Phase I/II Study of Humanized 3F8 Bispecific Antibody (Hu3F8-BsAb) in Patients With Relapsed/Refractory Neuroblastoma, Osteosarcoma, and Other GD2(+) Solid Tumors
Phase: PHASE1
Conditions: Neuroblastoma, Osteosarcoma, Other Solid Tumor Cancers
Sponsor: Y-mAbs Therapeutics

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CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
Phase I/II study of humanized 3F8 bispecific antibody (Hu3F8 BsAb) in patients with 
relapsed/refractory neuroblastoma, osteosarcoma, and other GD2(+) solid tumors 
Principal Investigator/Department: Shakeel Modak, MD/Pediatrics 
NCT No.: 03860207
IND No: 139393 
Version: A(10) 
Date: 13-Jan-2022 
This trial protocol is the property of Y-mAbs Therapeutics Inc. and is a confidential document. It is not 
to be copied or distributed to other parties without written approval from Y-mAbs Therapeutics Inc. 
Clinical Trial ID: 18-034 

 
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Approval of Clinical Trial Protocol 
 
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Key Contact Information 
Sponsor 
Y-mAbs Therapeutics, Inc. 
230 Park Avenue, Suite 3350 
New York, NY 10169 
USA 
Sponsor’s Medical Expert 
  
Chief Scientific Officer  
Global Head, Translational Medicine  
E-mail: 
  
Phone: 
 
Contact Details for Reporting of SAE/AE 
safetymailbox@ymabs.com 
In emergency situations, the completed Clinical Adverse Events Report forms or pregnancy forms can 
be faxed to: 
FAX +45 7879 6060 
Coordinating Investigator 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 

 
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Table of Contents 
1 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................................... 7 
2 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................................... 7 
2.1 
Phase I .................................................................................................................................................. 7 
2.2 
Phase II ................................................................................................................................................. 7 
3 
BACKGROUND AND RATIONALE ...................................................................................................... 8 
3.1 
Disease background .............................................................................................................................. 8 
3.2 
Rationale for anti-GD2 antibody .......................................................................................................... 9 
3.2.1 
GD2 as an ideal target for antibody-based therapy in NB and other solid tumors ....................... 9 
3.2.2 
Experience with 3F8: anti-GD2 murine monoclonal antibody in high risk NB ........................... 9 
3.2.3 
Experience with humanized 3F8 (hu3F8) in relapsed/refractory HR NB .................................. 10 
3.3 
Rationale for anti-GD2 bispecific antibody ........................................................................................ 10 
3.3.1 
Bispecific antibody to engage T cells ......................................................................................... 10 
3.3.2 
Humanized 3F8 bispecific antibody ........................................................................................... 11 
3.4 
Pre-clinical studies of hu3F8-BsAb .................................................................................................... 12 
3.4.1 
In vitro cytotoxicity .................................................................................................................... 12 
3.4.2 
Anti-tumor effect in mouse xenograft models ............................................................................ 13 
3.4.3 
Pre-clinical toxicology ................................................................................................................ 14 
3.4.4 
Pre-clinical pharmacokinetics (PK) ............................................................................................ 15 
3.5 
Rationale for phase I study of hu3F8-BsAb ....................................................................................... 15 
3.6 
Significance and implications ............................................................................................................. 17 
4 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................................ 17 
4.1 
Design ................................................................................................................................................. 17 
4.1.1 
Phase I ........................................................................................................................................ 17 
4.1.2 
Phase II ....................................................................................................................................... 18 
4.1.3 
Phase I Dose-Escalation Schedule .............................................................................................. 18 
4.2 
Intervention ......................................................................................................................................... 19 
5 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................................... 19 
6 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................................... 20 
6.1 
Subject Inclusion Criteria ................................................................................................................... 20 
6.1.1 
Diagnosis .................................................................................................................................... 20 
6.1.2 
Disease status .............................................................................................................................. 21 
6.1.3 
Other criteria ............................................................................................................................... 21 
6.2 
Subject Exclusion Criteria .................................................................................................................. 21 
7 
RECRUITMENT PLAN .......................................................................................................................... 22 
8 
PRETREATMENT EVALUATION ...................................................................................................... 22 
9 
TREATMENT/INTERVENTION PLAN .............................................................................................. 23 
9.1 
Phase I ................................................................................................................................................ 23 
9.1.1 
General Outline........................................................................................................................... 23 
9.1.2 
Dose-Escalation Plan and Dose Limiting Toxicity (DLT) ......................................................... 24 

 
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9.1.3 
Criteria for continuing on therapy beyond cycle 1. .................................................................... 26 
9.1.4 
Pharmacokinetic (PK) studies..................................................................................................... 26 
9.1.5 
Prohibited medication phase I .................................................................................................... 27 
9.2 
Phase II ............................................................................................................................................... 27 
9.2.1 
General outline ........................................................................................................................... 27 
9.2.2 
Prohibited medication and surgery phase II ............................................................................... 28 
9.3 
HAHA testing ..................................................................................................................................... 28 
9.4 
Immunological effects of hu3F8-BsAb .............................................................................................. 28 
9.5 
Bone marrow (BM) RNA ................................................................................................................... 28 
9.6 
Stool microbiome ............................................................................................................................... 29 
10 EVALUATION DURING TREATMENT/INTERVENTION ............................................................. 29 
11 TOXICITIES/SIDE EFFECTS ............................................................................................................... 35 
12 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ................................. 38 
13 CRITERIA FOR REMOVAL FROM STUDY ..................................................................................... 41 
14 BIOSTATISTICS ..................................................................................................................................... 42 
14.1 
Phase I ................................................................................................................................................ 42 
14.1.1 
Primary endpoint ........................................................................................................................ 42 
14.1.2 
Secondary endpoints ................................................................................................................... 45 
14.2 
Phase II ............................................................................................................................................... 46 
14.2.1 
Primary endpoint ........................................................................................................................ 46 
14.2.2 
Secondary endpoints ................................................................................................................... 47 
14.3 
Exploratory endpoints......................................................................................................................... 48 
14.3.1 
For Phase II: To assess overall survival and progression free survival ...................................... 48 
14.3.2 
To study immunological effects of hu3F8-BsAb ....................................................................... 48 
14.3.3 
To study tumor DNA, RNA ....................................................................................................... 48 
14.3.4 
To study stool microbiome ......................................................................................................... 49 
15 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ...... 49 
15.1 
Research Participant Registration ....................................................................................................... 49 
15.2 
Randomization .................................................................................................................................... 49 
16 DATA MANAGEMENT ISSUES ........................................................................................................... 49 
16.1 
Quality Assurance .............................................................................................................................. 49 
16.2 
Data and Safety Monitoring ............................................................................................................... 50 
17 PROTECTION OF HUMAN SUBJECTS ............................................................................................. 50 
17.1 
Privacy ................................................................................................................................................ 51 
17.2 
Adverse Event (SAE) Reporting ........................................................................................................ 51 
17.2.1 
Definition of Adverse Events ..................................................................................................... 51 
17.2.2 
Definition of Serious Adverse Events ........................................................................................ 52 
17.2.3 
Definition of Non-Serious Adverse Events ................................................................................ 52 
17.2.4 
Adverse Event Reporting Period ................................................................................................ 53 
17.2.5 
Recording of Adverse Events ..................................................................................................... 53 
17.2.6 
Events Requiring Immediate Reporting ..................................................................................... 56 
17.2.7 
Initial Reporting of AEs ............................................................................................................. 56 
17.2.8 
Contact details for reporting ....................................................................................................... 56 

 
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17.3 
Follow-Up on AEs .............................................................................................................................. 57 
17.4 
Reporting of SUSARs ........................................................................................................................ 57 
17.5 
Communication of Significant Safety Issues ...................................................................................... 57 
18 INFORMED CONSENT PROCEDURES ............................................................................................. 57 
19 REFERENCES ......................................................................................................................................... 59 
20 APPENDICES........................................................................................................................................... 65 
 
List of Tables 
Table 1 
GD2 expression of tumor cell lines and potency of hu3F8-BsAb ............................................ 13 
Table 2 
PK data ...................................................................................................................................... 15 
Table 3 
Maximum tolerated dose of anti-CD3 MoAbs ......................................................................... 16 
Table 4 
Dose escalation schedule .......................................................................................................... 19 
Table 5 
PK schedule- Cycle 1 and Dose-Escalated Cycles ................................................................... 26 
Table 6 
Phase I ....................................................................................................................................... 32 
Table 7 
Phase II ..................................................................................................................................... 33 
Table 8 
CRS revised grading system91 .................................................................................................. 35 
Table 9 
Hypothetical True Toxicity Rates ............................................................................................. 43 
Table 10 
Percent of simulated trials that selected each dose under each scenario................................... 44 
Table 11 
Percent of patients treated at each dose under each scenario .................................................... 44 
Table 12 
Average toxicities across trials at each dose ............................................................................. 44 
 
List of Figures 
Figure 1 
hu3F8-BsAb .............................................................................................................................. 11 
Figure 2 
TDCC assay in vitro ................................................................................................................. 12 
Figure 3 
TDCC assay comparing two versions of hu3F8-BsAbs ........................................................... 13 
Figure 4 
Melanoma M14 xenograft model.............................................................................................. 14 
Figure 5 
Neuroblastoma PDX model ...................................................................................................... 14 
Figure 6 
Study design .............................................................................................................................. 18 
 

 
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1 
PROTOCOL SUMMARY AND/OR SCHEMA 
This phase I/II trial will assess the toxicity and pharmacokinetics (PK) of the humanized anti-GD2 x 
anti-CD3 bispecific antibody (hu3F8-BsAb) in phase I and the anti-tumor activity of hu3F8-BsAb in 
phase II. In phase I, dosages of hu3F8-BsAb follow a dose-finding design in order to determine the 
maximum tolerated dose (MTD) in cohorts of patients with relapsed/refractory neuroblastoma (NB), 
osteosarcoma, or other GD2(+) solid tumors. The recommended phase II dose (RP2D) will be 
established.  Hu3F8-BsAb PK will be also evaluated. In phase II, patients with relapsed/refractory NB 
(Group 1) and osteosarcoma (Group 2) will be treated with hu3F8-BsAb at the RP2D and anti-tumor 
activity will be assessed.    
2 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Phase I 
Primary Objective:  
• To establish the safety of hu3F8-BsAb, and determine the maximum tolerated dose (MTD) and 
the recommended phase II dose (RP2D). 
Secondary Objectives: 
• To study the pharmacokinetics of hu3F8-BsAb. 
• To evaluate human anti-human antibody (HAHA). 
• Assess the anti-tumor activity and overall response rates of hu3F8-BsAb in patients with 
relapsed or refractory NB, osteosarcoma and other GD2(+) tumors. 
Exploratory Objectives: 
• To study immunological effects of hu3F8-BsAb  
• To study the effects of hu3F8-BsAb on bone marrow (BM) RNA 
• To study the effects of stool microbiome of the activity of hu3F8-BsAb. 
2.2 
Phase II 
Primary Objectives: 
• In Group 1: Assess the overall response rates of hu3F8-BsAb in patients with relapsed or 
refractory NB. 
In Group 2: Assess the progression free survival (PFS) in patients with relapsed or refractory 
osteosarcoma at 4 months from the first hu3F8-BsAb treatment.  

 
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Secondary Objectives: 
• To evaluate the duration of complete remission in groups 1 and 2. 
• In Group 2: Assess the overall response rates of hu3F8-BsAb in patients with relapsed or 
refractory osteosarcoma.  
• To continue to assess the safety/toxicity of hu3F8-BsAb. 
• To evaluate HAHA. 
Exploratory Objectives: 
• To assess overall survival (OS) and PFS after treatment with hu3F8-BsAb. 
• To study immunological effects of hu3F8-BsAb 
• To study the effects of hu3F8-BsAb on BM DNA and RNA (Neuroblastoma patients only). 
• To study the effects of stool microbiome of the activity of hu3F8-BsAb. 
3 
BACKGROUND AND RATIONALE 
3.1 
Disease background 
NB is the most common extracranial solid tumor of childhood; approximately 700 children are 
diagnosed each year in the United States. 50-60% of patients present with an unresectable primary 
tumor and metastasis in BM.1 Intensive chemotherapy with or without myeloablative therapy, surgery, 
radiation, and most recently, anti-GD2 immunotherapy have improved event free survival rates in 
patients with metastatic disease diagnosed >18months of age to approximately 40%.2-4 Somatic MYCN 
amplification is associated with a poorer prognosis. In addition, treatment for relapsed NB remains 
even more inadequate. A recent review of outcomes after relapse from the International Neuroblastoma 
Risk Group Project found that 5 year post-relapse overall survival for stage 4 NB was only 8%. Stage 
4 patients with MYCN amplification did worse, with a 5-year post-relapse overall survival (PRS) of 
only 4%. Thus, a search for more effective therapies for stage 4 patients and relapsed patients is 
warranted.5-7 
Osteosarcoma is a primary bone malignancy that occurs predominantly in children and adolescents 
with about 400 newly diagnoses each year in the United States. Patients with localized disease have 
65-70 % long-term relapse free survival with systemic chemotherapy (combination methotrexate, 
doxorubicin, and cisplatin [MAP]) and aggressive surgical resection,8 whereas >80% of patients with 
detectable metastases at diagnosis have relapse after contemporary therapy.9 When osteosarcoma 
recurs, the outcome is dismal. Complete surgical remission is one of the important favorable prognostic 
factors in recurrent osteosarcoma; 5-year PRS of patients who had complete resection of recurrence 
was 39% whereas and 3-year PRS of those who did not have complete surgery was 0%.10-13 Multiple 
clinical trials of novel agents including ixabepilone, oxaliplatin, trasutuzumab, IGF-1R inhibitors, and 
mTOR inhibitors have been conducted but no improvement of survival was achieved.14-18 A recent 

 
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retrospective analysis of seven phase II trials conducted by Children’s Oncology Group (COG) and its 
predecessor groups showed that PFS at 4 months from time of enrollment in patients with relapsed 
measurable disease was 12%.19 
Currently, the limits of treatment intensity have been reached in up-front therapies in NB and 
osteosarcoma, leaving limited options for cytotoxic therapies upon relapse; antibody based 
immunotherapy is therefore particularly appealing in this heavily pre-treated population given its lack 
of significant acute hematologic toxicity and absence of long term side effects.   
3.2 
Rationale for anti-GD2 antibody   
3.2.1 
GD2 as an ideal target for antibody-based therapy in NB and other solid 
tumors  
GD2 is an adhesion molecule abundant on NB and other solid tumors. Specifically, GD2 is expressed 
by 100% of NB,20 88% of osteosarcomas,21 >50% of melanomas,22 70% of desmoplastic small round 
cell tumors (DSRCT)23, and 93% of soft tissue sarcomas including liposarcoma, fibrosarcoma, 
malignant fibrous histiocytoma, leiomyosarcoma, and spindle cell sarcoma,24 as well as brain tumors.25 
It is rarely expressed in normal tissues except neurons and skin cells. This antigen is genetically stable 
and relatively inert on the cell membrane.  GD2 expression is rarely lost, even after relapse in patients 
previously treated with anti-GD2 therapy.26,27  
3.2.2 
Experience with 3F8: anti-GD2 murine monoclonal antibody in high risk NB 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 

 
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3.2.3 
Experience with humanized 3F8 (hu3F8) in relapsed/refractory HR NB   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
3.3 
Rationale for anti-GD2 bispecific antibody  
3.3.1 
Bispecific antibody to engage T cells 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3.3.2 
Humanized 3F8 bispecific antibody  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3.4 
Pre-clinical studies of hu3F8-BsAb 
 
 
3.4.1 
In vitro cytotoxicity 
 
 
 
 
 
 
 
 
 
 

 
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3.4.2 
Anti-tumor effect in mouse xenograft models 
 
 

 
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3.4.3 
Pre-clinical toxicology 
 
 
 
 
 
 

 
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3.4.4 
Pre-clinical pharmacokinetics (PK)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
3.5 
Rationale for phase I study of hu3F8-BsAb   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3.6 
Significance and implications 
 
  
 
 
 
 
 
  
 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
4.1.1 
Phase I 
Initially the phase I study will follow a dose-escalation escalation schema with 1 patient assigned per 
dose until the first  ≥Grade 2 toxicity (except for Grade 2 sinus bradycardia, sinus tachycardia, urticaria, 
fever, nausea, vomiting, diarrhea, urticaria, headache, paresthesia, electrolyte disturbances, pain)  is 
observed, then the subsequent dose allocation will follow the Continual Reassessment Method 
(CRM).75,76a. Eligible patients will include relapsed or refractory NB, osteosarcoma, and GD2 (+) solid 
tumors. In each cycle, hu3F8-BsAb is given on Days 1 and 8. PK is assessed by blood draws. Patients 
are monitored for DLT until Day 28. Patients with DLT will come off treatment. HAHA titer will be 
measured after each cycle. Extent of disease evaluation will be performed after the second dose of 
cycle 2 and cycle 4, then every 3 months thereafter. A total of 4 cycles will be given. If patients 
experience no life-threatening toxicity clearly attributable to hu3F8-BsAb, do not develop progression 
of disease (PD) and continue to meet all eligibility criteria, they have the option of receiving additional 
cycles up to 2 years from the start of hu3F8-BsAb treatment. Patients may continue therapy beyond 4 
cycles even if they achieve remission, see study design Figure 6.  
The duration of each subsequent cycle is 28 days with hu3F8-BsAb being given on Days 1 and 8.  MTD 
is defined as a maximum dose level at which ≤ 1 of 6 patients experiencing DLT. The RP2D will be 
decided based on the safety data in the phase I and can be MTD or lower. If MTD is not reached, RP2D 
may be determined on the basis of PK studies. If no DLT is observed, the RP2D will be determined as 
a minimum dose that gives the highest hu3F8-BsAb serum levels based on the PK data. For example, 
the RP2D of hu3F8 monoclonal antibody was decided as 9 mg/kg/cycle because the serum hu3F8 levels 
reached a plateau beyond 8.4 mg/kg/cycle with no DLT (see Section 3.2.3). After cycle 2, intra-patient 
dose escalation will be permitted i.e. patients can receive the highest dose that has been evaluated and 
proven safe by DLT assessment.  

 
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Figure 6 
Study design  
 
 
4.1.2 
Phase II 
After RP2D is determined, a phase II study will be carried out to assess the anti-tumor activity of 
hu3F8-BsAb. Two groups of patients will be studied: Group 1 will consist of patients with relapsed or 
refractory NB and Group 2 of relapsed or refractory measurable osteosarcoma. Hu3F8-BsAb is given 
on Days 1 and 8 of each cycle. The duration of each cycle is 28 days. HAHA titer will be measured 
after each cycle. Extent of disease evaluation (EOD) will be performed after the second dose of cycle 
2 and cycle 4, then every 3 months thereafter. A total of 4 cycles will be given, and patients with no 
life-threatening toxicity clearly attributable to hu3F8-BsAb, no PD, and continuing to meet all 
eligibility criteria have the option of receiving additional cycles up to 2 years from the start of the 
hu3F8-BsAb treatment. Patients may continue therapy beyond 4 cycles even if they achieve remission. 
For Group 1, the overall response rate will be evaluated and is defined as the proportion of patients 
achieving complete remission (CR) or partial response (PR) based on revised International 
Neuroblastoma Response Criteria (INRC) as the best response at the end of cycle 2 and cycle 4. (See 
Section 12). For Group 2, 4-month PFS will be assessed and is defined as the proportion of patients who 
have not developed PD at the end of 4 months from the first dose of Hu3F8-BsAb. In addition, we will determine 
the number of patients who have CR or PR as the best response at the end of cycle 2 and cycle 4. (see 
Section 12) 
4.1.3 
Phase I Dose-Escalation Schedule 
The phase I dose-escalation schedule schema is summarized in Table 4 below. Dose Level 1 is the 
starting dose, and the escalation and de-escalation schedule are described in Section 9.1. DLTs are 
defined in Section 9.1. 

 
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Table 4 
Dose escalation schedule 
Level 
Dose on day 1 
Dose on day 8 
Dosage per cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
Intervention 
Phase I 
Hu3F8-BsAb is given IV over ~1-3 hours on Days 1 and 8 for each cycle. In cycle 1, blood is drawn 
for PK studies as described in Section 9.1.4.  
Phase II 
Hu3F8-BsAb is given IV over ~1-3 hours on Days 1 and 8 for each cycle. 
5 
THERAPEUTIC/DIAGNOSTIC AGENTS 
The investigational medicinal product is fully humanized bispecific antibody (hu3F8-BsAb). 
Hu3F8-BsAb 
The Sponsor, Y-mAbs, will provide hu3F8-BsAb 2 mg/mL solution for intravenous infusion. No other 
medicinal products or auxiliary medicinal products will be provided by Y-mAbs. 
Hu3F8-BsAb drug product (DP) is manufactured in compliance with good manufacturing practice 
(GMP) regulations and no excipients of human or animal origin have been used. Final clinical DP 
formulation is a solution with 2 mg/mL hu3F8-BsAb buffered with sodium citrate dihydrate, citric acid 
monohydrate, and sodium chloride, and stabilized with Kolliphor P188 (Poloxamer 188). The final 
presentation is sterile filtered and filled into 2 mL vials.  

 
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Drug dilution and preparation procedure is provided in Appendix B. 
6 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
6.1.1 
Diagnosis 
Phase I 
• 
Patients must have either (1) a diagnosis of NB as defined by international criteria,77 i.e., 
histopathology (confirmed by the MSKCC Department of Pathology) or BM metastases plus 
high urine catecholamine levels, or (2) high grade osteosarcoma  verified by histopathology 
(confirmed by the MSKCC Department of Pathology), or (3)  other GD2-expressing solid tumor. 
• 
For tumors other than NB and osteosarcoma, only tumors known to be GD2 positive are eligible: 
melanoma, desmoplastic small round cell tumors, retinoblastoma, medulloblastoma, and soft 
tissue sarcomas including liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, 
leiomyosarcoma, and spindle cell sarcoma. Patients with medulloblastoma are eligible only if 
they have metastatic disease outside the CNS (e.g. in the bone marrow) 
• 
NB patients must have chemorefractory (e.g. refractory to standard induction chemotherapy 
including cyclophosphamide, vincristine, cisplatin, etoposide) or relapsed high-risk (HR) 
neuroblastoma. HR NB is defined as MYCN-amplified stage 3/4/4S of any age, or MYCN-
nonamplified stage 4 in patients > 18 months of age at diagnosis. 
• 
Osteosarcoma patients must have relapsed or refractory osteosarcoma after receiving standard 
systemic chemotherapy (e.g. combination methotrexate, doxorubicin, and cisplatin [MAP]). 
• 
For non-NB and non-osteosarcoma tumors known to be GD2(+), patients must have relapsed or 
refractory disease that is resistant to standard therapy. 
Phase II 
• 
Group 1:  
• NB patients must have chemo refractory or relapsed HR NB. HR NB is defined as MYCN-
amplified stage 3/4/4S of any age, or MYCN-nonamplified stage 4 in patients > 18 months of 
age at diagnosis.  
• The diagnosis of NB must be defined by international criteria77 i.e., histopathology (confirmed 
by the MSKCC Department of Pathology) or BM metastases plus high urine catecholamine 
levels.  
• 
Group 2:  
• Patients must have a diagnosis of high grade osteosarcoma defined by histopathology 
(confirmed by the MSKCC Department of Pathology).  

 
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• Patients must have relapsed or refractory osteosarcoma after receiving standard systemic 
chemotherapy (e.g. combination methotrexate, doxorubicin, and cisplatin [MAP]). 
 
All criteria below are common to both phase I and phase II: 
6.1.2 
Disease status  
• 
For NB patients, patients must have measurable or evaluable disease (e.g. abnormal findings in 
computed tomography (CT), magnetic resonance imaging (MRI), metaiodobenzylguanidine 
(MIBG) scan, or positron emission tomography (PET)) OR morphologic evidence of disease in 
bone marrow. 
• 
For osteosarcoma or other GD2(+) solid tumor patients, patients must have measurable disease. 
(See Section 12.4 for a definition of measurable disease) 
6.1.3 
Other criteria 
• 
Patients must be ≥ 1 year of age and < 18 years of age.  
• 
Patients with prior exposure to anti-GD2 antibodies must have a negative HAHA antibody titer . 
• 
Adequate hematopoietic function defined as: 
• Absolute neutrophil count ≥500/ul 
• Absolute lymphocyte count ≥500/ul   
• Platelet count ≥25,000/ul  
• 
Negative serum pregnancy test in women of child-bearing potential. 
• 
Women of child-bearing potential must be willing to practice an effective method of birth 
control while on treatment. 
• 
Signed informed consent indicating awareness of the investigational nature of this program.   
6.2 
Subject Exclusion Criteria 
• 
Patients who are in complete remission.  
• 
Existing severe major organ dysfunction. i.e. renal, cardiac, hepatic, neurologic, pulmonary, or 
gastrointestinal toxicity ≥ Grade 3 except for hearing loss, alopecia, anorexia, nausea, 
hyperbilirubinemia or hypomagnesemia from TPN, which may be Grade 3. 
• 
Hematologic and active CNS malignancies including CNS metastasis. 
• 
Active life-threatening infection. 
• 
Pregnant women or women who are breast-feeding. 

 
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• 
Inability to comply with protocol requirements. 
• 
History of autoimmune disease with potential CNS involvement or a current autoimmune 
disease. 
• 
Chemotherapy or immunotherapy within three weeks prior to study enrollment. T-cell based 
immunotherapies (e.g. CAR-modified T cells, checkpoint inhibitors) should have been 
completed >6 weeks prior to treatment with hu3F8-BsAb. 
7 
RECRUITMENT PLAN 
Patients will be offered participation in this study by their attending physician in the Department of 
Pediatrics at Memorial Sloan Kettering Cancer Center only.  Patients will be offered the opportunity 
to participate if they have relapsed or refractory high-risk NB, osteosarcoma, or GD2 (+) tumor as 
defined in Section 6.1. No patient will be identified by chart review or direct advertising. The 
consenting physician will be responsible for explaining the study, obtaining written informed consent 
and registering the patient on study.  Patients of both genders and all ethnic backgrounds are eligible 
for this study.  
Up to 30 patients will enroll in Phase I and up to 64 patients will enroll in Phase II. 
8 
PRETREATMENT EVALUATION 
Pretreatment evaluations should be completed within 30 days of start of treatment. Echocardiogram 
and electrocardiogram can be completed within 45 days prior to treatment.  All pretreatment evaluation 
should be performed after the completion of prior chemotherapy or immunotherapy. 
1. 
Complete history and physical examination.   
2. 
Blood pressure measurement (standing, sitting and lying down). 
3. 
Complete blood count, serum creatinine, blood urea nitrogen, serum aspartate 
aminotransferase, serum alanine aminotransferase, serum alkaline phosphatase, serum total 
bilirubin, albumin, sodium, potassium, chloride, bicarbonate, magnesium, phosphate, 
ferritin, and C-reactive protein (CRP). 
4. 
Echocardiogram (ECHO)  
5. 
Electrocardiogram 
6. 
Phase I only: C3 and CH50 
7. 
Phase I only: Urinalysis.  
8. 
Serum for analysis of HAHA if applicable (i.e., for patients previously treated with anti-
GD2 antibodies).  If the patient was previously treated with an antibody, any HAHA result 
since last antibody treatment can be used. 

 
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9. 
Blood for baseline cytokine studies (including IFN-ƴ, IL-6, IL-8, IL-10).78,79 
10. Blood for baseline lymphocyte subsets (including CD3, CD4, CD8, Foxp3, CD127, 
CD45RA, CCR7) and T cell activation/exhaustion markers (including CD25 and PD-1).  
11. For NB patients, BM aspirates and biopsies from bilateral iliac crests for morphology and 
detection of minimal residual disease. 
12. Imaging by computed tomography (CT) or magnetic resonance imaging (MRI) of primary 
tumor site and/or known site(s) of relapse (if applicable), or PET scan, Bone scan, and/or 
MIBG scan (if the patient has neuroblastoma), or other diagnostic imaging as appropriate 
for specific disease. 
13. Pregnancy test, if applicable, within 2 weeks of treatment. 
9 
TREATMENT/INTERVENTION PLAN 
9.1 
Phase I 
9.1.1 
General Outline  
 
  
 
 
 
During phase I approximately 0.5 ml of the first Bs-Ab infusion will be 
collected about half-way through the infusion and assayed in Neuroblastoma research laboratory to 
determine quantity of hu3F8-BsAb in the final infusion product. In cycle 1, blood is drawn for PK 
studies as described in Section 9.1.4. Patients are admitted for dose 1 of cycle 1 of treatment and will 
be inpatient for approximately 4 days (minimum 48 hours) though the duration of stay may change if 
clinically indicated. Subsequent doses can be administered inpatient or outpatient. Patients are 
monitored for DLT clinically with physical examination, CBC and complete chemistry until Day 28. 
Patients with DLT will come off treatment HAHA titer is measured after each cycle. HAHA draws 
require about 5mL of serum.  If HAHA develops, cycles are deferred for up to 4 months until HAHA 
titer until <1300 U/ml.  Extent of disease evaluation will be performed after the second dose of hu3F8-
BsAb in cycle 2 and cycle 4, every 3 months thereafter. (Table 6) A total of 4 cycles will be given.  
Patients with no life-threatening toxicity clearly attributable to hu3F8-BsAb, no PD, and continuing to 
meet all eligibility criteria (with subsequently explained exceptions) have the option of receiving 
additional cycles up to 2 years from the start of the hu3F8-BsAb treatment. Inclusion criteria that no 
longer apply for patients to receive subsequent cycles are: disease status, since patients achieving 
remission may continue; and prior T cell immunotherapy timing restrictions, since all patients will have 
received Cycle 1 of hu3F8-BsAb. Even patients who achieve remission may continue therapy beyond 

 
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4 cycles. DLT and dose-schedule are described in Section 9.1.2 and 9.1.3. After cycle 2, intra-patient 
dose escalation will be permitted i.e. patients can receive the highest dose that has been evaluated and 
proven safe by DLT assessment.  Patients will be admitted for at least 48 hours for their first escalated 
dose. 
The treatment and evaluation schedule may require minor adjustment as clinically indicated or due to 
circumstance (e.g. due to PDH closure for holidays or due to inclement weather). 
9.1.2 
Dose-Escalation Plan and Dose Limiting Toxicity (DLT) 
9.1.2.1 
Dose-Escalation Plan 
This is a Phase I trial to determine the MTD of hu3F8-BsAb that leads to DLT in approximately 15% 
of patients. Hu3F8-BsAb is dosed based on body weight (BW) rather than body surface area (BSA). 
Unlike chemotherapy for which clearance ultimately depends upon cardiac output which is dependent 
upon BSA, antibody distribution and clearance depend on total blood volume which is determined not 
by BSA, but by BW. Dose escalation will start at dose level 1, 0.0045 mcg/kg/dose (0.009 
mcg/kg/cycle). Dose-escalation will be performed in two stages. In the first stage, the trial will accrue 
1 patient per dose until the first ≥ Grade 2 toxicity (except for Grade 2 sinus bradycardia, sinus 
tachycardia, fever, nausea, vomiting, diarrhea, urticaria, headache, paresthesia, electrolyte 
disturbances, pain) is encountered. The subsequent dose allocation will follow the Continual 
Reassessment Method (CRM). CRM assumes a simple model for the probability of a DLT as a function 
of dose, and uses the occurrence of toxicities in the patients enrolled in the trial to sequentially 
determine which dose to administer to a new patient. Patients will be assigned at each dose one at a 
time. New subjects will be allocated a dose as suggested by the CRM algorithm based on the toxicities 
of previously accrued patients. If DLT data are not available for the previously accrued 1 or 2 patients, 
the CRM will proceed with the dose as calculated with available toxicities/data, however if there are 3 
enrolled patients with incomplete /outstanding DLT data, accrual will be paused. DLT data from at 
most 2 patients can be pending but no more than 2 patients are allowed to have incomplete DLT data. 
To protect patient safety, a dose escalation of more than one dose level is not permitted. We will 
examine 12 dose levels. (Table 4) Our initial estimates of DLT probabilities are: 0.001, 0.005, 0.01, 
0.025, 0.05, 0.075, 0.10, 0.15, 0.25, 0.35, 0.45, 0.50 for doses 1-12, respectively. Thus, our a priori 
belief is that dose level 8 is the MTD. We assume that the dose- toxicity follows a hyperbolic tangent 
model P(DLT=yes at dose d)=((tanh d+1)/2)^a, where a is the unknown parameter that we need to 
estimate in order to determine which dose is the MTD.A value of a=1.0 indicate that our prior beliefs 
were correct; while a value of a less than (greater than) 1.0 indicates that the combinations are more 
(less) toxic than believed. To reflect the uncertainty in our prior probability estimates, we assume it 
follows an exponential distribution (prior distribution) with mean 1.0. Dose escalation will be guided 
by the model after the occurrence of the first DLT. At that time, the above initial estimates of DLT 
might be revisited before model initiation to reflect the current knowledge on the safety profile and 
dose levels based on the observed data. We will enroll 30 evaluable patients. All patients who are 
enrolled in the study and receive their assigned dose are considered evaluable for toxicity. Additional 
subjects will be enrolled to replace any subjects who are enrolled, but do not receive treatment. In the 

 
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unlikely event that patient stops the drug due to HAHA before completing the first cycle, this patient 
will be considered inevaluable and will be replaced. If life-threatening toxicity occurs in any patient, 
further accrual at that dosage will be stopped pending review by the Principal Investigator (PI) or Co-
PI. Toxicity at each dosage level is evaluated during the 28 days following the first dose of hu3F8-
BsAb. No more than two patients will receive their first dose of hu3F8-BsAb within a 24 hour period. 
If no DLT is observed up to dose level 12 during the initial patient per dose escalation (e.g. no MTD), 
the RP2D will be determined as a minimum dose that gives the highest hu3F8-BsAb serum levels based 
on the PK data. 
9.1.2.2 
Dose Limiting Toxicities 
Toxicity will be monitored using CTCAE version 4.0. DLT only during cycle 1, i.e. Days 1 through 
28. Allowance will be made for the expected toxicities of hu3F8 from which hu3F8-BsAb was derived. 
(See Section 11.2). As stated above, in the first stage (1 patient per dose-level)  dose-escalation will be 
performed until ≥Grade 2 related toxicity (except for Grade 2 sinus bradycardia, sinus tachycardia, 
urticaria, fever, nausea, vomiting, diarrhea, urticaria, headache, paresthesia, electrolyte disturbances, 
pain) is encountered, then the subsequent dose allocation will follow the CRM.75,76 
During the CRM phase, any ≥Grade 3 toxicity attributable to hu3F8-BsAb will be considered dose-
limiting with the following exceptions: 
• Grade 3 cytokine release syndrome (CRS) improving to ≤Grade 1 CRS within ≤72 hours after 
starting systemic steroids (See Section 11.3 for a grading system and algorithm) 
• Grade 3 pain improving to ≤Grade 2 within ≤72 hours of its onset.  Grade 3 pain associated 
with myalgia is an expected clinical toxicity associated with cytokine release syndrome (CRS). 
• Grade 3 neutropenia or anemia 
• Grade 3 thrombocytopenia without clinically significant bleeding. 
• Grade 4 lymphopenia 
• Grade 3 elevations of AST, ALT if they return to <Grade 3 by day 28  
• Catheter related infections 
• DLT of hypertension is defined as persistent hypertension higher than 99th percentile for >48 
hours.   
The following Grade 3 toxicities are related to infusion of monoclonal antibodies and will not be 
considered DLT if they resolve to <Grade 3 within 24 hours: 
• Allergic reactions controlled with supportive care measures 
• Vasovagal reaction 
• Sinus bradycardia 

 
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• Sinus tachycardia 
• Urticaria (improved to at least Grade 2) 
• Fever 
The following Grade 3 toxicities will not be considered a DLT if they resolve within 48 hours: 
• Nausea 
• Vomiting 
• Diarrhea 
• Peripheral neuropathy (paresthesia) 
• Electrolyte disturbances 
In all other cases, DLT is defined as Grade 3 or greater toxicities occurring during cycle 1 with the 
exception of toxicities clearly related to disease activity or co-interventions. 
9.1.3 
Criteria for continuing on therapy beyond cycle 1.  
If patients experience DLT as described above, they will discontinue treatment.  Patients will need to 
fulfill all eligibility criteria before each cycle. However, patients can continue treatment without delay 
if they have ≤grade 4 lymphopenia. Cycles 2-4 may be delayed due to toxicities other than DLT for a 
maximum of four weeks i.e. maximum duration between dose 1 of the prior cycle and dose 1 of the 
next cycle can be ≤56 days. If HAHA titer of >1300 U/ml develops, cycles beyond cycle 1 may be 
delayed for up to 120 days. However, if the duration between cycles is >28 days, patients will be 
required to undergo extent of disease evaluation to ensure that there is no progressive disease. 
9.1.4 
Pharmacokinetic (PK) studies 
Blood (Table 5) will be drawn at various time points to study PK of hu3F8-BsAb. At each timepoint 
about 2 mL of blood will be collected for PK studies. For further details, see the laboratory manual. 
Table 5 
PK schedule- Cycle 1 and Dose-Escalated Cycles 
Day 
Time points 
1 
Prior to infusion of hu3F8-BsAb infusion 
1 
~ 5 mins, 3 hrs, ~ 6-8 hrs after the end of hu3F8-BsAb infusion 
2 
~24 hrs 
3 
~48 hrs   
4 
 ~72 hrs  
5 
 ~96 hrs 
6 
~120 hrs 

 
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Day 
Time points 
7 
 ~144 hrs  
8 
  ~168 hrs (prior to hu3F8-BsAb injection) 
If dose 2 of hu3F8-BsAb cannot be given on Day 8, a PK sample should still be drawn     
8 
~ 5 mins after the end of hu3F8-BsAb infusion dose 2 
9 
~24 hrs 
10 
~48 hrs 
11 
~72 hrs 
12 
~96 hrs 
13 
~120 hrs 
14 
 ~144 hrs 
15 
~168 hrs 
Approximately 22 
~336 hrs 
Approximately 28 
~480 hrs 
In addition, based on our prior studies demonstrating that Cmax is highly correlative with AUC for 
hu3F8, patients treated both in phase I and II will undergo a single blood draw ~ 5 minutes after each 
hu3F8-BsAb infusion for determining Cmax for repeat dosing. We will also draw blood for Ctrough 
prior to the second dose of hu3F8-BsAb, prior to each hu3F8-BsAb infusion in Phase I and prior to 
each cycle in Phase II. Each blood draw for Cmax and Ctrough will be about 2ml. Blood for HAHA 
testing can be used for Ctrough prior to each cycle (see 9.3). 
9.1.5 
Prohibited medication phase I 
No simultaneous systemic anti-cancer therapy is permitted while on study, however local radiotherapy 
or surgical resection of the tumor is allowed >28 days after first dose of hu3F8-BsAb in phase I 
provided at least one non-irradiated tumor site is available for evaluation. 
9.2 
Phase II 
9.2.1 
General outline 
Hu3F8-BsAb at R2PD determined in the phase I study is infused IV over ~1-3 hours on Days 1 and 8 
of each cycle. A total of 4 cycles will be given. The duration of each cycle is approximately 28 days. 
However, cycles may be delayed for up to 56 days if >grade 2 toxicity is encountered. In order to 
receive subsequent cycles, patients should continue to meet all eligibility criteria, should not have 
experienced life-threatening toxicity clearly attributable to hu3F8-BsAb, and should not have 
developed PD.  HAHA titer will be measured after each cycle. If HAHA develops, cycles are deferred 
for up to 120 days until HAHA titer until <1300 U/ml.  Extent of disease evaluation will be performed 
after the second dose of hu3F8-BsAb in cycle 2 and cycle 4, then every 3 months thereafter. After cycle 
4, patients have the option of receiving therapy for up to 2 years provided that they have not experienced 

 
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life-threatening toxicity clearly attributable to hu3F8-BsAb, not developed PD, continue to meet all 
eligibility criteria and HAHA titer is <1300U/ml. After cycle 4, duration between cycles can range 
from 28-120 days. Patients may continue therapy beyond 1 cycle even if they achieve remission. 
Patients will undergo physical examination, CBC and complete chemistry and immune correlates will 
be tested as described in Section 10. 
The treatment and evaluation schedule may require minor adjustment as clinically indicated or due to 
circumstance (e.g. due to PDH closure for holidays or due to inclement weather). 
9.2.2 
Prohibited medication and surgery phase II 
No simultaneous systemic anti-cancer therapy is permitted while on study, however local radiotherapy 
is allowed at any time provided at least one non-irradiated tumor site is available for evaluation.  
Patients may undergo surgery to any site prior to first extent of disease evaluation provided there 
another site of evaluable disease remains; patients may be rendered NED by surgery after their first 
EOD evaluation.   
All interventions below are common to both phase I and phase II 
9.3 
HAHA testing 
Blood (~5ml per draw) drawn before each cycle for HAHA testing will be measured using ELISA. Anti-
idiotype antibodies (Ab3, Ab3’) will be also tested with the same blood samples.81 
This blood sample may also be tested for HAMA. HAMA positivity is allowed and will not affect 
patients’ eligibility for treatment. 
9.4 
Immunological effects of hu3F8-BsAb 
Lymphocyte subsets (including CD3, CD4, CD8, Foxp3, CD127, CD45RA, CCR7) and T cell 
activation/exhaustion markers (including CD25, PD-1) will be tested before and after the hu3F8-BsAb 
treatment (See Section 10). Each draw will collect about 16 mL of serum. Analysis will be performed 
in the MSK Immune Monitoring Core Facility. CBC should be checked with blood collected on the 
same day. Cytokine levels (including IFN-ƴ, IL-6, IL-8, IL-10) will be measured before and after the 
hu3F8-BsAb treatment during cycle 1 of phase I, and analyzed in the MSK Immune Monitoring Core 
Facility. During subsequent cycles of phase I or in phase II, these cytokine levels will be measured if 
CRS is clinically suspected. Each draw for cytokine levels will collect about 4mL of serum.  
9.5 
Bone marrow (BM) RNA 
For NB patients, tumor RNA will be used for transcriptome and microRNA profiling. Tumor RNA in 
BM from blood will be used for minimal residual disease (MRD) testing, to be completed in the Cheung 
Lab at MSK. The samples will not have any associated patient-specific identifying information, but 
will be linked to clinical information such as patient age, gender, tumor stage, tumor recurrence status, 

 
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and tumor site.  Frozen tumors will be tested for tissue antigens and gangliosides (including but not 
limited to GM2, GD2, GD3]. 
9.6 
Stool microbiome 
Based on emerging data on the impact of stool microbiome on function of immunotherapeutic agents, 
a stool sample will be collected on all patients prior to first dose of hu3F8-BsAb, where feasible. 
Sequencing of stool microbiota will be performed and correlated with clinical and immunological 
response. 
10 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
History and physical exam  
• Phase I cycle 1: History and physical exams will be completed every day for the 
first 4 days, on Day 8, and weekly thereafter until Day 28.   
• For subsequent cycles in Phase I, and Phase II: Before each dose of hu3F8-BsAb 
and within 72 hours of treatment. 
10.2 
Patients are monitored by pulse oximeter during hu3F8-BsAb infusion and have blood 
pressure taken no later than 30 minutes after the end of infusion of hu3F8-BsAb.  In cycle 
1 and for all inpatient treatment, blood pressure measurement (standing, sitting and lying 
down) will be taken pre infusion, once daily throughout their hospital stay and at discharge. 
For treatment administered outpatient, blood pressure measurement (standing, sitting and 
lying down) will be taken pre infusion and at discharge. 
10.3 
CBC 
• Phase I cycle 1: CBC will be done approximately on Days 2, 5, 8 (prior to the 
second dose of hu3F8-BsAb), and approximately Days 15 and 28.  
• For subsequent cycles in Phase I, and Phase II: Before each dose of hu3F8-BsAb. 
(Pre-treatment CBC can be used for pre-cycle 1 CBC.) 
10.4 
C3 and CH50 
• Phase I only: C3 and CH50 will be tested on Day 2 during cycle 1. 
10.5 
Urinalysis 
• Phase I only: In cycle 1, urinalysis will be tested prior to each dose of hu3F8-
BsAb and approximately one week after the second dose. (Pre-treatment 
urinalysis can be used for pre-cycle1 test.) 
10.6 
Liver and kidney function blood tests (ALT, AST, alkaline phosphatase, albumin, bilirubin, 
BUN and creatinine), and serum electrolytes (sodium, potassium, chloride, bicarbonate, 
magnesium, and phosphate).   

 
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• Phase I cycle 1: Before each dose of hu3F8-BsAb, within 72 hours after each dose 
of hu3F8-BsAb, and on approximately Day 15. (Pre-treatment test can be used for 
pre-cycle1 test.) 
• For subsequent cycles in Phase I, and Phase II: Before each dose of hu3F8-BsAb. 
(Pre-treatment test can be used for pre-cycle1 test.) 
10.7 
Pregnancy test within 2 weeks before each cycle, if applicable. 
10.8 
Phase I only: Electrocardiogram will be done post the first infusion of hu3F8-BsAb on Day 
1 and prior to the second dose hu3F8-BsAb on Day 8 during cycle 1. This must be done on 
the same day as the dose, but does not need to be immediately post or immediately prior.  
10.9 
Phase I only: Pharmacokinetic studies will be done as described in Section 9.1.4  
10.10 
Phase I and II: Cmax and Ctrough will be measured as described in Section 9.1.4  
10.11 
Ferritin and C-reactive protein 
• Phase I cycle 1: On Day 8 (prior to the second dose of hu3F8-BsAb) and 
approximately on Day 28. 
• For subsequent cycles in phase I, and phase II: If CRS is suspected based on 
clinical symptoms. (See Section 11.3) 
10.12 
LDH 
• Phase I cycle 1: On Day 8 (prior to the second dose of hu3F8-BsAb) and 
approximately on Day 28. 
• For subsequent cycles in phase I, and phase II: If CRS is suspected based on 
clinical symptoms. (See Section 11.3) 
10.13 
Blood will be obtained before each cycle of hu3F8-BsAb to assay for HAHA titers, then 
approximately every 3 months for 24 months from first hu3F8-BsAb dose, and then 
approximately every 6 months for up to 5 years from first hu3F8 dose or until patient is off 
study, whichever is earlier. This blood sample may also be tested for HAMA. 
10.14 
Blood will be tested for cytokine studies including IFN-ƴ, IL-6, IL-8, IL-10. 
• Phase I cycle 1: cytokine studies should be tested prior to and ~ 6-8 hrs after the 
first and second infusion of hu3F8-BsAb, and on Days 2, 3, 4, 9, 10, and 11.  
• For subsequent cycles in Phase I and Phase II: If CRS is suspected based on 
clinical symptoms. (See Section 11.3) 
10.15 
Lymphocytes from heparinized blood will be collected for lymphocyte subset markers 
(including CD3, CD4, CD8, Foxp3, CD127, CD45RA, CCR7) and T cell 
activation/exhaustion markers (including CD25 and PD-1). 

 
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• Phase I Cycle 1:  On Days 2, 8 (prior to hu3F8-BsAb), 9, 10 and 11, and 
approximately Days 15 and 28. 
• For subsequent cycles in phase I, and phase II: Before each dose of hu3F8-BsAb.  
10.16 
For patients with a diagnosis of neuroblastoma, the following studies will be performed 
any time after the second dose of hu3F8-BsAb in cycle 2 and cycle 4, and then 
approximately every 3 months while on study: 
• BM aspirates and biopsies from bilateral iliac crests for standard histochemical 
studies, as well as for immunocytology and other molecular markers of 
disseminated NB. 
• Imaging by computed tomography (CT) or magnetic resonance imaging (MRI) of 
primary tumor site, plus metaiodobenzylguanidine (MIBG) scan or positron 
emission tomography (PET). 
10.17 
For patients with osteosarcoma or GD2(+) tumors, the following studies will be performed 
any time after the second dose of hu3F8-BsAb in cycle 2 and cycle 4*, and then 
approximately every 3 months while on study: 
• Disease evaluations with imaging by computed tomography (CT) or magnetic 
resonance imaging (MRI) of primary tumor site and/or known site(s) of relapse (if 
applicable), with/without positron emission tomography (PET) or bone scan, or 
other diagnostic imaging as appropriate for specific disease.  
*Cycle 4 scans should occur at approximately 4 months (+/- 1 month) in order for 
scans to be used to evaluate the 4 month disease control rate (see section 
14.2.1.2). 
10.18 
Pain Assessment (Phase I only): Pain scores will be assessed using the Face, Legs, Arms, 
Cry, Consolability (FLACC) scale82-84 and/or the numeric scale85, as appropriate (see 
Appendix A for pain scales). Pain scores will be evaluated at the following time points on 
days with hu3F8-BsAb treatment: (a) once prior to commencement of any study drug 
administration, (b) at least once during the acute pain episode when rescue pain medication 
doses are required (for hu3F8 this is towards the end of the 30 minute infusion or soon after 
completion of antibody infusion) and (c) ~1 hour after the end of infusion or prior to 
discharge from the Pediatric Day Hospital.  Pain scores will be assessed for all treatment 
cycles. Opioid requirements, rather than pain score, will be used to establish safety for the 
Phase I primary objective (Section 2.1). Pain scores will be used to assist clinical judgment 
(e.g. decision of pain medication use, observation of pain relief) and for documentation. 
10.19 
Phase I and II: stool sample collection as described in section 9.6. 

 
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All research blood (as identified below) will be completed where feasible. Patients who are 10 
kilograms or less in weight will only have research bloods drawn at the discretion of the Principal 
Investigator. 
Table 6 
Phase I 
Tests 
Pre-
treatment 
During Treatment 
During Follow-up 
Complete history and 
physical 
 
Cycle 1: Daily from Day 1 through Day 
4, on Day 8, then weekly thereafter 
until Day 28 
Subsequent Cycles: Before each dose 
of hu3F8-BsAb and within 72 hours of 
treatment 
- 
 
Pharmacokinetic studies 
(research blood) 
 
See Section 9.1 
Cycle 1: As shown in Table 5  
Subsequent Cycles: Before each dose 
of hu3F8-BsAb, ~5 minutes after 
hu3F8-BsAb infusion 
 
Complete blood count  
 
Cycle 1: Approximately Days 2, 5, 8 
(prior to the second dose of hu3F8-
BsAb), and approximately Days 15 and 
28. 
Subsequent Cycles: Before each dose 
of hu3F8-BsAb 
- 
Liver and Renal function tests 
(ALT, AST, alkaline 
phosphatase, albumin, 
bilirubin, BUN and 
creatinine) and serum 
electrolytes (sodium, 
potassium, chloride, 
bicarbonate, magnesium, and 
phosphate) 
 
Cycle 1: Before each dose of hu3F8-
BsAb, within 72 hours after each dose 
of hu3F8-BsAb and approximately Day 
15 
 
Subsequent Cycles:  Before each dose 
of hu3F8-BsAb 
 
- 
C3 & CH50 
 
Cycle 1 Only: Day 2 
- 
LDH 
 
Cycle 1: Day 8 and approximately Day 
28 
Subsequent Cycles: If CRS is suspected 
based on clinical symptoms 
 
Ferritin and C-reactive 
protein 
 
Cycle 1: Day 8 and approximately Day 
28 
Subsequent Cycles: If CRS is suspected 
based on clinical symptoms 
- 
SpO2 and Blood pressure 
measurement 
 Blood 
pressure 
measurement 
(standing, 
sitting, lying 
down) 
SpO2: During hu3F8-BsAb  
BP: No later than 30 minutes after the 
end of hu3F8-BsAb infusion 
Cycle 1: Blood pressure measurement 
(standing, sitting, lying down) pre 
infusion, once daily throughout hospital 
stay and at discharge. For outpatient 
treatment: pre infusion and at discharge 
- 

 
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Tests 
Pre-
treatment 
During Treatment 
During Follow-up 
Blood for HAHA  
 
Before each cycle 
Approximately q3 months for 
24 months from first hu3F8-
BsAb dose and then q6 
months for up to 5 years from 
first dose or until patient is 
off study, whichever is earlier 
Urinalysis 
 
Cycle 1: Prior to each dose of hu3F8-
BsAb and approximately one week 
after the second dose 
- 
Pregnancy test, if applicable 
 
Within 2 weeks before each cycle 
- 
Electrocardiogram 
 
Cycle 1: Post-infusion of the first dose 
and prior to the second dose on Day 8 
- 
ECHO 
 
- 
- 
Cytokine studies (research 
blood) 
 
Cycle 1: prior to and ~ 6-8 hrs after the 
first and second hu3F8-BsAb dose, and 
on Days 2, 3, 4, 9, 10 and 11  
Subsequent Cycles: If CRS is suspected 
based on clinical symptoms 
- 
Lymphocyte subsets, T cell 
activation/exhaustion markers 
(research blood) 
 
Cycle 1: on Days 2, 8 (prior to hu3F8-
BsAb), 9, 10, and 11, and 
approximately on Days 15 and 28 
Subsequent Cycles:  Before each dose 
of hu3F8-BsAb 
- 
Bone marrow studies* 
 
Any time after the second dose in cycle 
2 and cycle 4 and approximately every 
3 months thereafter 
- 
CT/MRI, MIBG scan* 
with/without PET, bone scan 
 
Any time after the second dose in cycle 
2 and cycle 4 and approximately every 
3 months thereafter 
- 
Pain Assessment 
 
On days of hu3F8-BsAb treatment: 
prior to hu3F8-BsAb administration, 
during acute pain episode, and ~1 hour 
after the end of infusion or prior to 
discharge from the PDH 
- 
Stool microbiome 
, where 
feasible 
- 
- 
*only for patients with neuroblastoma 
Table 7 
Phase II 
Tests 
Pre-
treatment 
During Treatment 
During Follow-Up 
Complete history and 
physical 
 
Before each dose of hu3F8-BsAb and within 
72 hours of treatment 
- 
Complete blood count 
 
 
Before each dose of hu3F8-BsAb  
- 

 
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Tests 
Pre-
treatment 
During Treatment 
During Follow-Up 
Liver and Renal function 
tests (ALT, AST, 
alkaline phosphatase, 
albumin, bilirubin, BUN 
and creatinine) and 
serum electrolytes 
(sodium, potassium, 
chloride, bicarbonate, 
magnesium, and 
phosphate) 
 
 
 
 
 
 
 
Before each dose of hu3F8-BsAb 
- 
 
LDH 
 
 
If CRS is suspected based on clinical 
symptoms 
 
Ferritin and CRP 
 
 
If CRS is suspected based on clinical 
symptoms 
- 
SpO2 and Blood pressure 
measurement 
 
 Blood 
pressure 
measurement 
(standing, 
sitting, lying 
down) 
SpO2: During hu3F8-BsAb infusion 
BP: No later than 30 minutes after the end 
of hu3F8-BsAb infusion 
Cycle 1: Blood pressure measurement 
(standing, sitting, lying down) pre infusion, 
once daily throughout hospital stay and at 
discharge. For outpatient treatment: pre 
infusion and at discharge 
- 
Blood for HAHA  
(if 
applicable) 
Before each cycle 
Approximately q3 months for 
24 months and then q6 
months for up to 5 years from 
first hu3F8 dose or until 
patient is off study, 
whichever is earlier 
Pregnancy test, if 
applicable 
 
Within 2 weeks before each cycle 
- 
Electrocardiogram 
 
- 
- 
ECHO 
 
- 
- 
Cytokine studies 
(research) 
 
If CRS is suspected based on clinical 
symptoms 
- 
Lymphocyte subsets, T 
cell activation/exhaustion 
markers  
(research) 
 
Before each dose of hu3F8-BsAb 
- 
Bone marrow studies* 
 
After the second dose of cycle 2 and cycle 4 
and approximately every 3 months 
thereafter 
- 
CT/MRI, MIBG scan* 
with/without PET, bone 
scan 
 
After the second dose of cycle 2 and cycle 4 
and approximately every 3 months 
thereafter 
- 
Stool microbiome 
, where 
feasible 
- 
- 
*only for patients with neuroblastoma 

 
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11 
TOXICITIES/SIDE EFFECTS 
11.1 
Information regarding the definition and reporting of adverse events, including serious 
adverse events, is provided in Section 17.2. 
11.2 
Hu3F8-BsAb is expected to be associated with the known side effects of m3F8 and hu3F8  
Common side effects: pain, paresthesia, hypertension, hypotension, sympathetic 
neuropathy, presyncope, syncope, tachycardia, urticaria, pruritus, flushing, fever, 
somnolence, nausea, and emesis. 
Less common side effects: diarrhea, serum sickness, hyponatremia, airway constriction, 
peripheral neuropathy, impaired accommodation of the eye, poor reactivity of pupils to 
light, transaminitis. 
Rare but serious side effects: anaphylaxis, posterior reversible encephalopathy syndrome 
(PRES) 
11.3    
Cytokine release syndrome (CRS) has been reported in patients with B cell leukemia or 
lymphoma treated by anti-CD19 T cell immunotherapies (e.g. blinatumomab, anti-CD19 
CAR-modified T cells). CRS correlated with anti-tumor efficacy, and the incidence, 
severity, and onset of CRS depend on therapeutic agents, cancer type, tumor burden, and 
patient’s immune system.64,65,67,79,86-89 Severe cytokine release syndrome is characterized 
by fever (≥ 3days), elevation of serum cytokines, and clinical toxicities (hypotension, 
hypoxia, neurological symptoms). In NB patients, 19 patients were treated by anti-GD2 
CAR-modified T cells therapy in a phase I study and severe CRS was not observed.90 In 
adults, severe CRS is characterized by hypotension, respiratory distress and cardiac 
changes including arrhythmias, acute coronary syndrome, and impaired LV function, and 
neurological symptoms such as seizures. Instead of grading CRS according to CTCAE 4.0, 
CRS will be graded using the CRS revised grading system by Lee et al.91 described below 
in Table 8. 
Table 8 
CRS revised grading system91 
Grade 
Toxicity 
Grade 1 
Symptoms are not life-threatening and require symptomatic treatment only, e.g. fever, 
nausea, fatigue, headache, myalgias, malaise 
Grade 2 
Symptoms require and respond to moderate intervention 
Oxygen requirement < 40% or 
Hypotension responsive to fluids or low dose of one vasopressor or  
Grade 2 organ toxicity 

 
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Grade 
Toxicity 
Grade 3 
Symptoms require and respond to aggressive intervention 
Oxygen requirement ≥ 40% or 
Hypotension requiring high dose for≥ 3 hours * or multiple vasopressors or  
Grade 3 organ toxicity or Grade 4 transaminitis 
Grade 4 
Life-threatening symptoms 
Requirement to ventilator support or 
Grade 4 organ toxicity (excluding transaminitis) 
Grade 5 
Death 
*High dose vasopressors are defined as follows: dopamine > 10 ug/kg/min; norepinephrine > 0.1 ug/kg/min; 
epinephrine> 0.1 ug/kg/min; or dobutamine> 10 ug/kg/min.  
11.3.1 
Management of Cytokine release syndrome 
The following algorithm will be used if severe cytokine release syndrome occurs. 
 
11.4 
Neurotoxicity is another side effect of blinatumomab or anti-CD19 CAR-modified T cells. 
It was rare (< 5%) in children compared to adult patients in blinatumomab clinical studies.67 
Pathophysiology of the neurological toxicity is not clear; it could be related to CRS or could 
be associated with leukemic cells in CNS, hence it is unclear whether this is restricted to 

 
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CD19 targeting immunotherapies or not.64,65 In the phase I study of anti-GD2 CAR-
modified T cells mentioned in Section 11.3, no patients developed neurological 
symptoms.90 In addition to CRS, patients treated with hu3F8-BsAb may develop 
neurological toxicities due to adverse events of opiate analgesics, posterior reversible 
encephalopathy syndrome (PRES) which has been described with m3F8 and hu3F8.64-66,79 
Patients who develop abnormal neurological symptoms need to be evaluated immediately 
and appropriate management should be instituted as soon as possible. This can include 
discontinuation of opiates, naloxone, management of hypertension and head imaging.  
11.4.1 
Management of Neurological toxicities 
 
The following algorithm will be used for the management of neurotoxicity.  
 
Grade 4 seizure, encephalopathy, depressed level of consciousness, or somnolence will 
require discontinuation of the hu3F8-BsAb. Except in the case of paresthesia, patients 
experiencing any grade 3 neurotoxicity (e.g. depressed level of consciousness, 
encephalopathy or somnolence) and patients with uncontrolled seizures will be considered 
as having DLT and not receive subsequent doses of hu3F8-BsAb.  If parasthesia resolves 
to <grade 3 within 48 hours it will not be considered a DLT and patient may continue to 
receive protocol treatment if all eligibility criteria are met. In addition, if patients 
experience seizures, at least 72 hours should elapse before the next dose of hu3F8-BsAb is 
administered. 

 
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11.5  
Management of Orthostatic Hypotension 
 
  
 
 
 
 
 
 
 
 
 
11.6 
If treatment is stopped due to toxicity, treatment may resume once the patient returns to 
meeting eligibility criteria as described in Section 6. 
12 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Response duration is calculated from first day of treatment with hu3F8-BsAb. 
12.2 
Patients are considered a response failure under this protocol if progressive disease is 
evident at any time. 
12.3 
Disease response for NB will use the revised International NB Response Criteria92:  
12.3.1 
Overall Response: 
Overall response will be defined by combining response of the individual components (i.e. 
soft tissue, bone, and bone marrow disease) (See 12.3.2-12.3.4). 
• 
Complete response/remission (CR): All components meet criteria for CR. 
• 
Partial response/remission (PR): PR in as least one component and all other 
components are either CR, minimal disease (MD) (bone marrow), PR (soft tissue 
or bone), or not involved (NI)*; no component with progression disease (PD). 
• 
Mixed response (MR): PR or CR in at least one component but at least one other 
component with stable disease (SD); no component with PD.  
• 
Stable disease (SD): SD in one component with no better than SD or NI* in any 
other component; no component with PD. 
• 
Progressive disease (PD): Any component with PD.  
*NI – Site not involved at study entry and remains uninvolved. 

 
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12.3.2 
Primary (soft tissue) Tumor Response: 
• 
CR: <10mm residual soft tissue at primary site AND Complete resolution of MIBG 
or FDG-PET uptake (for MIBG-nonavid tumors) at primary site. 
• 
PR: ≥30% decrease in longest diameter of primary site AND MIBG or FDG-PET 
uptake at primary site stable, improved, or resolved. 
• 
PD: >20% increase in longest diameter taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study) AND 
Minimum absolute increase of 5mm in longest dimension. 
• 
SD: Neither sufficient shrinkage for PR or sufficient increase for PD at the primary 
site. 
12.3.3 
Tumor Response at Metastatic Soft Tissue and Bone Sites: 
• 
CR: Resolution of all sites of disease, defined as: Nonprimary target and nontarget 
lesions measure <10mm AND Lymph nodes identified as target lesions decrease to 
a short axis <10mm AND MIBG uptake or FDG-PET uptake (for MIBG-nonavid 
tumors) of nonprimary lesions resolves completely. 
• 
PR: ≥30% decrease in sum of diameters of nonprimary target lesions compared 
with baseline AND all of the following: 
Nontarget lesions may be stable or smaller in size AND No new lesions AND ≥50% 
reduction in MIBG absolute bone score (relative MIBG bone score ≥ 0.1 to ≤ 0.5) 
or ≥50% reduction in number of FDG-PET-avid bone lesion 
• 
PD: Any of the following: 
Any new soft tissue lesion detected by CT/MRI that is also MIBG avid or FDG-
PET avid 
Any new soft tissue lesion seen on anatomic imaging that is biopsied and confirmed 
to be neuroblastoma or ganglioneuroblastoma 
Any new bone site that is MIBG avid 
A new bone site that is FDG-PET avif (for MIBG-nonavig tumors) AND has 
CT/MRI findings consistent with tumor OR has been conferment histologically to 
be neuroblastoma or ganglioneuroblastoma 
>20% increase in longest diameter taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study) AND minimum 
absolute increase of 5mm in sum diameters of target soft tissue lesions 
Relative MIBG score ≥1.2 

 
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• 
SD: Neither sufficient shrinkage for PR or sufficient increase for PD of nonprimary 
lesions. 
12.3.4 
Bone Marrow Metastatic Response: 
• 
CR: Bone marrow with no tumor infiltration on reassessment, independent of 
baseline tumor involvement. 
• 
PD: Any of the following: 
Bone marrow without tumor infiltration that becomes >5% tumor infiltration on 
reassessment OR 
• 
Bone marrow with rumor infiltration that increases by > two-fold and has >20% 
tumor infiltration on reassessment. 
• 
MD: Any of the following: 
Bone marrow with ≤5% tumor infiltration and remains >0 to ≤5% tumor infiltration 
on reassessment OR 
Bone marrow with no tumor infiltration that has ≤5% tumor infiltration on 
reassessment OR 
Bone marrow with >20% tumor infiltration that has >0 to ≤5% tumor infiltration 
on reassessment 
• 
SD: Bone marrow with tumor infiltration that remains positive with >5% tumor 
infiltration on reassessment but does not meet CR, MD, or PD criteria. 
12.4 
Disease response for non-neuroblastoma tumors will use the Response Evaluation Criteria 
in Solid Tumor (RECIST) Version 1.1.   
12.4.1 
Measurable Disease: 
The presence of at least one lesion that can be accurately measure in at least one dimension 
with the longest diameter at least 20 mm or lesions at least 10 mm on spiral scan is 
considered measurable disease. 
12.4.2 
Response Criteria 
• 
Complete Response (CR): Disappearance of all clinical and radiological evidence 
of target lesions. 
• 
Partial Response (PR): A greater than or equal to 30% decrease in the sum of the 
longest diameter of all index lesions in reference to the baseline sum of the longest 
diameters of the index lesions. 
• 
Stable Disease (SD): Response that is neither sufficient decrease to qualify as PR 
nor sufficient increase to qualify as Progressive Disease (PD). 

 
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• 
Progressive Disease (PD): A greater than or equal to 20% increase in the sum of 
the longest diameters of all index (“target”) lesions, taking as reference the smallest 
sum of the longest diameters recorded at or following baseline OR the appearance 
of one or more new site of disease. 
12.5 
Pseudoprogression (tumor growth from immune response rather than true disease 
progression) can be seen in early time points after T-cell mediated immunotherapy. If 
pseudoprogression is suspected, patients will be followed clinically and/or by scans about 
4 weeks later to determine if patient has true PD 
12.6 
Adequacy of trial: All patients who fulfill the eligibility requirements and complete the first 
cycle of hu3F8-BsAb will have an adequate trial and are considered evaluable for protocol.  
In phase I, patients will be considered evaluable if patients develop progressive disease 
after completing protocol treatment during cycle 1 but do not receive any other treatment 
before Day 28 of the DLT observation period. 
13 
CRITERIA FOR REMOVAL FROM STUDY 
13.1 
Patients come off treatment if there is PD at any time. Best clinical judgment will be used 
to determine whether a patient must undergo tests between cycles to make sure disease is 
not progressing.  Patients are followed for toxicities for 30 days from last treatment. 
13.2 
Patients come off treatment if they have DLT (during cycle 1 of phase I) or life-threatening 
toxicity clearly attributable to hu3F8-BsAb. Patients in the first stage of phase I (one patient 
per dose level cohort) who experience ≤ grade 2 toxicity, will not come off treatment but 
can continue at the same dose if they do not experience DLT and if toxicity subsides to 
<grade 2 within 35 days of dose 1 of Hu3F8-BsAb. 
13.3 
Patients who become pregnant during the study must be withdrawn from treatment 
13.4 
The investigators will make every reasonable effort to keep each patient in the study until 
all planned treatments and assessments have been performed. The investigators may 
discontinue study drug treatment for the following reasons: 
• 
Adverse events, including unacceptable toxicity or exacerbation of underlying 
disease, 
associated 
with 
study 
drug 
administration 
and 
necessitating 
discontinuation of treatment. Patients who are coming off treatment due to adverse 
events will be treated and followed according to established, acceptable medical 
practice. All pertinent information concerning the outcome of such treatment will 
be entered in the MSKCC institutional Clinical Research Database (CRBD). 
Patients will be followed until resolution or stabilization of the adverse event. 

 
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13.5 
Off Study Criteria: 
• 
Thirty days after the last dose of study drug for patients coming off treatment due 
to DP 
• 
For patients coming off treatment due to adverse events, patients will be followed 
until the date the event returns to baseline or <Grade 3 (whichever is higher) or the 
date patients start another treatment, whichever is earlier.  
• 
Death 
• 
Lost to follow-up 
• 
Withdrawal of consent. The patient's desire to withdraw from the study may occur 
at any time. The investigator should carefully consider whether the patient’s 
withdrawal of consent is due to an adverse event, and if so, record the adverse event 
as the reason for withdrawal. 
• 
Withdrawal by the physician for clinical reasons not related to study drug 
treatment in the absence of an adverse event. 
• 
Violation of the study protocol, including failure to return for required treatments 
or assessments.  Patients who fail to return for treatments will be included into the 
study assessment if they receive at least one dose of hu3F8-BsAb.  
14 
BIOSTATISTICS 
14.1 
Phase I 
14.1.1 
Primary endpoint 
The main objective of the study is to establish the maximum tolerated dosage (MTD) of hu3F8-BsAb. 
The MTD will be defined as the dose whose toxicity rate does not exceed an acceptable threshold of 
toxicity of 15%. DLT is defined in Section 9.1. In the first stage, the trial will accrue 1 patient per dose 
until the first ≥ Grade 2  related toxicity (except for Grade 2 sinus bradycardia, sinus tachycardia, fever, 
nausea, vomiting, diarrhea, urticaria, headache, paresthesia, electrolyte disturbances, pain) is 
encountered. The subsequent dose allocation will follow the CRM.  CRM assumes a simple model for 
the probability of a DLT as a function of dose, and uses the occurrence of toxicities in the patients 
enrolled in the trial to sequentially determine which dose to administer to a new patient. Patients will 
be assigned at each dose one at a time. New subjects will be allocated a dose as suggested by the CRM 
algorithm based on the toxicities of previously accrued patients.  If the DLT data are not available for 
the previously accrued 1 or 2 patients, the CRM will proceed with the dose as calculated    with available 
toxicities/data, however if there are 3 enrolled patients with incomplete /outstanding DLT data the 
accrual will be paused. DLT data from at most 2 patients can be pending but no more than 2 patients 
are allowed to have DLT data not complete. To protect patient safety, a dose escalation of more than 

 
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one dose level is not permitted. If no DLT is observed, the RP2D will be determined as a minimum 
dose that gives the highest hu3F8-BsAb serum levels based on the PK data. 
We will examine 12 dose levels as described in Table 4 (Section 9.1). Our initial estimates of DLT 
probabilities are: 0.001, 0.005, 0.01, 0.025, 0.05, 0.075, 0.10, 0.15, 0.25, 0.35, 0.45, 0.50 for doses 1-
12, respectively. Thus, our a priori belief is that dose level 8 is the MTD. The starting dose level will 
be dose level 1. We assume that the dose-toxicity follows a hyperbolic tangent model P(DLT=yes at 
dose d)=((tanh d+1)/2)^a, where a is the unknown parameter that we need to estimate in order to 
determine which dose is the MTD.A value of a=1.0 indicates that our prior beliefs were correct; while 
a value of a less than (greater than) 1.0 indicates that the combinations are more (less) toxic than 
believed. To reflect the uncertainty in our prior probability estimates, we assume it follows an 
exponential distribution (prior distribution) with mean 1.0. Dose escalation will be guided by the model 
after the occurrence of the first DLT. At that time, the above initial estimates of DLT might be revisited 
before model initiation to reflect the current knowledge on the safety profile and dose levels based on 
the observed data. 
We will enroll 30 evaluable patients; We expect to enroll 10-15 patients/year, and it is expected that 
the trial will be open to accrual for 36 months. All patients who are enrolled in the study and receive at 
least one dose of hu3F8-BsAb are considered evaluable for toxicity. Additional subjects will be 
enrolled to replace any subjects who are enrolled, but do not receive any treatment. An amendment in 
the dose levels was done after the inclusion of 5 patients to dose levels 1 to 4; however, the 
modifications only impacted dose level 5 and higher, therefore the 5 first patients are still part of the 
CRM and will be analyzed as planned. The amendment does not modify the operating characteristics 
of the CRM. 
14.1.1.1 
Operating characteristics 
Through 1000 simulated trials with the above parameters we expect the method to behave in the 
following way, assuming three different hypothetical scenarios for the true toxicity rates at each dose 
level: 
Table 9 
Hypothetical True Toxicity Rates 
Dose levels 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Scenario 
1 
0.01 
0.02 
0.05 
0.15 
0.25 
0.35 
0.35 
0.40 
0.45 
0.50 
0.50 
0.50 
Scenario 
2 
0.001 
0.005 
0.01 
0.02 
0.03 
0.05 
0.10 
0.15 
0.25 
0.35 
0.45 
0.60 
Scenario 
3 
0.001 
0.005 
0.01 
0.02 
0.03 
0.04 
0.05 
0.06 
0.07 
0.08 
0.09 
0.10 
 

 
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Table 10 
Percent of simulated trials that selected each dose under each scenario 
Dose levels 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Scenario 
1 
0.1 
1.5 
15.2 
47.2 
26.3 
5.4 
3.2 
0.9 
0.2 
0.0 
0.0 
0.0 
Scenario 
2 
0.0 
0.0 
0.0 
0.2 
1.0 
5.4 
18.5 
42.5 
26.3 
5.5 
0.5 
0.1 
Scenario 
3 
0.0 
0.0 
0.0 
0.2 
0.4 
1.2 
2.9 
10.7 
14.7 
15.7 
14.4 
39.8 
 
Table 11 
Percent of patients treated at each dose under each scenario 
Dose levels 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Scenario 
1 
3.9 
7.2 
19.5 
30.8 
20.8 
8.7 
5.1 
2.9 
0.8 
0.2 
0.06 
0.0 
Scenario 
2 
3.4 
4.3 
6.7 
6.6 
7.8 
9.9 
14.7 
23.2 
16.3 
5.3 
1.6 
0.2 
Scenario 
3 
3.4 
4.4 
6.7 
6.5 
6.9 
7.2 
8.6 
11.8 
11.9 
9.8 
8.7 
14.0 
 
Table 12 
Average toxicities across trials at each dose 
Dose levels 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Scenario 
1 
0.0 
0.0 
0.3 
1.4 
1.5 
1.0 
0.5 
0.3 
0.1 
0.0 
0.0 
0.0 
Scenario 
2 
0.0 
0.0 
0.0 
0.0 
0.1 
0.1 
0.4 
1.0 
1.2 
0.6 
0.2 
0.0 
Scenario 
3 
0.0 
0.0 
0.0 
0.0 
0.1 
0.1 
0.1 
0.2 
0.2 
0.2 
0.2 
0.4 
 
14.1.1.2 
Dose Allocation in CRDB Section for the Protocol 
Patient Registration and the CRDB CRM module are run independently. Once new patients are 
registered, the CRDB CRM module can be run by members of the protocol research team to generate 
the CRM report which includes the recommended dose level for the newly registered patient. 
During the first stage, one patient is accrued at a time starting at the first dose level and followed for 
DLT before the next patient is accrued.  Patients must be followed for 28 days to determine if they had 
a DLT.  If  no DLT is seen, then the next patient is accrued at the next higher dose level.  This process 

 
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will continue until a DLT is seen.  Once a DLT is seen, the study team should notify the CRDB Helpline 
and the study statistician in order to have the protocol switched to the model-based stage. The dose 
level of subsequent patients will be assigned by the CRM module. The CRM program uses information 
specified in the Biostatistics section of the protocol and the summarized toxicity data of previously 
treated patients as displayed in the CRM report to determine the next dose level to which the patient 
will be assigned.  Only eligible and evaluable patients are used in determining the next dose level. 
Patients accrued during the model-based stage must also be followed for 28 days to determine if they 
had a DLT. Since the protocol allows 2 patients to have incomplete toxicity data, then the CRM 
algorithm can still generate a dose assignment even if toxicity/DLT data are missing for up to 2 patients 
who were last registered to the protocol.  If toxicity data is missing on more than   2 patients or other 
required data is missing, the CRM module will not provide the next dose assignment and a message 
indicating missing data will be generated. 
The CRM report includes summary and detailed toxicity information and the recommended next dose 
level (determined by the CRM program). The report will normally be generated by the CRC; however 
other members of the research team can be given access to run the CRM module. The dose level for 
new patients is not automatically saved. The PI must check the report to determine if all toxicity data 
are correct and up-to-date. If the data are correct, the PI will acknowledge this and sign the last page 
of the report which displays the recommended dose assignment. The last page of the report also 
contains space to fill in the MRN and name of the newly registered patient who is to receive this dose 
assignment. The CRC will enter the dose level in CTMS after a patient is registered. 
If any data are incomplete or incorrect, the PI will inform the CRC.  The CRC will correct the data and 
indicate to the PI when this is done. The CRDB CRM module will be run again to determine the next 
patient’s dose level. The report will be generated and the PI will be notified to approve the assignment. 
The dose level will then be entered into CTMS. 
Although both children and adults are eligible for enrollment on this study, we do not anticipate any 
significant differences in target specific toxicity between adults and children based on our experience 
of over 780 children under age 12 and over 100 patients over age 12 (including >50 over age 18) in the 
past 20 years with m3F8 and hu3F8. Additionally, there are no reported significant differences in the 
toxicity of blinatumomab in children compared to adults; 65 thus children and adults will be enrolled 
and evaluated simultaneously on each dose level. 
14.1.2 
Secondary endpoints   
14.1.2.1 
Pharmacokinetics of hu3F8-BsAb 
PK will be measured by serial blood sampling during cycle 1 as listed in Table 5. PK analysis will be 
carried out by noncompartmental analysis of the serum concentration-time data. The following 
variables are determined: area under the serum concentration-time curve (AUC), the maximum serum 
concentration (Cmax), the time to reach the maximum concentration (tmax), and the terminal half-life 
(t1/2). The variables AUC and Cmax(ss) are dose normalized in order to calculate clearance (CLss), volume 

 
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of distribution (Vss) at steady state, the accumulation index for AUC (RA,AUC), Cmax (RA,Cmax), apparent 
terminal half-life, and mean residence time. 
14.1.2.2 
To assess the activity of hu3F8-BsAb against NB, osteosarcoma, and 
other GD2(+) tumors and to assess HAHA response 
For NB, anti-tumor activity will be measured by revised INRC. For osteosarcoma and other GD2(+) 
tumors, the response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST) Committee, version 1.1. as described in Section 12.93 The 
proportion of NB, osteosarcoma, and other GD2(+) tumor patients responding to therapy will be 
determined for each disease type. HAHA will be measured as previously described and the proportion 
of patients developing HAHA after hu3F8-BsAb therapy will be determined. The correlation between 
HAHA response and overall response (for neuroblastoma), disease control (for osteosarcoma), overall 
survival, and progression free survival will be assessed. The correlation between HAHA response and 
overall response rate (for neuroblastoma) or disease control rate (for osteosarcoma) will be tested using 
chi-square test. Kaplan-Meier method will be used for estimating overall survival and progression-free 
survival. Log-rank test will be used for assessing the correlation between HAHA response and the 
survivals (e.g. OS, PFS) in univariable analysis. Cox-Regression will be used for multivariable analysis 
for variables including known prognostic factors and HAMA response if p<0.05 in the univariable 
analysis. This information will be summarized separately by cancer type. 
14.1.2.3 
To study stool microbiome 
Sequencing of stool microbiota will be performed and correlated with clinical and immunological 
response. Given the heterogeneity of the diagnosis and stage in this study, this objective is exploratory 
no formal statistical comparisons will be made.   
14.2 
Phase II 
14.2.1 
Primary endpoint 
14.2.1.1 
For Group 1 (relapsed or refractory NB) 
The objective is to improve overall response rate (ORR) defined as the proportion of patients achieving 
CR or PR based on revised INRC as the best response at the end of cycle 2 and cycle 4. The phase II 
study of ch14.18 + GM-CSF for relapsed/refractory NB (POG 9347) demonstrated overall response 
rate of 17. 8% in a total 28 patients.94 Our phase II study of 3F8 + GM-CSF for refractory NB had ORR 
of 28.8% (13 CR+PR out of total 45).95 Based on these clinical trial results we decided that the historical 
ORR of refractory/relapsed NB by antibody therapy is < 25 %. 
Our null hypothesis is that the hu3F8-BsAb treatment has ORR < 25%. The alternative hypothesis is 
that the ORR after the hu3F8-BsAb treatment is 50%.  
We will accrue 30 patients. At the end of the trial 95% one-sided confidence interval for ORR will be 
computed using Wilson’s method. If the confidence interval does not include the null ORR rate of 25% 
we will consider this treatment successful. The sample size is based on confidence interval half-width 

 
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0.15 and desirable ORR rate of 50%. Based on simulation if the true rate is 50% the CI will not include 
25% with probability 90%.  
Patients who received at least 1 dose of hu3F8-BsAb will be included into the assessment even if they 
are removed from the study before completing cycle 4 due to any reasons. We expect to enroll 10-15 
patients/year, therefore accrual of this group will be completed in 2-3 years. 
14.2.1.2 
For Group 2 (relapsed or refractory osteosarcoma) 
The objective is to improve 4-month PFS. A retrospective analysis of seven phase II trials conducted 
by Children’s Oncology Group (COG) and its predecessor groups demonstrated that PFS at 4 months 
from time of enrollment in patients with relapsed measurable disease was 12% (95% CI: 6% to 19%).19  
Our null hypothesis is that the hu3F8-BsAb treatment has 4-month PFS <12% The alternative 
hypothesis is that the 4-month PFS after hu3F8-BsAb treatment is 40%. We will accrue 18 patients. At 
the end of the trial 95% one-sided confidence interval for 4 months PFS will be computed using 
Wilson’s method. If the confidence interval does not include the null rate of 12% we will consider this 
treatment successful. The sample size is based on confidence interval half-width 0.190 and desirable 4 
months PFS rate of 40%. Based on simulation if the true rate is 40% the CI will not include 12% with 
probability 90%.  
Patients who received at least 1 dose of hu3F8-BsAb will be included into the assessment even if they 
are removed from the study before completing cycle 4 due to any reasons.  We expect to enroll 5-10 
patients/year, therefore accrual of this group will be completed in 2-4 years. 
14.2.2 
Secondary endpoints 
14.2.2.1 
Evaluation of the duration of complete remission 
Duration of complete remission (CR) is defined only for patients who achieve CR after hu3F8-BsAb 
and will be calculated from the time of remission. Duration of CR will be estimated using the Kaplan-
Meier method. 
14.2.2.2 
For Group 2 (relapsed or refractory osteosarcoma): To assess the overall 
response rate 
Overall response rate (ORR) is defined as the proportion of patients achieving CR or PR based on RECIST 
v1.1 as the best response at the end of cycle 2 and cycle 4. A retrospective analysis of seven phase II 
trials conducted by Children’s Oncology Group (COG) and its predecessor groups demonstrated that 
2 out of 87 evaluable patients with relapsed osteosarcoma had CR or PR after treatment of the trial.19 
Hence, we decided that the historical ORR is <3%. We are not making a hypothesis of the ORR in 
patients treated by hu3F8-BsAb because this is not the primary objective of this study, however, we 
will compare the ORR in this study with the historical data. 

 
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14.2.2.3 
To assess the toxicity of hu3F8-BsAb and to assess HAHA response 
Toxicity of hu3F8-BsAb will be monitored using CTCAE version 4.0 and CRS revised grading system. 
(See Section 11) HAHA will be measured as previously described and the proportion of patients 
developing HAHA after hu3F8-BsAb therapy will be determined. 
14.3 
Exploratory endpoints 
14.3.1 
For Phase II: To assess overall survival and progression free survival 
Overall survival (OS) is defined as the time from the study enrollment to the time of death or last follow 
up. Progression free survival (PFS) is defined as the time from the study enrollment to the time of 
disease progression or last follow up. OS and PFS will be estimated using Kaplan-Meier method. 
Exploratory endpoints below are common to both Phase I and Phase II. They will be assessed separately 
for Phase I and Phase II and by disease group. 
14.3.2 
To study immunological effects of hu3F8-BsAb 
Biologic correlate studies include (1) host immunity, (2) host T cell cytotoxic capacity, and (3) T cell 
homing into the tumor. The parameters measured for each patient under “host immunity” include: the 
induction of HAHA, the induction of Ab3, the induction of Ab3’. Under “T cell cytotoxic capacity”, 
the following measurements will be made: (1) cytokine profiles including IFN-ƴ, IL-6, IL-8, IL-10 78,79, 
(2) changes in lymphocyte populations and their differentiation including CD3, CD4, CD8, Foxp3, 
CD127, CD45RA, CCR7, and (3) activation and exhaustion markers on T cells including CD25 and 
PD-1. “T cell homing” will be tested by immunohistochemistry of tumor samples if available. Host 
immunity, T cell cytotoxic capacities, and T cell homing will be tested for correlation with hu3F8-
BsAb dose, as well as for association with patient response and survival, using Benjamini-Hochberg 
adjustment for multiple comparisons.  However, given the heterogeneity of patients and disease stage, 
and the limited number of patients, multivariable statistical analysis is not planned. Nevertheless, these 
comparisons will provide insights into biologic effects of hu3F8-BsAb and parameters that may predict 
response and survival. The establishment of the feasibility of these critical assays will facilitate future 
phase I/II explorations of combination with other cytokines orbiologics. 
14.3.3 
To study tumor DNA, RNA 
For neuroblastoma patients only: tumor DNA and RNA matched to normal RNA, will be archived to 
profile tumor gene aberrations and gene expressions as well as to test correlation with MRD. This 
information will become relevant when combined with genome and expression data from current and 
future studies of hu3F8-BsAb. Given the heterogeneity of the diagnosis and stage in this study, this 
objective is exploratory no formal statistical comparisons will be made. 

 
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14.3.4 
To study stool microbiome 
Sequencing of stool microbiota will be performed and correlated with clinical and immunological 
response. Given the heterogeneity of the diagnosis and stage in this study, this objective is exploratory 
no formal statistical comparisons will be made. 
15 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. The individual signing the Eligibility Checklist is confirming that the participant 
is eligible to enroll in the study. Study staff are responsible for ensuring that all institutional 
requirements necessary to enroll a participant to the study have been completed and inform the Sponsor 
for review and approval of eligibility of the patient. 
15.2 
Randomization 
Not applicable 
16 
DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator (CRC) will be assigned to the study.  The responsibilities of the CRC 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. The data collected for this study will be entered into a secure database. Source documentation 
will be available to support the computerized patient record. 
16.1 
Quality Assurance 
Registration reports will be generated to monitor patient accruals and completeness of registration data.  
Routine data quality reports will be generated to assess missing data and inconsistencies.  Accrual rates 
and extext and accuracy of evaluations and follow-up will be monitored periodically throughout the 
study period and potential problems will be brought to the attention of the study team for discussion 
and action 
Random-sample data quality and protocol compliance audits will be conducted by the study team. 

 
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16.2 
Data and Safety Monitoring 
A Data Monitoring Committee (DMC) is established to assure patient safety and will function 
independently of all other individuals associated with the conduct of the trial, including site 
investigators participating in the trial. The DMC will consist of a minimum of 2 physicians whose 
expertise covers relevant specialties and, where applicable, a statistician.  
During the conduct of Phase I the DMC will evaluate available safety information and recommend 
trial continuation or termination. If continuation is recommended, the DMC will recommend to the 
sponsor whether the dose should be escalated, de-escalated, or held at the same level based on the 
CRM.   
At the completion of Phase I, the DMC will review relevant data and provide a recommendation 
regarding the MTD and RP2D.  
During the conduct of Part 2, DMC meetings will be held on a regular basis to review cumulative 
safety data and evaluate whether the trial should be modified, stopped, or continue unchanged. The 
Sponsor Safety Committee will evaluate the recommendations from the DMC after each DMC 
meeting. Any significant finding/recommendation from the DMC and endorsed by the Sponsor 
Safety Committee will be communicated to the regulatory authorities and Institutional Review Board 
(IRB)/Ethics Committee (EC) as appropriate, and to the sites. 
Responsibilities, procedures, content of the DMC packages, and workflow of the DMC are specified 
in the DMC Charter. 
17 
PROTECTION OF HUMAN SUBJECTS 
The investigator agrees to conduct this study in accordance with the International Conference on 
Harmonization (ICH) principles of Good Clinical Practice and with the Declaration of Helsinki (1989). 
The investigator will conduct all aspects of this study in accordance with all national, state, and local 
laws of the applicable regulatory agencies. 
• Most patients will be children, adolescents, and young adults because of the nature of these 
tumors.  Patients of both sexes and all ethnic backgrounds are eligible for this study.  
Alternative treatments are available and will be discussed with patient or legal guardian.   
• Consent Process: Participation in this trial is voluntary.  All patients will be required to sign a 
statement of informed consent, which must conform to MSKCC IRB guidelines. 
• Benefits: It is not known whether this treatment will improve the overall survival of the 
patient. 
• Risks: The potential risks of this therapy as described in Section 11 of this protocol may 
outweigh the potential benefits in an individual patient.  The potential risks are related to 
adverse effects that could be induced by administration of hu3F8-BsAb. 

 
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• Costs: Patients are responsible for the costs of physician visits and usual laboratory tests, 
hospitalizations, inpatient and outpatient care.  Patients are not responsible for the cost of 
hu3F8-BsAb, and the costs of the research bloods: HAHA, cytokine studies, and studies on 
lymphocytes.  Patients If there is an injury as a result of this research study, emergency care, 
hospitalization, and outpatient care will be made available by Memorial Hospital and billed to 
the patient as part of the medical expenses.  No money will be provided by Memorial Hospital 
as compensation for research-related injury.  Patients will not be paid for taking part in this 
study.   
• Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential.  
17.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals/entities described in the Research Authorization form. A 
Research Authorization form must be approved by the IRB and Privacy Board (IRB/PB).  
The consent indicates that individualized de identified information collected for the purposes of this 
study may be shared with other qualified researchers. Only researchers who have received approval 
from MSK will be allowed to access this information which will not include protected health 
information, such as the participant’s name, except for dates. It is also stated in the Research 
Authorization that their research data may be shared with others at the time of study publication. 
17.2 
Adverse Event (SAE) Reporting 
17.2.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product which 
does not necessarily have a causal relationship with the treatment. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:  
• A clinically significant worsening of a concomitant illness.  
• A laboratory abnormality which is clinically significant, i.e. an abnormality that suggests a 
disease and/or organ toxicity and is of a severity that requires active management. Active 
management includes interventional treatment or further investigations, for example change of 
medicine dose or more frequent follow-up due to the abnormality. 

 
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Pre-existing condition, (i.e., a disorder present before the AE reporting period started and noted on the 
medical history/physical examination form) should not be reported as an AE unless the condition 
worsens, or episodes increase in frequency during the AE reporting period. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. A medical condition for which an unscheduled procedure was performed should, 
however, be reported if it meets the definition of an AE. For example, an acute appendicitis should be 
reported as the AE and not the appendectomy. 
17.2.2 
Definition of Serious Adverse Events 
Each AE is to be classified by the Investigator as either serious or non-serious. This classification of 
the seriousness of the AE determines the reporting procedures to be followed. An AE that meets one 
or more of the following criteria/outcomes is classified as serious: 
• Is fatal or life-threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization2 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Medically important event3 
1: The term "life-threatening" in the definition of "serious" refers to an event in which the patient, in view of either the 
Investigator or Sponsor, was at risk of death at the time of the event; it does not refer to an event, that hypothetically might 
have caused death if it were more severe. Death alone is not considered an AE; it is an outcome of an AE. 
Reports of death should be accompanied by the corresponding AE term for the event that led to death. However, sudden 
death or death due to unexplainable cause should be reported as an SAE, while follow-up is pursued to determine the cause.  
2: Hospitalization is defined as admission to a hospital/inpatient (irrespective of the duration of physical stay) or is not 
admitted to a hospital/not an inpatient but stays at the hospital for treatment or observation for more than 24 hours. Events 
leading to hospitalizations for the following reasons should not be reported as SAEs: 
• 
Trial-related purposes, not associated with any deterioration in condition  
• 
Social reasons in the absence of any deterioration in the patient’s general condition 
• 
Elective surgery or other scheduled hospitalization periods that were planned before the patient was included in 
this trial. 
3: Medical and scientific judgment must be exercised in deciding whether an AE is believed to be “medically important”. 
Medically important events may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the definition above. 
17.2.3 
Definition of Non-Serious Adverse Events 
A non-serious AE is any AE which does not fulfil the definition of an SAE.  

 
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17.2.4 
Adverse Event Reporting Period  
17.2.4.1 
Non-Serious Events 
Non-serious AEs should be reported from the day of first IMP (Hu3F8 BsAb) administration until 30 
days after the last IMP administration. Non-serious AEs occurring between signing the ICF and the 
first IMP administration must be recorded as medical history. 
17.2.4.2 
Serious Adverse Events 
Serious AEs should be reported from signing the ICF until 30 days after the last IMP administration. 
17.2.4.3 
Adverse Events during Follow-up 
During the follow-up period SAEs at least possibly related to IMP and new onset of secondary 
malignancies, regardless of causality, should be reported until end of trial. 
17.2.4.4 
Adverse Events with Onset after End-of-Trial 
If the Investigator becomes aware of an SAE after end of trial with a suspected causal relationship to 
the IMPs, it should immediately be reported to Sponsor. 
17.2.5 
Recording of Adverse Events 
All events meeting the definition of an AE must be collected and reported in the eCRF. SAEs and Dose 
Limiting Toxicities (DLTs) should be reported both in the eCRF and on the Clinical AE Report form.  
During each contact with the trial site staff, the patient must be asked about AEs, for example by asking: 
“Have you experienced any problems since the last contact?” All AEs, observed by the Investigator or 
patient, must be reported by the Investigator. 
17.2.5.1 
Diagnosis 
The Investigator should report the diagnosis, if available. If no diagnosis is available, the Investigator 
should record each sign and symptom as individual AEs using separate AE forms. For a cytokine 
release syndrome (CRS) event, both the diagnosis and the CRS related symptoms should be 
documented as individual events and graded according to Lee et. al. 2014 and CTCAE 4.0, respectively.  
17.2.5.2 
Onset Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom. The onset of time should be 
reported for all events if known, as a minimum the time should be entered if the event starts on a dosing 
day of IMP or if the duration of the event is less than 24 hours. 
17.2.5.3 
End Date and Time 
The end date should be filled in if the outcome of an AE is fatal, recovered/resolved or 
recovered/resolved with sequelae. The end time should be entered for all events for which start time 

 
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should be entered i.e. if the event starts on a dosing day of or if the duration of the event is less than 24 
hours. 
17.2.5.4 
Severity 
For all AEs, apart from cytokine release syndrome, the Investigator will use the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 to describe the severity of the AE. AEs of cytokine 
release syndrome will be graded using the CRS revised grading system by Lee et al.91 described in 
Table 8 in Section 11.3. If the severity changes over the course of the event, the grade assigned by the 
Investigator should be the most severe, that occurred during the AE period. 
17.2.5.5 
Outcome 
Investigator must judge outcome of the AE by the following terms: 
• Death  
• Not Recovered 
• Recovered  
• Recovered or Resolved with Sequelae 
• Recovering or Resolving 
• Unknown * 
*Should only be used if patient is lost to follow-up. 
17.2.5.6 
Relationship to Investigational Medicinal Product 
The Investigator must assess whether the event is related to the IMP (Hu3F8 BsAb). A suspected 
adverse drug reaction is defined as one in which there is a reasonable possibility that the IMP caused 
the AE. Relatedness must be assessed and reported from the first time the AE is being reported. When 
assessing the causal relationship of an AE to an IMP, the following should be taken into consideration: 
Not related (unlikely) 
The AE is not related to the IMP which means the AE: 
• Does not follow a reasonable temporal sequence from IMP administration 
• Is readily explained by the patient’s clinical state or by other modes of therapy administered to 
the patient 
• Is clearly not related to the IMP 
Possibly Related 

 
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• The AE follows a reasonable temporal sequence from IMP administration but could have 
been produced by the patient’s clinical state, medical history, or the trial 
procedures/conditions. 
Alternative etiology should be provided for all AEs assessed as possibly related to IMP. 
Probably Related 
The AE is probably related to the IMP, which means the AE: 
• Follows a reasonable temporal sequence from IMP administration 
• Abates spontaneously upon discontinuation of the IMP (de-challenge) without any curative 
treatment 
• Is confirmed by reappearance of the same reaction on repeat exposure (re-challenge) (if 
applicable) 
• Cannot be reasonably explained by the known characteristics of the patient’s clinical state or 
medical history 
Definite 
The AE is clearly related to the IMP, with no other possible alternative etiologies 
 
17.2.5.7 
Action Taken with Investigational Medicinal Product 
The action taken with the IMP should be noted as: 
• Dose Increased 
• Dose Not Changed 
• Dose Decreased 
• Administration Interrupted 
• Treatment Discontinued 
• Not applicable* 
• Unknown 
• Hospitalized  

 
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•  
*: should be used if the AE occurs before first treatment, IMP has been discontinued for other reasons or after end of 
treatment. 
17.2.6 
Events Requiring Immediate Reporting  
The following events require reporting to Sponsor within 24 hours of knowledge (for details see Section  
17.2.7): 
• SAE 
• DLT 
• Pregnancy 
17.2.6.1 
Pregnancy  
Any pregnancy, including partner pregnancy, that occurs during trial participation must be reported to 
Sponsor within 24 hours of knowledge using the pregnancy form. Pregnant trial patients must be 
discontinued from IMP treatment immediately (see Section 13). The pregnancy must be followed up 
to determine outcome and status of mother and child. The child must be followed at least to the age of 
one month. Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE. Spontaneous abortions must be reported as an SAE. 
17.2.7 
Initial Reporting of AEs 
SAEs/DLTs:  
The paper Clinical AE Report form must be reported from site to Sponsor within 24 hours of the 
Investigator’s first knowledge of the event. The paper Clinical AE Report form is to be sent to the 
designated drug safety provider.  
All AEs: 
The eCRF AE form should be updated in accordance with agreed data entry timelines. 
17.2.8 
Contact details for reporting 
Completed paper Clinical AE Report forms and paper pregnancy forms must immediately be reported 
to: 
safetymailbox@ymabs.com 
In emergency situations, the completed Clinical AE Report forms or pregnancy forms can be faxed 
to: 
FAX +45 7879 6060 
 

 
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17.3 
Follow-Up on AEs 
SAE/DLTs: 
• New Follow-up information available at site must be reported within 24 hours of knowledge. 
• Follow-up information requested from Sponsor must be replied to within three working days. 
The eCRF AE form should be updated in accordance to agreed data entry timelines  
• If an ongoing SAE changes in intensity, relationship to IMP or as new information becomes 
available for the event, the paper Clinical AE Report Form should be completed and sent to the 
designated drug safety provider within 24 hours of the change in assessment.  
• Grade 3 or higher non-serious AEs that are considered treatment related and all SAEs 
(including DLTs) should be followed on a regular basis, according to the Investigator’s clinical 
judgment, until the event has been resolved or until the Investigator can assess it as chronic or 
stable. This includes follow-up after end of treatment. 
Non SAEs: 
• Non-serious AEs should be followed until they are either resolved, returned to baseline, or 
until the end of trial for the patient, whichever comes first.  
17.4 
Reporting of SUSARs  
Sponsor will ensure that all relevant information about Suspected Unexpected Serious Adverse 
Reactions (SUSARs) is reported to regulatory authorities in accordance with regulatory requirements. 
The Contract Research Organization (CRO) appointed by Sponsor will notify Investigators of SUSARs 
in accordance with local requirements. Furthermore, Investigators will be informed of any trial related 
SAEs that may warrant a change in any trial procedure. The CRO appointed by Sponsor will inform 
the Institutional Review Boards (IRBs) of SUSARs in accordance with local requirement, unless 
locally this is an obligation of the Investigator.  
The Sponsor assessment of expectedness for the IMP (Hu3F8 BsAb) will be performed according to 
the current version of the Investigator’s Brochure. 
17.5 
Communication of Significant Safety Issues 
In the event of any significant safety related issues, the Sponsor will decide upon immediate action to 
be taken and will communicate to regulatory authorities, Investigators, IRB, and patients as needed 
within regulatory timelines. 
18 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their inclusion 

 
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in the study. Participants will also be informed that they are free to withdraw from the study at any 
time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following:  
1. 
The nature and objectives, potential risks and benefits of the intended study.  
2. 
The length of study and the likely follow-up required. 
3. 
Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. 
The name of the investigator(s) responsible for the protocol. 
5. 
The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must receive 
a copy of the signed informed consent form. 
 
 

 
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19 
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20 
APPENDICES 
 
Appendix A 
Pain Scales 
FLACC SCALE  
  
CATEGORIES 
SCORING 
  
0 
1 
2 
FACE 
No particular expression or 
smile 
Occasional grimace or 
frown, withdrawn, 
disinterested. 
Frequent to constant 
quivering chin, clenched 
jaw. 
LEGS 
Normal position or relaxed. 
Uneasy, restless, tense. 
Kicking, or legs drawn up. 
ACTIVITY 
Lying quietly, normal position 
moves easily. 
Squirming, shifting back 
and forth, tense. 
Arched, rigid or jerking. 
CRY 
No cry, (awake or asleep) 
Moans or whimpers; 
occasional complaint 
Crying steadily, screams or 
sobs, frequent complaints. 
CONSOLABILITY 
Content, relaxed. 
Reassured by occasional 
touching hugging or being 
talked to, distractible. 
Difficulty to console or 
comfort 
 
Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs 
2003;29:140-6. 
Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait AR. The revised FLACC observational pain 
tool: improved reliability and validity for pain assessment in children with cognitive impairment. 
Paediatr Anaesth 2006;16:258-65. 
Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring 
postoperative pain in young children. Pediatr Nurs 1997;23:293-7. 
 
 

 
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Numeric Pain Rating Scale 
 
 
Faces Pain Rating Scale 
 
 
 
Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs 1988;14:9-17. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix B 
 
Memorial Sloan Kettering Cancer Center 
Pediatric Pharmacy 
IRB #18-034 
Humanized 3F8 Bispecific Antibody (Hu3F8-BsAb) Standard 
Operating Procedure for Dose Preparation 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 

 
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o 
 
 
 
 
 

Signature Page for CLIN-000159 v4.0
Signature Page for CLIN-000159 v4.0
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