuation, the date that is 3 years after the date of decision of development discontinuation 
or the date of being notified of the discontinuation). However, the Sponsor or the in-country 
caretaker must retain the records until the date of reexamination completion if the drug requires 
post-approval reexamination according to the provisions of the Pharmaceuticals and Medical 
Devices Act and if the period to complete the reexamination is more than 5 years. 
• 
The date that is 3 years after the premature termination of the study. 
When further retention of the records becomes impossible, the investigative site must notify the Sponsor 
or the in-country caretaker and move the relevant records to a mutually agreed place. 
The investigator will retain the relevant documents or records related to the study according to the 
instructions of the director of the investigative site. 
16.1 Retention of Source Documents Related to Plasma Asparaginase Activity  
Source documents related to plasma asparaginase activity measurement will be retained at the analytical 
laboratory. The retention period will be until either of the following dates, whichever comes later. Further 
handling of the documents will be discussed between the study director and the Sponsor or in-country 
caretaker. 
• 
The date that is 5 years after the date of the marketing authorization granted for SHP674 (or, in 
the case of development discontinuation, the date that is 3 years after the date of being notified of 
the discontinuation). In this regard, however, the date of reexamination completion will be 
applied if the drug requires post-approval reexamination according to the provisions of the 
Pharmaceuticals and Medical Devices Act and if the period to complete the reexamination is 
more than 5 years. 
• 
The date that is 3 years after the premature termination of the study. 
16.2 Retentions of Source Documents Related to Laboratory and Other Tests 
 The retention period will be until either of the following dates, whichever comes later. Further handling 
of the documents will be discussed between the study director and the Sponsor or in-country caretaker. 
• 
The date that is 5 years after the date of the marketing authorization granted for SHP674 (or, in 
the case of development discontinuation, the date that is 3 years after the date of being notified of 
the discontinuation). In this regard, however, the date of reexamination completion will be 
applied if the drug requires post-approval reexamination according to the provisions of the 
Pharmaceuticals and Medical Devices Act and if the period to complete the reexamination is 
more than 5 years. 
• 
The date that is 3 years after the premature termination of the study. 

 
 
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16.3 Biological Sample Archiving 
Blood samples derived from subjects who provide consent for the storage and use of samples for 
research will be stored until the time of marketing approval of SHP674, the test drug for this study, in 
Japan or the time of completion of the final clinical study report for this study, whichever comes later. The 
samples will then be discarded after being treated appropriately so that they cannot be used by others for 
other research. 
17 STUDY ADMINISTRATIVE STRUCTURE 
See Attachment 1 to the protocol (supplement). 
18 MAIN RESPONSIBILITIES OF THE INVESTIGATOR 
See Attachment 2 to the protocol (supplement). 

 
 
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19 REFRENCES 
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14. Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, et al. Early postinduction 
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