Conditions: High-risk Neuroblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This was an open-label, multi-center, single-arm, Phase 1 study. The purpose of this study was for evaluating the safety and pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese participants with high-risk neuroblastoma

Detailed description:

Arms:
arm 1: The study recruited participants who were hospitalized (with full resuscitation equipment) on Day 1 of each cycle and received continuous infusion of dinutuximab beta for 10 consecutive days in 35-day cycles. Participants could be discharged from the hospital at the investigator's discretion. Participants continued to receive 13-cis-retinoic acid orally for 14 days after completion of dinutuximab beta infusion (day 12-25 in each cycle).

Interventions: intervention 1: Dinutuximab Beta intervention 2: 13-cis-Retinoic Acid
Intervention descriptions: intervention 1: Dinutuximab beta was administered intravenously at a dosage of 10 milligrams/ meters squared (mg/m2) per day for 10 consecutive days intervention 2: 13-cis-Retinoic Acid was administered orally at a daily total dose of 160 mg/m2, divided into approximately two equal doses given twice daily for 14 days following the conclusion of dinutuximab beta infusion.

Protocol document:
Prot_000.pdf: 
BGB-dinutuximab beta-101 
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Page 1 
CLINICAL STUDY PROTOCOL 
TITLE PAGE  
Protocol Title:  
An Open-Label, Multi-Center, Single-Arm, Phase 1 Study 
Evaluating the Safety and Pharmacokinetics of Dinutuximab Beta 
as Maintenance Therapy in Chinese Patients with High-Risk 
Neuroblastoma 
Protocol Number: 
 
BGB-dinutuximab beta-101 
Phase: 
1 
Investigational Products: 
Dinutuximab beta (BGB-dinutuximab beta), 13-Cis-Retinoic Acid 
IND Number: 
EUDRACT Number: 
Not applicable 
Not applicable 
Proposed Indication(s): 
High-risk neuroblastoma  
Sponsor: 
BeiGene (Beijing) Co., Ltd. 
Room 101, 201, 402, 502, Building 1, No. 30 Science Park Road 
Zhong-Guan-Cun Life Science Park 
Changping District 
Beijing, 102206  
China  
Sponsor Medical Monitor: 
 
Telephone:
 
Email: 
 
 
Original Protocol Version 0.0: 15 June 2020 
Protocol Amendment 1.0: 
09 June 2023 
 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries. This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries. Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries. 
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FINAL PROTOCOL APPROVAL SHEET  
An Open-Label, Multi-Center, Single-Arm, Phase 1 Study Evaluating the Safety and 
Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients with High-
Risk Neuroblastoma 
BeiGene, Ltd., Approval: 
 
 
 
 
(See electronic signature)                         _ 
Sponsor Medical Monitor 
 
 
 
 
(See electronic signature) ______________ 
Date 
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INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
An Open-Label, Multi-Center, Single-Arm, Phase 1 Study Evaluating 
the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance 
Therapy in Chinese Patients With High-Risk Neuroblastoma 
Protocol Identifier: 
BGB-dinutuximab beta-101 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name 
and address of the center in which the study will be conducted. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
LIST OF ABBREVIATIONS AND TERMS ................................................................................12 
1. 
INTRODUCTION AND RATIONALE .....................................................................13 
1.1. 
Neuroblastoma ............................................................................................................13 
1.2. 
Dinutuximab Beta .......................................................................................................14 
1.2.1. 
Nonclinical Data for Dinutuximab Beta .....................................................................14 
1.2.2. 
Clinical Pharmacology ................................................................................................15 
1.2.3. 
Preliminary Efficacy and Safety Data With Dinutuximab beta ..................................15 
1.3. 
Study Rationale ...........................................................................................................17 
1.3.1. 
Rationale for Selection of Dose ..................................................................................17 
1.4. 
Benefit-Risk Assessment ............................................................................................17 
1.5. 
Study Conduct ............................................................................................................18 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................19 
3. 
STUDY DESIGN .......................................................................................................20 
3.1. 
Summary of Study Design ..........................................................................................20 
4. 
STUDY POPULATION .............................................................................................22 
4.1. 
Inclusion Criteria ........................................................................................................22 
4.2. 
Exclusion Criteria .......................................................................................................23 
5. 
STUDY TREATMENT ..............................................................................................24 
5.1. 
Formulation, Packaging, and Handling ......................................................................24 
5.1.1. 
Dinutuximab Beta .......................................................................................................24 
5.1.2. 
13-cis-retinoic acid .....................................................................................................24 
5.2. 
Dosage, Administration, and Compliance ..................................................................24 
5.2.1. 
Dinutuximab Beta .......................................................................................................25 
5.2.2. 
13-cis-retinoic acid .....................................................................................................26 
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5.3. 
Overdose .....................................................................................................................26 
5.4. 
Dose Delay or Modification .......................................................................................26 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................28 
6.1. 
Premedication .............................................................................................................28 
6.2. 
Continuous Morphine Infusion Schedule ...................................................................28 
6.3. 
Prohibited Concomitant Medications .........................................................................29 
6.4. 
Medications to Be Used With Caution .......................................................................30 
7. 
STUDY PERIODS, VISITS, OR PROCEDURES ....................................................31 
7.1. 
Screening Period .........................................................................................................31 
7.1.1. 
Informed Consent and Screening Log ........................................................................31 
7.2. 
Enrollment ..................................................................................................................31 
7.3. 
Treatment Period ........................................................................................................31 
7.4. 
End-of-Treatment Visit ...............................................................................................33 
7.5. 
Follow-up Periods .......................................................................................................33 
7.5.1. 
Safety Follow-up Period .............................................................................................33 
7.5.2. 
Loss to Follow-up .......................................................................................................34 
7.6. 
Discontinuation From Study Treatment or From the Study .......................................34 
7.6.1. 
Patient Discontinuation From Study Treatment (End of Treatment for an 
Individual Patient) ......................................................................................................34 
7.6.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ........................................................................................................................35 
7.7. 
End of Study ...............................................................................................................35 
8. 
STUDY ASSESSMENTS ..........................................................................................36 
8.1. 
Screening Assessments ...............................................................................................36 
8.1.1. 
Oxygen-Saturation measurement ................................................................................36 
8.2. 
Safety Assessments .....................................................................................................36 
8.2.1. 
Vital Signs ..................................................................................................................36 
8.2.2. 
Physical Examinations ................................................................................................36 
8.2.3. 
Ophthalmologic Examination .....................................................................................37 
8.2.4. 
Performance Status .....................................................................................................37 
8.2.5. 
Laboratory Safety Tests ..............................................................................................37 
8.2.6. 
Echocardiography/Multigated Acquisition Scan ........................................................38 
8.2.7. 
Electrocardiograms .....................................................................................................38 
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8.2.8. 
Adverse Events ...........................................................................................................38 
8.3. 
Pharmacokinetic Assessment ......................................................................................38 
8.4. 
Tumor and Response Evaluations ..............................................................................39 
8.5. 
Biomarkers ..................................................................................................................39 
8.6. 
Visit Windows ............................................................................................................39 
8.7. 
Unscheduled Visits .....................................................................................................39 
9. 
SAFETY MONITORING AND REPORTING .........................................................41 
9.1. 
General Plan to Manage Safety Concerns ..................................................................41 
9.1.1. 
Eligibility Criteria .......................................................................................................41 
9.1.2. 
Abnormal Liver Function Tests ..................................................................................41 
9.1.3. 
Safety Monitoring Plan ...............................................................................................41 
9.2. 
Adverse Events ...........................................................................................................42 
9.2.1. 
Definitions and Reporting ...........................................................................................42 
9.2.2. 
Assessment of Severity ...............................................................................................42 
9.2.3. 
Assessment of Causality .............................................................................................43 
9.2.4. 
Follow-up of Adverse Events .....................................................................................43 
9.2.5. 
Laboratory Test Abnormalities ...................................................................................44 
9.3. 
Definition of a Serious Adverse Event .......................................................................45 
9.4. 
Suspected Unexpected Serious Adverse Reaction .....................................................45 
9.5. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................46 
9.5.1. 
Adverse Event Recording Period ................................................................................46 
9.5.2. 
Reporting Serious Adverse Events .............................................................................46 
9.5.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................46 
9.5.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................47 
9.5.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................47 
9.5.3. 
Eliciting Adverse Events ............................................................................................47 
9.5.4. 
Progressive Disease ....................................................................................................48 
9.5.5. 
Deaths .........................................................................................................................48 
9.5.6. 
Recording Pregnancies ...............................................................................................48 
9.5.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................48 
9.5.8. 
Recording Infusion-Related Reactions .......................................................................49 
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9.6. 
Risks Associated With Dinutuximab Beta .................................................................49 
10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................51 
10.1. 
Statistical Analysis ......................................................................................................51 
10.1.1. 
General Consideration ................................................................................................51 
10.1.2. 
Analysis Sets ...............................................................................................................51 
10.1.3. 
Patient Disposition ......................................................................................................51 
10.1.4. 
Demographic and Other Baseline Characteristics ......................................................52 
10.1.5. 
Prior and Concomitant Medications ...........................................................................52 
10.2. 
Safety Analyses ..........................................................................................................52 
10.2.1. 
Extent of Exposure .....................................................................................................52 
10.2.2. 
Adverse Events ...........................................................................................................53 
10.2.3. 
Laboratory Analyses ...................................................................................................53 
10.2.4. 
Vital Signs ..................................................................................................................53 
10.2.5. 
Ophthalmologic Examination .....................................................................................53 
10.2.6. 
Physical Examinations ................................................................................................54 
10.3. 
Pharmacokinetic Analyses ..........................................................................................54 
10.4. 
Exploratory Efficacy Analyses ...................................................................................54 
10.5. 
Other Exploratory Analyses .......................................................................................54 
10.6. 
Sample Size Consideration .........................................................................................54 
10.7. 
Interim Analyses .........................................................................................................55 
11. 
STUDY COMMITTEES ............................................................................................56 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................57 
12.1. 
Access to Information for Monitoring ........................................................................57 
12.2. 
Access to Information for Auditing or Inspections ....................................................57 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................58 
13.1. 
Regulatory Authority Approval ..................................................................................58 
13.2. 
Quality Assurance .......................................................................................................58 
13.3. 
Study Site Inspections.................................................................................................58 
13.4. 
Drug Accountability ...................................................................................................58 
14. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................60 
14.1. 
Ethical Standard ..........................................................................................................60 
14.2. 
Institutional Review Board/Independent Ethics Committee ......................................60 
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14.2.1. 
Protocol Amendments ................................................................................................60 
14.3. 
Informed Consent .......................................................................................................61 
14.4. 
Patient and Data Confidentiality .................................................................................61 
14.5. 
Financial Disclosure ...................................................................................................63 
15. 
DATA HANDLING AND RECORD KEEPING ......................................................64 
15.1. 
Data Collection and Management Responsibilities ....................................................64 
15.1.1. 
Data Entry in the Electronic Case Report Form .........................................................64 
15.1.2. 
Data Collection ...........................................................................................................64 
15.1.3. 
Data Management/Coding ..........................................................................................64 
15.2. 
Study Records Retention ............................................................................................65 
15.3. 
Protocol Deviations ....................................................................................................66 
15.4. 
Study Report and Publications....................................................................................66 
15.5. 
Study and Study Center Closure .................................................................................66 
15.6. 
Information Disclosure and Inventions ......................................................................67 
16. 
REFERENCES ...........................................................................................................69 
17. 
APPENDICES ............................................................................................................71 
 
LIST OF TABLES  
Table 1: 
Efficacy of Dinutuximab Beta in Clinical Studies in European Patients ...................15 
Table 2: 
Dinutuximab Beta Formulation ..................................................................................24 
Table 3: 
Recommended Dinutuximab Beta Dose Modification ...............................................26 
Table 4: 
Dinutuximab Beta PK Sampling Schedule .................................................................38 
Table 5: 
Guidance for Duration of Recording New or Worsening Adverse Events ................46 
Table 6: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................47 
Table 7: 
Populations for Analysis .............................................................................................51 
Table 8: 
Protocol-Required Safety Laboratory Assessments ...................................................74 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................21 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene (Beijing) Co., Ltd. 
Investigational Products: Dinutuximab beta, 13-Cis-Retinoic Acid 
Title of Study: An open-label, multi-center, single-arm, Phase 1 study evaluating the safety and 
pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese patients with high-risk 
neuroblastoma 
Protocol Identifier: BGB-dinutuximab beta-101 
Phase of Development: 1 
Number of Patients: Approximately 8 patients 
Study Centers: 
Approximately 1 to 3 centers in China 
Study Objectives: 
Primary: 
• 
To assess the safety and tolerability of ≤ 5 treatment cycles of dinutuximab beta in 
combination with 13-cis-retinoic acid (RA) as maintenance therapy in Chinese patients 
with high-risk neuroblastoma 
• 
To characterize the pharmacokinetics (PK) of dinutuximab beta in Chinese patients 
Exploratory: 
• 
To explore the preliminary anti-tumor activity and event free survival rate (EFS), of ≤ 5 
treatment cycles of dinutuximab beta in combination with 13-cis-RA as maintenance 
therapy in Chinese patients with high risk neuroblastoma, if applicable 
Study Endpoints: 
Primary: 
• 
Adverse events (AEs) characterized by type, frequency, severity (as graded by the National 
Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] 
version 5.0), timing, seriousness, and relationship to study drug(s); and other safety 
assessments 
• 
PK parameters of dinutuximab beta, including but not limited to area under the 
concentration-time curve (AUC), maximum serum concentration (Cmax), minimum serum 
concentration (Cmin), time to Cmax (tmax), and half-life (t1/2) if data permits 
 
Exploratory: 
• 
EFS is defined as the time from initiating study drug(s) to disease progression, death from 
any cause, relapse, secondary malignancy as assessed by investigators, including EFS rate 
at 6 months as measured by Kaplan-Meier method 
 
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Study Design 
This is an open-label, multi-center, single-arm, Phase 1 study evaluating the safety and 
pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese patients with high-risk 
neuroblastoma.  
After providing written informed consent, completing all screening assessments, and being confirmed 
as eligible for study participation, approximately 8 patients will be enrolled to receive dinutuximab 
beta plus 13-cis-RA therapy: 
• 
Dinutuximab beta at 100 mg/m2/cycle will be given as continuous long-term infusion 
(LTI) for 10 days from Day 1 to Day 11 in every 35-day cycle. 
• 
Patients will receive 13-cis-RA 160 mg/m²/day, divided into close to 2 equal doses and 
given orally twice a day for 14 days, starting on the next day after completion of 
dinutuximab beta infusion. 
• 
Up to 5 cycles of administration will be applied for both dinutuximab beta and 13-cis-RA. 
Study Assessments: 
• 
AEs will be characterized by type, frequency, severity (as graded by the NCI CTCAE 
version 5.0), timing, seriousness, and relationship to study drug will be recorded; other 
safety assessments to be performed including vital signs, physical examinations, 
ophthalmologic examination, performance status, laboratory safety tests, etc. 
• 
Blood samples will be collected on Day 1, 3, 8, 11, 15 (optional), 22 (optional), and 29 in 
Cycle 1, and on Day 1 and 11 in Cycle 2, 3, and 4 to characterize the PK of dinutuximab 
beta.  
• 
Tumor assessments or monitoring will be performed by the investigators at Screening 
Visit, end of treatment Cycle 3, and end of treatment visit. International Neuroblastoma 
Response Criteria (INRC) (Brodeur et al 1993) is recommended as a reference for response 
evaluation in patients evaluable for tumor assessment. 
Duration of Patient Participation:  
Patients will receive study drugs until the completion of the 5 treatment cycles (ie. 25 weeks), tumor 
relapse, progressive disease (PD), unacceptable toxicity, death, or other discontinuation criterion is 
met. 
Study Population:  
Patients aged ≥ 12 months with high-risk neuroblastoma who have previously received induction 
chemotherapy and achieved at least a partial response followed by myeloablative therapy and stem cell 
transplantation  
Key Eligibility Criteria: 
• 
Patients aged ≥ 12 months  
• 
Diagnosis of high-risk neuroblastoma according to the International Neuroblastoma Staging 
System (INSS) criteria, ie, INSS Stage 4 without MYCN amplification (MNA) and aged ≥ 18 
months; or INSS Stage 2-4 with MNA 
• 
Patients who have previously received induction chemotherapy and achieved a partial or 
complete response followed by myeloablative therapy and stem cell transplantation 
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Investigational Products, Dose, and Mode of Administration: 
Dinutuximab beta 
• 
Dinutuximab beta at 100 mg/m2/cycle will be given as continuous long-term infusion (LTI) for 
10 days from Day 1 to Day 11 in every 35-day cycle. 
• 
Up to 5 cycles of infusion will be administered. 
13-cis-RA 
• 
13-cis-RA will be given orally at a dose of 160 mg/m²/day, divided into close to 2 equal doses 
twice a day for 14 days, started on the next day after completion of dinutuximab beta infusion. 
• 
Up to 5 cycles of oral administration will be applied. 
Reference Therapy, Dose, and Mode of Administration: 
Not applicable 
Statistical Methods: 
Analysis Sets 
• 
The Safety Analysis Set will include patients who have received at least 1 dose of study drug. 
• 
The PK Analysis Set will include patients who have at least one available post-baseline PK 
data in Safety Analysis Set. 
Safety Analyses 
Safety is the primary endpoint and will be assessed by adverse events as characterized by type, 
frequency, severity (as graded by the NCI-CTCAE version 5.0), time, seriousness, and relationship to 
study drug(s), vital signs and laboratory abnormalities. Extent of exposure, physical examinations, and 
ECG findings will also be used in determining the safety profile. Descriptive statistics will be used to 
analyze all safety data in the Safety Analysis Set. 
Pharmacokinetic Analyses 
Serum concentration-time data of each patient will be tabulated and graphically presented on linear 
semi-logarithmic scales. PK parameters will be determined using a standard non-compartmental 
method in PK analysis set. Descriptive statistics will be used, including means, standard deviations, 
medians, ranges, geometric mean, and coefficient of variation (CV) % associated to the geometric 
mean as appropriate. 
Exploratory Efficacy Analyses 
No formal hypothesis testing is planned in this trial. Tumor assessment based on investigator 
assessment will be used to calculate EFS as well as time-point estimates including EFS-6m by 
Kaplan-Meier method. 95% confidence intervals will be constructed to describe the precision of the 
point estimates of interest (eg, median EFS, EFS-6m) if estimable.  
A listing of patients in Safety Analysis Set will be provided. 
Sample Size Consideration 
The study plans to enroll approximately 8 patients as recommended for PK studies by CDE technical 
guidance on clinical pharmacokinetic study of chemical drugs (Center of Drug Evaluation (CDE) of 
National Medical Products Administration (NMPA) 2005). Therefore, a sample size of approximately 
8 patients is proposed in this single arm study for PK assessment consideration. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
Cmax 
maximum serum concentration 
CT 
computed tomography 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End-of-Treatment (Visit) 
GD2 
disialoganglioside 2 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
PK 
pharmacokinetic(s) 
ULN 
upper limit of normal 
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1. 
INTRODUCTION AND RATIONALE  
1.1. 
Neuroblastoma  
Neuroblastoma commonly refers to a spectrum of neuroblastic tumors (including neuroblastoma, 
ganglioneuroblastoma, and ganglioneuroma). Neuroblastomas have a rather heterogeneous 
character and may vary in terms of location, histopathologic appearance, and biologic 
characteristics as well as in their clinical behavior; which can cover a broad spectrum from 
spontaneous regression to maturation, to a benign ganglioneuroma, or to an aggressive disease 
with metastatic dissemination leading to death (Chinese Children Cancer Group and Pediatric 
Surgery Society of Chinese Medical Association 2015). 
Neuroblastoma is mainly a pediatric disease that currently represents the third most common 
form of childhood cancer after leukemia and brain tumors. It is the most common solid 
extracranial tumor in the pediatric population, representing 8% to 10% of all childhood tumors 
(Papaioannou et al 2005; Colon et al 2011). 
Most patients with neuroblastoma are diagnosed under the age of 5 years, and most present with 
metastatic disease and/or high-risk features. The incidence is 10.2 cases per million children 
under 15 years of age, and nearly 500 new cases are reported annually in the United States (US) 
(Colon et al 2011). In the European Union (EU), the annual incidence of neuroblastoma in the 
pediatric population (0 to 14 years) is 0.12 in 10,000 people and that in the general population is 
0.03 in 10,000 people. International reports have shown that the incidence rates of neuroblastoma 
are highest among high-income countries in Europe and North America and lower in low-income 
countries in Africa, Asia, and Latin America (Lacayo et al 2019). The lower incidence of 
neuroblastoma in developing, low-income countries could be attributed to underdiagnosis. 
High-risk neuroblastoma, a mainly pediatric disease, remains one of the major challenges in 
pediatric oncology and is characterized at diagnosis by metastatic disease beyond 18 months of 
age and unfavorable biological features e.g. v-myc myelocytomatosis viral related oncogene 
(MYCN) amplification as the most prominent one (Cohn et al 2009). Despite the introduction of 
novel treatment strategies, including high-dose chemotherapy followed by autologous bone 
marrow or stem cell transplantation, the outcome of these patients remains poor, relapses 
occurring even after such extensive chemotherapeutic interventions (Maris et al 2010; Modak et 
al 2010; Qarziba EU SmPC).  
Since the majority of patients with high-risk disease eventually experience local or systemic 
relapse even after achieving complete remission after first-line therapy, much attention has been 
focused on maintenance treatment of minimal residual disease (MRD). Maintenance treatment 
consists of biological therapies that include differentiation-inducing agents such as retinoid 
derivatives or immunotherapy with monoclonal antibodies. Retinoids induce terminal 
differentiation of neuroblastoma cells and apoptosis in vitro. Today, 13-cis-retinoid acid (RA) 
given 2 weeks per month over 6 months post-transplantation is part of most high-risk protocols. 
Development of effective maintenance therapeutic strategies appears to be the only realistic way 
to further improve outcome in this disease. In this regard, there has been growing interest in 
major areas of adjuvant therapy of malignant diseases, including tumor-specific immunotherapy. 
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One concept in the treatment of neuroblastoma is the application of monoclonal antibodies 
directed against neuroblastoma cells. The chimeric monoclonal antibody (mAb) ch14.18, which 
recognizes the disialoganglioside (GD2) on neuroblastoma cells, is expressed by almost all 
neuroblastoma cells. This antibody could therefore have an important role in the treatment of 
neuroblastoma.  
The first chimeric anti-GD2 antibody was produced in murine, non-secreting myeloma cells 
(ch14.18/SP2/0, dinutuximab) (Gillies et al 1989) and later, the ch14.18 construct was recloned 
into Chinese hamster ovary (CHO) cells leading to dinutuximab beta (ch14.18/CHO). 
In a phase 3 study, patients with high-risk neuroblastoma who had a response to induction 
therapy and stem-cell transplantation were randomly assigned to receive standard therapy 
(6 cycles of 13-cis-RA) or immunotherapy (6 cycles of 13-cis-RA and five concomitant cycles of 
ch14.18/SP2/0 in combination with alternating GM-CSF and interleukin-2). Immunotherapy was 
superior to standard therapy with regard to rates of event free survival (EFS) (66 ± 5% versus 46 
± 5% at 2 years, p=0.01) and overall survival (86 ± 4% versus 75 ± 5% at 2 years, p=0.02 
without adjustment for interim analyses) (Yu et al 2010).  
1.2. 
Dinutuximab Beta  
Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody that is specifically 
directed against the carbohydrate moiety of GD2. Dinutuximab beta has been shown in vitro to 
bind to GD2-expressing neuroblastoma cell lines and to induce both complement-dependent 
cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Dinutuximab beta is indicated 
for the treatment of high-risk neuroblastoma in patients ≥ 12 months who have previously 
received induction chemotherapy and achieved at least a partial response followed by 
myeloablative therapy and stem cell transplantation (SCT); as well as in patients with a history 
of relapsed or refractory neuroblastoma with or without residual disease (Qarziba EU SmPC). 
A summary of nonclinical and clinical data for dinutuximab beta is provided below; additional 
data are presented in the Dinutuximab Beta Investigator’s Brochure. 
1.2.1. 
Nonclinical Data for Dinutuximab Beta  
Specific antigen binding (KDiss=15 to 22 nM) of dinutuximab beta to GD2 has been shown in 
vitro via surface plasmon resonance (SPR) as well as via a competition ELISA analysis 
(EC50=4.5 ng/mL). In vitro effector function studies also showed dinutuximab beta-triggered 
cytolytic activities on LAN-1 (neuroblastoma) cells in a complement-dependent cytotoxicity 
assay (EC50= 57 ng/mL), in an antibody-dependent cell-mediated cytotoxicity assay 
(EC50=2.0 ng/mL), and in a whole blood test of cytolytic activity (EC50=64.6 ng/mL), 
respectively. 
The in vivo antitumor activity of dinutuximab beta was demonstrated in a syngeneic mouse 
model. Dose-dependent and antigen-specific suppression of metastases was demonstrated in 
mice treated with dinutuximab beta 4 and 12 mg/kg/day for 5 consecutive days. The anti-tumor 
effect could be abrogated by depletion of NK cells, confirming that antibody-dependent cell-
mediated cytotoxicity is the main cause of dinutuximab beta-triggered anti-tumor activity. 
No stand-alone safety pharmacology studies have been performed with dinutuximab beta in 
accordance with ICH guideline S9 2016. However, tests of neurological, cardiovascular, and 
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respiratory function parameters including repeated-dose toxicity studies in guinea pigs and 
cynomolgus monkeys showed no test item-related changes.  
1.2.2. 
Clinical Pharmacology  
The pharmacokinetics of dinutuximab beta based on 10-day continuous intravenous infusion of 
10 mg/m2/day (equal to a total dose of 100 mg/m2/course) were evaluated in Studies 
APN311-303 and APN311-202. Mean plasma Cmax levels for Cycle 1 were reached on the last 
day of infusion, with a Cmax mean ± SD of 13.36 ± 5.89 µg/mL in APN311-303 and 11.91 ± 4.25 
µg/mL in APN311-202. The volume of distribution was stated to be 5 to 6.5 L/m2. In Study 
APN311-202, Cmax proportionally increased over the dose range of 10 to 30 mg/m2/day. 
While no excretion or metabolism studies have been conducted to date, the expected metabolic 
pathway for dinutuximab beta involves its degradation into small peptides and individual amino 
acids by ubiquitous proteolytic enzymes. The half-life (t1/2) for Cycle 1 of dinutuximab beta was 
around 190 hours (ie, 8 days), with a t1/2 median (range) of 186.52 (70.13-295.37) hours in 
APN311-303 and 178.01 (77.14-396.23) hours in APN311-202. Pharmaceutic(s) (PK) 
parameters for Cycles 2 to 5 were similar to those for Cycle 1, but with a tendency to increased 
Cmax and AUC values from cycle to cycle due to a slight drug accumulation. The mean 
accumulation ratio for Cmax and AUC increased from Cycle 2 to 5, with the range of 1.29 to 1.57 
and 1.32 to 1.61, respectively.  
1.2.3. 
Preliminary Efficacy and Safety Data With Dinutuximab beta  
Efficacy  
The efficacy of dinutuximab beta for the treatment of neuroblastoma was evaluated in 5 clinical 
studies. The main compassionate-use Study APN311-303 showed therapeutic efficacy of 
dinutuximab beta administered as a continuous 10-day infusion in patients with relapsed and 
refractory neuroblastoma and in those who had received first-line therapy only. The efficacy of 
dinutuximab beta was confirmed in 4 additional complementary studies that provided efficacy 
data for both relapsed/refractory and first-line patients for continuous infusion versus short-term 
(8 h) infusion and for patients receiving concomitant interleukin-2 (IL-2) treatment with 
immunotherapy versus immunotherapy alone. 
Dinutuximab beta either given as short-term infusion (STI) (5 x 8 hours) or long-term infusion 
(LTI) (10 days, 24 hours) demonstrated significant clinical benefits to patients with high-risk 
neuroblastoma in terms of ORR, EFS, and overall survival (OS). The overall response rate 
(ORR), EFS and OS across studies are presented in Table 1. In historic control groups, OS at 
2 years was between 20% and 30%. 
Table 1: 
Efficacy of Dinutuximab Beta in Clinical Studies in European Patients  
 
Study APN311- 
 
303a 
202a 
201b 
101bc 
302b 
 
(N=54) 
V1 
(N=44) 
V2 
(N=76) 
(N=35) 
(N=15) 
w/o IL2 
(N=187) 
with IL-2 
(N=198) 
Evaluable (N) for response 
37 
32 
45 
20 
12 
65 
70 
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Study APN311- 
 
303a 
202a 
201b 
101bc 
302b 
 
(N=54) 
V1 
(N=44) 
V2 
(N=76) 
(N=35) 
(N=15) 
w/o IL2 
(N=187) 
with IL-2 
(N=198) 
Response (CR, PR, VGPR) 
41% 
50% 
56% 
75% 
33% 
44% 
51% 
Evaluable (N) for EFS+OS 
53 
44 
76 
35 
ND 
180 
190 
EFS at 3 years 
31% 
41% 
54% 
40% 
ND 
55% 
61% 
OS at 3 years 
66% 
54% 
77% 
55% 
ND 
64% 
69% 
a Continuous 24-hour infusion. b 8-hour infusion. c No IL-2 co-treatment 
V1, first part of Study 202, based on Original Protocol; V2, second part of Study 202, based on Protocol 
Amendment 1.0; CR, complete response; EFS, event free survival; IL-2, interleukin 2; N, number of patients; ND, 
not determined; OS, overall survival; PR, partial response; VGPR, very good partial response; w/o, without. 
Resource: Dinutuximab Beta Investigator’s Brochure. 
The efficacy was independent of disease state at baseline. However, compared to multimodality 
treatment for relapsed/refractory neuroblastoma without immunotherapy, treatment including 
dinutuximab beta showed significant advantages. Also, the effects were independent of IL-2 
co-administration. Monotherapy with dinutuximab beta showed similar survival outcomes as 
combination treatment with IL-2 when used as part of the maintenance phase of first-line therapy 
for high-risk neuroblastoma patients (study APN311-302). The results are also comparable to 
therapy with ch14.18/SP2/0 (ch14.18 monoclonal antibody produced in murine SP2/0 cells) plus 
intravenous IL-2 and granulocyte macrophage colony-stimulating factor although this asset was 
assessed in a population of complete responders only (Yu et al 2010). 
Safety  
The most prominent adverse reaction with dinutuximab beta is severe neuropathic pain, 
especially during the first courses, due to the binding of dinutuximab beta to GD2 on nerve cells. 
Standard pain management including opioids, gabapentin, and nonsteroidal anti-inflammatory 
drugs should thus be established by experienced physicians when dinutuximab beta is 
administered. Hypersensitivity reactions are commonly observed with monoclonal antibody 
treatment and were also frequently observed with dinutuximab beta treatment (63%) including 
pyrexia, pruritus, tachycardia, and hypertension. Capillary leak syndrome is a common adverse 
reaction of IL-2 and has also occurred frequently with dinutuximab beta (40%). Other frequently 
reported adverse events (AEs) varied across studies but commonly included constipation, nausea, 
vomiting, cough, increased liver enzymes, anemia, decreased neutrophils, and decreased 
platelets. Most AEs were Grade 1 to Grade 3; Grade 4 events occurred with incidences between 
6% and 45% across studies. A continuous treatment regimen led to a clearly improved 
pain-toxicity profile compared with the 8-hour infusion regimen. The omission of subcutaneous 
IL-2 as co-treatment with the 8-hour infusion regimen greatly reduced side effects. To ensure 
patient’s safety, administration of dinutuximab beta must be performed by a healthcare 
professional well experienced in managing severe allergic reactions including anaphylaxis. 
Infusion of dinutuximab beta must be initiated in an environment where full resuscitation 
services are immediately available. 
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1.3. 
Study Rationale  
High-risk neuroblastoma is a rare disease in China and has a poor prognosis. Compared with 
medical treatment in western countries, the diagnosis and treatment of neuroblastoma in China 
needs to be improved. Dinutuximab beta is approved as Qarziba in the EU and is on the list of 
urgently needed drugs issued by the Center for Drug Evaluation (CDE) in 2018. Although 
dinutuximab beta, as a monoclonal antibody, is unlikely to show ethnic differences (Zhao et al 
2012; Navid et al 2010), this study was proposed in Chinese patients to assess pharmacokinetics 
and safety and verify any ethnic differences with regard to use and dosage. The study is designed 
to provide PK data in 8 Chinese patients and to confirm the safety and tolerability of 
dinutuximab beta when administered as a continuous infusion at a dose of 10 mg/m2/day for 10 
days for up to five 35-day cycles. 
1.3.1. 
Rationale for Selection of Dose  
The approved dose and schedule of dinutuximab beta to be used in this study was selected based 
on previous studies in which the same dose and schedule of dinutuximab beta 10 mg/m2/day for 
10 days in 35-day cycles was used. In Study APN311-101, a dose of 100 mg/m2/cycle was 
confirmed (8-hour infusion, 5 days). In Study APN311-202, the dose schedule of 
100 mg/m2/cycle (10 mg/m2/day, 10-day continuous infusion) was used as a starting point; this 
dose was then confirmed as safe and efficacious in the dose schedule finding part and the 
confirmatory part. 
A population PK analysis was conducted on the data obtained from Studies APN311-101, -202, 
and -303. Median values of body surface area (BSA) were used for PK simulation of different 
age groups (< 2 years to > 18 years). The predicted typical exposure (Cmax and AUC24h) was 
similar in all subjects ≤ 12 years and decreased slightly for older patients, which in turn 
supported the dose justification based on BSA for a wide age range. 
The effect of race on the exposure of IgG1 mAb is often insignificant after the difference in body 
weight or BSA has been taken into account (Zhao et al 2012). Therefore, the exposure of 
dinutuximab beta is not likely to be ethnically different as the dosing is based on BSA. Further, 
the Cmax in the Japanese study APN311-102 (N = 9) was similar to that in Studies APN311-202 
and -303 that used the schedule of dinutuximab beta 10 mg/m2/day for 10 days in 35-day cycles. 
Therefore, the same dose and schedule was selected for use in this study for Chinese patients. 
Recent data from Study APN311-302 showed that the addition of IL-2 in combination with 
dinutuximab beta infusions does not increase event-free survival (EFS) and overall survival (OS) 
in high-risk neuroblastoma patients but does show an inferior safety profile compared with 
dinutuximab beta alone. The focus of this study is to evaluate PK in Chinese patients; 
coadministration with IL-2 is not expected to affect the PK characteristics of dinutuximab beta 
but may increase toxicity. Therefore, IL-2 is not included as a cotreatment in this study. 
1.4. 
Benefit-Risk Assessment  
For patients with high-risk neuroblastoma, treatment options are limited. Treatment with an 
anti-GD2 antibody (dinutuximab beta) is globally known to prolong EFS and OS and is used as 
the standard-of-care of maintenance treatment throughout the USA and EU. 
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To date, over 1489 patients with neuroblastoma have been treated with short-term (8-hour) 
infusions or continuous (24-hour) infusions of dinutuximab beta in combination with IL-2 or as a 
single-agent treatment. Response to treatment with dinutuximab beta has been consistently 
shown in all completed clinical studies to date. 
Dinutuximab beta is associated with considerable but manageable toxicities. The most prominent 
adverse reaction with dinutuximab beta is neuropathic pain. Skilled pain management including 
the use of morphins is a prerequisite when dinutuximab beta is administered. Additional 
dinutuximab beta-related frequent toxicities include pyrexia, hypersensitivity reactions, pruritus, 
capillary leak syndrome, cytokine release syndrome, hypotension, and tachycardia. A continuous 
infusion regimen of dinutuximab beta over 10 days, ie, a lower dinutuximab beta concentration 
per hour of infusion, leads to an improved pain-toxicity profile; meanwhile, omission of 
co-treatment IL-2 can also reduce side effects and result in better compliance. Noteworthy, 
administration of this compound must be performed by well-trained physicians with experience 
in treating oncologic pediatric patients and severe allergic reactions. Patient safety during and 
after administration must be closely monitored. 
All possible benefits and risks will be discussed thoroughly with the patient and/or his/her legally 
authorized representative. The ICF will be signed by patient and/or his/her legally authorized 
representative before study entry. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dinutuximab beta can be found from Qarziba EU SmPC. 
In conclusion, the benefit of outcome improvements outweighs the risk related to dinutuximab 
beta infusion when treating patients with high–risk neuroblastoma. 
1.5. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of ≤ 5 
treatment cycles of dinutuximab beta in 
combination with 13-cis-retinoic acid (RA) as 
maintenance therapy in Chinese patients with 
high-risk neuroblastoma  
Adverse events (AEs) characterized by type, 
frequency, severity (as graded by the National 
Cancer Institute-Common Terminology Criteria 
for Adverse Events [NCI-CTCAE] version 5.0), 
timing, seriousness, and relationship to study 
drug(s); and other safety assessments 
To characterize the pharmacokinetics (PK) of 
dinutuximab beta in Chinese patients 
PK parameters of dinutuximab beta, including but 
not limited to area under the concentration-time 
curve (AUC), maximum serum concentration 
(Cmax), minimum serum concentration (Cmin), time 
to Cmax (tmax), and half-life (t1/2), if data permits. 
Exploratory 
To explore the preliminary anti-tumor activity and 
event free survival rate (EFS), of ≤ 5 treatment 
cycles of dinutuximab beta in combination with 
13-cis-RA as maintenance therapy in Chinese 
patients with high risk neuroblastoma, if 
applicable 
EFS is defined as the time from initiating study 
drug(s) to disease progression, death from any 
cause, relapse, secondary malignancy as assessed 
by investigators, including EFS rate at 6 months 
as measured by Kaplan-Meier method 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, multi-center, single-arm, Phase 1 study evaluating the safety and 
pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese patients with high-risk 
neuroblastoma. 
Potential patients will be screened for eligibility before study enrollment (screening period 
≤ 28 days). The study will recruit approximately 8 patients who will be hospitalized (with a full 
resuscitation equipment) on Day 1 of each cycle and will receive continuous infusion of 
dinutuximab beta administered at a dose of 10 mg/m2/day for 10 consecutive days in 35-day 
cycles (total dose 100 mg/m2/cycle). Patients must be administered in a unit with a full 
resuscitation equipment. Patients will be discharged from the hospital at the investigator’s 
discretion. Patients will continue to receive 13-cis-RA 160 mg/m²/day, divided into close to 2 
equal doses and given orally twice a day for 14 days after completion of dinutuximab beta 
infusion. 
Patients may receive up to five 35-day cycles in the absence of relapse, disease progression or 
unacceptable toxicity. 
Refer to Figure 1 for an overview of the study design and Appendix 1 for details on study 
assessments and procedures that will be carried out during the study. 
The maximum duration of participation (Screening Visit to Safety Follow-up Visit) for individual 
patients will be approximately 35 weeks. Each patient will participate in the screening period 
(≤ 28 days), study intervention infusion period (≤ 25 weeks), and a post-infusion period 
(≤ 6 weeks). Additional clinical follow-up might be needed depending on findings during the 
study. 
 
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Figure 1: 
Study Schema 
 
Abbreviations: EOT, end of treatment; PK, pharmacokinetic(s). 
All patients will be closely monitored for AEs throughout the study and for 40 days after the last 
dose of study drug. AEs will be graded according to the NCI-CTCAE version 5.0. Refer to 
Section 9 for additional and specific information regarding AE monitoring and reporting. 
PK analysis will be performed for dinutuximab beta. 
Tumor assessments or monitoring will be performed by the investigators at Screening Visit, end 
of treatment Cycle 3, and end of treatment Visit per their clinical practice. International 
Neuroblastoma Response Criteria (INRC) (Brodeur et al 1993) is recommended as a reference 
for response evaluation (Section 8.4) in patients evaluable for tumor assessment. Refer to 
Section 7.6 for additional considerations regarding treatment continuation and withdrawal. 
Patients who, at the time of progression, have an ongoing AE that leads to treatment 
discontinuation and who have completed the scheduled Safety Follow-up Visit will be followed 
up until the event resolves, the investigator assesses the event as stable, the patient is lost to 
follow-up, or the patient starts a new anticancer therapy, end of study, whichever comes first. 
Patients who have discontinued study drug(s) should return to the site for an End-of-Treatment 
(EOT) Visit as detailed in Section 7.4. After the EOT Visit, patients will have scheduled 
follow-up visits for safety (Appendix 1). 
Study procedures and assessments are further detailed in Section 7 and Section 8, respectively, 
and the Schedule of Assessments can be found in Appendix 1. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient must meet all the following inclusion criteria to be considered eligible for 
participation in this study: 
1. Signed informed consent form (ICF) and ability to comply with study requirements: 
patient or his/her parent/guardian must be capable of giving signed informed 
consent/assent as described in Section 14.3 including compliance with the requirements 
and restrictions listed in the ICF and in this protocol. 
2. Age ≥ 12 months at consent 
3. Diagnosis of high-risk neuroblastoma according to the International Neuroblastoma 
Staging System (INSS) criteria, ie, INSS Stage 4 without MYCN amplification (MNA) 
and aged ≥ 18 months; or INSS Stage 2-4 with MNA 
4. Patients who have previously received induction chemotherapy and achieved a partial or 
complete response followed by myeloablative therapy and stem cell transplantation. Stem 
cell transplantation should be completed within 120 days of dinutuximab beta first 
administration. The date patients complete the last stem cell transplantation is defined as 
day zero (Day 0). 
5. Not receiving standard or experimental treatments within 2 weeks before study treatment 
start and full recovery from the short-term major toxic effects of any prior treatment 
6. Consistency of contraceptive use by men or women with local regulations regarding the 
methods of contraception for those participating in clinical studies 
NOTE: The reliability on sexual abstinence for male and/or female enrollment eligibility 
needs to be evaluated in relation to the duration of the clinical study and the preferred 
and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
7. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and 180 days after the last dose of study 
drug(s), and have a negative urine or serum pregnancy test ≤ 7 days of the first dose of 
study drug(s) (Appendix 4). 
8. Nonsterile males must be willing to use highly effective method of birth control for the 
duration of the study and for 180 days after the last dose of study drug(s) (Appendix 4).   
• A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
• Males with known “low sperm counts” (consistent with “subfertility”) are not to be 
considered sterile for purposes of this study. 
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9. Life expectancy of ≥ 12 weeks 
10. Performance status ≥ 70% (Lansky Score or Karnofsky, see Appendix 3) 
11. Laboratory tests: 
− ANC ≥ 1.5 x 109/L, platelets ≥100 x 109/L, and hemoglobin > 80 g/L 
− ALT and AST ≤ 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic 
metastases are present; and total bilirubin < 1.25 x ULN 
− Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 
60 mL/min/1.73m2 
12. Negative test for hepatitis B surface antigen (HBsAg). 
13. Pulse oximetry > 94% on room air 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from this study: 
1. Hypersensitivity to ≥ 1 component of dinutuximab beta antibody or against mouse 
proteins 
2. Actively progressive disease (not stabilized) or recurrent disease at the time of inclusion 
into the study 
3. Significant intercurrent illnesses and/or any of the following: 
− Symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance 
− Significant psychiatric disabilities or uncontrolled seizure disorders 
− Active infections or active peptic ulcer, unless these conditions are corrected or 
controlled 
− Clinically significant neurologic deficit or objective peripheral neuropathy 
(> Grade 2) 
− Clinically significant, symptomatic pleural effusions 
4. Previous treatment with anti-GD2 antibody before enrolling in this study 
5. Any condition that required systemic treatment with either corticosteroids or other 
immunosuppressive medication ≤ 14 days before the first dose of study drug(s).  
6. Concurrent treatment with any non-study anticancer therapies 
7. Patients with active hepatitis C infection should be excluded. Note: Cured hepatitis C 
patients (as defined by a positive hepatitis C virus (HCV) antibody test and negative 
HCV RNA test) can be enrolled 
8. Known history of HIV infection 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Dinutuximab Beta  
Formulation  
Infusion: A volume of 4.5 ± 0.25 mL, which corresponds to a minimum extractable dose of 
20 mg/vial, is filled into 6-mL type 1 glass vials.  
Table 2: 
Dinutuximab Beta Formulation 
The vials are closed with halobutyl rubber stoppers and sealed with aluminum flip-off caps. The 
actual antibody content of the respective batch of dinutuximab beta is indicated on the label on 
the vials. 
Packaging, Labeling, And Handling  
Dinutuximab beta will be supplied in a commercial presentation by sponsor. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. Refer to the 
Pharmacy Manual for details regarding administration, accountability, and disposal. Please also 
refer to Dinutuximab Beta’s Prescribing Information for other details regarding Dinutuximab 
beta. 
5.1.2. 
13-cis-retinoic acid  
The 13-cis-RA (TeeWasH®), a liquid-filled capsule, will be supplied by sponsor. Management 
(ie, handling, storage, administration, and disposal) of 13-cis-RA will be in accordance with 
relevant local guidelines and/or prescribing information. The contents of the label will be in 
accordance with all applicable local regulatory requirements. 
For the other details regarding 13-cis-RA, please refer to the local label of 13-cis-retinoic acid or 
Pharmacy Manual accordingly.  
5.2. 
Dosage, Administration, and Compliance  
Accurate records of all study drug(s) received, dispensed, returned, and disposed of should be 
maintained in the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration. 
Content 
4.5 ± 0.25 mg/mL 
Buffer 
20 mM histidine, 5% sucrose, 0.01% Tween 20, water for 
injection 
pH  
5.5-6.5 
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5.2.1. 
Dinutuximab Beta  
Dosage  
Total dose: 100 mg/m2/cycle 
Patients may receive up to five 35-day cycles in the absence of disease progression or 
unacceptable toxicity. 
Dinutuximab beta is administered at a dose of 10 mg/m2/day as a 24-hour continuous infusion 
for 10 days (total dose 100 mg/m2/cycle) for five 35-day cycles. 
Preparation of Infusion  
The solution for infusion must be prepared under aseptic conditions. The solution must not be 
exposed to direct sunlight or heat. 
The patient-specific daily dose of dinutuximab beta is calculated based on BSA. Dinutuximab 
beta should be diluted aseptically to the patient-specific concentration/dose with sodium chloride 
9 mg/mL (0.9%) solution for infusion, containing 1% human albumin (eg, 5 mL of 20% human 
albumin per 100 mL of 0.9% sodium chloride solution). 
For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, or 
sufficient for up to 5 days of continuous infusion. The daily dose is 10 mg/m2. The amount of 
solution to be infused per day (within a treatment course of 10 consecutive days) should be 48 
mL; with 240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL 
syringe, or 250 mL in an infusion bag suitable for the employed infusion pump, ie, an overfill of 
2 mL (syringe) or 10 mL (infusion bag) to allow for dead volumes of the infusion systems.  
Administration of The Infusion  
The solution for infusion should be administered via a peripheral or central intravenous line. 
Other intravenously co-administered agents should be delivered via a separate infusion line. The 
container should be inspected visually for particulates before administration. It is recommended 
that a 0.22 micrometer in-line filter is used during infusion. 
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can 
be applied, eg, syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note that 
elastomeric pumps are not considered suitable in combination with in-line filters. 
The investigator may need to reduce or delay doses or stop treatment if certain side effects occur. 
It allows the investigator to decrease at 50% of the previous dose or interrupt the infusion. In this 
instance, the total amount does not need to equal 240 hours of infusion per cycle ideally (total 
dose of 100 mg/m2/cycle). The investigator must record the reasonable reason for providing any 
alternative dose during treatment. 
Refer to Qarziba EU SmPC for storage of the diluted solution and disposal. 
Compliance  
Compliance will be assessed by the investigator and/or study personnel at each patient visit along 
with information provided by the patient and documented accordingly. The investigator and/or 
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study personnel will keep accurate records of the quantities of agents dispensed and used by each 
patient. This information must be captured in the source document at the end of each cycle. 
5.2.2. 
13-cis-retinoic acid  
Patients will receive 13-cis-RA (TeeWasH®) at a total daily dose of 160 mg/m²/day, 
administered in close to 2 equal oral doses twice a day for 14 days after completion of 
dinutuximab beta infusion. Doses will need to be rounded to the nearest 10 mg. Capsules come 
as 10 mg sizes and can be emptied into a high fat food such as ice cream or chocolate mousse to 
administer. Investigators can adjust the dose of 13-cis-RA for the patient’s conditions by 
following the 13-cis-RA prescription or investigators’ experience in using 13-cis-RA. If the total 
daily doses are odd numbers of 13-cis-RA capsules, the number of capsules for each time can be 
unequal. In that case, if the daily doses are 11 capsules, patients would receive 5 capsules in the 
morning and 6 capsules in the evening or 6 capsules in the morning and 5 capsules in the 
evening. 
Suggested supportive care for 13-cis-RA: 
• Topical vitamin E should be applied to the lips twice a day during 13-cis-RA oral 
administration therapy if cheilitis develops 
• Patients should avoid direct sun exposure while on 13-cis-RA 
• Patients should avoid exposure to vitamin A products during 13-cis-RA 
5.3. 
Overdose  
In the case of overdose, patients should be carefully observed for signs or symptoms of adverse 
reactions and supportive care administered, as appropriate. 
5.4. 
Dose Delay or Modification  
Dose modification 
This protocol allows some alteration from the currently outlined infusion schedule of 
dinutuximab beta, but the maximum cumulative exposure will not exceed 100 mg/m2/cycle. 
Based on the Investigator’s evaluation of the severity of adverse drug reactions to dinutuximab 
beta, patients may undergo a dose reduction of 50% or a temporary interruption of the infusion. 
As a consequence, either the infusion period is prolonged or, if tolerated by the patient, the 
infusion rate may be increased up to 3 mL/h (continuous infusion), in order to administer the 
total dose. 
Regarding the dose modification of 13-cis-RA, please refer to local label of 13-cis-retinoic acid. 
Table 3: 
Recommended Dinutuximab Beta Dose Modification 
Adverse reaction 
Severity 
Treatment modification 
Any 
Grade 1 or 2 
Decrease infusion rate to 50%. 
After resolution, resume infusion at original rate. 
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Hypersensitivity reaction 
eg, Hypotension 
Interrupt infusion and administer supportive 
measures. 
After resolution, resume infusion at original rate. 
Dilated pupils with sluggish light reflex ± photophobia 
Interrupt infusion. 
After resolution, resume infusion at 50% rate. 
Any 
≥ Grade 3 
Interrupt infusion and administer supportive 
measures. 
Resume infusion at 50% rate if adverse drug 
reaction (ADR) resolves or improves to Grade 1 or 2 
within 3 days of onset. 
If 50% dose reduction is tolerated for ≥ 1 day, 
consider advancing infusion to full rate as tolerated. 
If toxicity (≥ Grade 3) recurs at 50% dose reduction, 
treatment should be discontinued. If toxicity 
(≥ Grade 3) recurs while at 100% infusion rate, stop 
infusion and reduce dose to 50% if toxicity resolves 
or improves to ≤ Grade 2 within 3 days of onset. Do 
not increase dose to 100% again. 
Capillary leak syndrome 
 
Interrupt infusion and administer supportive 
measures. 
Resume at 50% rate if ADR resolves or improves to 
Grade 1 or 2. 
Capillary leak syndrome requiring 
ventilator support; allergic 
reaction (anaphylaxis), skin 
toxicity, severe neuropathic pain, 
any other Grade 4 toxicity (which 
does not recover to Grade 1 or 2 or 
baseline within 5 weeks) 
Grade 4 
Discontinue infusion. Contact sponsor to confirm if 
patient may continue infusion at the start of the 
subsequent cycle.  
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6. 
PRIOR AND CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter and prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving within 30 days before the first dose of 
dinutuximab beta: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.1. 
Premedication  
Antihistamine premedication (eg, diphenhydramine) should be administered by intravenous 
injection approximately 20 minutes or orally based on the physician’s judgment before starting 
each dinutuximab beta infusion. It is recommended that antihistamine administration be repeated 
every 4 to 6 hours as required during dinutuximab beta infusion. 
Patients should be closely monitored for anaphylaxis and allergic reactions, particularly during 
the first and second treatment course. 
Pain  
Neuropathic pain usually occurs at the beginning of the treatment and premedication with 
analgesics, including intravenous opioids, before each infusion of dinutuximab beta is required. 
A triple therapy including nonopioid analgesics (according to World Health Organization 
guidelines), gabapentin, and opioids is recommended for pain treatment. The individual dose 
may vary widely. 
Nonopioid analgesics  
Nonopioid analgesics should be used permanently during the treatment, eg, paracetamol or 
ibuprofen (refer to local label for details regarding administration). 
Gabapentin  
The patient should be primed with 10 mg/kg/day, starting 3 days before dinutuximab beta 
infusion. The daily dose of gabapentin is increased to 2 x 10 mg/kg/day orally the next day and 
to 3 x 10 mg/kg/day orally the day before the onset of dinutuximab beta infusion and thereafter. 
The maximum single dose of gabapentin is 300 mg. This dosing schedule should be maintained 
as long as required by the patient. 
Oral gabapentin should be tapered off after weaning off intravenous morphine infusion at the 
latest after dinutuximab beta infusion therapy has been stopped. 
6.2. 
Continuous Morphine Infusion Schedule  
Opioids are the standard pain treatment given alongside dinutuximab beta to prevent severe 
visceral and neuropathic pain. The amount of opioid required in the continuous infusion setting 
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is less than that in the short-term infusion setting. The first day and cycle usually requires more 
amount of opioid than subsequent days and cycles. Opioids should therefore be started and then 
gradually weaned off according to the needs of the patient. Except for respiratory depression and 
sedation, the AEs in children and in adults are essentially the same (nausea, vomiting, 
constipation, pruritus, urinary retention, and lowered seizure threshold). The safety and efficacy 
of continuous intravenous administration of opioids for pain management are well established for 
all age groups. The risk of dependence is classified as low. 
Tramadol should be used for moderate to severe pain, but for severe to very severe pain, 
morphine is preferred unless it is poorly tolerated by certain individuals, in which case other 
opioids can be used. 
During the first cycle, intravenous morphine should initially be given as follows: 
A morphine sulphate bolus (0.02 to 0.05 mg/kg/h) should be administered before the start of 
continuous infusion of dinutuximab beta. Thereafter, it is recommended to administer morphine 
sulphate at a continuous infusion rate of 0.03 mg/kg/h on the first day. The morphine dose can 
ideally be tapered on a daily basis over the first 5 days (to 0.02 mg/kg/h to 0.01 mg/kg/h to 
0.005 mg/kg/h). Boluses can be either self-administered or administered by a nurse at 
0.02 mg/kg/dose. If continuous morphine is required for > 5 days, the dose should be decreased 
at the end of treatment by 20% each day. It is expected that intravenous morphine can be rapidly 
tapered off. Depending on the individual patient’s pain tolerance, subsequent cycles can be 
started with intravenous morphine, including the bolus loading dose, and tapered until a safe and 
well-tolerated outpatient pain management regimen is in place; for example, 
• Oral morphine: administered at a dose of 0.2 to 0.4 mg/kg every 4 to 6 hours 
• Oral tramadol: if pain is well-controlled on low doses of oral morphine 
• Transdermal fentanyl patches: in centers where these are used regularly for pain 
control. The equivalent morphine to transdermal fentanyl dose rate in µg/h will be 
calculated based on the current use of intravenous morphine according to the 
manufacturers guidance and the dose will be gradually decreased according to pain 
symptoms. 
The use of long-acting morphine is not recommended in this situation as it takes 48 hours to 
stabilize the dose, which is not practical. 
6.3. 
Prohibited Concomitant Medications  
The following medications are prohibited during the study or as otherwise noted: 
• Any chemotherapy, hormonal anticancer therapy, radiotherapy, or experimental 
anticancer medications other than those that are study related, until patients have 
completed end of study assessments at the Safety Follow-up Visit or have 
discontinued study drug with dinutuximab beta prematurely 
• Systemic glucocorticoids or other drugs with known immunosuppressive activity 
within 2 weeks of starting and 1 week after completing treatment with dinutuximab 
beta except to treat life-threatening conditions 
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• The use of intravenous immunoglobulin (IVIG), because IVIG may interfere with the 
dinutuximab beta-mediated antibody-dependent cellular cytotoxicity, within 2 weeks 
of starting and 1 week after completing treatment with dinutuximab beta 
• Tetracycline is prohibited when the patient is taking 13-cis-RA 
6.4. 
Medications to Be Used With Caution  
Potential interaction between study drug and concomitant medication  
No interaction studies have been performed. Monoclonal antibodies (mAbs) are considered to 
have a low potential for drug-drug interactions with other therapeutic proteins or small 
molecules, as mAbs are mainly delivered by parenteral administration and are metabolized via 
the reticuloendothelial system or target-mediated disposition to peptides and amino acids. 
Therefore, as an intravenous IgG1 mAb, the concern for drug-drug interactions of dinutuximab 
beta is very low. However, in Study APN311-201, dinutuximab beta induced the release of 
cytokines, in particularly that of IL-6 and TNFα. Cytokines can affect expression levels of 
cytochrome P450 (CYP450), and IL-6 is known to decrease the activity of CYP450. A risk for 
indirect reduction of CYP450 activity may occur due to higher TNFα and IL-6 levels. Therefore, 
interactions with concomitantly used small molecules metabolized by CYP450, cannot be 
excluded. Caution should be applied when dinutuximab beta is co-administered with CYP450 
substrates with a narrow therapeutic index. 
If CYP450 substrates will be used, the medical monitor and clinical pharmacologist should be 
consulted. Please refer to Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers (FDA 2016) for a complete list of CYP450 substrates.  
For 13-cis-RA, detail information could consult the relevant prescribing local label of 
13-cis-retinoic acid. 
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7. 
STUDY PERIODS, VISITS, OR PROCEDURES  
7.1. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before the first dose of study drug. A patient 
who agrees to participate in this study will sign the ICF before undergoing any study-specific 
screening assessment. Refer to Section 8.1 for instructions regarding screening assessments. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site. 
The investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
7.2. 
Enrollment  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined. No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
7.3. 
Treatment Period  
Patients enrolled by the sponsor will be treated as described in Section 5.2. 
Refer to Section 7.6 for additional considerations regarding treatment continuation and 
withdrawal. 
Assessments before the start of dinutuximab beta infusion on Day 1 of each cycle:  
• Oxygen-Saturation measurement  
• Physical examination including vital signs, height, and weight 
• Performance status 
• 12-Lead ECG  
• Chest X-ray 
• Complete blood count including differential count*  
• Biochemistry* 
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• Urinalysis* 
• Pregnancy test in WOCBP 
• Blood sampling for PK (30 minutes before infusion) in Cycle 1, 2, 3 and 4 
*If clinical chemistry, hematology, coagulation and urinalysis at screening are not performed 
≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should be repeated 
and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be 
reviewed within 72 hours before study drug administration. 
Assessments during dinutuximab beta infusions:  
• Performance status (on each infusion day) 
• Blood sampling for PK (infusion starting time ±1 hour on Day 3 and Day 8 in 
Cycle 1)  
• The following assessments must be regularly repeated during dinutuximab beta 
infusions according to routine medical care procedures to ensure safe treatment of the 
patients: 
− Physical examination including vital signs 
− Complete blood count (including differential count) and biochemistry on Day 8 
• Electrocardiography (ECHO) or multigated acquisition scan (MUGA) scan as 
clinically indicated 
On Day 11 of each cycle, evaluations and blood sampling must be done just before the end of 
dinutuximab beta infusion, ie, within a couple of minutes before the end of infusion. Evaluations 
must include the following: 
• Physical examination including vital signs 
• Performance status 
• 12-Lead ECG 
• Complete blood count (including differential count) and biochemistry 
• Blood sampling for PK (5 minutes before the end of infusion) in Cycle 1, 2, 3 and 4 
Assessments after dinutuximab beta infusions:  
• Complete blood count (including differential count) and biochemistry (Days 15, 22, 
and 29) 
• Blood samples for PK (Day 15 and Day 22 [optional], and Day 29 in Cycle 1) 
The guidelines for pain control must be followed strictly for the whole study duration. If a 
patient has an unacceptable pain-toxicity profile, he/she might need more intense pain treatment 
such as intravenous morphine after Day 5. If this is the case, in the following cycles, the 
treatment team should again try to taper intravenous morphine. 
AEs and concomitant medications are documented throughout all phases. 
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7.4. 
End-of-Treatment Visit  
Patients completing all 5 cycles should undergo the following assessments at the end (± 1 week) 
of the last cycle: 
• Complete physical examination (including vital signs) 
• Ophthalmologic examination by an ophthalmologist 
• ECHO or MUGA scan 
• 12-Lead ECG 
• Complete blood count (including differential count) and biochemistry 
• Urinalysis 
• Coagulation profile 
• Performance status 
• Tumor evaluation will be done (using MRI [magnetic resonance imaging] and/or CT 
scan and/or 123I-MIBG scan and/or 18F-FDG-PET and/or bone marrow assessment) 
Patients who discontinue study intervention early (receiving < 5 cycles) should also undergo 
EOT assessments, if clinically reasonable. 
The EOT Visit is to be conducted ≤ 7 days after the investigator determined that the patient must 
permanently discontinue study drug. If routine laboratory tests (eg, hematology, clinical 
chemistry) were completed ≤ 7 days before the EOT Visit, these tests do not need to be repeated. 
A tumor assessment is not required at the EOT Visit if ≤ 6 weeks have passed since the last 
assessment. If EOT Visit did not occur until the planned Safety Follow-up Visit, then it can be 
used as replacement for the Safety Follow-up Visit. 
Post-study treatment is allowed after the EOT Visit, at the discretion of the investigator, 
according to the treatment guideline and the local practice. 
See Section 7.4 for assessments to be performed for the EOT Visit. 
See Section 7.5.1 for details on the Safety Follow-up Visit. 
7.5. 
Follow-up Periods  
7.5.1. 
Safety Follow-up Period  
Patients who permanently discontinue study drug will be asked to return to the clinic for the 
Safety Follow-up Visit, which is required to be conducted within 40 days [± 7 days] after the last 
dose of study drug or before the initiation of new anticancer therapy, whichever occurs first. 
All AEs, including serious adverse events (SAEs), will be collected as described in Section 9.5. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
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7.5.2. 
Loss to Follow-up  
If attempts to contact the patient by telephone are unsuccessful, additional attempts should be 
made to obtain protocol-required follow-up information: it may be possible to obtain the 
information from other contacts such as referring physicians or relatives. Attempts to establish 
contact should be documented in the patient’s source documents. If a patient cannot be contacted 
despite all attempts, the patient will be considered lost to follow-up, and death information 
should be obtained through a public record search if local agencies permit. 
7.6. 
Discontinuation From Study Treatment or From the Study  
7.6.1. 
Patient Discontinuation From Study Treatment (End of Treatment for an 
Individual Patient)  
Patients have the right to discontinue study drug at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from study drug at any time. Patients who 
discontinue study drug for reasons other than relapse or progressive disease (PD) should be 
followed for assessments of preliminary anticancer activity (Section 8.4) and safety 
(Section 8.2), if possible. 
The primary reason for discontinuation from study drug should be documented on the 
appropriate eCRF. Patients may discontinue study drug for reasons including but not limited to 
the following: 
• Relapse 
• PD 
• AE 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she were to continue the study drug 
• Use of any concurrent anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard or investigational agents (including Chinese [or other 
Country] herbal medicine and Chinese [or other Country] patent medicines) for the 
treatment of cancer [regardless of cancer type]) 
• Patient noncompliance 
− Study site staff should first counsel patients who are significantly noncompliant 
(eg, missing 2 treatment cycles) on the importance of study drug compliance and 
drug accountability. The investigator may, in consultation with the medical 
monitor, discontinue patients from treatment who are consistently noncompliant. 
Treatment with dinutuximab beta should be permanently discontinued if the following toxicities 
occur: 
• Grade 3 or 4 anaphylaxis 
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• Prolonged Grade 2 peripheral motor neuropathy 
• Grade 3 peripheral neuropathy 
• Grade 3 vision eye toxicity 
• Grade 4 hyponatremia (< 120 mEq/L) despite appropriate fluid management 
• Recurrent or Grade 4 capillary leak syndrome (requires ventilator support) 
If dinutuximab beta or 13-cis-RA is discontinued permanently before cycle 5 for reasons other 
than relapse or PD, the other drug could be continued per the study protocol. 
7.6.2. 
Patient Discontinuation From the Study (End of Study for an Individual Patient)  
Patients may discontinue from the study for reasons that include but are not limited to the 
following: 
• Patient withdrawal of consent 
• Death 
• Lost to follow-up 
• Completion of all study assessments 
7.7. 
End of Study  
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, completes all study 
assessments, or is lost to follow-up, whichever comes first. Alternatively, the end of study is 
when the sponsor decides to terminate the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early include but are not limited to the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients must be seen for an EOT Visit and Safety 
Follow-up Visit as described in Section 7.4 and Section 7.5.1. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing IRBs/IECs of the early termination of the study. 
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8. 
STUDY ASSESSMENTS  
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Where applicable, dosing will occur only if the clinical assessment and local laboratory test 
values (that must be available before any dosing) have been reviewed and found to be acceptable 
per protocol guidelines. 
8.1. 
Screening Assessments  
Screening evaluations will be performed ≤ 28 days before the first dose of study drug(s) (refer to 
Appendix 1 for details). Patients who agree to participate will sign the ICF before undergoing 
any study-specific screening assessment. The screening period begins on the first day that a 
screening assessment is conducted. Screening evaluations may be repeated as needed within the 
screening period. The investigator is to assess patient eligibility according to the latest screening 
assessment results. 
Results of standard-of-care tests or examinations performed before informed consent has been 
obtained and ≤ 28 days before the first dose of study drug(s) may be used for the purposes of 
screening rather than repeating the standard-of-care tests unless otherwise indicated. 
Procedures conducted only during the Screening Visit are described in this section. For the 
description of assessments that are conducted during screening as well as throughout the study, 
refer to Safety Assessments (Section 8.2), PK Assessments (Section 8.3), Tumor and Response 
Evaluations (Section 8.4 ) sections. 
Rescreening under limited conditions may be allowed after consultation with BeiGene (eg, when 
a patient’s laboratory result narrowly misses a laboratory criterion and it is correctable and not 
due to rapidly deteriorating condition or PD). Rescreening is allowed only once. 
8.1.1. 
Oxygen-Saturation measurement  
Patients will undergo an oxygen-saturation measurement (on room air). The measurements will 
be kept in the patients’ records as source documents. The findings will be recorded in the eCRF. 
8.2. 
Safety Assessments  
8.2.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic). Pulse rate and blood pressure will be measured while the patient is in a 
spine position after resting for 5 minutes. 
8.2.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of 1) the head, eyes, ears, nose, and throat; 2) cardiovascular; 3) dermatological; 
4) musculoskeletal; 5) respiratory; 6) gastrointestinal; and 7) neurological systems. Any 
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abnormality identified during screening will be graded according to NCI-CTCAE version 5.0 
and recorded in the eCRF with appropriate disease/condition terms. 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs in the eCRF. Refer to Section 9.2 for AE definitions, reporting, and follow-up 
requirements. 
8.2.3. 
Ophthalmologic Examination  
Patients will undergo an eye examination by an ophthalmologist. The findings of each 
examination will be recorded in the eCRF. Any significant abnormality present at screening 
should be recorded as medical history if assessed at the screening visit or as an AE if occurring 
after screening. 
8.2.4. 
Performance Status  
Patients will be assessed for performance status. For children ≤ 16 years of age, a Lansky 
Play-Performance Scale (Lansky et al 1985) will be used, and for those > 16 years of age, the 
Karnofsky Performance Scale (Mor et al 1984) will be used (Appendix 3). 
8.2.5. 
Laboratory Safety Tests  
Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will 
be conducted as outlined in Appendix 2 per the timepoints shown in Appendix 1. 
If clinical chemistry, hematology, coagulation and urinalysis at screening are not performed 
≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should be repeated 
and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be 
reviewed within 72 hours before study drug administration. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically relevant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 40 days after the last dose of study drug should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified where possible and 
the sponsor notified. 
• All protocol-required laboratory assessments as defined in Appendix 2 must be 
conducted in accordance with the laboratory manual and the Schedule of Assessments 
(Appendix 1). 
• If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in patient 
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management or are considered clinically relevant by the investigator (eg, are 
considered an SAE or an AE or require dose modification), then the results must be 
recorded in the eCRF. 
8.2.6. 
Echocardiography/Multigated Acquisition Scan  
Patients will undergo ECHO/MUGA scanning. The ECHO/MUGA scan recordings will be kept 
in the patient’s records as source documents. The findings of each examination will be recorded 
in the eCRF. Any significant abnormality present at screening should be recorded as medical 
history if assessed at the screening visit or as an AE if occurring after screening. 
8.2.7. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the site. 
All ECGs are to be obtained before other assessments scheduled at that same time (eg, vital sign 
measurements, blood draws). The patient should rest in a semirecumbent supine position for 
≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate 
(eg, television, radio, conversation) before each ECG collection. 
At each timepoint (see Appendix 1), 3 consecutive 12-lead ECGs should be performed 
approximately 2 minutes apart to determine the mean QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) interval. 
8.2.8. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE version 5.0. 
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 9.5. 
8.3. 
Pharmacokinetic Assessment  
Blood will be collected to characterize the PK of dinutuximab beta. Blood sampling (1 ml) for 
PK assessment will be collected at the timepoints specified in Table 4. The actual collection date 
and time of each blood sample will need to be recorded on the eCRF. 
Table 4: 
Dinutuximab Beta PK Sampling Schedule 
Cycle 
Cycle 1 (35 days per cycle) 
Cycle 2, 3, and 4 
Time 
D1 
Predose 
D3 
 
D8 
 
D11 
 
D15a 
D22a 
D29a 
D1 
Predose 
D11 
Window Allowed 
-30 minsb 
± 1 hc 
± 1 hc 
-5 minsd 
 
 
 
-30 minsb 
-5 minsd 
PK Serum Sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: PK, pharmacokinetic(s). 
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a PK sampling on Day 15 and Day 22 in Cycle 1 is optional. That adjustment needs to be aligned with 
pharmacologists. PK sampling on Day 29 in Cycle 1 is required even if the infusion time will be delayed or 
extended.  
b 30 minutes before starting infusion. 
c Infusion starting time ± 1 hour.   
d 5 minutes before the end of infusion, even if the infusion time will extend to the next days. 
Blood samples for PK analysis will be collected into serum separator tube (SST) collection 
tubes. Shipping, storage, and handling of samples will be managed through a central laboratory. 
Samples will be shipped to the designated bioanalytical laboratory for quantification of serum 
dinutuximab beta concentrations. Full details on sample collection, processing, storage, and 
shipment will be provided in the laboratory manual. 
8.4. 
Tumor and Response Evaluations  
Tumor assessments or monitoring will be performed by the investigators at Screening Visit, end 
of treatment Cycle 3 and end of treatment Visit per their clinical practice. INRC (Brodeur et al 
1993) is recommended as a reference for response evaluation in patients evaluable for response. 
Tumor imaging will be performed ≤ 28 days before the first dose of study drug(s). Results of 
standard-of-care tests or examinations performed before informed consent has been obtained and 
≤ 28 days before the first dose of study drug(s) may be used for the purposes of screening rather 
than repeating the standard-of-care tests.  
Tumor assessments may include MRI and/or CT scan and/or 123I-MIBG scan and/or 
18F-FDG-PET and/or bone marrow assessment. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to 
assess disease sites at screening must be used throughout the study (eg, the same contrast 
protocol for CT scans).  
8.5. 
Biomarkers  
Not applicable. 
8.6. 
Visit Windows  
All visits on Day 1 of every cycle must occur within ± 3 days from the scheduled date, unless 
otherwise noted (see Appendix 1). All assessments will be performed on the day of the specified 
visit unless an acceptable time window is specified. Assessments scheduled on the day of study 
drug administration (Day 1) of each cycle should be performed before study drug infusion unless 
otherwise noted. Laboratory results must be reviewed before dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
event, the visit should be scheduled for the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule. 
8.7. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; Lansky Play-Performance 
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Scale/Karnofsky Performance Scale (see Section 8.2.4 and Appendix 3); AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and clinical chemistry laboratory assessments. The date and reason for the 
unscheduled visit must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests 
may be performed based on the investigator assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 
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9. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
9.1. 
General Plan to Manage Safety Concerns  
9.1.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with dinutuximab beta were considered. 
9.1.2. 
Abnormal Liver Function Tests  
The finding of an elevated ALT or AST (> 3 x baseline value) in combination with either an 
elevated total bilirubin (> 2 x ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered an indicator of severe liver injury. Therefore, 
investigators must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST increase > 3 x baseline value in combination with 
total bilirubin > 2 x ULN (of which 35% is direct bilirubin) 
• Treatment-emergent ALT or AST increase > 3 x baseline value in combination with 
clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF and reported to the sponsor immediately (ie, ≤ 24 
hours after learning of the event). 
9.1.3. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE version 5.0. 
All enrolled patients will be evaluated clinically and with standard laboratory tests at regular 
intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs (see Table 5), vital signs, physical examinations, ophthalmologic 
examination, performance status, laboratory measurements (hematology, clinical chemistry, etc), 
and other assessments including those listed in Appendix 2. 
At the start of each cycle, study drug(s) will be administered only after clinical laboratory results 
have been reviewed. Administration of dinutuximab beta will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (for additional information, see Section 5.2). 
Investigators are instructed to report all AEs (includes pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in Section 9.6. 
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9.2. 
Adverse Events  
9.2.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
drug(s), whether considered related to study drug(s) or not. 
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug(s) administration even 
though the condition might have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug(s) or a concurrent medication (overdose per se should not be reported as an AE 
or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records before submission to the sponsor. 
9.2.2. 
Assessment of Severity  
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon NCI-CTCAE version 5.0. 
Toxicities that are not specified in NCI-CTCAE will be defined as follows: 
• 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 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or life-
threatening [Grade 4]); whereas, seriousness is classified by the criteria based on the regulatory 
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definitions. Seriousness serves as the guide for defining regulatory reporting obligations from the 
sponsor to applicable regulatory authorities as described in Section 9.5.2. 
9.2.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug(s) and the 
occurrence of each AE or SAE using best clinical judgment. Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the AE or SAE to the study drug(s) should be considered and investigated. The 
investigator should consult the Dinutuximab Beta’s Prescribing Information in the determination 
of his/her assessment. 
There may be situations when an SAE has occurred and the investigator has only limited 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before transmission of the SAE report to 
the sponsor because the causality assessment is one of the criteria used when determining 
regulatory reporting requirements. The investigator may subsequently change his/her opinion of 
causality considering follow-up information and may amend the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on all information available at the time of reporting. An AE is considered 
related if there is “a reasonable possibility” that the AE may have been caused by the study 
drug(s) (ie, there are facts, evidence, or arguments to suggest possible causation). A number of 
factors should be considered in making this assessment, including: 
• Temporal relationship of the AE to the administration of study drug/study procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug(s) 
• Biological plausibility 
• An AE should be considered “related” to study drug(s) if any of the following criteria 
are met; otherwise, the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
− There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely. 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug[s]). However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
9.2.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
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All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the timeframes outlined in Section 9.5.2. 
9.2.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and that significantly worsen during the study. The definition of “clinically significant” 
is left to the judgment of the investigator. In general, these are the laboratory test abnormalities 
or other abnormal assessments that: 
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to treatment interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis 
(ie, cholestasis) should be recorded on the AE eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the AE eCRF unless the etiology changes. The initial severity of 
the event should be recorded and the severity or seriousness should be updated any time the 
event worsens. 
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9.3. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it was more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are NOT considered to be SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
9.4. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the study drug’s reference safety information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the Dinutuximab Beta’s Prescribing Information. 
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9.5. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
9.5.1. 
Adverse Event Recording Period  
After informed consent has been signed but before the administration of the study drug(s), only 
SAEs should be reported. 
After the first dose of study drug(s), all AEs and SAEs, regardless of relationship to study drug, 
will be reported until 40 days after last dose of study drug. All SAEs considered related to the 
study drug(s) that are brought to the attention of the investigator should be reported regardless of 
time since the last dose of treatment. 
AEs and SAEs should be recorded according to the details in Table 5. For the follow-up period 
for AEs, see Section 9.2.4. For the definition of treatment-emergent adverse events (TEAEs), see 
Section 10.2.2. 
Table 5: 
Guidance for Duration of Recording New or Worsening Adverse Events  
Event Type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEs a          
Signing of informed consent 
Up to 40 days after last dose of 
study drug; initiation of new 
anticancer therapy, death, 
withdrawal of consent, or loss to 
follow-up, whichever comes 
first 
All nonserious AEs 
First dose of study drug 
Up to 40 days after last dose of 
study drug; initiation of new 
anticancer therapy, death, 
withdrawal of consent, or loss to 
follow-up, whichever comes 
first 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
 a All SAEs considered related to the study drug(s) that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment. 
9.5.2. 
Reporting Serious Adverse Events  
9.5.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 6. 
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Table 6: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for 
sending initial 
report 
Documentation 
method 
Timeframe for 
sending follow-
up report 
Documentation 
method 
Reporting 
method 
All SAEs 
Within 24 hours 
of first 
knowledge of 
the SAE 
SAE report 
As expeditiously 
as possible 
SAE report 
Email or fax 
SAE report form 
Abbreviations: SAE, serious adverse event. 
9.5.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours, as outlined above in Section 9.5.2.1. The SAE report 
will always be completed as thoroughly as possible, including all available details of the event 
and forwarded to the sponsor or designee within the designated timeframes. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 9.2.3. 
The sponsor will provide contact information for SAE receipt. 
9.5.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 9.5.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a drug under clinical 
investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All suspected unexpected serious adverse reactions (as defined in Section 9.4) will be submitted 
to all applicable regulatory authorities and investigators for dinutuximab beta studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
safety reports from the sponsor in the investigator site file. 
9.5.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
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• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
9.5.4. 
Progressive Disease  
As PD is expected in this study population, the term “disease progression” should not be reported 
as an AE term. Instead the symptoms, signs, or clinical sequelae that result from PD should be 
reported as the AE term(s). For instance, in a patient who presents with pleural effusion resulting 
from PD of metastasis to the lungs, the event term should be reported as “pleural effusion” 
instead of “disease progression.” If a patient experiences fatal multiorgan failure due to PD, the 
term “multiorgan failure” should be reported as the SAE with death as the outcome, instead of 
“fatal disease progression” or “death due to disease progression.” All nonserious AEs, SAEs, and 
deaths, regardless of relatedness to PD, should be recorded and reported. 
9.5.5. 
Deaths  
Death is an outcome and not usually considered an AE. If the only information available is death 
and the cause of death is unknown, then the death is reported as an AE (eg, “death,” “death of 
unknown cause,” or “death unexplained”). 
9.5.6. 
Recording Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving study 
drug(s) or within 180 days after the last dose of dinutuximab, a pregnancy report form must be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should always be reported as a 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug(s) should be recorded and reported as a SAE. 
9.5.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information documents: 
• Dinutuximab Beta’s Prescribing Information 
• local label of 13-cis-retinoic acid 
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9.5.8. 
Recording Infusion-Related Reactions  
The symptoms of infusion-related reactions may include but are not limited to fever, chills/rigor, 
nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, 
myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory distress  
syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Each of the 
individual signs and symptoms of an infusion reaction should be recorded as a separate AE in the 
eCRF and identified as an infusion-related reaction. Refer to the eCRF completion guidelines for 
details. 
9.6. 
Risks Associated With Dinutuximab Beta  
Hypersensitivity Reactions  
Severe infusion-related reactions including cytokine release syndrome (CRS) and anaphylactic 
and hypersensitivity reactions may occur despite the use of premedication. Occurrence of a 
severe infusion-related reaction (including CRS) requires immediate discontinuation of 
dinutuximab beta therapy and may necessitate emergency treatment.  
CRS frequently manifests itself within minutes to hours of initiating the first infusion and is 
characterized by systemic symptoms such as fever, hypotension, and urticaria.  
Anaphylactic reactions may occur as early as within a few minutes of the first infusion with 
dinutuximab beta and are commonly associated with bronchospasm and urticaria. 
Treatment of Hypersensitivity Reactions  
Antihistamines, epinephrine (adrenaline), and prednisolone for intravenous administration should 
be immediately available at the bedside during administration of dinutuximab beta to manage 
life-threatening allergic reactions. Treatment for such reactions should include prednisolone and 
epinephrine administered by intravenous bolus every 3 to 5 minutes as necessary according to 
clinical response. In case of bronchial and/or pulmonary hypersensitivity reaction, epinephrine 
(adrenaline) inhalation is recommended and should be repeated every 2 hours according to 
clinical response. 
Capillary Leak Syndrome  
Capillary leak syndrome (CLS) is characterized by a loss of vascular tone and extravasation of 
plasma proteins and fluid into the extravascular space. CLS usually develops within hours after 
initiation of treatment, whereas clinical symptoms (ie, hypotension, tachycardia) are reported to 
occur after 2 to 12 hours. Careful monitoring of circulatory and respiratory function is required. 
Neurological Disorders of The Eye  
Eye disorders may occur as dinutuximab beta binds to optic nerve cells. No dose modification is 
necessary in the case of an impaired visual accommodation that is correctable with eyeglasses, as 
long as this is judged to be tolerable. 
Treatment must be interrupted in patients who experience Grade 3 vision toxicity (ie, subtotal 
vision loss per toxicity scale). In case of any eye problems, patients should be referred promptly 
to an ophthalmology specialist. 
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Peripheral Neuropathy  
Occasional occurrences of peripheral neuropathy have been reported with dinutuximab beta. 
Cases of motor or sensory neuropathy lasting > 4 days must be evaluated and non-inflammatory 
causes such as disease progression, infections, metabolic syndromes, and concomitant 
medication should be excluded. 
Treatment should be permanently discontinued in patients experiencing any objective prolonged 
weakness attributable to dinutuximab beta administration. For patients with moderate (Grade 2) 
neuropathy (motor with or without sensory), treatment should be interrupted and may be 
resumed after neurologic symptoms resolve. 
Systemic Infections  
Patients are likely to be immunocompromised as a result of prior therapies. As they typically 
have a central venous catheter in situ, they are at risk of developing systemic infection. Patients 
should have no evidence of systemic infection and any identified infection should be controlled 
before starting therapy. 
Hematologic Toxicities  
Occurrence of hematologic toxicities such as erythropenia, thrombocytopenia, or neutropenia has 
been reported with dinutuximab beta. Grade 4 hematologic toxicities improving to ≤ Grade 2 or 
baseline values by start of next treatment course do not require dose modification. 
Laboratory Abnormalities  
Regulatory monitoring of liver function and electrolytes is recommended. 
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10. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
10.1. 
Statistical Analysis  
10.1.1. 
General Consideration  
For qualitative variables, the population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented. Quantitative 
variables will be summarized using descriptive statistics, including N, mean, standard deviation, 
median, minimum, and maximum values. Geometric mean and geometric coefficient of variation 
(CV) % will be included for PK parameters, where applicable. Coefficient of variation will not 
be presented for change-from-baseline results. 
All derivations, statistical analyses, summaries, and listings will be generated using SAS Version 
9.2 or higher (SAS Institute, Inc., Cary, North Carolina). Non-compartmental PK parameter 
calculations will be performed using Phoenix® WinNonlin® (Certara, Princeton, New Jersey). 
Graphics may be prepared using the same versions of SAS, or Phoenix WinNonlin, or with 
SigmaPlot 12.5, or higher (Systat Software, Inc., San Jose, California). 
10.1.2. 
Analysis Sets  
For purposes of analysis, the following analysis sets are defined: 
Table 7: 
Populations for Analysis 
Population (Analysis Set) 
Description 
Safety Analysis Set 
The Safety Analysis Set (SAS) will include patients who have 
received at least 1 dose of study drug. 
Pharmacokinetic (PK) Analysis 
Set 
The PK Analysis Set (PKS) will include patients who have at least 
one available post-baseline PK data in Safety Analysis Set. 
The safety analysis set (SAS) will be the primary analysis set for all safety analyses and the 
pharmacokinetic analysis set (PKS) will be used in pharmacokinetic analysis.  
The safety analysis set (SAS) will be the primary analysis set for all efficacy analyses. 
10.1.3. 
Patient Disposition  
The number of patients treated, discontinued from study drug(s) and/or the study, and those with 
important protocol deviations will be counted in SAS. The primary reason for study drug(s) 
and/or study discontinuation will be summarized according to the categories in the eCRF. The 
end-of-study status (dead, withdrew consent, or lost to follow-up) at the data cutoff date will be 
summarized using the data from the eCRF. 
Important protocol deviations will be summarized and listed by category. 
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10.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized in the Safety Analysis Set 
and descriptive statistics. 
Baseline patient characteristics will include a summary of the following: 
• Patient demographics 
• Baseline disease characteristics 
• Prior anti-cancer therapies 
Other patient characteristics will be summarized as deemed appropriate. 
10.1.5. 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of first dose of 
study drug(s). Concomitant medications will be defined as medications that 1) started before the 
first dose of study drug(s) and were continuing at the time of the first dose of study drug(s), or 
2) started on or after the date of the first dose of study drug(s) up to 40 days after the patient’s 
last dose (as of the Safety Follow-up Visit). Concomitant medications will be coded using the 
World Health Organization Drug Dictionary drug codes and will be further coded to the 
appropriate Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior 
and concomitant medications will be summarized and listed by drug and drug class. A listing of 
prior and concomitant medications will be provided. 
10.2. 
Safety Analyses  
Safety is the primary endpoint and will be assessed by AEs as characterized by type, frequency, 
severity (as graded by the NCI-CTCAE version 5.0), time, seriousness, and relationship to study 
drug(s), vital signs and laboratory abnormalities. Extent of exposures, Physical examinations, 
and ECG findings will also be used in determining the safety profile. TEAEs will be reported as 
the number (percentage) of patients with TEAEs by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term. Descriptive summary statistics (eg, n, mean, 
standard deviation, median, minimum, and maximum for continuous variables; n [%] for 
categorical variables) and changes from baseline will be determined for laboratory parameters 
and vital signs. 
Safety data will be summarized using the SAS. 
10.2.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring treatment interruption, dose delay, and drug 
discontinuation because of AEs will be summarized. Frequency of the above dose adjustments 
and discontinuation will be summarized by category. Reasons for dose modifications will be 
summarized as well. 
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Patient data listings will be provided for all dosing records and for calculated summary statistics. 
10.2.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA (version 20.1 or higher) lowest level term, preferred 
term, and primary system organ class. 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug(s) and up to 40 days following last dose of 
study drug or initiation of new anticancer therapy, whichever occurs first. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE version 5.0 within a system organ class and preferred term, even 
if the patient experienced ≥ 1 TEAE within a specific system organ class and preferred term. The 
number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug(s). 
Treatment-related AEs include those events considered by the investigator to be related to study 
drug or with missing assessment of the causal relationship. SAEs, deaths, ≥ Grade 3 TEAEs, 
treatment-related TEAEs, and TEAEs that led to treatment discontinuation, treatment 
interruption, or dose delay will be summarized. 
10.2.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, clinical chemistry) values will be evaluated for each 
laboratory parameter as appropriate. Abnormal laboratory values will be flagged and identified 
as those outside (above or below) the normal range. Reference (normal) ranges for laboratory 
parameters will be provided. Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, and maximum for continuous variables; n [%] for categorical variables) for 
laboratory parameters and their changes from baseline will be calculated. Laboratory values will 
be summarized by visit and by visit with the maximum postbaseline change. 
Laboratory parameters that are graded by NCI-CTCAE version 5.0 or higher will be summarized 
by NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, 
parameters with NCI-CTCAE grading in both high and low directions (eg, calcium, glucose, 
magnesium, potassium, and sodium) will be summarized separately. 
10.2.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
and body temperature) and changes from baseline will be presented by visit for all visits. Vital 
signs will be listed by patient and visit. 
10.2.5. 
Ophthalmologic Examination  
Ophthalmologic examination results will be listed by patient if available. 
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10.2.6. 
Physical Examinations  
Physical examination results will be listed by patients. 
10.3. 
Pharmacokinetic Analyses  
Blood samples will be collected on Day 1, 3, 8, 11, 15 (optional), 22 (optional), and 29 in Cycle 
1, and on Day 1 and 11 in Cycle 2, 3 and 4 to measure serum concentrations of dinutuximab 
beta. Serum concentration-time data of each patient will be tabulated and graphically presented 
on linear semi-logarithmic scales. PK parameters will be determined using a standard non-
compartmental analysis method in PK analysis set. Descriptive statistics will be used, including 
means, standard deviations, medians, ranges, geometric mean, and CV % associated to the 
geometric mean as appropriate. A listing of patients excluded from the analysis set and 
individual data points excluded from the analysis will be provided. 
PK parameters will include, but are not limited to the following as allowed by data: 
• Cmax (ng/mL): Maximum serum concentration 
• tmax (hour): Time to maximum serum concentration 
• Cmin (ng/mL): Minimum serum concentration 
• t1/2 (hour): Half-life 
• AUC0-t (ng·h/mL): Area under the serum concentration-time curve from zero to the 
last measurable concentration 
• AUC0-∞ (ng·h/mL): Area under the serum concentration-time curve from zero to 
infinity 
10.4. 
Exploratory Efficacy Analyses  
No formal hypothesis testing is planned in this trial. Tumor assessment based on investigator 
assessment will be used to calculate EFS as well as time-point estimates including EFS-6m by 
Kaplan-Meier method. 95% confidence intervals will be constructed to describe the precision of 
the point estimates of interest (e.g. median EFS, EFS-6m) if estimable.  
Event-free survival (EFS) is defined as the time from initiating study drug(s) to disease 
progression, death from any cause, relapse, secondary malignancy as assessed by investigators. 
A listing of patients in Safety Analysis Set will be provided. 
10.5. 
Other Exploratory Analyses  
Not applicable. 
10.6. 
Sample Size Consideration  
The study plans to enroll approximately 8 patients as recommended for PK studies by Center of 
Drug Evaluation (CDE) technical guidance on clinical pharmacokinetic study of chemical drugs 
(CDE of National Medical Products Administration (NMPA) 2005). Therefore, a sample size of 
approximately 8 patients is proposed in this single-arm PK study. 
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10.7. 
Interim Analyses  
Not applicable. 
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11. 
STUDY COMMITTEES  
Not applicable. 
 
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12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include but are not limited to the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
12.1. 
Access to Information for Monitoring  
In accordance with International Council for Harmonisation GCP guidelines, the study monitor 
must have direct access to the investigator’s source documentation to verify the data recorded in 
the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries in the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
12.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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13. 
QUALITY ASSURANCE AND QUALITY CONTROL  
13.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
13.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
13.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
13.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug(s). This includes acknowledgment of receipt of each shipment 
of study drug(s) (quantity and condition), patient drug dispensation records, and returned or 
destroyed study drug(s). Dispensation records will document quantities received from BeiGene’s 
designated depot or its designee and quantities dispensed to patients, including batch/lot number, 
date dispensed, patient identifier number, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements specified in the 
Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the study 
following final drug inventory reconciliation by the monitor, the study site will dispose of and/or 
destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet BeiGene’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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14. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
14.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the International Council for Harmonisation E6 guideline for GCP and the 
principles of the Declaration of Helsinki or the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the patient. The study will also 
comply with the requirements of the International Council for Harmonisation E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
14.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC. Copies 
of the IEC/IRB correspondence and approval of the amended ICF/other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
Investigational New Drug Safety Reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
14.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
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14.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements. 
The ICFs must be signed and dated by the patient (if the patient is capable) and patient’s legally 
authorized representative before his or her participation in the study. The case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
14.4. 
Patient and Data Confidentiality  
The investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study. 
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
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• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives. 
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) designated 
by sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws. If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of the United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (China NMPA), and all other national and local 
health authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs 
for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from the sponsor. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
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If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
14.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators and/or disclose those 
financial interests, as required, to the appropriate health authorities. This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor. 
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 
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15. 
DATA HANDLING AND RECORD KEEPING  
15.1. 
Data Collection and Management Responsibilities  
15.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
15.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
15.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol will be stored by BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor will make site visits to review protocol compliance, compare 
eCRFs against individual patient’s medical records, and ensure that the study is being conducted 
according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits, and will be carried out with due consideration to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by lowest level term, preferred term, and primary 
system organ class. Concomitant medications will be coded using the World Health Organization 
Drug Dictionary. Concomitant diseases/medical history will be coded using MedDRA. 
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15.2. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file and/or 
2) patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include but not be limited to 
documents such as the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, pathology and 
special assessment reports, consultant letters, screening and enrollment logs, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements including 
but not limited to the following: archival at an off-site facility or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and BeiGene to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the Contract Research Organization (CRO) managing the biological samples, for the shorter 
of: a period of up to 10 years or as allowed by your IRB/IEC. 
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15.3. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. Notwithstanding, in China, unless otherwise provided by China GCP, 
investigator shall not deviate from this protocol without IRB/IEC and BeiGene’s approval.  
15.4. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies). BeiGene will 
ensure that the report meets the standards set out in the International Council for Harmonisation 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated report 
may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. For a multicenter study, the first publication or disclosure of 
study results shall be a complete, joint multicenter publication, or disclosure coordinated by the 
sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
15.5. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return/provide all study data to the sponsor 
• Resolution and closure of all data queries 
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• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including but not limited to those for PK) to the assay 
laboratory for central laboratory analysis according to protocol and laboratory manual 
requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to: safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations. If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study. 
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
15.6. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel.  
This information and data will not be used, by the investigator or other study center personnel for 
any purpose other than conducting the study, without the prior written consent of the sponsor. 
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These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 15.4 
If a written contract for the conduct of the study, which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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16. 
REFERENCES  
Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for 
neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 
Aug;11(8):1466-77. 
CDE meeting minutes for Qarziba pre-BLA communication dated 27 March 2019. 
Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) 
Technical Guideline for Clinical Pharmacokinetics Research of Chemical Drugs. 2005. Assessed 
May 20, 2020.http://www.nmpa.gov.cn/gsz05106/07.pdf.  
Colon NC and Chung DH. Neuroblastoma. Adv Pediatr. 2011;58(1):297‐311. 
Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) 
classification system: an INRG Task Force report. J Clin Oncol 2009;27(2):289-97. 
Chinese Children Cancer Group and Pediatric Surgery Society of Chinese Medical Association. 
Expert consensus on the diagnosis and treatment of children’s neuroblastoma. Chin J Pediatr 
Surg. 2015;36(1):3-7. 
Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. Assessed September 15, 2014. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
Dinutuximab Beta’s Prescribing Information. Assessed May 17, 2023. 
https://www.ema.europa.eu/en/documents/product-information/qarziba-epar-product-
information_en.pdf 
European Medicines Agency, Committee for Human Medicinal Products (CHMP). ICH 
Guideline S9: Q&As on Nonclinical Evaluation for anticancer pharmaceuticals. 2014. Accessed 
July 26, 2016. https://www.infarmed.pt/documents/15786/1568238/S9/f39561e6-8e69-4bf4-
91bf-81fc679e5b01. 
EUSA Investigator’s Brochure, Dinutuximab beta. Version 3.0, May 2019. 
US Department of Health and Human Services Food and Drug Administration (FDA). Drug 
development and drug interactions: table of substrates, inhibitors and inducers. Accessed 
September 26, 2016. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers.  
Gillies SD, Lo KM, Wesolowski J. High-level expression of chimeric antibodies using adapted 
cDNA variable region cassettes. J Immunol Methods 1989;125(1-2):191-202. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 2016. Assessed 
August 8, 2017. http://www.icmje.org.  
Lacayo NJ, Davis KL. What is the global prevalence of pediatric neuroblastoma. Assessed 
September 17, 2019. https://www.medscape.com/answers/988284-188893/what-is-the-global-
prevalence-of-pediatric-neuroblastoma. 
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Lansky LL, List MA, Lansky SB, et al. Toward the development of a play performance scale for 
children (PPSC). Cancer. 1985;56(7 Suppl):1837-40. 
Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202-11. 
Modak S and Cheung NK. Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer 
Treat Rev. 2010;36(4):307-17. 
Mor V, Laliberte L, Morris JN, et al. The Karnofsky Performance Status scale. An examination 
of its reliability and validity in a research setting. Cancer 1984;53: 2002-07. 
Navid F, Santana VM, Barfield RC. Anti-GD2 antibody therapy for GD2-expressing tumors. 
Curr Cancer Drug Targets. 2010;10(2):200‐9. 
Papaioannou G and McHugh K. Neuroblastoma in childhood: review and radiological findings. 
Cancer Imaging. 2005;5(1):116‐27. 
Risk Management Plan (RMP) for Qarziba, Version 1.0, 07 Aug 2019. 
Qarziba (dinutuximab beta) [EU summary of product characteristics]. EUSA Pharma; 2020. (for 
reference: https://www.ema.europa.eu/en/medicines/human/EPAR/qarziba) 
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 
antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 
2010;363(14):1324-34. 
Zhao L, Ren TH, Wang DD. Clinical pharmacology considerations in biologics development. 
Acta Pharmacol Sin. 2012;33(11):1339-47. 
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17. 
APPENDICES  
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
 
Screening 
(Day −28  
to Day −1) 
 
 
 
 
Cycles 1 to 5 
EOT/early 
termination b 
Safety  
follow-up c 
Visit day 
 
Day 1a 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11a 
Day 12 
Day 15 
Day 22 
Day 25 
Day 29 
Day 35 
-7 to 7 
days or 
0 to 7 
days 
+ 40 
days 
Visit window 
 
± 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
± 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygen saturation on room air 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test in WOCBPd 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg/HCV-Abe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Height/weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinations f  
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
Vital signs 
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
Performance status 
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
ECHO or MUGA scan 
X 
As clinically indicated 
X 
X 
12-Lead ECG g 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Chest X-Ray h 
 
X 
As clinically indicated 
 
 
Complete blood count 
(including differential 
count)/biochemistry i, j 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Urinalysis i, j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Coagulation i, j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Dinutuximab beta infusion k 
 
  X------------------Continuous infusion---------------------X 
 
 
 
 
 
 
 
 
13-cis-RA 
 
 
 
 
 
 
 
 
 
 
 
 
X------------------X 
 
 
 
 
PK sampling in Cycle 1l 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
Xm 
Xm 
 
X 
 
 
 
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PK sampling in Cycle 2-4 l 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Tumor assessments n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse events 
  X------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant medications o 
  X------------------------------------------------------------------------------------------------------------------------------------------X 
Abbreviations: AE, adverse event; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; EOT, end of treatment; HBsAg, hepatitis B surface antigen; 
HCV-Ab, hepatitis C virus antibody; INRC, international neuroblastoma response criteria; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; MUGA, 
multigated acquisition scan; PK, pharmacokinetic(s); QTcF, QT interval corrected for heart rate using Fridericia’s formula; WOCBP, woman of childbearing potential; 123I, 
iodone-123. 
a Day 1 evaluations must be done before the start of the dinutuximab beta infusion. Day 11 evaluations must be done just before the end of the dinutuximab beta infusion. 
b The EOT Visit is conducted within ± 1 week of the end of Cycle 5. For early termination, the EOT Visit is conducted ≤ 7 days after the investigator determines that the patient 
must permanently discontinue the study drug or the patient decides to withdraw from the study before the end of Cycle 5. 
c Safety Follow-up Visit: within 40 days [± 7 days] after last dose of study drug; initiation of new anticancer therapy, death, withdrawal of consent, or loss to follow-up, 
whichever comes first. 
d Pregnancy test in WOCBP is described in Appendix 4.  
e If HCV-Ab positive, HCV-RNA test will be required for eligibility check. 
f Physical examinations is presented in Section 8.2.2.  
g At each timepoint, 3 consecutive 12-lead ECGs should be performed approximately 2 minutes apart to determine the mean QTcF interval. 
h Chest X-ray should be performed within 7 days before the start of dinutuximab beta infusion in each cycle. It can be skipped if chest MRI or CT scan has been performed 
already before administration per investigator’s discretion.  
i If clinical chemistry, hematology, coagulation and urinalysis at screening are not performed ≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should 
be repeated and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be reviewed within 72 hours before study drug administration 
(Section 8.2.5). 
j The test for clinical chemistry, hematology, coagulation, and urinalysis, excluding PK sampling, will be performed within 72 hours before study drug administration on Day 1 
of each cycle. All laboratory tests with values considered clinically abnormal during participation in the study or within 40 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor (Section 8.2.5). 
k The recommended dose of dinutuximab beta depends on the patient’s body surface area (BSA) and the actual dose is calculated on every Day 1 of Cycle 1 to 5 (BSA = SQRT 
[weight (kg) x height (cm)/ 3600]). 
l PK sampling time refers to Table 4 provided in Section 8.3. 
m PK sampling on Day 15 and Day 22 in Cycle 1 is optional. 
n Tumor assessments will be performed by the investigators at Screening Visit, end of treatment Cycle 3 and end of treatment Visit per their clinical practice. The INRC 
(Brodeur et al 1993) is recommended as a reference for response evaluation in patients evaluable for response. Tumor assessments may include MRI and/or CT scan and/or 
123I-MIBG scan and/or 18F-FDG-PET and/or bone marrow assessment. 
o Concomitant medications will be defined as medications that started before the first dose of study drug(s) and were continuing at the time of the first dose of study drug(s), or 
started on or after the date of the first dose of study drug(s) up to 40 days after the patient’s last dose (as of the Safety Follow-up Visit) in Section 10.1.5. 
 
X: evaluations must be regularly repeated during the timepoints indicated according to routine medical care to ensure safe treatment of the patient. 
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Table 8: 
Protocol-Required Safety Laboratory Assessments 
Clinical chemistry 
Hematology 
Coagulation 
Urinalysisa 
Alanine aminotransferase 
Aspartate 
aminotransferase 
Total bilirubin 
Potassium 
Sodium 
Total calcium 
Creatinine 
Chloride 
C-reactive protein 
Gamma-glutamyl 
transferase 
 
Hemoglobin 
Platelet count 
White blood cell count 
Lymphocyte count 
Neutrophil count 
Basophils 
Prothrombin time 
Activated partial 
thromboplastin time 
International 
normalized ratio 
Glucose 
Protein 
Blood 
Ketones 
 
In case of abnormal result: urinary sediment assessment (red blood cells per high-power field, white blood cells per 
high-power field, cellular casts) 
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APPENDIX 3. PERFORMANCE STATUS  
Lansky Play-Performance Scale (for patients ≤ 16 years) 
100 - Fully active, normal 
90 - Minor restrictions in physically strenuous activity 
80 - Active but tires more quickly 
70 - Both greater restriction of and less time spent in play activity 
60 - Up and around but minimal active play; keeps busy with quieter activities 
50 - Gets dressed but lies around much of the day; no active play but able to participate in 
all quiet play and activities 
40 - Mostly in bed; participates in quiet activities 
30 - In bed; needs assistance even for quiet play 
20 - Often sleeping; play entirely limited to very passive activities 
10 - No play; does not get out of bed 
0 - Unresponsive 
Karnofsky Performance Scale (for patients > 16 years) 
100 - Normal, no complaints, no evidence of disease 
90 - Able to carry on normal activity; minor signs or symptoms of disease 
80 - Normal activity with effort; some signs or symptoms of disease 
70 - Cares for self; Unable to carry on normal activity or do active work 
60 - Requires occasional assistance but is able to care for most of own needs 
50 - Requires considerable assistance and frequent medical care 
40 - Disabled; requires special care and assistance 
30 - Severely disabled; hospitalization hospitalisation is indicated although death is not imminent 
20 - HospitalizationHospitalisation necessary; very sick, active supportive treatment necessary 
10 – Moribund; fatal processes progressing rapidly 
0 - Dead 
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APPENDIX 4. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control 
(Clinical Trials Facilitation Group 2014). These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation: 
− Oral, injectable, or implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized male partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for azoospermia has been demonstrated in a semen sample 
examination as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study drug).  
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is 
in line with the patient’s usual and preferred lifestyle. Periodic abstinence 
(eg, calendar, ovulation, symptothermal, or postovulation methods), declaration of 
abstinence for the duration of exposure to study drug(s), and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with another acceptable method listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
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Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group 2014. 
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STATISTICAL ANALYSIS PLAN 
 
 
Study Protocol Number: 
BGB-dinutuximab beta-101 
Study Protocol Title: 
An Open-Label, Multi-Center, Single-Arm, Phase 1 Study 
Evaluating the Safety and Pharmacokinetics of Dinutuximab Beta 
as Maintenance Therapy in Chinese Patients with High-Risk 
Neuroblastoma 
Date: 
6 July 2023 
Version: 
1.0 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
1. ................ INTRODUCTION ........................................................................................................5 
2. ................ STUDY OVERVIEW ...................................................................................................5 
3. ................ STUDY OBJECTIVES ................................................................................................6 
3.1. ............. Primary Objective .........................................................................................................6 
3.2. ............. Secondary Objective .....................................................................................................7 
3.3. ............. Exploratory Objective ...................................................................................................7 
4. ................ STUDY ENDPOINTS ..................................................................................................7 
4.1. ............. Primary Endpoint(s) ......................................................................................................7 
4.2. ............. Secondary Endpoints ....................................................................................................7 
4.3. ............. Exploratory Endpoints ..................................................................................................7 
5. ................ SAMPLE SIZE CONSIDERATIONS .........................................................................7 
6. ................ STATISTICAL METHODS .........................................................................................7 
6.1. ............. Analysis Sets .................................................................................................................7 
6.2. ............. Multiplicity Adjustment................................................................................................8 
6.3. ............. Data Analysis General Considerations .........................................................................8 
6.3.1. .......... Definitions and Computations ......................................................................................8 
6.3.2. .......... Conventions ..................................................................................................................8 
6.3.3. .......... Handling of Missing Data .............................................................................................9 
6.4. ............. Patient Characteristics ..................................................................................................9 
6.4.1. .......... Patient Disposition ........................................................................................................9 
6.4.2. .......... Protocol Deviations ......................................................................................................9 
6.4.3. .......... Demographic and Other Baseline Characteristics ........................................................9 
6.4.4. .......... Disease History ...........................................................................................................10 
6.4.5. .......... Prior Anticancer Therapies .........................................................................................10 
6.4.6. .......... Prior and Concomitant Medications ...........................................................................10 
6.4.7. .......... Medical History ..........................................................................................................10 
6.5. ............. Efficacy Analysis ........................................................................................................10 
6.5.1. .......... Efficacy Endpoint(s) ...................................................................................................10 
6.6. ............. Safety Analyses ..........................................................................................................11 
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6.6.1. .......... Extent of Exposure .....................................................................................................11 
6.6.2. .......... Adverse Events ...........................................................................................................12 
6.6.3. .......... Laboratory Values ......................................................................................................13 
6.6.4. .......... Vital Signs ..................................................................................................................14 
6.6.5. .......... Electrocardiograms (ECG) .........................................................................................14 
6.7. ............. Pharmacokinetic Analyses ..........................................................................................14 
6.7.1. .......... Reporting of Pharmacokinetic Concentrations for Descriptive Statistics ..................15 
6.7.2. .......... Plots of Pharmacokinetic concentrations ....................................................................15 
6.7.3. .......... Reporting of PK parameters for Descriptive Statistics ...............................................15 
7. ................ INTERIM ANALYSES ..............................................................................................16 
8. ................ CHANGES IN THE PLANNED ANALYSIS ...........................................................16 
9. ................ REFERENCES ...........................................................................................................17 
APPENDIX 1. SCHEDULE OF ASSESSMENT.......................................................................18 
APPENDIX 2. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES...............21 
 
 
LIST OF TABLES  
Table 1: ..... Handling of Intercurrent Events and Missing Values of Event Free Survival ...........11 
Table 2: ..... Laboratory Tests .........................................................................................................13 
Table 3: ..... Statistical Analysis Plan Changes ...............................................................................16 
Table 4: ..... Dinutuximab Beta PK Sampling Schedule .................................................................20 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the concentration-time curve 
BLQ 
below the limit of quantification 
CV 
coefficient of variation 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CTCAE 
common terminology criteria for adverse events 
ECG 
electrocardiogram 
EFS 
event free survival 
EOT 
end of treatment 
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
PK 
pharmacokinetic 
QTcF 
corrected QT interval by Fredericia 
RA 
retinoic acid 
SAE 
serious adverse event 
SD 
standard deviation 
TEAE 
treatment emergent adverse event 
tmax 
Time to maximum serum concentration 
t1/2 
half-life 
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1. 
INTRODUCTION  
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for BGB-dinutuximab beta-101. The 
focus of this SAP is for the final analysis specified in the study protocol.  
2. 
STUDY OVERVIEW  
This is an open-label, multi-center, single-arm, Phase 1 study evaluating the safety and 
pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese patients with high-risk 
neuroblastoma.  
Potential patients will be screened for eligibility before study enrollment (screening period 
≤ 28 days). The study will recruit approximately 8 patients who will be hospitalized (with a full 
resuscitation equipment) on Day 1 of each cycle and will receive continuous infusion of 
dinutuximab beta administered at a dose of 10 mg/m2/day for 10 consecutive days in 35-day 
cycles (total dose 100 mg/m2/cycle). Patients must be administered in a unit with a full 
resuscitation equipment. Patients will be discharged from the hospital at the investigator’s 
discretion. Patients will continue to receive 13-cis-RA 160 mg/m²/day, divided approximately 
into 2 equal doses and given orally twice a day for 14 days after completion of dinutuximab beta 
infusion. 
Patients may receive up to five 35-day cycles in the absence of relapse, disease progression or 
unacceptable toxicity. 
Refer to Figure 1 for an overview of the study design and Appendix 1 for details on study 
assessments and procedures that will be carried out during the study. 
The maximum duration of participation (Screening Visit to Safety Follow-up Visit) for 
individual patients will be approximately 35 weeks. Each patient will participate in the screening 
period (≤ 28 days), study intervention infusion period (≤ 25 weeks), and a post-infusion period 
(≤ 6 weeks). Additional clinical follow-up might be needed depending on findings during the 
study. 
 
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Figure 1: 
Study Schema 
 
Abbreviations: EOT, end of treatment; PK, pharmacokinetic(s). 
All patients will be closely monitored for AEs throughout the study and for 40 days after the last 
dose of study drug.  
PK analysis will be performed for dinutuximab beta.  
Tumor assessments or monitoring will be performed by the investigators at Screening Visit, end 
of treatment Cycle 3, and end of treatment Visit per their clinical practice. International 
Neuroblastoma Response Criteria (INRC) ( Brodeur et al 1993) is recommended as a reference 
for response evaluation in patients evaluable for tumor assessment. Patients who, at the time of 
progression, have an ongoing AE that leads to treatment discontinuation and who have 
completed the scheduled Safety Follow-up Visit will be followed up until the event resolves, the 
investigator assesses the event as stable, the patient is lost to follow-up, or the patient starts a 
new anticancer therapy, end of study, whichever comes first.  
Patients who have discontinued study drug(s) will return to the site for an End-of-Treatment 
(EOT) Visit. After the EOT Visit, patients will have scheduled follow-up visits for safety. 
3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective  
• To assess the safety and tolerability of ≤5 treatment cycles of dinutuximab beta in 
combination with 13-cis-retinoic acid (RA) as maintenance therapy in Chinese 
patients with high-risk neuroblastoma. 
• To characterize the pharmacokinetics (PK) of dinutuximab beta in Chinese patients. 
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3.2. 
Secondary Objective  
There is no secondary endpoint. 
3.3. 
Exploratory Objective  
• To explore the preliminary anti-tumor activity and event free survival rate (EFS), of 
≤5 treatment cycles of dinutuximab beta in combination with 13-cis-RA as 
maintenance therapy in Chinese patients with high risk neuroblastoma, if applicable 
4. 
STUDY ENDPOINTS  
4.1. 
Primary Endpoint(s)  
• Adverse events (AEs) characterized by type, frequency, severity (as graded by the 
National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-
CTCAE] version 5.0), timing, seriousness, and relationship to study drug(s); and 
other safety assessments. 
• PK parameters of dinutuximab beta, including but not limited to area under the 
concentration-time curve (AUC), maximum serum concentration (Cmax), minimum 
serum concentration (Cmin), time to Cmax (tmax), and half-life (t1/2), if data permits. 
4.2. 
Secondary Endpoints  
There is no secondary endpoint. 
4.3. 
Exploratory Endpoints  
• EFS is defined as the time from initiating study drug(s) to disease progression, death 
from any cause, relapse, secondary malignancy as assessed by investigators, including 
EFS rate at 6 months as measured by Kaplan-Meier method 
5. 
SAMPLE SIZE CONSIDERATIONS  
The study plans to enroll 8 patients as recommended for PK studies by Center of Drug 
Evaluation (CDE) technical guidance on clinical pharmacokinetic study of chemical drugs (CDE 
of National Medical Products Administration (NMPA) 2005). Therefore, a sample size of 8 
patients is proposed in this single-arm PK study. 
6. 
STATISTICAL METHODS  
6.1. 
Analysis Sets  
The Safety Analysis Set includes all patients who received any dose of any study drug. The 
safety analysis set is used for all primary safety and efficacy analyses 
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The PK analysis set includes patients who have at least one available post-baseline PK 
data in Safety Analysis Set. The PK analysis set will be used for PK analyses. 
6.2. 
Multiplicity Adjustment  
Since no formal hypothesis is tested in this study, multiplicity adjustment is not needed. 
6.3. 
Data Analysis General Considerations  
6.3.1. 
Definitions and Computations  
Study drugs include dinutuximab beta and 13-cis-RA therapy. 
Study day will be calculated in reference to the date of the first dose of study drug. For 
assessments conducted on or after the first dose, the study day will be calculated as assessment 
date – the first dose date + 1). For assessments conducted before the first dose, study day is 
calculated as (assessment date –the first dose date). There is no study day 0. In the situation 
where the event date is partial or missing, the date will appear partial or missing in the listings. 
Study day and any corresponding durations will be presented based on the imputations specified 
in Appendix 1. 
Unless otherwise specified, a baseline value is defined as the last non-missing value collected 
before the first dose of study drug. 
All calculations and analyses will be conducted using SAS® Version 9.4 or higher. 
6.3.2. 
Conventions  
No formal hypothesis will be tested in this study. Data will be mainly analyzed descriptively. 
Confidence intervals will be constructed to describe the precision of the point estimates of 
interest.  
Unless otherwise specified, the following conventions will be applied to all analyses: 
• 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal place. 
• 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded 
up to 1 decimal place. 
• Duration of image-based event will be based on the actual date the radiograph was 
obtained rather than the associated visit date. 
• For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
• For by-visit observed data analyses, percentages will be calculated based on the 
number of patients with non-missing data as the denominator, unless otherwise 
specified. 
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• For continuous endpoints, summary statistics will include n, mean, standard 
deviation, median, Q1, Q3 and range (minimum and maximum). 
• For discrete endpoints, summary statistics will include frequencies and percentages. 
6.3.3. 
Handling of Missing Data  
Missing data will not be imputed unless otherwise specified elsewhere in this SAP. Missing 
dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures. Specific rules are provided in Appendix 2. 
By-visit endpoints will be analyzed using observed data unless otherwise specified.  
6.4. 
Patient Characteristics  
6.4.1. 
Patient Disposition  
The number (percentage) of patients treated, discontinued from the study, reasons for 
discontinued from the study, and the duration of study follow-up will be summarized in the 
safety analysis set. The patients who discontinued treatment and the primary reason for the end 
of treatment will be summarized among patients who were treated. 
The following patient disposition information will be summarized separately for dinutuximab and 
13-cis-RA when appropriate: 
• Number of patients treated 
• Number (%) of treated patients who discontinued from treatment  
• Reason(s) for treatment discontinuation 
• Number (%) of treated patients who discontinued from study 
• Reason(s) for study discontinuation 
6.4.2. 
Protocol Deviations  
Important protocol deviation criteria will be established, and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be listed.  
6.4.3. 
Demographic and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized using descriptive statistics 
in the safety analysis set, including the following variables: 
• Age  
• Sex 
• Height 
• Weight 
• BMI 
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• Performance status 
6.4.4. 
 Disease History  
The number (percentage) of patients reporting a history of disease and characteristics, as 
recorded on the eCRF, will be summarized in the safety analysis set. A listing of disease history 
will be provided. 
6.4.5. 
Prior Anticancer Therapies  
Prior systemic therapies, prior anti-cancer radiotherapy, and prior stem cell transplantation will 
be summarized in the safety analysis set. The variables include number of patients with any prior 
anti-cancer therapy, number of prior regimens, and best overall response for prior systemic 
therapies, and transplantation type, number of transplantations for prior stem cell transplantation. 
The therapies with the same sequence/regimen number are counted as one prior therapy. 
6.4.6. 
Prior and Concomitant Medications  
Prior medications are defined as medications that started and stopped before the first dose of 
study drug. Concomitant medications will be defined as medications that (1) started before the 
first dose of study drug and were continuing at the time of the first dose of study drug, or 
(2) started on or after the date of the first dose of study, before the last dose of any study 
medication and continue up to 40 days after the patient's last dose (as of the Safety Follow-up 
Visit). 
Prior and concomitant medications will be coded using the version B3 202203 or higher of 
World Health Organization Drug Dictionary (WHO DD) drug codes. They will be further 
classified to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name in the safety analysis set. A 
listing of prior and concomitant medications will be provided. 
6.4.7. 
Medical History  
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.1 or higher. The number (percentage) of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by system organ class and preferred term 
in the safety analysis set. A listing of medical history will be provided. 
6.5. 
Efficacy Analysis  
6.5.1. 
Efficacy Endpoint(s)  
 
The analysis of event free survival (EFS) is based on the safety analysis set. EFS is defined as 
the time from initiating study drug(s) to disease progression, death from any cause, relapse, 
secondary malignancy as assessed by investigators. The distribution of EFS, including median, 
Q1 and Q3, and event-free rates at the 6th month, will be estimated using the Kaplan-Meier 
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method for each treatment group. Ninety-five percent CIs for median and Q1 and Q3 of EFS will 
be estimated using the method of Brookmeyer and Crowley (Brookmeyer and Crowley, 1982), 
and 95% CIs for event-free rates will be estimated using Greenwood's formula (Greenwood, 
1926). 
 The censoring rules for the primary analysis of EFS are presented in Table 1.   
Table 1: 
Handling of Intercurrent Events and Missing Values of Event Free Survival 
 
Derivation rules 
Outcome  
No event at the time of data 
cut-off or withdrawal from 
study or lost to follow up 
Date of last adequate radiologic assessment prior 
to or on date of data cut-off or withdrawal from 
study 
Censored  
Intercurrent events 
Discontinuation of the 
treatment 
Tumor assessment data collected after 
discontinuation of study treatment will be used 
for analysis (treatment policy strategy) 
No impact 
New anticancer therapy 
started prior to EFS events. 
Last adequate disease assessment before the new 
anticancer therapy (hypothetical strategy) 
 
Censored  
Missing values not related to intercurrent events 
Patients’ withdrawal from the 
study or lost to follow-up 
Last adequate disease assessment prior to patient 
withdrawal from the study (hypothetical strategy) 
Censored  
No baseline or post-baseline 
disease assessments without 
death 
Date of the first dose  
Censored  
disease assessments with 
death  
Date of death 
Event  
6.6. 
Safety Analyses  
All safety analyses will be performed based on the safety analysis set. Safety and tolerability will 
be assessed, where applicable, by incidence, severity, and change from baseline values for all 
relevant parameters including AEs, laboratory values, vital signs, ECG findings. Summaries will 
be separated for dinutuximab and 13-cis-RA only for extent of exposure and related treatment 
emergent adverse events (TEAEs, as defined in Section 6.6.2 ). 
6.6.1. 
Extent of Exposure  
The following measures of the extent of exposure will be summarized separately for 
dinutuximab and 13-cis-RA: 
• Duration of exposure (days): calculated as following:  
− For dinutuximab: earlier of (last dose date + 24 days, data cutoff date) + 1 - first 
dose date 
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− For 13cis-RA: earlier of (last dose date + 21 days, data cutoff date) + 1 - first dose 
date 
• Number of treatment cycles received: defined as the number of the last treatment 
cycles in which at least one dose of the study drug is administered. 
 
• Total dose received per patient (mg/m2 and mg): defined as the cumulative dose of 
the study drug during the treatment period of the study, with and without BSA 
adjustment. 
• Actual dose intensity per cycle (mg/m2/cycle): defined as the total dose received by a 
patient divided by the number of treatment cycles received. 
• Relative dose intensity per cycle (%): defined as the total dose received divided by 
protocol specified planned total dose for 5 cycles. 
• Dose reduction 
− Number of dose reductions and reasons 
− Number of dose-reduced cycles 
• Dose interruption 
− Number of dose reductions and reasons 
− Number of dose-interrupted cycles 
• Dose delay and reason 
6.6.2. 
Adverse Events  
AEs will be graded by investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology 
using MedDRA. Adverse events will be coded to the MedDRA (Version 25.1 or higher) lowest 
level term closest to the verbatim term, along with the linked MedDRA preferred term (PT) and 
primary system organ class (SOC). 
A treatment-emergent adverse event (TEAE) is defined as an AE that had onset or increase in 
severity level date on or after the date of the first dose of study drug through 40 days after the 
last dose (permanent discontinuation of study drug) or the initiation of new anti-cancer therapy, 
whichever is earlier. Summary tables will generally focus on those AEs that were treatment-
emergent (TE). All AEs, treatment-emergent or otherwise, will be presented in patient data 
listings. 
An AE overview table, including the number and percentage of patients with TEAEs, treatment-
emergent serious adverse events (SAEs), TEAEs with Grade 3 or above, TEAEs that led to 
death, TEAEs that led to treatment discontinuation, TEAEs that led to dose reduction, TEAEs 
that led to dose interruption, TEAEs that led to dose delay, treatment-related TEAEs grade 3 or 
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above. Treatment-related AEs include those events considered by the investigator to be related to 
study drug or with a missing assessment of the causal relationship. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC, PT and the worst grade. A patient will be counted only once by the highest severity grade 
within an SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC 
and PT. The number (percentage) of patients with treatment-emergent SAEs, treatment-related 
TEAEs, TEAEs with grade 3 or above, treatment-related SAEs, TEAEs that led to death, and 
TEAEs that led to treatment discontinuation, dose modifications, and infusion-related reactions 
will be summarized by SOC and PT. TEAEs with grade 3 or above will also be summarized by 
PT in descending order. 
Patient data listings of SAEs, fatal AEs will be provided. 
All deaths and causes of death will be summarized including those occurred during the study 
treatment period and those reported during the safety follow-up period after treatment 
completion/discontinuation. 
6.6.3. 
Laboratory Values  
Laboratory safety tests will be evaluated for selected parameters described in Table 2. 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables) for laboratory parameters and their changes 
from baseline will be summarized by visit. 
Laboratory parameters ALT, AST, total bilirubin, hemoglobin, platelet counts, WBC count, 
neutrophil and lymphocyte that are graded in NCI CTCAE Version 5.0 will be summarized by 
shifts from baseline CTCAE grades to maximum post-baseline grades. In the summary of 
laboratory parameters by CTCAE grade, parameters with CTCAE grading in both high and low 
directions will be summarized separately.  
Patient data listings of all laboratory data collected will be provided. 
Table 2: 
Laboratory Tests 
Clinical chemistry 
Hematology 
Coagulation 
Urinalysis 
Alanine aminotransferase 
Aspartate 
aminotransferase 
Total bilirubin 
Potassium 
Sodium 
Total calcium 
Creatinine 
Hemoglobin 
Platelet count 
White blood cell count 
Lymphocyte count 
Neutrophil count 
Basophils 
Prothrombin time 
Activated partial 
thromboplastin time 
International 
normalized ratio 
Glucose 
Protein 
Blood 
Ketones 
 
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Clinical chemistry 
Hematology 
Coagulation 
Urinalysis 
Chloride 
C-reactive protein 
Gamma-glutamyl 
transferase 
 
 
6.6.4. 
Vital Signs  
Descriptive statistics for vital sign parameters systolic and diastolic blood pressure (BP), pulse 
rate, temperature, and weight and changes from baseline will be presented by visit. 
6.6.5. 
Electrocardiograms (ECG)  
Actual value and change from baseline for the QT interval, heart rate and corrected QT interval by 
Fredericia (QTcF) will be summarized. The average of the readings for the visit will be used for 
the summary. 
The number and percentage of patients satisfying the following QT and QTcF conditions at any 
time post-baseline will be summarized: 
• 450, > 480, or > 500 msec  
• maximum increase > 30 or > 60 msec 
6.7. 
Pharmacokinetic Analyses  
Actual dose and blood draw times will be used to calculate the PK parameters. Parameters will 
be listed individually and summarized using descriptive statistics.  
The following PK parameters will be calculated as appropriate for the data collected. Other PK 
parameters may be calculated if supported by the data. 
• Cmax: Maximum serum concentration 
• tmax: Time to maximum serum concentration 
• Cmin: Minimum serum concentration 
• t1/2: Half-life 
• AUC0-t: Area under the serum concentration-time curve from zero to the last 
measurable concentration 
• AUC0-∞: Area under the serum concentration-time curve from zero to infinity 
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Calculation and presentation of PK parameters will be based on the Work Instruction: Best 
Practice Guidance: Non-Compartmental Pharmacokinetic Data Analysis for Clinical Studies. 
Version 1.0, Document Number VV-QDOC-13140. 
 
6.7.1. 
Reporting of Pharmacokinetic Concentrations for Descriptive Statistics  
The PK analyst will appropriately flag and annotate treatment of any anomalous concentrations, 
exclusions and any special treatment for descriptive statistics and plots. The concentration and 
time data will be listed individually and summarized using descriptive statistics.  
The following conventions will be used for reporting descriptive statistics for concentration data. 
• PK concentrations should be reported in listings at the same level of precision as that 
in the source data.  
• If a concentration at a given time point is below the assay quantification limit (BLQ), 
the concentration shall be reported as the term “BLQ” with the lower limit of 
quantitation (LLOQ) defined in the footnotes. BLQ values shall be treated as zero for 
computation of descriptive statistics. BLQ values will not be included for calculations 
of geometric mean and geometric coefficient of variation (CV%).  
• If the calculated mean concentration is BLQ, the mean value shall be reported in 
outputs (such as tables) as BLQ and SD and geometric CV% shall be reported as ND 
(not determined). Minimum, median, and maximum may be reported.  
6.7.2. 
Plots of Pharmacokinetic concentrations  
Concentration versus time data will be plotted individually and summarized graphically using 
arithmetic mean (+SD) plots by treatment group, respectively in linear and log-linear scale. 
Arithmetic mean concentrations that are BLQ shall be set to zero for plotting on both linear scale 
but not shown in log-linear scale.  
6.7.3. 
 Reporting of PK parameters for Descriptive Statistics   
The PK analyst will appropriately flag and annotate treatment of any anomalous PK parameters, 
exclusions and any special treatment for descriptive statistics. 
• All the PK parameters should have at least the following summary statistics: sample 
size (n), mean, standard deviation (SD), coefficient of variance (CV%), median, 
minimum, maximum, geometric mean, geometric CV%.  
• For in-text tables, Geometric mean (geometric CV%) will be the default method of 
reporting PK parameters. tmax should be presented as median, range (minimum, 
maximum), when presenting the summary statistics.  t1/2 should be presented as 
geometric mean, range (minimum, maximum). 
• For any parameters that n ≤ 2, SD should not be presented. 
• The units for all PK parameters will be provided.  
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• It is recognized that the number of decimals in reported concentrations, for example: 
“9632.94401 ng/mL” or “9.963294401 ug/mL" are highly improbable and will be 
queried (since bioanalytical assays generally do not have this level of precision). 
Usually the first-in-human dose escalation trial will provide the numerical range of 
PK parameters eg. AUC range from 10 to 10,000 ng.hr/mL and Cmax range from 1 to 
1000 ng/mL.   
In this scenario, for reporting PK parameters such as AUC and Cmax, the following 
guidance is provided for rounding:  
− If the numerical value is below 100 then one decimal place may be used eg, 0.1 or 
99.9. 
− For values ranging from >100, whole numbers should be used eg, 100 or 9999.  
− If > 10,000 the clinical pharmacologist may decide on changing units eg, from 
μg/ml to mg/ml. 
− For reporting times eg, for tmax or t1/2, if <1 hr use 2 decimals; time up to 24 hr 
should be reported to one decimal place eg., 23.5 hr, time >24 hr should be 
rounded to nearest whole number eg, 105 hr.  
7. 
INTERIM ANALYSES  
No interim analysis is planned. 
8. 
CHANGES IN THE PLANNED ANALYSIS  
Table 3: 
Statistical Analysis Plan Changes  
SAP version 
Approval date 
Change made from 
Rationale of the 
change 
Description of the 
change 
1.0 
06 July, 2023 
Protocol 
Amendment 1.0 
No or very few 
important protocol 
deviations are 
expected. 
Remove summary 
of important 
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9. 
REFERENCES  
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) 
Technical Guideline for Clinical Pharmacokinetics Research of Chemical Drugs. 2005. Assessed 
May 20, 2020.http://www.nmpa.gov.cn/gsz05106/07.pdf. 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926;33:1-26. 
ICH.Addendum on Estimands and Sensitivity Analyses in Clinical Trials to the Guideline on 
Statistical Principles for Clinical Trials: E9(R1). 2019. 
Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, 
Evans AE, Favrot M, Hedborg F, et al. Revisions of the international criteria for neuroblastoma 
diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466-77. 
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APPENDIX 1. 
SCHEDULE OF ASSESSMENT  
 
 
Screening 
(Day −28  
to Day −1) 
 
 
 
 
Cycles 1 to 5 
EOT/early 
termination b 
Safety  
follow-up c 
Visit day 
 
Day 1a 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11a 
Day 12 
Day 15 
Day 22 
Day 25 
Day 29 
Day 35 
-7 to 7 
days or 
0 to 7 
days 
+ 40 
days 
Visit window 
 
± 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
± 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygen saturation on room air 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test in WOCBPd 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg/HCV-Abe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Height/weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinations f  
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
Vital signs 
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
Performance status 
X 
 X---------------------------------------------------------------X 
 
 
 
 
 
 
X 
X 
ECHO or MUGA scan 
X 
As clinically indicated 
X 
X 
12-Lead ECG g 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Chest X-Ray h 
 
X 
As clinically indicated 
 
 
Complete blood count 
(including differential 
count)/biochemistry i, j 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Urinalysis i, j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Coagulation i, j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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Dinutuximab beta infusion k 
 
  X------------------Continuous infusion---------------------X 
 
 
 
 
 
 
 
 
13-cis-RA 
 
 
 
 
 
 
 
 
 
 
 
 
X------------------X 
 
 
 
 
PK sampling in Cycle 1l 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
Xm 
Xm 
 
X 
 
 
 
PK sampling in Cycle 2-4 l 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Tumor assessments n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse events 
  X------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant medications o 
  X------------------------------------------------------------------------------------------------------------------------------------------X 
Abbreviations: AE, adverse event; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; EOT, end of treatment; HBsAg, hepatitis B surface antigen; 
HCV-Ab, hepatitis C virus antibody; INRC, international neuroblastoma response criteria; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; MUGA, 
multigated acquisition scan; PK, pharmacokinetic(s); QTcF, QT interval corrected for heart rate using Fridericia’s formula; WOCBP, woman of childbearing potential; 123I, 
iodone-123. 
a Day 1 evaluations must be done before the start of the dinutuximab beta infusion. Day 11 evaluations must be done just before the end of the dinutuximab beta infusion. 
b The EOT Visit is conducted within ± 1 week of the end of Cycle 5. For early termination, the EOT Visit is conducted ≤ 7 days after the investigator determines that the patient 
must permanently discontinue the study drug or the patient decides to withdraw from the study before the end of Cycle 5. 
c Safety Follow-up Visit: within 40 days [± 7 days] after last dose of study drug; initiation of new anticancer therapy, death, withdrawal of consent, or loss to follow-up, 
whichever comes first. 
d Pregnancy test in WOCBP is described in Appendix 4 of the protocol.  
e If HCV-Ab positive, HCV-RNA test will be required for eligibility check. 
f Physical examinations is presented in Section 8.2.2 of the protocol.  
g At each timepoint, 3 consecutive 12-lead ECGs should be performed approximately 2 minutes apart to determine the mean QTcF interval. 
h Chest X-ray should be performed within 7 days before the start of dinutuximab beta infusion in each cycle. It can be skipped if chest MRI or CT scan has been performed 
already before administration per investigator’s discretion.  
i If clinical chemistry, hematology, coagulation and urinalysis at screening are not performed ≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should 
be repeated and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be reviewed within 72 hours before study drug administration (Section 8.2.5 
of the protocol). 
j The test for clinical chemistry, hematology, coagulation, and urinalysis, excluding PK sampling, will be performed within 72 hours before study drug administration on Day 1 
of each cycle. All laboratory tests with values considered clinically abnormal during participation in the study or within 40 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor (Section 8.2.5 of the protocol). 
k The recommended dose of dinutuximab beta depends on the patient’s body surface area (BSA) and the actual dose is calculated on every Day 1 of Cycle 1 to 5 (BSA = SQRT 
[weight (kg) x height (cm)/ 3600]). 
l PK sampling time refers to Table 4. 
m PK sampling on Day 15 and Day 22 in Cycle 1 is optional. 
n Tumor assessments will be performed by the investigators at Screening Visit, end of treatment Cycle 3 and end of treatment Visit per their clinical practice. The INRC 
(Brodeur et al 1993) is recommended as a reference for response evaluation in patients evaluable for response. Tumor assessments may include MRI and/or CT scan and/or 
123I-MIBG scan and/or 18F-FDG-PET and/or bone marrow assessment. 
o Concomitant medications will be defined as medications that started before the first dose of study drug(s) and were continuing at the time of the first dose of study drug(s), or 
started on or after the date of the first dose of study drug(s) up to 40 days after the patient’s last dose (as of the Safety Follow-up Visit) in Section 10.1.5 of the protocol. 
 
X: evaluations must be regularly repeated during the timepoints indicated according to routine medical care to ensure safe treatment of the patient. 
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Table 4: 
Dinutuximab Beta PK Sampling Schedule 
Cycle 
Cycle 1 (35 days per cycle) 
Cycle 2, 3, and 4 
Time 
D1 
Predose 
D3 
 
D8 
 
D11 
 
D15a 
D22a 
D29 
D1 
Predose 
D11 
Window Allowed 
-30 minsb 
± 1 hc 
± 1 hc 
-5 minsd 
 
 
 
-30 minsb 
-5 minsd 
PK Serum Sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: PK, pharmacokinetic(s). 
a PK sampling on Day 15 and Day 22 in Cycle 1 is optional. That adjustment needs to be aligned with 
pharmacologists. PK sampling on Day 29 in Cycle 1 is required even if the infusion time will be delayed or 
extended.  
b 30 minutes before starting infusion. 
c Infusion starting time ± 1 hour.   
d 5 minutes before the end of infusion, even if the infusion time will extend to the next days.
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APPENDIX 2. 
IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES  
In general, missing or partial dates will not be imputed at the data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only. 
1. Prior/Concomitant Medications/Procedures 
When the start date or end date of medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rules will be applied to 
impute partial dates for medications: 
If the start date of medication is partially missing, impute as follows: 
• If both month and day are missing, then set to January 01 
• If only day is missing, then set to the first of the month 
If the end date of medication is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31 
• If only day is missing, then set to last day of the month 
If start date or end date of medication is completely missing, do not impute. If the imputed of a 
medication end date > last known alive date or end of study date, then set to the last known alive 
date or end of study date, whichever occurs first. 
2. Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment-emergent by default. The following rules will be applied to impute 
partial dates for adverse events: 
If the start date of an adverse event is partially missing, impute as follows: 
• If both month and day are missing, then the imputed day and month will be January 
01 or the first dosing date if they have the same year, whichever is later. 
• If only day is missing, then the imputed day will be the first day of the month or the 
first dosing date if they have the same month and year, whichever is later 
• If the start date is completely missing, the imputed day will be the first dosing date as 
long as AE end date is not before the first dosing date. 
If the end date of an AE is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31 
• If only day is missing, then set to last day of the month 
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• If the end date is completely missing, do not impute. 
If the imputed AE end date > last known alive date or end of study date, then set to the last 
known alive date or end of study date, whichever occurs first. 
3. Deaths 
In case complete death dates are not recorded, impute as follows: 
• If both month and day are missing, then the imputed month and day will be 01Jan or 
the last date of a patient known to be alive + 1, whichever is later. 
• If only day is missing, the death will be assumed to be on the first day of the month or 
the last date of a patient known to be alive +1, whichever is later. 
4. Subsequent Anti-cancer Therapies 
If the start date of a subsequent anti-cancer therapy is incomplete or missing, impute as follows:  
• If both month and day are missing, then the imputed month and day will be 01Jan or 
the last day of the month for the last adequate disease assessment if they have the 
same year. 
• If only day is missing, then the imputed day will be the first day of the month. 
5. Diagnosis 
If a diagnosis date is partially missing, impute as follows: 
• If both month and day are missing, then set to January 01 
• If only day is missing, then set to the first of the month 
If a diagnosis date is completely missing, do not impute. 
6. Prior Therapy/Response to Prior Therapy 
If a prior therapy or response to prior therapy date is partially missing, impute as follows: 
• If only day is missing, then set to the 15th of the month or the first study drug dose 
date, whichever is earlier. An imputed start date can be no later than the end date and 
vice versa. 
• If month and day are missing, then set to be June 15th or the first study drug dose date, 
whichever is earlier. An imputed start date can be no later than the end date and vice 
versa.  
 
Version
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