Clinical trial NCT04750239
Conditions: SCLC
Sponsor: Y-mAbs Therapeutics
Start date: 2021-08-17; Completion date: 2022-04-08
Enrollment: 3 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Adult patients with small-cell lung cancer (SCLC) will be treated with nivatrotamab a monoclonal anti GD2×CD3 bispecific antibody to investigate the safety and tolerability of the drug.

Detailed description:
The study will include a phase 1 dose escalation part to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). This will be conducted following a modified Bayesian Optimal Interval Design (mBOIN) design. For the purpose of dose escalation, dose-limiting toxicities (DLTs) will be collected and assessed for a period of 28 days (the DLT evaluation period).

A phase 2 dose expansion part will follow the phase 1 dose escalation. In phase 2, patients will be stratified according to whether they have platinum sensitive or platinum-resistant SCLC. Phase 2 will assess the long term safety and tolerability of nivatrotamab as well as the clinical activity of nivatrotamab when administered at the obtained MTD/RP2D in phase 1.

Arms: arm 1: Subcutaneous administration of nivatrotamab up to 13 cycles
Interventions: intervention 1: Nivatrotamab
Intervention descriptions: intervention 1: Anti GD2×CD3 monoclonal bi-specific antibody

Protocol documents:
Prot_SAP_000.pdf: 
 
Clinical Trial Protocol
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CONFIDENTIAL 
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Y-mAbs Therapeutics 
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CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
Safety and clinical activity of nivatrotamab, an anti GD2×CD3 bispecific 
antibody, in relapsed/recurrent metastatic small-cell lung cancer 
An open-label, single-arm, multicenter, phase 1/2 trial 
 
 
 
Clinical Trial ID: 402 
IND No: 153595 
EudraCT No: 2022-000201-27  
Version 8.0_20-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. 
 
 


 
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Approval of Clinical Trial Protocol 
 
 Protocol Author 
 
 
Y-mAbs Therapeutics, Inc. 
  
Director Clinical Operation  
 
Please refer to the e-signature 
page 
  
 
 Print Name: 
 Signature: 
 Date: 
 
 
 
 
 Medical Monitor/Expert 
 
 
Y-mAbs Therapeutics, Inc. 
 
Chief Scientific Officer, Global 
Head, Translational Medicine 
 
Please refer to the e-signature 
page 
  
 
 Print Name: 
 Signature: 
 Date: 
 
 
 
 Biometrics 
 
 
Y-mAbs Therapeutics Inc. 
 
Senior Project Statistician 
 
Please refer to the e-signature 
page 
  
 
 Print Name: 
 Signature: 
 Date: 
 
 
 


 
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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 
 
SVP, 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 +0045 7879 6060 
Coordinating Investigator 
 
 
UPMC Hillman Cancer Center  
5150 Centre Ave. 5th Floor 
Pittsburgh, PA 15232 
Approval by signature of the Clinical Trial Report (CTR) on behalf of all Investigators 
Information regarding Investigators conducting the trial, the trial monitor, clinical laboratories 
and/or technical departments and/or institutions involved in the trial will be provided as 
separate documents referencing the protocol. 


 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................ 10 
2 
PROTOCOL SYNOPSIS .................................................................................................. 15 
3 
FLOW CHART .................................................................................................................. 25 
4 
MEDICAL AND SCIENTIFIC JUSTIFICATION FOR THE TRIAL ....................... 31 
4.1 
Disease Background ........................................................................................................ 31 
4.2 
Rationale for the Development of GD2×CD3 Bispecific Antibody for the 
Treatment of SCLC ......................................................................................................... 32 
4.3 
Nivatrotamab Profile ....................................................................................................... 33 
4.3.1 
Non-clinical Data for Nivatrotamab ........................................................................... 33 
4.3.2 
Clinical Data for Nivatrotamab .................................................................................. 34 
4.3.3 
Nivatrotamab Dose Selection and Administration Schedule ..................................... 35 
4.4 
Choice of Trial Population .............................................................................................. 37 
4.5 
Choice of Trial Design and Dosing Strategy .................................................................. 38 
4.6 
Benefit–Risk Assessment ................................................................................................ 39 
5 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................... 41 
5.1 
Trial Objectives ............................................................................................................... 41 
5.1.1 
Primary Objective ....................................................................................................... 41 
5.1.2 
Secondary Objectives ................................................................................................. 41 
5.1.3 
Exploratory Objectives ............................................................................................... 41 
5.2 
Endpoints ......................................................................................................................... 41 
5.2.1 
Primary Endpoints ...................................................................................................... 41 
5.2.2 
Secondary Endpoints .................................................................................................. 42 
5.2.3 
Exploratory Endpoints ................................................................................................ 43 
6 
DESCRIPTION OF TRIAL DESIGN AND TRIAL POPULATION .......................... 44 
6.1 
Overall Trial Design ........................................................................................................ 44 
6.2 
Overall Trial Plan ............................................................................................................ 45 
6.2.1 
Phase 1: Dose Escalation ............................................................................................ 45 
6.2.1.1 
Dose Regimen ........................................................................................................ 45 
6.2.1.2 
Dose Levels............................................................................................................ 46 
6.2.1.3 
Dose Escalation Stages .......................................................................................... 46 
6.2.1.4 
Dose Escalation Rules ........................................................................................... 47 
6.2.1.5 
Stopping Criteria for the Dose Escalation ............................................................. 48 
6.2.1.6 
Determination of MTD and RP2D ........................................................................ 48 
6.2.2 
Phase 2: Dose Expansion ............................................................................................ 49 
6.2.2.1 
Dose Regimen ........................................................................................................ 49 
6.2.3 
Definition of Dose-limiting Toxicity .......................................................................... 49 
6.2.4 
Dose Modifications .................................................................................................... 50 
6.2.5 
Trial Stopping Rules ................................................................................................... 51 
6.2.6 
Recruitment Period ..................................................................................................... 51 
6.2.7 
Screening/Pre-treatment Evaluation ........................................................................... 51 
6.2.8 
Screening Failures and Re-screening ......................................................................... 52 


 
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6.2.9 
Study Treatment Assignment ..................................................................................... 52 
6.2.9.1 
Phase 1 ................................................................................................................... 53 
6.2.9.2 
Phase 2 ................................................................................................................... 53 
6.2.10 
Visit Schedule ............................................................................................................. 53 
6.2.10.1 
Phase 1 ................................................................................................................... 53 
6.2.10.2 
Phase 2 ................................................................................................................... 55 
6.2.11 
End of Treatment Visit ............................................................................................... 55 
6.2.12 
Unscheduled Visits ..................................................................................................... 55 
6.2.13 
Follow-up ................................................................................................................... 56 
6.2.13.1 
Phase 1 ................................................................................................................... 56 
6.2.13.2 
Phase 2 ................................................................................................................... 56 
6.2.14 
End of Trial ................................................................................................................. 56 
6.3 
Trial Population ............................................................................................................... 56 
6.3.1 
Number of Patients ..................................................................................................... 56 
6.3.2 
Patient Selection ......................................................................................................... 56 
6.3.2.1 
Inclusion Criteria ................................................................................................... 56 
6.3.2.2 
Exclusion Criteria .................................................................................................. 57 
6.3.3 
Premature Discontinuation of Treatment ................................................................... 59 
6.3.3.1 
Treatment Discontinuation Criteria ....................................................................... 59 
6.3.4 
Withdrawal from the Trial .......................................................................................... 59 
6.3.5 
Patient Replacement ................................................................................................... 59 
7 
TREATMENTS .................................................................................................................. 60 
7.1 
Investigational Medicinal Product .................................................................................. 60 
7.1.1 
Nivatrotamab Administration ..................................................................................... 60 
7.1.2 
Treatment Schedule .................................................................................................... 60 
7.1.2.1 
Phase 1 (dose escalation) ....................................................................................... 61 
7.1.2.2 
Phase 2 (dose expansion) ....................................................................................... 61 
7.1.2.3 
Treatment Modification and Delays ...................................................................... 61 
7.1.2.4 
Treatment after Discontinuation of IMP ................................................................ 61 
7.1.3 
Packaging and Labelling ............................................................................................ 61 
7.1.4 
Storage and Handling ................................................................................................. 61 
7.1.5 
Drug Accountability and Compliance Check ............................................................. 62 
7.1.5.1 
Medication Errors .................................................................................................. 62 
7.1.6 
Device ......................................................................................................................... 62 
7.1.7 
Technical Complaint................................................................................................... 62 
7.2 
Other Therapies and Procedures ..................................................................................... 63 
7.2.1 
Concomitant Therapy ................................................................................................. 63 
7.2.2 
Pre-medications prior to nivatrotamab injection ........................................................ 63 
7.2.2.1 
Cytokine Release Syndrome .................................................................................. 63 
7.2.2.2 
Pain ........................................................................................................................ 65 
7.2.3 
Recommended supportive medication ....................................................................... 66 
7.2.4 
Management of Selected Adverse Reactions ............................................................. 66 
7.2.4.1 
Grading and Management of Cytokine Release Syndrome ................................... 66 


 
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7.2.4.2 
Grading and Management of Immune effector-cell associated neurotoxicity ....... 68 
7.2.4.3 
Management of Hypotension ................................................................................. 71 
7.2.4.4 
Management of Orthostatic Hypotension .............................................................. 72 
7.2.4.5 
Management of Neuropathic Pain ......................................................................... 72 
7.2.5 
Therapy and Procedures Allowed During the Trial.................................................... 73 
7.2.6 
Prohibited Therapy and Procedures During the Trial ................................................. 73 
8 
PROCEDURES AND ASSESSMENTS ........................................................................... 75 
8.1 
Eligibility and Safety Assessments ................................................................................. 75 
8.1.1 
Demographics ............................................................................................................. 75 
8.1.2 
Medical History/Current Medical Conditions ............................................................ 75 
8.1.3 
Physical Examination ................................................................................................. 75 
8.1.3.1 
Neurological Examination ..................................................................................... 76 
8.1.3.2 
Height and body weight ......................................................................................... 76 
8.1.4 
ECOG Performance Status ......................................................................................... 76 
8.1.5 
Vital Signs .................................................................................................................. 76 
8.1.6 
Echocardiogram, MUGA, and ECG ........................................................................... 76 
8.1.7 
CT of the Neck, Thorax, and Abdomen ..................................................................... 76 
8.1.8 
Cranial/Spinal MRI .................................................................................................... 77 
8.1.9 
Clinical Laboratory Assessments ............................................................................... 77 
8.1.9.1 
Hematology ............................................................................................................ 77 
8.1.9.2 
Safety Laboratory Evaluations............................................................................... 77 
8.1.10 
Urinalysis .................................................................................................................... 77 
8.1.10.1 
Creatinine Clearance .............................................................................................. 77 
8.1.11 
Pregnancy Test ........................................................................................................... 78 
8.1.12 
Peripheral Blood Cytokines ........................................................................................ 79 
8.1.13 
Anti-Drug-Antibodies ................................................................................................. 79 
8.1.14 
Concomitant Medication ............................................................................................ 79 
8.1.15 
Adverse Events ........................................................................................................... 79 
8.2 
Response Assessments .................................................................................................... 79 
8.3 
Pharmacokinetics Assessment......................................................................................... 79 
8.4 
Assessment of GD2 Expression (optional) ..................................................................... 80 
9 
ADVERSE EVENTS ......................................................................................................... 81 
9.1 
Definition of Adverse Events .......................................................................................... 81 
9.2 
Definition of Serious Adverse Events ............................................................................. 81 
9.3 
Definition of Non-serious Adverse Events ..................................................................... 82 
9.4 
Definition of Predefined Adverse Events of Special Interest ......................................... 82 
9.5 
Adverse Event Reporting Period ..................................................................................... 83 
9.5.1 
Non-serious Adverse Events Reporting ..................................................................... 83 
9.5.2 
Serious Adverse Events Reporting ............................................................................. 83 
9.5.3 
Adverse Events During Follow-Up ............................................................................ 83 
9.5.4 
Adverse Events with Onset After End-of-trial ........................................................... 83 
9.6 
Recording of Adverse Events .......................................................................................... 83 
9.6.1 
Diagnosis .................................................................................................................... 84 


 
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9.6.1.1 
Cytokine release syndrome .................................................................................... 84 
9.6.1.2 
Neurological Adverse Events ................................................................................ 84 
9.6.2 
Onset Date and Time .................................................................................................. 84 
9.6.3 
End Date and Time ..................................................................................................... 84 
9.6.4 
Signs and Symptoms of the Cancer Disease .............................................................. 84 
9.6.5 
Severity ....................................................................................................................... 85 
9.6.6 
Outcome ..................................................................................................................... 85 
9.6.7 
Relationship to Investigational Medicinal Product .................................................... 85 
9.6.8 
Action Taken with the Investigational Medicinal Product ......................................... 86 
9.7 
Events Requiring Immediate Reporting .......................................................................... 86 
9.7.1 
Pregnancy ................................................................................................................... 86 
9.8 
Initial Reporting of Adverse Events ................................................................................ 87 
9.8.1 
Contact Details for Adverse Event Reporting ............................................................ 87 
9.9 
Follow Up on Adverse Events ........................................................................................ 87 
9.9.1 
Reporting of SUSARs ................................................................................................ 88 
9.9.2 
Communication of significant safety issues ............................................................... 88 
9.9.3 
Data Monitoring Committee ....................................................................................... 88 
10 
LABORATORIES ............................................................................................................. 90 
10.1 
Clinical Laboratory Assessments .................................................................................... 90 
10.2 
Pharmacokinetic Assessments......................................................................................... 90 
10.3 
Immunogenicity .............................................................................................................. 90 
11 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ............. 91 
11.1 
General Overview ........................................................................................................... 91 
11.2 
Sample Size ..................................................................................................................... 91 
11.3 
Analysis Populations of Interest ...................................................................................... 92 
11.3.1 
Full Analysis Set ......................................................................................................... 92 
11.3.2 
Safety Analysis Set ..................................................................................................... 92 
11.3.3 
DLT Evaluable Analysis Set ...................................................................................... 92 
11.3.4 
PK Analysis Set .......................................................................................................... 92 
11.4 
Statistical Analysis .......................................................................................................... 93 
11.4.1 
Dose-limiting Toxicities ............................................................................................. 93 
11.4.2 
Maximum Tolerated Dose .......................................................................................... 93 
11.4.3 
Adverse Events ........................................................................................................... 93 
11.4.4 
Safety Laboratory Parameters .................................................................................... 94 
11.4.5 
Vital Signs .................................................................................................................. 94 
11.4.6 
Electrocardiogram ...................................................................................................... 94 
11.4.7 
Analyses of Anti-tumor Activity ................................................................................ 94 
11.4.7.1 
Imaging Data.......................................................................................................... 94 
11.4.7.2 
Response Evaluation .............................................................................................. 94 
11.4.7.3 
Progression-free Survival ...................................................................................... 95 
11.4.7.4 
Duration of Response............................................................................................. 96 
11.4.8 
Overall Survival .......................................................................................................... 96 
11.4.9 
PK Analysis ................................................................................................................ 96 


 
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11.4.10 
Analysis of Anti-Drug Antibody Formation .............................................................. 98 
11.4.11 
Exploratory Objectives ............................................................................................... 98 
11.4.12 
Interim Analysis ......................................................................................................... 98 
11.4.13 
Subgroup Analyses ..................................................................................................... 98 
11.4.14 
Handling of Missing Data........................................................................................... 98 
11.5 
Reporting of Trial Results ............................................................................................... 98 
12 
ETHICS .............................................................................................................................. 99 
12.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .................. 99 
12.2 
Ethical Conduct of the Trial ............................................................................................ 99 
12.3 
Patient Information and Informed Consent ..................................................................... 99 
12.4 
Confidentiality ............................................................................................................... 100 
13 
MONITORING AND QUALITY ASSURANCE ......................................................... 101 
13.1 
Compliance with Good Clinical Practice ...................................................................... 101 
13.2 
Protocol Compliance ..................................................................................................... 101 
13.3 
Changes to the Protocol................................................................................................. 101 
13.4 
Training of Personnel .................................................................................................... 101 
13.5 
Monitoring ..................................................................................................................... 101 
13.5.1 
Monitoring of Pharmacies ........................................................................................ 102 
13.6 
Source Data Verification ............................................................................................... 103 
13.6.1 
Source Data............................................................................................................... 103 
13.6.2 
Direct Access to Source Data/Documents ................................................................ 103 
13.6.3 
Access to Information for Monitoring ...................................................................... 103 
13.6.4 
Access to Information for Auditing or Inspections .................................................. 103 
13.6.5 
Quality Assurance .................................................................................................... 104 
14 
DATA HANDLING AND RECORD KEEPING .......................................................... 105 
14.1 
Electronic Case Report Forms....................................................................................... 105 
14.1.1 
Corrections to Data ................................................................................................... 105 
14.1.2 
Data Entry Timelines ................................................................................................ 105 
14.2 
Trial Documents at Site and Record Retention ............................................................. 105 
14.3 
Data Management ......................................................................................................... 106 
15 
PREMATURE TERMINATION OF THE TRIAL ...................................................... 107 
15.1 
Sponsor Criteria for Pausing Patient Enrolment ........................................................... 107 
15.2 
Criteria for Termination of the Trial ............................................................................. 107 
16 
REPORTING AND COMMUNICATION OF RESULTS .......................................... 109 
16.1 
Publication ..................................................................................................................... 109 
16.2 
Use of Information ........................................................................................................ 109 
17 
INSURANCE .................................................................................................................... 110 
18 
REFERENCES ................................................................................................................. 111 
19 
APPENDICES .................................................................................................................. 114 
Appendix 1 
Statistical properties of the modified BOIN-design .............................. 114 
Appendix 2 
Protocol amendment summary of key changes ..................................... 120 
 


 
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List of Tables 
Table 3-1 
Schedule of time and events: screening, treatment, and follow-up (phase 1 - 
dose escalation) ...................................................................................................... 25 
s: ECG performed pre-dose on dosing days.Table 3-2 Schedule of time and events: phase 
2 (dose expansion) 
27 
Table 6-1 
Treatment cycle dosing days.................................................................................. 45 
Table 6-2 
Dose levels of nivatrotamab in the dose escalation phase ..................................... 46 
Table 6-3 
Phase 1 dose escalation rules based on the number of patients with DLTs ........... 47 
Table 7-1 
Investigational medicinal product (IMP) ............................................................... 60 
Table 7-2 
CRS Revised Grading System ............................................................................... 67 
Table 7-3  
ASTCT ICANS consensus grading for adults ....................................................... 69 
Table 7-4  
ICE assessment tool for the grading of ICANS ..................................................... 70 
Table 7-5  
Neuropathic pain management .............................................................................. 72 
Table 8-1 
Pharmacokinetics assessment time points ............................................................. 80 
Table 11-1 
Probabilities of observing adverse events .............................................................. 92 
Table 11-2 
List of PK parameters ............................................................................................ 97 
 
List of Figures 
Figure 4-1  
 
 
..................................................................................................................... 36 
Figure 4-2  
 
 
* ...................................................... 37 
Figure 6-1 
Trial design outline for the 402 trial ...................................................................... 44 
Figure 7-1 
Cytokine release syndrome (CRS) management algorithm (CRS grade ≥2) ........ 68 
Figure 7-2 
Treatment algorithm for the management of neurotoxicity (ICANS) in the 
402 trial .................................................................................................................. 71 
Figure 9-1 
Adverse event reporting ......................................................................................... 83 
Figure 19-1 
Flow-chart of the BOIN-design ........................................................................... 115 
Figure 19-2 
 ........... 116 
Figure 19-3 
 ......... 117 
Figure 19-4 
 ........................................................ 118 
Figure 19-5 
...................................... 119 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABS 
Absolute count 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil counts 
AP 
alkaline phosphatase 
ASCT 
autologous stem cell transplantation 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
BiPAP 
bilevel positive airway pressure 
BOIN 
Bayesian Optimal Interval design 
BUN 
blood urea nitrogen 
CDR 
complementarity-determining region 
Cmax 
peak plasma concentration 
CNS 
central nervous system 
CPAP 
continuous positive airway pressure 
CR 
complete response 
CRA 
clinical research associate 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
clinical trial report 
CV 
coefficient of variation 
DAS 
DLT evaluable analysis set 


 
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DCR 
disease control rate 
DFS 
disease free survival 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ED 
extensive stage disease 
ECG 
electrocardiogram 
EEG 
electroencephalography 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOT 
end of treatment 
F 
fraction absorbed 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FMOL 
femtomole 
FSH 
follicle-stimulating hormone 
H 
hours 
HCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
I 
immune 
IB 
Investigator’s brochure 
ICANS 
immune effector cell-associated neurotoxicity syndrome 
ICE 
immune effector cell-associated encephalopathy 
ICH 
International Council for Harmonisation 


 
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ICP 
intracranial pressure 
ID 
identification number 
IEC 
independent ethics committees 
Ig 
immunoglobulin 
IL 
interleukin 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
iRECIST 
immune response evaluation criteria in solid tumors 
IRR 
infusion-related reaction 
IV 
intravenous 
IVF 
intravenous fluids 
Ka 
absorption rate constant 
LD 
limited stage disease 
LDH 
lactic dehydrogenase 
LLOQ 
lower level of quantification 
LVEF 
left ventricular ejection fraction 
mAbs 
monoclonal antibodies 
mBOIN 
modified Bayesian Optimal Interval Design 
mcg 
microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
N/A 
not applicable 
NOAEL 
no-observed-adverse-effect level 


 
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NSAID 
nonsteroidal anti-inflammatory drug 
PD 
progressive disease 
PDL1 
anti-programmed death-ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PKAS 
PK analysis set 
PO 
per oral 
PR 
partial response 
PT 
preferred term 
PTT 
partial thromboplastin time 
OR 
overall response 
ORR 
objective response rate 
OS 
overall survival 
RBC 
red blood cell count 
RECIST 
response evaluation criteria in solid tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SCR 
screening 
scFv 
single-chain variable fragment 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SOC 
system organ class 
SNRI 
selective norepinephrine reuptake inhibitors  


 
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SRS 
stereotactic radiosurgery 
SSRIs 
selective serotonin reuptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
TCA 
tricyclic antidepressants 
TEAE 
treatment-emergent AE 
t.i.d 
three times daily 
TNM 
tumor-node-metastasis 
ULN 
upper limit of normal 
ULOQ 
upper level of quantification 
US 
United States 
VLD 
very limited disease 
WBC 
white blood cell count 
WBRT 
whole brain radiotherapy 
 
 
 


 
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2 
PROTOCOL SYNOPSIS 
Title 
Safety and clinical activity of nivatrotamab, an anti GD2×CD3 bispecific 
antibody, in relapsed/recurrent metastatic small-cell lung cancer - An open-
label, single-arm, multicenter, phase 1/2 trial 
Investigational 
New Drug 
(IND) 
153595 
Investigational 
site locations 
USA and Europe 
Co-ordinating 
Investigator 
 
 
UPMC Hillman Cancer Center  
5150 Centre Ave. 5th Floor 
Pittsburgh, PA 15232 
Sponsor 
Y-mAbs Therapeutics Inc. 
230 Park Avenue, Suite 3350 
New York, NY 10169 
USA 
Trial ID 
402 
Trial design 
This is an open-label, multicenter, phase 1/2 trial with the aim to assess the 
safety and tolerability of increasing doses of nivatrotamab administered 
subcutaneously (SC) in patients with small-cell lung cancer (SCLC). 
 
The study will include a phase 1 dose escalation part to determine the 
maximum tolerated dose (MTD) and the recommended phase 2 dose 
(RP2D). This will be conducted following a modified Bayesian Optimal 
Interval Design (mBOIN) design. For the purpose of dose escalation, dose-
limiting toxicities (DLTs) will be collected and assessed for a period of 28 
days (the DLT evaluation period). 
 
A phase 2 dose expansion part will follow the phase 1 dose escalation. In 
phase 2, patients will be stratified according to whether they have 
platinum -sensitive or platinum-resistant SCLC. Phase 2 will assess the 
long-term safety and tolerability of nivatrotamab as well as the clinical 
activity of nivatrotamab when administered at the obtained MTD/RP2D in 
phase 1. 
 
 


 
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Figure: Trial design outline 
 
* excluding toxicities clearly related to disease progression or intercurrent 
illness. 
Patient 
population 
The patient population for phase 1 of the trial will consist of patients with 
relapsed extensive or limited stage SCLC regardless of platinum sensitivity. 
Patients will be eligible after failure or intolerance of first-line 
platinum-containing treatment but not more than 3 lines of systemic 
therapy. Patients must be at least 18 years of age; however, there is no 
upper age limit as long as the patient meets the criteria for patient selection. 
 
In phase 2, patients will be stratified into 2 groups based on whether they 
have platinum-sensitive or platinum-resistant disease. Platinum-sensitive 
disease is defined as a platinum-free interval of ≥90 days post last dose of 
frontline chemotherapy; platinum-resistant disease is defined as a 
platinum-free interval of <90 days. 
Objectives 
Primary Objective 
Phase 1 
• To determine the MTD and the RP2D of nivatrotamab 
• To assess the safety and tolerability of different doses of nivatrotamab 
 
Phase 2 
• To assess the long-term safety of nivatrotamab administered at RP2D 
 


 
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Secondary Objectives 
Phase 1 
• To assess the anti-tumor activity of nivatrotamab 
• To assess the pharmacokinetics (PK) of different doses of nivatrotamab 
• To assess the development of anti-drug antibodies to nivatrotamab 
 
Phase 2 
• To assess the anti-tumor activity of nivatrotamab 
• To assess the development of anti-drug-antibodies (ADA) against 
nivatrotamab 
 
Exploratory Objectives 
Phase 1 and Phase 2 
To explore GD2 expression from tumor tissue (optional) 
Endpoints 
Primary Endpoints 
Phase 1 
• The MTD (defined by a modified Bayesian Optimal Interval Design 
[mBOIN]) and the RP2D of nivatrotamab 
• The overall incidence and severity of adverse events (AEs) for different 
doses of nivatrotamab 
 
Phase 2 
• Incidence and severity of AEs for nivatrotamab dosed at RP2D 
 
Secondary Endpoints 
Phase 1 
• 
Anti-tumor activity 
o Measured according to the response evaluation criteria in solid 
tumors (RECIST) version 1.1 
▪ Objective response rate (ORR) 
▪ Disease control rate (DCR): complete response (CR) + partial 
response (PR) + stable disease (SD) as well as the proportion 
of patients in disease control at 4, 8, 16, and 24 weeks 
▪ Duration of response (DoR) 
▪ Progression-free survival (PFS) 
o Measured according to the immune response evaluation criteria in 
solid tumors (iRECIST) 
▪ iORR 


 
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▪ iDCR: iCR + iPR + iSD as well as the proportion of patients in 
disease control at 4, 8, 16, and 24 weeks 
▪ iDoR 
▪ iPFS 
o Overall survival (OS) 
• PK of different doses of nivatrotamab 
• Proportion of patients who develop anti-drug-antibodies at any time 
 
Phase 2 
• 
Anti-tumor activity 
o Measured according to RECIST version 1.1 
▪ ORR 
▪ DCR: CR + PR + SD as well as the proportion of patients in 
disease control at 4, 8, 16, and 24 weeks 
▪ DoR 
▪ PFS 
o According to iRECIST 
▪ iORR 
▪ iDCR: iCR + iPR + iSD as well as the proportion of patients in 
disease control at 4, 8, 16, and 24 weeks 
▪ iDoR 
▪ iPFS 
o OS 
• Proportion of patients who develop anti-drug-antibodies at any time 
 
Exploratory Endpoints 
Phase 1 and Phase 2 
Assessment of GD2 expression, from paraffin embedded tumor tissue 
(optional) 
Patient 
selection 
criteria 
Inclusion criteria 
1. Signed and dated informed consent has been provided prior to any 
trial-related procedures. 
2. Patient willing and able to comply with the trial protocol 
3. Age ≥18 years at the time of informed consent 
4. Histologically or cytologically proven SCLC. Radiographical 
relapse/progression after minimum 1 line of platinum-containing 
chemotherapy with PR or CR as the best response (only applicable 
for phase 2) and not more than 3 prior lines of therapy 
5. Measurable disease according to RECIST v1.1 


 
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6. Eastern Cooperative Oncology Group (ECOG) performance status 
0-–1 
7. Expected survival >3 months 
8. Platelet counts ≥100,000 cells/mm3 
9. Hemoglobin ≥9 g/dL 
10. Absolute neutrophil count (ANC) ≥1000 cells/mm3 
11. Adequate liver function defined by aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase 
(ALP) ≤3 × upper limit of normal (ULN), and serum bilirubin ≤1.5 
× ULN with the following exceptions 
a. In patients with documented liver metastases, AST, ALT, 
and ALP ≤5 × ULN and serum bilirubin ≤1.5 × ULN 
12. Adequate renal function with serum creatinine ≤1.5 mg/dL or 
creatinine clearance ≥50 mL/min as calculated using the 
Cockcroft-Gault equation 
13. Serum albumin >3.0 g/dL 
14. Women of child-bearing potential must agree to appropriate 
contraception during treatment and for a period of 30 days after 
the last dose of study drug. Fertile male patients must agree to the 
use of condoms during treatment and for a period of 30 days after 
the last dose of the investigational medicinal product (IMP). For a 
sterilized male patient to be exempt from the requirement to use 
contraception after IMP treatment, he must have undergone 
surgical sterilization (vasectomy). 
 
Exclusion criteria 
1. Systemic chemotherapy, radiotherapy, immunotherapy, or major 
surgery administered within 3 weeks prior to the first planned 
dosing of the IMP per protocol 
2. Patients receiving any other investigational therapy for their cancer 
within 3 weeks prior to the first planned dosing of the IMP per 
protocol 
3. Patients who never received platinum-containing regimen for SCLC 
(defined as less than 2 cycles of platinum doublet) 
4. Persistent > grade 1 toxicity from previous treatment with 
checkpoint inhibitors 
5. Any immunosuppressive concomitant medication (i.e., 
salazopyrine, methotrexate, steroids etc.) 
6. Inability to wean off steroid, unless tapered to 0 mg/day minimum 
10 days prior to the first treatment in case of prior use 
7. Any active, uncontrolled viral, fungal, or bacterial infection 


 
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8. Any medical history within 3 months prior to enrolment with need 
for anticonvulsant therapy 
9. Patients with diagnosis of autoimmune diseases or 
immunodeficiencies or documented infection with human 
immunodeficiency virus (HIV) or hepatitis B or C virus (active) 
10. Previous autologous stem cell transplantation or solid organ 
transplantation 
11. Active heart disease including myocardial infarction within the last 
6 months before first dose. This includes cardiac insufficiency with 
left ventricular ejection fraction (LVEF) <50% 
12. Active CNS metastases. Patients with treated CNS metastases are 
eligible if they are clinically stable without any new neurological 
symptoms and if there is no radiological evidence of new or 
enlarging CNS metastases. CNS-directed treatment (surgery, 
radiation) must be completed 4 weeks prior to the first IMP 
administration.   
Furthermore, patients are excluded if they have: 
• Leptomeningeal carcinomatosis  
• Uncontrolled seizures. Patients with known seizure 
are eligible if they are stable and have been without 
seizure 4 weeks prior to the first IMP administration 
13. Patients who experienced severe or recurrent (>grade 2) 
immune-mediated AEs or IRRs, including those that lead to 
permanent discontinuation while on treatment with 
immune-oncology agents 
14. Prior treatment with anti-GD2 antibody or bispecific antibodies 
15. Patients with Limited Disease (LD), who are candidates for local or 
regional therapy 
16. Impending need for palliative radiotherapy or surgery for 
pathological fractures and/or for medullary compression up to 
3 weeks prior to the first planned dosing of the IMP per protocol 
(palliative radiation for other reasons within 2 weeks) 
17. History of other active malignancy within the past 3 years prior to 
the first planned dosing of the IMP per protocol (excluding non-
melanoma skin cancers, carcinoma in situ of the cervix, ductal 
carcinoma in situ of the breast, incidental prostate cancer (T1a, 
Gleason score ≤ 6, prostate specific antigen (PSA) less than 0.5 
ng/ml) 
18. Patients with a significant intercurrent illness (any ongoing serious 
medical problem unrelated to cancer or its treatment) that is not 
covered by the detailed exclusion criteria and that is expected to 


 
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interfere with the action of the trial IMP or significantly increase the 
severity of the toxicities experienced from trial treatment 
19. Patients who are pregnant or breastfeeding 
20. Patients with a body weight of < 45 kg 
21. Patients with prior orthostatic hypotension  
Methodology 
Phase 1 (dose escalation): The dose escalation phase will consist of up to 13 
cycles (Cycles 1 to 13), each cycle being of 14 days’ duration. Thus, patients 
will receive up to 26 weeks of treatment. In Cycle 1,
 
 
 
 
 
 
 
 
 
 
 
 
 Intermediate dose levels can be introduced at any time after 
discussion with the data monitoring committee (DMC). There will be 
13 treatment cycles, each cycle being of 2 weeks’ duration. Thus, patients 
will receive up to 26 weeks of treatment. 
 
The dose escalation will be conducted following an mBOIN design. It will 
consist of 2 stages: the initial accelerated titration stage followed by a 
standard titration stage. In the accelerated titration stage, patients will be 
recruited and treated in single-patient cohorts. These single-patient cohorts 
may optionally be expanded with up to 2 additional patients for the purpose 
of obtaining additional PK and/or pharmacodynamic data.  
 
The accelerated titration stage will end and the standard titration stage 
begin if either, a) dose level 3 is reached, or b) during the DLT evaluation 
period (28 days), a patient is observed with i) any grade ≥ 2 AE (excluding 
toxicities clearly related to disease progression or intercurrent illness), or ii) 
a protocol-defined DLT, whichever occurs first. 
In the standard titration stage, patients will be allocated to dose-levels 
typically in cohorts of 3. However, as the mBOIN design allows cohort-
sizes to vary, actual cohort sizes may differ from 3. 
 


 
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Determination of MTD and RP2D: The mBOIN-based MTD will be 
preliminarily estimated statistically as the dose level with the observed 
DLT rate closest to the target toxicity level (i.e., 28%). After the mBOIN 
dose -escalation algorithm has been completed, the DMC and the Sponsor 
will determine the MTD and the RP2D. The selection of the RP2D will 
balance the frequency and severity of AEs with any observed dose response 
for clinical activity. It will be based on a review of the available safety 
information, including AEs and safety laboratory values, relevant PK data, 
and observations made after the end of the DLT evaluation period. The 
RP2D may not exceed the MTD. 
 
For the purpose of dose escalation, DLTs will be collected and assessed 
throughout Cycles 1 and 2, covering a treatment period of 4 weeks. This 
will allow for the evaluation of up to 3 IMP administrations. 
 
Phase 2 (dose expansion): In phase 2, the RP2D will be used to further 
assess safety and tolerability, as well as the clinical activity of 
nivatrotamab. 
Number of 
patients 
(planned) 
Up to 39 patients are planned to be dosed in phase 1 (dose escalation) and 
30 additional patients in phase 2 (dose expansion). No more than 69 
patients in total will be dosed in the trial. 
Investigational 
Medicinal 
Product (IMP) 
For this trial, the Sponsor, Y-mAbs, will provide nivatrotamab, 2 mg/mL. 
No other medicinal products or auxiliary medicinal products will be 
provided by Y-mAbs. The IMP, nivatrotamab, will be administered SC 
according to the treatment schedule. 
Trial period(s) 
and duration 
Pre-treatment evaluations should be completed within 21 days of the start 
of treatment. The dose escalation and expansion phases will consist of 13 
cycles (Cycles 1 to 13), each cycle being of 14 days’ duration with a 12-
month follow-up after the end of treatment. 
It is estimated that at least 24 months will be needed to recruit the planned 
number of patients. The recruitment periods are estimated to be at least 18 
months for phase 1 and 6 months for phase 2. 
Statistical 
considerations 
Up to 39 patients may be included in the dose escalation phase (phase 1). 
This number includes up to 10 additional patients who may be added to any 
dose-level in this phase. 
 
DLTs observed during the DLT evaluation period will be listed and 
summarized in a table by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term (PT). The 


 
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information from the DLTs will be used to guide the escalation and de-
escalation rules as per the mBOIN-design and ultimately determine the 
MTD. 
 
Upon completion of the mBOIN-design, the MTD is preliminarily 
estimated as the dose for which the isotonic estimate of the DLT rate is 
closest to the target toxicity level. If there are ties, either the highest dose 
level when the estimate of the DLT rate is smaller than the target or the 
lowest dose level when the estimate of the DLT rate is greater than the 
target, will be selected from the ties. 
 
The overall observation period for safety analyses (AEs) will be divided 
into 3 parts: 
• Pre-treatment period: From the day of the patient’s informed consent 
to the day before the first dose of nivatrotamab 
• On-treatment period: From the day of the first dose of nivatrotamab 
to 30 days after the last dose of nivatrotamab 
• Post-treatment period: From 31 days after the last dose of 
nivatrotamab and thereafter 
Descriptive statistics will be presented for baseline values, absolute 
values, and changes from baseline in safety laboratory parameters. Vital 
signs will be listed. Abnormal electrocardiogram (ECG) observations will 
be listed and summarized. Clinical activity of nivatrotamab will be based 
on imaging data, response evaluation (according to both RECIST 1.1 and 
iRECIST), PFS, DoR, and OS. All imaging data will be listed. The OR rate 
will be presented including corresponding, for binomial distribution, exact 
95% confidence intervals. The DCR as well as proportions of patients in 
disease control at 4, 12, and 28 weeks (± 7 days for each of the 3 timepoints) 
will be analyzed and presented in the same way as OR. PFS will be derived 
for all patients and presented graphically as well as summarized using 
survival analysis methods: distribution functions will be estimated using 
the Kaplan-Meier technique and plotted. The Kaplan-Meier quartile 
estimates of PFS including 2-sided 95% confidence intervals will be 
presented. The DoR will be calculated, censored, and presented in the same 
way as PFS. OS will be analyzed using the same Kaplan-Meier 
methodology as for PFS. 


 
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Immunogenicity data will be listed and positive/negative host immune 
response to nivatrotamab and presence of binding antibodies will be 
summarized (positive/negative). 
PK information will also be listed and summarized. 
GD2 expression from tumor tissue will be summarized and presented 
graphically. The relationship between GD2 expression from tumor tissue 
and relative reduction in tumor size from baseline, OR, and PFS may be 
investigated by graphical presentations as well as non-parametric 
correlation, linear, logistic, and Cox-regression analyses, as appropriate. 
Covariates, such as dose may be included in the regression analyses. 
All statistical tests will be 2-sided with an α (significance) level of 0.05. No 
subgroups beyond the sensitivity/resistance to previous platinum therapy 
strata in phase 2 are defined. Missing safety data will in general not be 
imputed. 
 


 
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3 
FLOW CHART 
Table 3-1 
Schedule of time and events: screening, treatment, and follow-up (phase 1 - dose escalation) 
Treatment / Measurements / 
Evaluations 
SCR 
Cycle 1 (D1 to 14); 1 cycle = 14 daysa 
DLT evaluation period = 2 cycles 
Cycle 2 to 13 
EOT 
±4d 
Follow 
upd 
<21 
days 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, concomitant 
illness  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Physical examination 
Xf 
X 
X 
 
 
X 
X 
 
 
X 
 
 
 
Xf 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
ECOG score 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Vitals signs 
X 
Xq 
Xq 
X 
X 
Xq 
Xq 
X 
X 
Xq 
Xq 
X 
X 
X 
 
HCG in FOCP (urine or blood) 
X 
 
 
 
 
 
 
 
 
Xg 
 
 
 
X 
 
Urinalysis (dipstick) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Cranial and Spinal MRIh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
Xs 
X 
 
 
Xs 
X 
 
 
Xs 
X 
 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
Xi 
 
 
 
Xi 
 
 
Hospitalizationj 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
Premedication 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
PK, see Table 8-1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
AE (CTCAE version 5) 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRS gradingl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ICE scorel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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Treatment / Measurements / 
Evaluations 
SCR 
Cycle 1 (D1 to 14); 1 cycle = 14 daysa 
DLT evaluation period = 2 cycles 
Cycle 2 to 13 
EOT 
±4d 
Follow 
upd 
<21 
days 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical activity assessmentm 
CT (baseline + from Cycle 3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Xo 
IL-6 assessmentr 
(Dosing Day+1) 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
ADA (including predose) p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
a: In cases of toxicities, for patients who remain eligible for further treatment, a treatment delay of up to 3 weeks is acceptable to allow for resolution of ≥ grade 3 hematological 
and non-hematological toxicities (that do not meet the treatment discontinuation criteria) down to ≤ grade 2 or returned to baseline value at study entry (e.g. lab values). 
b: Cycles 2 (inpatient Days 1 and 2) and 3 only, unless patient is hospitalized due to cytokine release syndrome (CRS) 
c: Cycle 2 only 
d: All patients to be followed up for safety reporting for 30 days after the last investigational medicinal product (IMP) dosing. Thereafter, long-term safety will be recorded by 
registration of related SAEs up to 12 months after the last dose. Vital status and disease progression for follow up on progression-free survival (PFS) and overall survival (OS) will 
be up to 12 months after the last dose. The Investigator should collect CT scan reports for tumor assessments every 8 weeks or according to the local standard of care. The FU 
assessments can be done locally at the referral site. 
e: This will only include anti-cancer therapy. 
f: Physical examination at screening and the EOT visit should include a neurological examination. 
g: Every second cycle (e.g., Cycle 2, 4, 6, 8, 10, and 12) 
h: For baseline. In addition, an MRI must be performed if a patient develops a central nervous system (CNS) AE ≥ grade 2. 
i: Echocardiogram/MUGA to be performed on Day 11 of treatment cycle 1, and Day 4 of cycle 2. Assessment must be analyzed and reviewed by Investigator prior to dosing in 
cycle 2 and cycle 3 
j: Mandatory 48 hours hospitalization in Cycles 1 and 2; optional thereafter (pending clinical signs of possible CRS).  
From Cycle 3 onward, the minimum patient monitoring time following dosing will be 6 h; the patient may be observed for this duration as an outpatient or be hospitalized 
depending on AEs and Investigator’s judgement. 
k: All AEs (including SAE, and AESIs) should be reported from the signing of the informed consent until 30 days after the patient’s last dose of IMP. Thereafter and during the 
follow-up period, only SAEs considered related to IMP, study procedures and secondary malignancies (regardless of causality) should be reported. DLTs should be reported from 
the first dose of IMP and the following 28 days. 
l: CRS grading and ICE score should be performed predose on dosing days and once per day when the patient is attending the ward for the first 3 cycles, thereafter only if clinically 
indicated. If the ICE score decreases from baseline, neurotoxicity should be assessed with the use of the ICANS grading system (see section 7.2.4). 


 
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m: CT scan of the neck, chest, and abdomen at screening and Week 4, 8, 16, and 24, with an assessment window of ±4days. Confirmatory scanning for patients who have obtained 
PR or CR will be undertaken approximately 4 weeks after the initial response. 
n: Only if more than 6 weeks since last CT scan  
o: Assessment of response by the Primary Investigator (progression and survival). 
p: Pre-dose on Day 1 and 8 of Cycle 1, Day 1 of Cycles 2-13, and EOT. 
q: Vital signs to be monitored and registered every 2 hours on Day 1 and Day 2 of cycle 1 and cycle 2 during daytime and every 4 h during nighttime. 
r: Cycle 1 day 1 the IL-6 sample must be taken pre-dose (baseline), all other IL-6 samples should be taken the day after IMP administration (dosing day +1) and should be taken at 
the same time of the day (±60 min) 
s: ECG performed pre-dose on dosing days.


 
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Table 3-2 
Schedule of time and events: phase 2 (dose expansion) 
Treatment / Measurements / 
Evaluations 
SCR 
Cycle 1 (D1 to 14); 1 cycle = 14 daysa 
DLT evaluation period = 2 cycles 
Cycle 2 to 13 
EOT 
±4d 
Follow 
upd 
<21 
days 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, concomitant 
illness 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Physical examination 
Xf 
X 
X 
 
 
X 
X 
 
 
X 
 
 
 
Xf 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
 
ECOG score 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Vitals signs 
X 
Xq 
Xq 
X 
X 
Xq 
Xq 
X 
X 
Xq 
Xq 
X 
X 
X 
 
HCG in FOCP (urine or blood) 
X 
 
 
 
 
 
 
 
 
Xg 
 
 
 
X 
 
Urinalysis (dipstick) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Cranial and Spinal MRIh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
Xs 
X 
 
 
Xs 
X 
 
 
Xs 
X 
 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
Xi 
 
 
 
Xi 
 
 
Hospitalizationj 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
Premedication 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
PK, see Table 8-1 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
AE (CTCAE version 5) 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRS gradingl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ICE scorel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical activity assessmentm 
CT (baseline + from Cycle 3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Xo 
IL-6 assessmentr 
(Dosing Day+1) 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 


 
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Treatment / Measurements / 
Evaluations 
SCR 
Cycle 1 (D1 to 14); 1 cycle = 14 daysa 
DLT evaluation period = 2 cycles 
Cycle 2 to 13 
EOT 
±4d 
Follow 
upd 
<21 
days 
 
 
 
 
 
 
 
 
 
 
 
 
ADA (including predose) p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
a: In cases of toxicities, for patients who remain eligible for further treatment, a treatment delay of up to 3 weeks is acceptable to allow for resolution of ≥ grade 3 hematological 
and non-hematological toxicities (that do not meet the treatment discontinuation criteria) down to ≤grade 2 or returned to baseline value at study entry (e.g. lab values). 
b: Cycles 2 (inpatient Days 1 and 2) and 3 only, unless patient is hospitalized due to cytokine release syndrome (CRS). 
c: Cycle 2 only. 
d: All patients will be followed up for safety reporting for 30 days after the last IMP dosing. Thereafter, long-term safety will be recorded by registration of related SAEs up to 
12 months after the last dose. Vital status and disease progression for follow up on PFS and OS will be up to 12 months after the last dose. The Investigator should collect CT 
scan reports for tumor assessments every 8 weeks or according to the local standard of care. The FU assessments can be done locally at the referral site. 
e: This will only include anti-cancer therapy. 
f: Physical examination at screening and the EOT visit should include a neurological examination. 
g: Every second cycle (e.g., Cycle 2, 4, 6, 8, 10, and 12). 
h: For baseline. In addition, an MRI must be performed if a patient develops a central nervous system (CNS) AE ≥ grade 2. 
i: Echocardiogram/MUGA to be performed on Day 11 of treatment cycles 1, and Day 4 of cycle 2. Assessment must be analyzed and reviewed by investigator prior to dosing in 
cycle 2 and cycle 3. 
j: Mandatory 48 hours hospitalization in Cycles 1 and 2; optional thereafter (pending clinical signs of possible CRS).  
From Cycle 3 onward, the minimum patient monitoring time following dosing will be 6 h; the patient may be observed for this duration as an outpatient or be hospitalized 
depending on AEs and Investigator’s judgement. 
k: All AEs (including SAE, and AESIs) should be reported from the signing of the informed consent until 30 days after the patient’s last dose of IMP. Thereafter and during the 
follow-up period, only SAEs considered related to IMP, study procedures and secondary malignancies (regardless of causality) should be reported. DLTs should be reported from 
the first dose of IMP and the following 28 days. 
l: CRS grading and ICE score should be performed at predose on dosing days and once per day when the patient is attending the ward for the first 3 cycles, thereafter only if 
clinically indicated. If the ICE score decreases from baseline, neurotoxicity should be assessed with the use of the ICANS grading system (see section 7.2.4). 
m: CT scan of the neck, chest, and abdomen at screening and Week 4, 8, 16, and 24, with an assessment window of ±4days. Confirmatory scanning for patients who have obtained 
PR or CR will be undertaken approximately 4 weeks after the initial response. 
n: Only if more than 6 weeks since last CT scan. 
o: Assessment of response by the Primary Investigator (progression and survival) 
p: Pre-dose on Day 1 and 8 of Cycle 1, Day 1 of Cycles 2, 4 and 13, and/or EOT. 


 
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q: Vital signs to be monitored and registered every 2 h on Day 1 and Day 2 of cycle 1 and cycle 2 during daytime and every 4 h during night time 
r: Cycle 1 day 1 the IL-6 sample must be taken pre-dose (baseline), all other IL-6 assessments should be taken the day after IMP administration (dosing day +1) and should be 
taken at the same time of the day (±60 min) 
s: ECG performed pre-dose on dosing days. 
 
 
 


 
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4 
MEDICAL AND SCIENTIFIC JUSTIFICATION FOR THE TRIAL 
4.1 
Disease Background 
Lung cancer is the second most common cancer in both men and women with an estimate of 
more than 200,000 new cases diagnosed annually in the US 1. Small-cell lung cancer (SCLC) 
accounts for approximately 13% to 15% of all lung cancers, hence about 30,000 cases per year in 
the US 1-4. This high-grade neuroendocrine tumor is characterized by rapid growth and early 
development of metastases to both regional lymph nodes and distant sites, including the central 
nervous system (CNS) 5. 
SCLC is often classified into staging systems, for example, limited stage disease (LD) vs. 
extensive stage disease (ED) or the tumor-node-metastasis (TNM) system 6. Stage is the major 
prognostic factor for SCLC; however, a diagnosis of SCLC generally carries with it a poor 
prognosis: 20% to 40% of LD and less than 5% of ED patients survive 2 years or more 7. 
At presentation, only a minority of patients (~5%) have operable TNM stage I disease 
(very limited disease, VLD); this group has the best prognosis with possibility of cure and a 
5-year overall survival (OS) of 50% 8. About 25% of patients present with unilateral thoracic 
involvement, TNM stages I to III (i.e., LD), allowing for an attempt at controlling the disease 
with concomitant chemo-radiotherapy, i.e., platinum-etoposide and radiotherapy. Most patients 
with LD relapse subsequently within 2 years due to lymphatic spread and failure of local 
therapy. Median survival at 2 years among LD patients varies from 15 to 20 months, with 
OS being 20% to 40% 4. 
The majority of patients (≥70%) present with metastatic disease (i.e., stage IV) or ED, wherein 
the disease has most often spread within the lung tissue, to lymph nodes, and to the liver, bone, 
and brain. Patients with such advanced disease have, on average, disease-free survival (DFS) of 
5.5 months and median survival of less than 10 months 8. Five-year survivors are exceedingly 
rare 9. 
Currently, the only approved first-line treatment approach for ED in SCLC is platinum-based 
chemotherapy with or without the addition of an immune checkpoint inhibitor, namely, 
atezolizumab or durvalumab 10, 11. Platinum (cisplatin or carboplatin) remains the cornerstone for 
the treatment of SCLC of any stage, with high initial responses (including rapid responses and 
symptomatic improvement) reported in 70% to 80% of patients following first-line platinum- 
and immunotherapy-based treatment regimens; nevertheless, virtually all SCLC patients with ED 
develop tumor progression, mostly within 6 months 12, 13. 
Until recently, in the second-line setting, the topoisomerase I inhibitor, topotecan, was the only 
drug approved by the US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA). In randomized clinical trials, topotecan has been associated with overall 
response (OR) rates of 16.9% to 21.9%, median progression-free survival (PFS) of 3.4 to 


 
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3.5 months, and median OS of 7.8 to 8.7 months 14, 15. Outcomes are particularly poor among 
patients with platinum-resistant disease, generally indicated by tumor progression within 90 days 
of completion of first-line therapy 16; the OR rates in these patients are usually below 10% 17. In 
a typical clinical population, the response rate thus rarely exceeds 15%. 
There is no globally approved therapeutic agent for patients with progressive SCLC following 
second‑line treatment. However, for this patient population, FDA granted accelerated approvals 
to 2 compounds: nivolumab in August 2018 (based on the CheckMate 032 trial; 
ClinicalTrials.gov id: NCT01928394) and pembrolizumab in June 2019 (based on the Keynote 
trials 158 [NCT02628067] and 028 [NCT02054806]). Third-line treatment with checkpoint 
inhibitors are associated with benefit in a small percentage of patients, primarily in the 
platinum-sensitive subpopulation, with objective response rates (ORRs) ranging from 11% to 
33% in clinical trials 18, 19. Unfortunately, despite such response rates, most patients treated in 
these trials did not appear to benefit, as evidenced by median PFS of only 1.4 to 2 months. As a 
consequence to neither of the trials meeting the predefined endpoint of OS, the indication of 
checkpoint inhibitors in 3rd line for SCLC was subsequently withdrawn in December 2020 
(nivolumab) 20 and March 2021(pembrolizumab) 21. 
Recently, FDA granted accelerated approval to the RNA polymerase II inhibitor, lurbinectedin, 
as monotherapy for patients with metastatic SCLC with disease progression during or after 
platinum-based chemotherapy 22. Efficacy of lurbinectedin was demonstrated in the PM1183-8B-
005-14 trial (ClinicalTrials.gov id: NCT02454972), a multicenter open-label, multi-cohort 
(basket) trial enrolling 105 patients with metastatic SCLC. Among the 105 patients, the ORR 
was 30% with a median response duration of 5.1 months. The median PFS was 3.9 months and 
the 6-month PFS rate was 33.6%. In the subgroup of patients with platinum-resistant disease, the 
ORR was 22% (45% in platinum-sensitive patients), median PFS was 2.6 months, and the 6-
month PFS rate was 18.8%. At a median follow-up of 17.1 months, the median OS with 
lurbinectedin was 9.3 months; the 12-month OS rate was 34.2%. The grade 3–4 adverse event 
(AE) frequency was 34% and events comprised mainly myelosuppression (hematological 
toxicities). 
4.2 
Rationale for the Development of GD2×CD3 Bispecific Antibody for the 
Treatment of SCLC 
SCLC develops early resistance to conventional treatments, therefore, showing early progression 
and lack of sensitivity to further pharmacological treatment. As such, SCLC had been considered 
“a graveyard for drug development,” with chemotherapy remaining the standard treatment for 
first- and second-line management until quite recently. Thus, there is a considerable need to 
develop novel therapeutic approaches in SCLC. 
It has been known for many years that SCLC cells, similar to those of many other tumors of 
neural crest origin, almost uniformly express GD2, a cell-surface glycolipid disialoganglioside 23, 
24. Recently, dinutuximab (Unituxin®), a chimeric anti-GD2 IgG1 (immunoglobulin G, subtype 
1) antibody was tested in a clinical phase 3 trial (the DISTINCT trial, ClinicalTrials.gov id: 


 
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NCT03098030) in relapsed SCLC patients. In this trial, irinotecan or topotecan as monotherapy 
or irinotecan in combination with dinituximab was investigated. The trial failed to meet its OS 
endpoint. However, dinituximab was only administered once every 3 weeks at a dose of 10 
mg/m2 or approximately 18 mg total dose. This dose frequency likely was insufficient and 
represents only 14% of dose intensity as compared to the labelled dose schedule (17.5 mg/m2 × 4 
per treatment cycle for the label indication of neuroblastoma) 25. The most common AEs in this 
trial were pain, thrombocytopenia, lymphopenia, infusion-related reactions (IRRs), hypotension, 
increased alanine aminotransferase (ALT), capillary leak syndrome, neutropenia as well as 
electrolyte disturbances and gastrointestinal symptoms. 
Naxitamab (3F8), an anti-GD2 antibody, has been developed by Y-mAbs Therapeutics, Inc. 
(hereafter, Y‑mAbs) for the treatment of relapsed/refractory neuroblastoma. In November 2020, 
the biological license application for naxitamab received approval from the FDA. Naxitamab has 
been shown to localize to all extracranial sites of the SCLC disease. Furthermore, using identical 
complementarity-determining region (CDR), Y-mAbs has developed an anti-GD2×CD3 
T cell-redirecting bispecific antibody (BiCloneTM). BiClone comprises a novel tetravalent 
structure, humanized format, with an introduced mutation to reduce FcgR binding while 
retaining FcRn binding. Advantages of using the BiClone format include (i) possibility of using a 
very low dose (mcg range) and hence, a likely better safety profile; (ii) possibility of using a 
more frequent dosing regimen, which may potentially improve efficacy outcomes; and (iii) a 
subcutaneous (SC) administration approach, which may reduce the cytokine release 
syndrome (CRS). CRS is a key common dose-limiting side effect observed with CD3-based 
bispecific antibodies administered by the intravenous (IV) route. Pre‑clinical efficacy of the 
BiClone format has been demonstrated in vitro in SCLC cell lines (e.g., NCI-H524, NCI-H69 
[unpublished data]) and in vivo in neuroblastoma and melanoma xenograft models 26. 
4.3 
Nivatrotamab Profile 
Nivatrotamab is a T-cell engaging antibody utilizing the BiClone format which is currently being 
evaluated in human clinical trials. 
4.3.1 
Non-clinical Data for Nivatrotamab 
 
 
 
 
 
 
 
 
 
 


 
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4.3.3 
Nivatrotamab Dose Selection and Administration Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.4 
Choice of Trial Population 
For decades, the landscape of treatment options for patients with SCLC has been dominated by 
platinum-containing chemotherapeutic regimens, and chemotherapy remains the gold standard 
first line therapy. After disease progression, second line options have been associated with a 
modest chance of response and significant toxicity, and survival for the patient group with ED 


 
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has not improved significantly over the past many years. Thus, there is a strong rationale for 
exploring new treatment modalities in SCLC. 
This trial will be conducted in 2 phases (phases 1 and 2, see section 6.2). The patient population 
for phase 1 of the trial will consist of patients with relapsed extensive or limited stage SCLC 
regardless of platinum sensitivity. Patients will be eligible after failure or intolerance of first-line 
platinum-containing treatment but not more than 3 lines of systemic therapy. Patients must be at 
least 18 years of age; however, there is no upper age limit as long as the patient meets the criteria 
of patient selection (see inclusion criteria, section 6.3.2.1). See also section 6.3.2.2 (exclusion 
criteria). In phase 2, patients will be stratified into 2 groups based on whether they have platinum 
sensitive or resistant disease. 
In the present protocol, platinum-sensitive disease is defined as a platinum-free interval of 
≥90 days post last dose of frontline chemotherapy; platinum-resistant disease is defined as a 
platinum-free interval of ≤90 days post last dose of frontline chemotherapy 16. 
 
4.5 
Choice of Trial Design and Dosing Strategy 
This proposed trial is the second clinical trial with nivatrotamab. In this trial, a change in the 
route of administration from IV infusion to SC administration has been proposed to reduce 
possible IRRs, in particular CRS, which are known to occur with other bispecific, T-cell 
engaging mAbs; such reactions have also been seen in trial 18-034, the FIH trial with 
nivatrotamab. Based on the availability of safety data from the trial 18-034, a modified Bayesian 
Optimal Interval (mBOIN) design has been chosen for the phase1 part of the trial in order to 
identify the recommended phase 2 dose (RP2D) for further SC administration of nivatrotamab 
(in phase 2). In order to evaluate safety to direct exposure in a small number of patients, a 
flat-dose strategy has been chosen. The start dose will be lower than the dose in trial 18-034 that 
has been deemed safe by the internal review board at Memorial Sloan Kettering Cancer Center, 
New York, USA, the location of the FIH (18-034) trial. 
The mBOIN design is similar to the standard 3+3 as well as 3+3+3 study designs 28. Some 
features of the BOIN design include 29: 
• BOIN is devised to identify the MTD, while controlling the risks of observing DLTs. 
• BOIN provides a better estimate of the MTD than the traditional 3+3 design, partly 
because BOIN allows dose levels to be revisited. 
• The number of patients in a cohort may differ from 3, allowing flexibility in the conduct 
of the trial. 
In this trial, the BOIN design will be modified to: 
• Have an accelerated and standard titration part in phase 1 (the dose escalation phase) 
• Allow stopping at a dose level with 6 DLT-evaluable patients 


 
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With a target toxicity level of 28 %, the design obtains characteristics that are similar to the 
3+3+3 design, e.g., there are similarities in how 2 DLTs in 6 or 9 patients are addressed in 
Table 6-3. 
See section 19, Appendix 1 for more details on the mBOIN design to be used in this trial. 
To collect further data on the clinical activity, safety, tolerability, and PK, the selected dose 
(RP2D) from the dose escalation phase will be studied in phase 2 of the trial. 
4.6 
Benefit–Risk Assessment 
Patients with relapsed/refractory SCLC have a marked unmet need with an estimated OS of less 
than 1 year. Thus far, only a few treatment options have been approved for use in patients 
subsequent to failure of or progression following frontline therapy. 
The importance of T-cells has been substantiated by the efficacy of checkpoint inhibitors 
(anti-programmed death-ligand 1 [PDL1]) in the frontline setting, including in SCLC. 
Furthermore, GD2 is a membrane molecule expressed on the majority of SCLC cells. Hence, 
targeting SCLC through GD2 via a T-cell redirecting approach will potentially add benefit to a 
population failing the currently available treatment options. 
Based on data from the 18-034 (FIH) trial and experience with other products having a similar 
mode of action, the safety profile of nivatrotamab is considered manageable with appropriate 
risk mitigation measures in place. The key potential risks are CRS, including potential CNS 
effects and GD2-mediated toxicities (e.g., hypotension and neuropathic pain). 
In the FIH trial 18-034, where patients were exposed to nivatrotamab via the IV route, 2 subjects 
at dose level 6 (9.3 mcg/kg/cycle) experienced SAEs that were deemed related to treatment and 
evaluated as DLTs, namely, CTCAE grade 3 syncope and grade 3 sympathetic nerve neuropathy 
with orthostatic hypotension. These DLTs may represent a GD2-mediated neuropathy. No 
reports of severe pain (≥CTCAE grade 3) were reported. CRS events were graded in accordance 
with the grading system published by Lee et al. 201430 rather than CTCAE grading. Five patients 
at dose levels 4–6 experienced CRS with 2 events being serious: 1 grade 2 event at dose level 5 
and 1 grade 3 event at dose level 6. All patients with CRS recovered. The types of CNS events 
seen due to the immune response with other CD3-engagers (e.g., seizures, speech disorders, 
confusion) were not observed. Other findings of note in the 18-034 trial include 3 subjects at 
dose levels 5–6 with SAEs of decreased lymphocyte count (CTCAE grade 4) considered related 
to nivatrotamab. The events resolved within 2 to 5 days and may be due to the migration of T 
lymphocytes into tissues following activation. Decreased lymphocyte count was the only 
CTCAE grade 4 event considered related to nivatrotamab. No AEs had a fatal outcome. 
With respect to the safety of patients in this study, the starting dose is kept at a lower level than 
the dose level considered safe in the 18-034 trial. Administration of nivatrotamab will be 
performed in a clinical setting with immediate access to equipment and appropriately qualified 


 
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staff for resuscitating and stabilizing individuals in case of an acute emergency. Subjects will be 
closely monitored with hospitalization until 48 h after dosing for at least the first 2 treatment 
cycles in phase 1. 
 
 
 
An external DMC will further assure patient safety and 
provide recommendations on dose escalation. Dosing of nivatrotamab will also be via the SC 
route, which may reduce the risk of developing both CRS and GD2-mediated toxicities. 
Overall, the anticipated benefits for patients in the target indication are considered to outweigh 
the potential risks. 


 
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5 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1 
Trial Objectives 
5.1.1 
Primary Objective 
Phase 1 
• To determine the MTD and the RP2D of nivatrotamab 
• To assess the safety and tolerability of different doses of nivatrotamab 
Phase 2 
• To assess the long-term safety of nivatrotamab administered at the RP2D 
5.1.2 
Secondary Objectives 
Phase 1 
• To assess the anti-tumor activity of nivatrotamab 
• To assess the PK of different doses of nivatrotamab 
• To assess the development of anti-drug antibodies to nivatrotamab 
Phase 2 
• To assess the anti-tumor activity of nivatrotamab 
• To assess the development of anti-drug-antibodies against nivatrotamab 
5.1.3 
Exploratory Objectives 
Phases 1 and 2 
• To explore GD2 expression from tumor tissue (optional) 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
Phase 1 
• The MTD (defined by an mBOIN design) and the RP2D of nivatrotamab 
• The overall incidence and severity of AEs for different doses of nivatrotamab 
Phase 2 
• Incidence and severity of AEs for nivatrotamab dosed at the RP2D 


 
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5.2.2 
Secondary Endpoints 
Phase 1 
• 
Anti-tumor activity 
 
o Measured according to the response evaluation criteria in solid tumors (RECIST) 
version 1.1 
▪ ORR 
▪ Disease control rate (DCR): complete response (CR) + partial response (PR) + 
stable disease (SD) as well as the proportion of patients in disease control at 
4, 8, 16, and 24 weeks 
▪ Duration of response (DoR) 
▪ PFS 
 
o Measured according to the immune response evaluation criteria in solid tumors 
(iRECIST) 
▪ iORR 
▪ iDCR: iCR + iPR + iSD as well as the proportion of patients in disease control 
at 4, 8, 16, and 24 weeks 
▪ iDoR 
▪ iPFS 
o OS 
• PK of different doses of nivatrotamab 
• Proportion of patients who develop anti-drug-antibodies at any time 
Phase 2 
• 
Anti-tumor activity 
 
o Measured according to RECIST version 1.1 
▪ ORR 
▪ DCR: CR + PR + SD as well as the proportion of patients in disease control at 
4, 8, 16, and 24 weeks 
▪ DoR 
▪ PFS 
 


 
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o Measured according to iRECIST 
▪ iORR 
▪ iDCR: iCR + iPR + iSD as well as the proportion of patients in disease control 
at 4, 8, 16, and 24 weeks 
▪ iDoR 
▪ iPFS 
o OS 
• Proportion of patients who develop anti-drug-antibodies at any time 
5.2.3 
Exploratory Endpoints 
Phase 1 and Phase 2 
Assessment of GD2 expression from archived paraffin-embedded tumor tissue (optional) 


 
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6 
DESCRIPTION OF TRIAL DESIGN AND TRIAL POPULATION 
6.1 
Overall Trial Design 
This is an open-label, multicenter, phase 1/2 trial with the aim to assess the safety and 
tolerability of increasing doses of nivatrotamab administered SC in patients with SCLC. 
The study will include a phase 1 dose escalation part to determine the MTD and RP2D 
(Figure 6-1). This will be conducted following an mBOIN design (section 19, Appendix 1). For 
the purpose of dose escalation, DLTs will be collected and assessed for a period of 28 days (the 
DLT evaluation period, see section 6.2.3). Dose escalation rules will be based on the number of 
patients with DLTs (see section 6.2.1.4). 
A phase 2 dose expansion part will follow phase 1 dose escalation. In phase 2, patients will be 
stratified according to whether they have platinum-sensitive or platinum-resistant SCLC 
(Figure 6-1). Phase 2 will assess longer-term safety and tolerability nivatrotamab as well as the 
clinical activity of nivatrotamab when administered at the obtained MTD/RP2D in phase 1. 
Up to 39 patients with advanced and/or refractory solid malignancies are planned to be dosed in 
phase 1 (dose escalation) and 30 additional patients with similar malignancies in phase 2 (dose 
expansion). No more than 69 patients in total will be dosed in the trial. 
Figure 6-1 
Trial design outline for the 402 trial 
 
Abbreviations: AE = adverse event; Gr = grade; MTD = maximum tolerated dose; RP2D = recommended phase 2 
dose* excluding toxicities clearly related to disease progression or intercurrent illness. 
 


 
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6.2 
Overall Trial Plan 
6.2.1 
Phase 1: Dose Escalation 
6.2.1.1 
Dose Regimen 
The dose escalation phase will consist of up to 13 cycles (Cycles 1 to 13), each cycle being of 
14 days’ duration. Thus, patients will receive up to 26 weeks of treatment. In Cycle 1 of phase 1, 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 In addition, there is a possibility to add 
2 additional intermediate dose levels. However, if the MTD is not reached and/or the RP2D 
cannot be established, the Sponsor will evaluate if the dose escalation is to be continued; this will 
be done after preparing a safety summary and presenting safety and PK data to an external DMC 
to reach an agreement. Any further dose escalation will be implemented via protocol 
amendment. 


 
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6.2.1.2 
Dose Levels 
The proposed dose levels in the dose escalation phase are shown in Table 6-2. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CRS, cytokine release syndrome 
6.2.1.3 
Dose Escalation Stages 
The dose escalation phase will consist of 2 stages: the initial accelerated titration stage followed 
by a standard titration stage (Figure 6-1). 
In the accelerated titration stage, patients will be recruited and treated in single-patient cohorts. 
These single-patient cohorts may optionally be expanded with up to 2 additional patients for the 
purpose of obtaining additional PK and/or pharmacodynamic data. 
The initial accelerated titration stage will end, and the single-patient cohort mandatorily 
expanded with (at least) 2 additional patients once either: 
•  Dose level 3 is reached, or  
• During the DLT evaluation period (28 days), a patient is observed with: 
o any grade ≥ 2 AE (excluding toxicities clearly related to disease progression or 
intercurrent illness), or 
o a protocol defined DLT (section 6.2.3), 
whichever occurs first. 
This will mark the end of the accelerated titration stage and the beginning of the standard 
titration stage. Hereafter, patients will be allocated to dose-levels typically in cohorts of 3. As the 
mBOIN design allows cohort-sizes to vary, the actual cohort sizes may differ from 3. 


 
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In the standard titration stage, cohorts will be allowed to include only 2 patients who are evaluable 
for DLT, provided that none of the 2 patients have experienced any related, grade ≥3 AE during 
the DLT evaluation period. 
If patients are withdrawn prematurely without having experienced a DLT, they will be 
considered non-evaluable and may be replaced. 
In cohorts that include more than 1 patient in the dose escalation part, there will be sequential 
enrolment. At a particular dose level, there must be at least 3 days between the first dose of the 
first patient and the first dose of the subsequent patients in the same cohort. 
6.2.1.4 
Dose Escalation Rules 
The dose escalation will be conducted following an mBOIN design (for further details, see 
section 19, Appendix 1). 
Table 6-3 
Phase 1 dose escalation rules based on the number of patients with DLTs 
Decision based on the number of 
patients with DLTs (NDLT) 
Number of patients evaluable for DLT at the current dose level 
 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if NDLT ≤ 
0 
0 
0 
1 
1 
1 
1 
2 
Remain on dose level if NDLT = 
NA 
1 
1 
NA 
2 
2 
2 
3 
De-escalate if NDLT ≥ 
1 
2 
2 
2 
3 
3 
3 
4 
Disallow dose-level if NDLT ≥ 
NA 
3 
3 
4 
4 
4 
5 
5 
Abbreviations: DLT = dose-limiting toxicity; NA = not applicable 
It will not be allowed to escalate or de-escalate to dose levels on which an unacceptable level of 
toxicity has been observed; these dose levels are disallowed, as addressed by the last row in 
Table 6-3 above. 
Dose escalation will be recommended by the DMC and will be determined by the Sponsor’s 
safety committee upon review of the safety data obtained during the DLT evaluation period as 
well as available data beyond the DLT evaluation period from all patients in the trial. Dose 
escalation will be allowed when the DMC has recommended the dose and the dosing schedule 
for the next dose level and the Sponsor’s safety committee has approved it. 
To better understand the safety, tolerability, PK, pharmacodynamics, or anti-tumor activity of 
nivatrotamab, up to 10 additional patients in total may be allocated in parallel to dose levels that 
are considered safe for such allocation (i.e., dose levels at or below the currently investigated 
one). This could be based on recommendations provided by the DMC. DLT information from 
patients in such additional cohorts will be taken into account for decisions on the dose level for 
the next cohort; the dose escalation rules shown in Table 6-3 can still be followed. 


 
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When a DLT in such an additional cohort is observed and the updated DLT information on a 
previously investigated lower dose level leads to decisions that come in conflict with previously 
taken decisions, the DMC will recommend the dose level for the next cohort. It will be possible 
to de-escalate from the starting dose, provided it is not disallowed due to toxicity. 
6.2.1.5 
Stopping Criteria for the Dose Escalation 
The dose escalation will stop when either: 
• The maximum sample size for phase 1 (N=39) has been reached (section 11.2). 
• There are 9 DLT-evaluable patients at the current dose level, and according to the mBOIN 
rules, the decision is to remain at the same dose level. 
• The lowest therapeutic dose is disallowed (i.e., the starting dose is considered too toxic). 
The dose escalation may also stop if there are 6 DLT-evaluable patients with 1 DLT on the 
current dose-level, provided that a higher dose-level has been evaluated and the number of DLTs 
on that higher dose-level leads to a de-escalation. 
6.2.1.6 
Determination of MTD and RP2D 
The mBOIN-based MTD will be preliminarily estimated statistically as the dose level with the 
observed DLT-rate closest to the target toxicity level (i.e., 28%%), as described in section 11.4.2. 
After the mBOIN-based dose-escalation algorithm has been completed, the DMC and the 
Sponsor will determine the MTD and the RP2D, both of which may differ from the 
aforementioned preliminary statistical estimate. The RP2D cannot exceed the MTD. 
The selection of the RP2D will be based on pharmacokinetic, pharmacodynamic, safety and 
efficacy data from Phase 1. The selection of RP2D will be informed by exposure-response 
analyses (cf. Section 11.4.9) and Frequency and severity of AEs will be balanced with any 
observed dose response for clinical activity. In the absence of compelling results as interpreted 
by the DMC and the Sponsor, the RP2D will be the highest dose administered that does not 
exceed the MTD. If there is evidence that a dose level lower than the MTD (which might not 
have been reached at this stage) has adequate clinical activity (whether determined by imaging 
data, pharmacodynamics endpoints, or predicted efficacious dose), the DMC and the Sponsor’s 
safety committee may decide that the RP2D has been determined and that the dose escalation 
may be stopped. 
Based on the available data, the DMC may recommend introduction of intermediate dose levels 
in between the pre-planned dose levels and may also suggest changing the dosing frequency. 


 
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6.2.2 
Phase 2: Dose Expansion 
6.2.2.1 
Dose Regimen 
In phase 2, the RP2D identified in phase 1 will be used (in order to assess the long-term safety 
and anti-tumor activity of nivatrotamab at this dose). It will be based on a review of the available 
safety information, including AEs and safety laboratory values, relevant PK data, and 
observations made after the end of the DLT evaluation period. 
6.2.3 
Definition of Dose-limiting Toxicity 
DLTs include the following events: 
Clinically significant AE (CTCAE version 5.0) or a significant laboratory abnormality (as 
defined below) that occurs during the DLT assessment period, excluding toxicities clearly 
related to disease progression or intercurrent illness. The established external, independent 
DMC will evaluate relatedness of an event in order for it to qualify for a DLT or not.  
DLT criteria will be categorized as follows: 
1. 
Thrombocytopenia grade 3 with clinically significant bleeding and neutropenia 
(i.e., myelosuppression) > grade 3, excluding neutropenia lasting <7 days and   
2. 
Non-hematological toxicities ≥ grade 3, defined as 
a. 
Grade 3 non-hematological laboratory abnormalities requiring medical 
intervention, which are not mentioned in the list of exceptions below. 
b. 
Any non-hematological AE of ≥ grade 3 that is not mentioned in the list 
of exceptions below. 
3. 
Death occurring during DLT evaluation period, not related to disease progression 
or complications or intercurrent illness as determined by the DMC 
4. 
Injection site reaction ≥ grade 3 
5. 
Dose delay of >21 days (failure to recover from any toxicity, which results in 
delayed dosing of the subsequent dose) 
6. 
CRS grade 3 or higher 
7. 
Immune effector cell-associated neurotoxicity syndrome (ICANS) grade 3 or 
higher 
8. 
Peripheral sensory neuropathy grade 4  
9. 
Peripheral sensory neuropathy grade 3 with no sign of clinical improvement 
within 21 days as evaluated by the investigator. 
10. 
Pain grade 3 or higher lasting 24 h or more despite optimal analgesic therapy 
administered according to the local standard of care 
11. 
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12. 
Any AST/ALT and bilirubin elevation meeting Hy’s law criteria (a,b,c and d) 
a. ALT or AST elevation > 3X upper limit of normal (ULN)  
b. Total bilirubin elevation > X2 ULN 
c. Absence of initial findings of cholestasis 
d. No other reason to be found i.e. due to infection (i.e. hepatitis), liver disease or 
other drug effect 
List of exceptions: non-hematological exceptions 
The following AEs will not constitute DLTs (however, they should be reported as AEs/SAEs 
according to the reporting guidelines). 
• Grade 3 laboratory values considered not clinically significant 
• Grade 3 headache, nausea, diarrhea, and vomiting, persisting for <48 h (with adequate 
supportive care) 
• Grade 3 elevations of ALT/AST ≤ 8 x ULN or baseline ALT/ AST (in case baseline above 
ULN at study entry) improved to < grade 3 within 14 days) 
• Grade 3 hypertension lasting <48 h 
• Grade 3 Fever lasting <72 h  
• Grade 3 Fatigue lasting < 7 days 
AEs that are self-limited and resolve within a short time frame will not constitute DLTs; 
however, they should be reported as AEs/SAEs according to the reporting guidelines.  
For the purpose of dose escalation, DLTs will be collected and assessed throughout Cycles 1 
and 2, covering a treatment period of 4 weeks. This will allow for the evaluation of up to 
3 investigational medicinal product (IMP) administrations. 
DLTs must be entered in the clinical AE report form and reported from the site to the Sponsor 
within 24 h of the Investigator’s first knowledge of the event. In case any of the side effects 
mentioned in the DLT definitions occur during Cycles 2 to 5 in Phase 1, these will be discussed 
at the first upcoming preplanned DMC meeting, and the Sponsor’s safety committee will 
evaluate the DMC recommendations for further dosing. 
6.2.4 
Dose Modifications 
Patients developing grade 3 toxicity not meeting the DLT criteria, that is not resolved/decreased 
to a lower grade within 36 h, will have treatment paused until toxicity is maximum grade 2 or 
returned to baseline value at study entry (e.g. lab values). 


 
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If the grade 3 toxicity is considered clinically significant by the investigator, patients will be 
planned for continued dosing at one lower dose level (dose level -1). No dose modification 
indicated for toxicities grade 1-2. 
 
6.2.5 
Trial Stopping Rules 
If any of the following occur, administration of the IMP will be stopped, and recruitment will be 
put on hold at least temporarily until DMC feedback is received to confirm if the trial can 
continue: 
1) One or more patients experience unexpected, sudden death during the treatment period 
2) Treatment related death before the EOT visit 
3) SAEs or frequency of AEs that, in the judgement of the Sponsor, are deemed to warrant 
immediate review by the DMC. 
4) Any other safety finding assessed as related to nivatrotamab that, in the opinion of the 
DMC or Sponsor, contraindicates further dosing of trial patients. 
If any of these occur, an immediate cumulative review of safety data with focus on the SAE/ AE 
in question will be conducted by the DMC to determine whether dosing and further recruitment 
should be resumed, the protocol modified, or whether the trial should be discontinued. Review 
and approval of the Sponsor Safety Committee is required for resumption of the trial in case the 
trial is interrupted due to one of the above-mentioned safety findings. 
When applicable, regulatory authorities and ECs/IRBs will be notified of actions taken with the 
trial. 
6.2.6 
Recruitment Period 
It is estimated that at least 24 months will be needed to recruit the planned number of patients. 
The recruitment periods are estimated to be at least 18 months for phase 1 and 6 months for 
phase 2. 
6.2.7 
Screening/Pre-treatment Evaluation 
Pre-treatment evaluations should be completed within 21 days prior to the start of treatment 
(Day 1 of Cycle 1). Please refer to the screening (SCR) visit in the flowcharts for a summary of 
the procedures to be undertaken related to screening/pre-treatment evaluation in the trial 
(section 3). 
Procedures to be performed only at screening: 
(i)  
Eligibility check (based on inclusion and exclusion criteria [see section 6.3.2]; the 
most recent imaging and laboratory assessment must be used to evaluate eligibility) 
(ii)  
Obtaining informed consent (written informed consent must be obtained from each 
patient within a reasonable time prior to the performance of any trial-related 


 
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procedure. Local recommendations regarding handling of informed consent will be 
followed) 
(iii)  
Recording of medical history (including concomitant disease and smoking history) 
and data pertaining to demographic and baseline characteristics 
Additionally, patients will undergo recording of information on concomitant medication and 
concurrent procedures, a physical examination (including a neurological examination [see 
section 8.1.3.1]), assessment of vital signs, height, body weight, Eastern Cooperative Oncology 
Group [ECOG] performance scoring, β-human chorionic gonadotropin [HCG] test (for 
pregnancy detection in females of childbearing potential), a 12-lead electrocardiogram (ECG), 
echocardiogram or multigated acquisition scan (MUGA), computed tomography (CT) scan of 
the primary tumor site, cranial and spinal magnetic resonance imaging (MRI) to evaluate CNS 
metastasis, clinical safety laboratory assessments (hematology, coagulation and clinical 
chemistry), assessment of SAEs, and urinalysis. 
Any data that is generated within the screening period and is considered standard of care as per 
local procedures is permitted to be used for the evaluation of patient eligibility even if the 
evaluation is performed prior to signing of the informed consent form (see also section 8). 
For phase 1, all patients will be locally screened and centrally treatment allocated (see also 
section 6.2.9). Results needed for inclusion of a patient in the trial must be available before a 
patient can be declared eligible for the study. Once the results of the screening evaluations become 
available and the patient is found to meet all eligibility criteria, the Investigator will complete an 
eligibility form and inform the Sponsor (for review and approval of eligibility of the patient). 
6.2.8 
Screening Failures and Re-screening 
Screening failures are patients who consent to participate in the trial but are not subsequently 
enrolled to receive the trial treatment. For screening failure patients, the date of informed consent 
and reason for screening failure along with demographic data and data on any SAEs must be 
captured in the electronic case report form (eCRF). 
Any SAEs must be followed up as described in section 9. 
Re-screening of screening failures will be allowed (see section 6.2.10.1 regarding patients 
re-entering screening). If a patient is re-screened the patient should receive a new patient 
identifier (ID), i.e. a patient can have multiple screening IDs. If a patient is re-screened the 
patient must sign a new informed consent form (ICF). 
6.2.9 
Study Treatment Assignment 
This being an open-label trial, the patient, the Investigator, and the Sponsor will know the 
administered treatment. 


 
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6.2.9.1 
Phase 1 
In phase 1, patients will be treated according to the dose levels indicated in section 6.2.1.2 
 
 Patients will be allocated to the relevant dose level after completion of 
screening. The treatment assignment will be coordinated centrally. If an Investigator identifies a 
patient and confirms that the patient is eligible for enrollment into the study, he/she will 
accordingly give the Sponsor sufficient notice by sending an eligibility form by email. 
The Sponsor will confirm in writing the patient enrollment number and the dose level at which 
the patient may be treated. The Investigator will complete the prescription form and send it to the 
pharmacy. The pharmacy will prepare the IMP accordingly. 
6.2.9.2 
Phase 2 
In phase 2, the procedure of treatment assignment will be identical except that a uniform dose 
level will be administered to all patients (the RP2D). This being an open-label trial, the 
investigator, the patient, and the Sponsor will know the treatment. 
6.2.10 
Visit Schedule 
6.2.10.1 
Phase 1 
The visit schedule for phase 1 is summarized in the flow chart in Table 3-1. The calculation of 
all study visits and time points of assessments are based on Day 1, which is defined as the first 
day of nivatrotamab injection. 
Screening period (Day –20 to Day 0) 
For details on the procedures to be performed at screening, see section 6.2.7. All patients who 
have signed the informed consent form will be recorded on the screening log. A patient is 
considered as being enrolled into the study as soon as the consent form is signed and will be 
assigned a unique subject identification number (ID). If a patient is screened but ultimately not 
treated, the reason will be recorded in the eCRF. A patient can re-enter screening for the study if 
at a later time point the inclusion/exclusion criteria are met. In this case, most recent screening 
evaluations will be used. If outside the screening period of 21 days repeated full screening must 
be effectuated. 
During screening, if specific assessments are evaluated more than once, then the result of the 
most recent assessment will be relevant for eligibility evaluation. 
 
 
 
 
 
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6.2.10.2 
Phase 2 
The visit schedule for phase 2 is summarized in the flow chart in Table 3-2. The calculation of 
all study visits and time points of assessments are based on Day 1, which is defined as the first 
day of nivatrotamab injection. The visit schedule is similar to that of Phase 1. 
6.2.11 
End of Treatment Visit 
At both phase 1 and phase 2, an “end of treatment” (EOT) visit should be made when the patient 
completes treatment or permanently discontinues the IMP. The EOT visit will be performed at 
the time of discontinuation, within 30 days after the last IMP dose and prior to initiation of any 
new anticancer treatment. In case of premature study discontinuation, the EOT visit should be 
performed immediately. The reason for discontinuation from treatment must be documented in 
the eCRF. 
The EOT visit will include the following assessments: physical examination, vital signs and 
body weight, ECOG performance score, neurological examination, recording of concomitant 
medication and concurrent procedures, safety laboratory assessments (hematology, coagulation 
and clinical chemistry), HCG test (for females of childbearing potential), anti-drug antibodies, 
AEs/SAEs, urinalysis, and CT scanning of the primary tumor site (if the last prior tumor 
assessment was >6 weeks from date of the EOT visit). 
6.2.12 
Unscheduled Visits 
If any assessments need re-evaluation, an additional response assessment is needed, or follow up 
on an (S)AE is required, the patient can be called for an unscheduled visit at the discretion of the 
Investigator. Data obtained during unscheduled visits pertaining to the clinical trial will be 
collected as unscheduled visits in the eCRF. 


 
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6.2.13 
Follow-up 
6.2.13.1 
Phase 1 
All patients will be followed up for safety reporting for 30 days after the last IMP dosing. 
Thereafter, long-term safety will be recorded by registration of related SAEs up to 12 months 
after the last dose. The Investigator must commit to provide data on vital status and disease 
progression for follow up on PFS and OS up to 12 months after the last dose. In phase 1, ORR 
will be assessed at predefined timepoints, including at Week 24. The Investigator should collect 
CT scan reports for tumor assessments every 8 weeks or according to the local standard of care. 
The FU assessments can be done locally at the referral site.  
6.2.13.2 
Phase 2 
Follow up in phase 2 will be similar to that in phase 1. All patients will be followed up for 
safety reporting for 30 days after the last IMP dosing. Moreover, long-term safety will be 
recorded by registration of related SAEs up to 12 months after the last dose. Vital status and 
disease progression for follow up on PFS and OS will be up to 12 months after the last dose. In 
phase 2, ORR will be assessed at pre-defined timepoints, including at Week 24. The Investigator 
should collect CT scan reports for tumor assessments every 8 weeks or according to the local 
standard of care. The FU assessments can be done locally at the referral site. 
6.2.14 
End of Trial 
End of trial is defined as last patient’s last visit, follow-up contact or death in the long-term FU 
period. 
6.3 
Trial Population 
6.3.1 
Number of Patients 
Up to 39 patients are planned to be dosed in phase 1 and 30 additional patients in phase 2. No 
more than 69 patients in total will be dosed in the trial. 
6.3.2 
Patient Selection 
To be eligible, the patient must meet all the following inclusion criteria and must not violate any 
of the exclusion criteria (section 6.3.2.2). 
6.3.2.1 
Inclusion Criteria 
1. 
Signed and dated informed consent has been provided prior to any trial-related 
procedures. 
2. 
Patient willing and able to comply with the trial protocol 
3. 
Age ≥18 years at the time of informed consent 
4. 
Histologically or cytologically proven SCLC. Radiographical relapse/progression after 
minimum 1 line of platinum-containing chemotherapy with PR or CR as the best 
response (not required for phase I) and not more than 3 prior lines of therapy 


 
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5. 
Measurable disease according to RECIST v1.1 
6. 
ECOG performance status 0–1 
7. 
Expected survival >3 months 
8. 
Platelet counts ≥100,000 cells/mm3 
9. 
Hemoglobin ≥9 g/dL 
10. Absolute neutrophil count (ANC) ≥1000 cells/mm3 
11. Adequate liver function defined by AST, ALT, alkaline phosphatase (ALP) ≤3 × upper 
limit of normal (ULN), and serum bilirubin ≤1.5 × ULN with the following exceptions 
a. 
In patients with documented liver metastases, AST, ALT, and ALP ≤5 × ULN 
and serum bilirubin ≤1.5 × ULN 
12. Adequate renal function with serum creatinine ≤1.5 mg/dL or creatinine clearance 
≥50 mL/min as calculated using the Cockcroft-Gault equation31  
13. Serum albumin >3.0 g/dL 
14. Women of child-bearing potential must agree to appropriate contraception during 
treatment and for a period of 30 days after the last dose of the study drug. Fertile male 
patients must agree to the use of condoms during treatment and for a period of 30 days 
after the last dose of the IMP. For a sterilized male patient to be exempt from the 
requirement to use contraception after IMP treatment, he must have undergone surgical 
sterilization (vasectomy). 
6.3.2.2 
Exclusion Criteria 
1. 
Systemic chemotherapy, radiotherapy, immunotherapy, or major surgery administered 
within 3 weeks prior to the first planned dosing of the IMP per protocol 
2. 
Patients receiving any other investigational therapy for their cancer within 3 weeks prior 
to the first planned dosing of the IMP per protocol 
3. 
Patients who never received platinum-containing regimen for SCLC (defined as less than 
2 cycles of platinum doublet) 
4. 
Persistent > grade 1 toxicity from previous treatment with checkpoint inhibitors 
5. 
Any immunosuppressive concomitant medication (i.e., salazopyrine, methotrexate, 
steroids etc.) 
6. 
Inability to wean off steroid unless tapered to 0 mg/day minimum 10 days prior to the 
first treatment in case of prior use 
7. 
Any active, uncontrolled viral, fungal, or bacterial infection 
8. 
Any medical history within 3 months prior to enrolment with need for anticonvulsant 
therapy 


 
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9. 
Patients with a diagnosis of autoimmune diseases or immunodeficiencies or documented 
infection with human immunodeficiency virus (HIV) or hepatitis B or C virus (active) 
10. Previous autologous stem cell transplantation (ASCT) or solid organ transplantation 
11. Active heart disease including myocardial infarction within the last 6 months before the 
first dose. This includes cardiac insufficiency with left ventricular ejection fraction 
(LVEF) <50% 
12. Active CNS metastases. Patients with treated CNS metastases are eligible if they are 
clinically stable without any new neurological symptoms and if there is no radiological 
evidence of new or enlarging CNS metastases. CNS-directed treatment (surgery, 
radiation) must be completed 4 weeks prior to the first IMP administration32  
Furthermore, patients are excluded if they have:  
• Leptomeningeal carcinomatosis  
• Uncontrolled seizures. Patients with known seizure are eligible if they are stable 
and have been without seizure 4 weeks prior to the first IMP administration  
13. Patients who experienced severe or recurrent (>grade 2) immune-mediated AEs or IRRs, 
including those that lead to permanent discontinuation while on treatment with immuno-
oncology agents 
14. Prior treatment with anti-GD2 antibody or bispecific antibodies 
15.  Patients with Limited Disease (LD) who are candidates for local or regional therapy 
16. Impending need for palliative radiotherapy or surgery for pathological fractures and/or 
for medullary compression up to 3 weeks prior to the first planned dosing of the IMP per 
protocol (palliative radiation for other reasons within 2 weeks) 
17. History of other active malignancy within the past 3 years prior to the first planned 
dosing of the IMP per protocol (excluding non-melanoma skin canncers, carcinoma in 
situ of the cervix, ductal carcinoma in situ of the breast, incidental prostate cancer (T1a, 
Gleason score ≤6, prostate specific antigen (PSA) less than 0.5 ng/ml) 
18. Patients with a significant intercurrent illness (any ongoing serious medical problem 
unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria 
and that is expected to interfere with the action of the trial IMP or significantly increase 
the severity of the toxicities experienced from trial treatment 
19. Patients who are pregnant or breastfeeding 
20. Patients with a body weight of < 45 kg 
21. Patients with prior orthostatic hypotension 


 
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6.3.3 
Premature Discontinuation of Treatment 
6.3.3.1 
Treatment Discontinuation Criteria 
A patient should be discontinued from treatment with the IMP if any of the following 
situations occur: 
• Any DLT (see section 6.2.3) 
• Disease progression - confirmed PD (confirmed immune PD [iCPD]) or as clinically 
judged by the Investigator 
• Patients with suspected progression, i.e., unconfirmed PD (unconfirmed immune PD 
[iUPD]), are allowed to continue treatment if they are considered to be clinically stable in 
the opinion of the Investigator until confirmatory radiological assessment (CT scan) is 
performed. 
• In case of decreased ejection fraction (EF) of grade 3 (EF, 39%–20% or ≥20% drop from 
baseline), and the event is considered treatment-related. 
• Investigator’s decision for medical or safety reasons 
• If the patient receives prohibited anti-tumor therapy/procedures during the trial 
• Patient chooses to withdraw from the therapy at any time 
• Pregnancy 
6.3.4 
Withdrawal from the Trial 
A patient must be withdrawn from trial if one of the following applies: 
• Patients may be withdrawn from the trial at the discretion of the Investigator or Sponsor 
due to a safety concern or if judged non-compliant with trial procedures. 
• Patient chooses to withdraw from the trial at any time. 
• Other circumstances that would endanger the health of the patient if he/she were to 
continue his/her participation in the trial. 
• Patient becomes lost to follow-up 
Reasons for withdrawal and discontinuation of any patient from the trial will have to be 
documented in the eCRF. 
6.3.5 
Patient Replacement 
If patients are withdrawn pre-maturely without having experienced a DLT, they will be 
considered non-evaluable and may be replaced. 
 


 
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7 
TREATMENTS 
7.1 
Investigational Medicinal Product 
For this trial, the Sponsor, Y-mAbs, will provide nivatrotamab, 2 mg/mL. No other medicinal 
products or auxiliary medicinal products will be provided by Y-mAbs. 
Please refer to the IMP manual for more details on preparation and administration of 
nivatrotamab. For further information on nivatrotamab, see the Investigator’s brochure (IB). 
Table 7-1 
Investigational medicinal product (IMP) 
IMP 
Nivatrotamab 2 mg/mL 
Route 
Subcutaneous (SC)  
Pharmaceutical form 
Solution for SC use 
Unit strength 
2 mg/mL 
7.1.1 
Nivatrotamab Administration 
The IMP, nivatrotamab, will be administered SC according to the treatment schedule 
(section 7.1.2). Nivatrotamab should only be administered in a hospital or clinic with immediate 
access to equipment, medications, and appropriately qualified staff for resuscitating and 
stabilizing individuals in an acute emergency, along with ready availability of an intensive care 
unit and other hospital facilities. Neurological consultation services should be readily available 
to address any neurological events that may arise as a result of IMP treatment. For the first 2 
cycles in both the dose escalation phase of the study (phase 1) and the dose expansion phase 
(phase 2), patients will be admitted to a hospital inpatient unit on the day of injection and will 
remain hospitalized until 48 h after completion of the IMP injection. Hospitalization 
requirements for subsequent cycles will be determined on the basis of the clinical course during 
the first cycle; for example, patients who experience an injection-related reaction or CRS during 
Cycle 1 may require hospitalization for subsequent IMP doses and cycles. 
IMP Administration Details 
Nivatrotamab will be administered SC at a site easily visible for the patient, i.e., upper thigh, 
upper arm, or abdomen to allow observation of potential injection site reaction. The selected 
dose should be administered at 1 site only, i.e., it should not be divided into separately injected 
fractions. Moreover, the IMP must not be administered intramuscularly. The time of injection 
should be chosen carefully with regard to the time points for safety assessments, 
PK/pharmacodynamic measurements, and the required duration of in-house monitoring of the 
patient. 
7.1.2 
Treatment Schedule 
 
 
 


 
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7.1.2.1 
Phase 1 (dose escalation) 
 
 
 
7.1.2.2 
Phase 2 (dose expansion) 
All patients in the phase 2 part of the study will be treated at the recommended dose defined in 
the phase 1 part of the study (RP2D) (also see section 6.2.2). 
7.1.2.3 
Treatment Modification and Delays 
In cases of toxicities, for patients who remain eligible for further treatment, a treatment delay of 
up to 3 weeks is acceptable to allow for resolution of ≥ grade 3 hematological and 
non-hematological toxicities (that do not meet the treatment discontinuation criteria) down to 
≤ grade 2 or returned to baseline value at study entry (e.g. lab values). 
7.1.2.4 
Treatment after Discontinuation of IMP 
After discontinuation of the IMP, the patient should be treated at the discretion of the 
Investigator. 
7.1.3 
Packaging and Labelling 
Packaging and labelling of nivatrotamab will be outsourced to a clinical packaging contract 
manufacturing organization. All products will be labelled according to the rules governing 
medicinal products in the European Union (Annex 13, EudraLex, Volume 4) and local 
requirements. Each unit of the IMP will be uniquely numbered. The IMP provided must be used 
solely for this trial and as described in this protocol and for no other purpose. Further detailed 
information on packaging and labelling is provided in the IMP manual. 
7.1.4 
Storage and Handling 
The IMP provided by the Sponsor must be stored according to the clinical label claim in a secure 
location with controlled access. It must be stored separately from normal clinical stock. The 
storage conditions must be monitored for adherence to the claims. Temperature monitoring data 
must be reviewed by the clinical research associate (CRA) during monitoring visits. Any 
deviations in storage temperature must be reported immediately, and the IMP must not be used 
until acceptance of such use is received. Monitoring must be done using a calibrated, stationary, 
and continuous recording system. As a minimum, a calibrated min/max thermometer is required 
for monitoring. 
Detailed information on the storage and handling of the IMP is available in the IMP manual. 


 
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7.1.5 
Drug Accountability and Compliance Check 
Each trial site will be supplied with sufficient IMPs for the trial on an ongoing basis. The 
supplies will be ordered by the site in sufficient time to ensure that enough IMPs are available 
for treatment. Drug accountability must be documented in the eCRF. 
The Investigator or designee is responsible for drug accountability and record maintenance (i.e., 
receipt, accountability, and final disposition records). All expired or damaged IMP must be 
stored separately from non-allocated trial products. Non-allocated IMP including expired or 
damaged IMP must be accounted as unused, at the latest at closure of the trial site. For more 
information on accountability procedures, please refer to the IMP manual. 
Clinical personnel at the trial site will record in the source notes the route of administration, 
timing, and site of all administrations of IMP. Any reasons for non-compliance should be 
documented in the hospital records. 
Drug accountability on a patient level will be documented by keeping copies of the IMP order 
form and the IMP administration form. The documentation will be reviewed periodically and 
verified by the CRA over the course of the trial. 
7.1.5.1 
Medication Errors 
Medication errors must be reported in the medication error page of the eCRF. 
Medication errors and uses outside what is foreseen in the protocol may include: 
• Administration of the wrong drug 
• Wrong route of administration, such as intramuscular or IV instead of SC 
• Accidental administration of a lower or higher dose than intended. An overdose is defined 
as an IMP dose received by the patient that exceeds the protocol -specified dose by at least 
10%. An underdose is defined as an IMP dose received by the patient that is at least 10% 
lower than the protocol-specified dose. 
If a medication error results in an AE, the AE must also be reported in the eCRF. If the event 
qualifies as an SAE, it must be reported using the paper clinical AE report form in addition to the 
AE form in the eCRF. 
7.1.6 
Device 
Not applicable. 
7.1.7 
Technical Complaint 
A technical complaint is any written or oral communication that states any dissatisfaction with 
the product characteristics and alleges a product defect. A technical complaint can be related to, 
for example, the product appearance (discoloration, presence of particles or sediment); product 
container (damaged or missing seal); product label (damaged, missing, misleading); or 


 
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consignment (wrong number of vials in the package). A technical complaint should be also 
initiated if the product is suspected to be falsified. 
Please refer to the IMP manual for information regarding reporting of a technical complaint. 
7.2 
Other Therapies and Procedures 
7.2.1 
Concomitant Therapy 
A concomitant medication is any medication received by the patient other than the IMP, 
including all pre-medication. All concomitant medications (including over the counter) that the 
patient is receiving at the time of enrollment or during the trial must be entered in the eCRF with 
the following information: 
• Generic name 
• Start date 
• Stop date of administration or ongoing at trial termination 
• Indication/reason for use 
• Dose 
• Frequency 
Any changes to concomitant medication during the trial should be recorded in the eCRF. If a 
change is due to an AE/SAE, then this must be recorded according to section 9. 
During follow up, only information on new anti-cancer therapy will be collected. 
7.2.2 
Pre-medications prior to nivatrotamab injection 
All medications, pre-medication and supportive concomitant medication should be captured 
under concomitant medication in the eCRF. 
7.2.2.1 
Cytokine Release Syndrome 
In order to mitigate expected reactions to administration of a monoclonal bispecific antibody and 
prevent CRS, premedication with dexamethasone should be administered before IMP dosing (via 
SC injection). In addition, the premedication package will contain a non-NSAID (nonsteroidal 
anti-inflammatory drug) antipyretic (acetaminophen or equivalent) and an antihistamine 
(loratadine or equivalent).  
 
Administer the following pre-dose medications to reduce the risk of acute injection-related 
reactions, CRS, allergic reactions, nausea/vomiting to all patients prior to every injection of 
nivatrotamab: 


 
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Pre-medication in Cycle 2 and subsequent cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
• 
 
 
 
 
 
 
 
7.2.2.2 
Pain 
Injection of nivatrotamab may be followed by development of neuropathic pain. The clinical 
manifestations are varied and could involve the abdomen, lower back, and extremities. 
Pain is expected to develop by onboarding of IMP to GD2, with estimated onset on Day 1-2 after 
IMP administration. As many patients might already receive opioids and/or medication for 
neuropathic pain at enrolment, the below recommendations should be considered as a guideline, 
and treatment accommodated to each patient at the investigators’ discretion. 
To prevent the development of severe neuropathic pain, the following pre-emptive analgesia 
with peroral gabapentin is recommended and should be followed (at home) prior to dosing in all 
cycles: 
• 
 
 
 
 
 
 
 
 


 
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7.2.3 
Recommended supportive medication 
 
 
 
 
 
  
 
 
 
 
7.2.4 
Management of Selected Adverse Reactions 
7.2.4.1 
Grading and Management of Cytokine Release Syndrome 
CRS should be graded in accordance with CRS Revised Grading System by Lee et al.27 shown in 
Table 7-2 below. 
 
 
 


 
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Table 7-2 
CRS Revised Grading System 
CRS parameter 
CRS Grading1 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever* 
Temperature ≥38°C 
(≥100.4°F) 
Temperature ≥38°C 
(≥100.4°F) 
Temperature ≥38°C 
(≥100.4°F) 
Temperature ≥38°C 
(≥100.4°F) 
 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
 
And/or2 
Hypoxia 
None 
Requiring low-flow 
nasal cannula3 or 
blow-by oxygen 
delivery 
Requiring high-flow 
nasal cannula,3 face 
mask, nonrebreather 
mask, or Venturi 
mask 
Requiring positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation, and 
mechanical 
ventilation) 
Organ toxicities associated with CRS do not influence the grading. 
* Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS and then 
receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever will no longer be required to grade 
subsequent CRS severity. In this case, CRS grading will be driven by hypotension and/or hypoxia. 
1 CRS with a fatal outcome should be recorded as a grade 5 event. 
2 CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5° C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
3 Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/min. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min. 
 
CRS should be managed according to the management algorithm described in Figure 7-2 below. 
Tocilizumab (anti-cytokine therapy) should be dosed at 8 mg/kg (maximum 800 mg/dose) 
infused over 1 h with appropriate pre-medications. In the absence of clinical improvement within 
24 h or should rapid deterioration occur, a second dose of tocilizumab could be administered; 
however, a second-line agent (e.g., a corticosteroid) should also be introduced simultaneously 
(Figure 7-1). 


 
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Figure 7-1 
Cytokine release syndrome (CRS) management algorithm (CRS grade ≥2) 
 
 
 
Abbreviations: IV = intravenous; IVF = intravenous fluids 
This algorithm is based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus 
grading for cytokine release syndrome and neurologic toxicity 27 
7.2.4.2 
Grading and Management of Immune effector-cell associated 
neurotoxicity 
The neurotoxicity assessments should be performed and graded in accordance with the ASTCT 
immune effector cell-associated neurotoxicity syndrome, ICANS, consensus grading scheme for 
adults27, as presented in Table 7-3. 
The immune effector cell-associated encephalopathy (ICE) score is calculated as per Table 7-4. 
Any neurological AEs observed as part of the assessment (e.g., seizures) should be recorded as 
described in section 9. 
Dexamethasone 10 mg IV every 6 h
AND/OR
Repeat tocilizumab 8 mg/kg IV once


 
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Table 7-3  
ASTCT ICANS consensus grading for adults 
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score* 
7–9 
3–6 
0–2 
0 (patient is unarousable and unable 
to perform ICE) 
Depressed level 
of consciousness1 
Awakens 
Spontaneously 
Awakens 
to voice 
Awakens only to 
tactile stimulus 
Patient is unarousable or requires 
vigorous or repetitive tactile stimuli 
to arouse. Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure, 
focal or generalized, 
that resolves rapidly 
or nonconvulsive 
seizures on EEG that 
resolve with 
intervention 
Life-threatening prolonged seizure 
(>5 min) or repetitive clinical or 
electrical seizures without return to 
baseline in between 
Motor findings2 
N/A 
N/A 
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging3 
Diffuse cerebral edema on 
neuroimaging; decerebrate or 
decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or 
Cushing’s triad 
Abbreviations: ASTCT = American Society for Transplantation and Cellular Therapy; 
EEG = electroencephalography; ICANS = immune effector cell-associated neurotoxicity syndrome; 
ICE = immune effector cell-associated encephalopathy; ICP = intracranial pressure; N/A = not applicable 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause, for example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as grade 3 ICANS. 
* A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia; however, a 
patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
1 Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication) 
2 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE 
version 5.0; however, they do not influence ICANS grading. 
3 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE version 5.0. 
 
 


 
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Table 7-4  
ICE assessment tool for the grading of ICANS 
Domain 
Assessment(s) 
Points 
Orientation 
Orientation to year, month, city, hospital 
4 
Naming 
Ability to name 3 objects (e.g., point to clock, pen, button) 
3 
Following commands 
Ability to follow simple commands (e.g., “Show me 2 fingers” 
or “Close your eyes and stick out your tongue”) 
1 
Writing 
Ability to write a standard sentence (e.g., “Our national bird is 
the bald eagle”) 
1 
Attention 
Ability to count backwards from 100 by 10 
1 
Abbreviations: ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = immune effector 
cell-associated encephalopathy 
Scoring 
• 
10 = no impairment 
• 
7–9 = grade 1 ICANS 
• 
3–6 = grade 2 ICANS 
• 
0–2 = grade 3 ICANS 
• 
0 due to patient unarousable and unable to perform ICE assessment = grade 4 ICANS 
Management of neurotoxicity will be based on the following algorithm (Figure 7-2). 


 
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Figure 7-2 
Treatment algorithm for the management of neurotoxicity (ICANS) in the 
402 trial 
 
Abbreviations: ICANS = immune effector cell-associated neurotoxicity syndrome; IV = intravenous 
This algorithm is based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus 
grading for cytokine release syndrome and neurologic toxicity 27 
7.2.4.3 
Management of Hypotension 
 
 
  
 
 
 
 
 
  
 
 


 
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7.2.4.4 
Management of Orthostatic Hypotension 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.4.5 
Management of Neuropathic Pain 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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7.2.5 
Therapy and Procedures Allowed During the Trial 
Any treatment needed for patient wellbeing (including supportive care) that will not interfere 
with IMP administration may be given at the discretion of the Investigator. 
7.2.6 
Prohibited Therapy and Procedures During the Trial 
The following are prohibited during the trial: 
• Any anti-tumor therapy other than the IMP and mandatory concomitant medications, for 
example: 
o Cytotoxic and/or cytostatic drugs 
o Radiation therapy to primary tumor, CNS, or other target lesions 
o Immunotherapy 
• Any other investigational agent 
• Chronic (>7 days) systemic high-dose corticosteroid therapy (i.e., >10 mg dexamethasone 
daily) 
• Any other immunosuppressive therapies (except for transient use of corticosteroids) 


 
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• Substrates of CYP450 isozymes considered by the investigator to have narrow therapeutic 
index must be paused or not initiated for 9 days after first dose and 2 days after second 
dose (corresponding to day 1 to 9, both included) 
 
 


 
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8 
PROCEDURES AND ASSESSMENTS 
An overview of all trial-related procedures and assessments at each visit is provided in the visit 
schedule flow charts, Table 3-1(phase 1) and Table 3-2 (phase 2). Written informed consent 
must be obtained from each patient prior to undertaking any trial specific procedure. 
8.1 
Eligibility and Safety Assessments 
Assessment of the patient’s eligibility criteria will be performed as outlined in sections 6.2.7 and 
6.3.2, including a review of all laboratory measurements performed during the screening period. 
8.1.1 
Demographics 
Information on the patient’s demographics will be collected in the eCRF during screening.  
The following demographic information will be entered: 
• Age or date of birth, if allowed by local legislation 
• Gender 
• Ethnic origin if allowed by local legislation  
• Race if allowed by local legislation 
Current and prior smoking status must be recorded for each patient. 
8.1.2 
Medical History/Current Medical Conditions 
Medical history will include general and disease-specific medical history, including a history of 
past and current medical conditions and a full history of the course of the patient’s SCLC, 
including all prior treatments such as prior systemic regimens and radiotherapy. 
All concomitant illnesses should be recorded. A concomitant illness is defined as any illness, 
other than the disease being investigated (SCLC), which is present at the start of the trial or is 
found as a result of the screening procedure. 
The information to be collected for SCLC medical history and concomitant illnesses will include 
• Diagnosis 
• Date of onset 
• Date of resolution 
• Date of relapse (for SCLC) 
8.1.3 
Physical Examination 
Comprehensive physical examinations of all body systems will be performed as outlined in 
section 3. Physical examination should include an assessment of the general appearance and a 
review of systems (dermatologic; head; eyes; ears; nose; mouth, throat, and neck; extremities; 
thyroid; lymph nodes; and respiratory, cardiovascular, gastrointestinal, musculoskeletal, and 
neurologic systems). 


 
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8.1.3.1 
Neurological Examination 
During the screening and at the end-of-study visit, a neurological examination according to local 
standards will be performed. It will include examination of the following functions: level of 
consciousness, orientation, vision, cranial nerves and brain stem functions, pyramidal and 
extrapyramidal motor system, reflexes, muscle tone and trophic findings, coordination, sensory 
system, and neuropsychological findings (e.g., speech, cognition and emotion). The presence of 
tremors should also be evaluated. 
8.1.3.2 
Height and body weight 
Height (without shoes) must be measured at screening and entered in the eCRF rounded to 
nearest centimeter. 
Body weight must be measured without overcoat and shoes and entered in the eCRF rounded to 
nearest kilogram; see flowchart (section 3). 
8.1.4 
ECOG Performance Status 
Patients’ performance status will be assessed using the ECOG performance score (see section 3). 
8.1.5 
Vital Signs 
Body temperature (e.g., tympanic or rectal), heart rate, oxygen saturation, and blood pressure 
(systolic/diastolic, patients should be supine/sitting for 5 mins before assessment) will be 
measured as part of vital signs. The Investigator is recommended to monitor the patient’s vital 
signs continuously (in Cycles 1 and 2); see flowchart (section 3).  
On Day 3 and 4 (Cycle 1 and 2), vital signs should be measured during the outpatient visit; 
moreover, from Cycle 3 onward, vital signs should be measured once on dosing day (Day 1). In 
case the patient’s symptomatology or body temperature measurements rises suspicion of 
orthostatic hypotension (for definition, see section 7.2.4.3), it is recommended that the patient 
stay hospitalized for monitoring (this monitoring will not qualify as a DLT). 
8.1.6 
Echocardiogram, MUGA, and ECG 
In order to exclude pre-existing or developing cardiac failure, an LVEF of ≥50% is required at 
screening, assessed by either echocardiogram or MUGA. Monitoring of cardiac function is 
required during the trial including repeat ECG (12-lead) to be performed as outlined in section 3. 
Monitoring of LVEF should be done by either repeat echocardiogram or MUGA (same modality 
per patient); for the time of assessments, see section 3. In case of decreased ejection fraction 
(EF) of grade 3 (EF, 39%–20% or ≥20% drop from baseline), if this event is considered 
treatment-related, the patient should discontinue treatment and proceed into follow up. 
8.1.7 
CT of the Neck, Thorax, and Abdomen 
Assessment of SCLC target lesions and tumor burden must be performed via CT scanning, and 
the date of completion of the first CT should not exceed 21 days prior to the first dosing. 
Screening CT scanning result should be measurable according to RECIST 1.1 


 
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8.1.8 
Cranial/Spinal MRI 
MRI evaluation of the CNS is mandatory at baseline in order to evaluatebrain or leptomeningeal 
metastasis and assure absence of spinal metastasis; in addition, an MRI must be performed if a 
patient develops a neurological (CNS) AE ≥ grade 2 during the trial. 
8.1.9 
Clinical Laboratory Assessments 
All clinical laboratory assessments must be conducted in accordance with the flowcharts in 
section 3. 
8.1.9.1 
Hematology 
Hemoglobin; hematocrit, red blood cell (RBC), white blood cell (WBC) count; differential blood 
count to determine the absolute numbers of lymphocytes (absolute (ABS), %), neutrophils(ABS, 
%), eosinophils (ABS, %)and monocytes (ABS, %); basophils (ABS, %), mean corpuscular 
volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and 
platelet count are to be performed for safety analyses. Blood samples will be taken at screening, 
at the start of a treatment cycle (prior to the start of IMP administration), at different time points 
during the treatment and treatment-free periods, and at the EOT visits. 
With regard to blood samples taken at screening, samples taken for standard procedures up to 
48 h prior to screening can be used. As regards samples collected prior to the start of IMP 
administration, these samples may be obtained up to 48 h before the start of treatment; however, 
the results must be available before treatment start. 
8.1.9.2 
Safety Laboratory Evaluations 
Serum chemistry 
AST, ALT, alkaline phosphatase (AP), lactic dehydrogenase (LDH), total bilirubin, albumin, 
creatinine, urea/blood urea nitrogen (BUN) (as applicable), glucose, calcium, sodium, potassium, 
chloride, phosphorus, and magnesium will be assessed. 
Coagulation 
Coagulation parameters will include international normalized ratio (INR), partial thromboplastin 
time (PTT), fibrinogen, and D-dimer. 
8.1.10 
Urinalysis 
The presence of glucose, protein, and blood in urine will be assessed by dipstick. 
If proteinuria is suspected (repeated protein on dipstick at 2 consecutive tests), a 24 h collection 
of urine should be performed and analysed for protein content. 
8.1.10.1 
Creatinine Clearance 
An estimated glomerular filtration rate (eGFR) using creatinine clearance will be used to detect 
any kidney function impairment. 


 
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8.1.11 
Pregnancy Test 
A urine or serum pregnancy test (HCG) will be performed in all female pre-menopausal women 
(unless of non-childbearing potential); see flowchart (section 3). 
Non-child-bearing potential in female patients will be confirmed by one of the following: 
• Females who have not reached menarche or 
• Females who have not had menses within the past 12 months and have a 
follicle-stimulating hormone (FSH) ≥40 IU/L or 
• Females who have not had menses within the past 24 consecutive months if an FSH 
measurement is not available or 
• Females who have undergone surgical sterilization (e.g., hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) 
Pregnancy and contraceptive requirements for female patients of child-bearing 
potential 
Women of child-bearing potential must have a negative pregnancy test at screening and will be 
excluded if they do not agree to use highly effective contraception during treatment and for a 
period of 30 days after the last nivatrotamab administration. 
Highly effective contraceptive methods are those that can achieve a failure rate of <1% per year 
when used consistently and correctly. Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomised partner1 
                                                 
1 Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner 
of the female patient and that the vasectomised partner has received medical assessment of surgical success. 
 


 
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• Sexual abstinence2 
Contraceptive requirements for male patients 
Male patients with female partners of child-bearing potential must use contraception (condom) 
during treatment and for 30 days after the last IMP treatment. 
8.1.12 
Peripheral Blood Cytokines 
Serum cytokine levels (IL-6) will be monitored in all patients enrolled in phase 1 and phase 2, in 
accordance with the flowcharts in section 3. Blood samples for the measurement of peripheral 
blood cytokines will be taken pre-dose on cycle 1 day 1 and on dosing day (+1) and should 
optimally be taken at the same time of the day (± 60 min) as the blood sample were taken cycle 1 
day 1. 
8.1.13 
Anti-Drug-Antibodies 
Blood samples for the assessment of binding anti-drug antibodies will be taken in accordance 
with the flowchart in section 3. . For further details, see the laboratory manual. 
8.1.14 
Concomitant Medication 
All concomitant medications will be recorded, starting on the first day of screening and until 
the EOT visit. Administration of subsequent anti-cancer therapy during the follow up period 
will be recorded. 
8.1.15 
Adverse Events 
AEs and SAEs should be recorded and reported in accordance with section 9. 
8.2 
Response Assessments 
Responses will be assessed at predefined timepoints (see section 3). Response assessment will be 
based on the criteria described in RECIST version 1.1 34. Application of the iRECIST criteria in 
the evaluation of PD will also be done in order to protect patients from going off treatment in 
case of unconfirmed PD (according to RECIST1.1) and iUPD (according to iRECIST) due to 
pseudo-progression/tumor flare 35. Confirmatory scanning for patients who have obtained PR or 
CR will be undertaken approximately 4 weeks after the initial response. 
For definitions of response, please see section 11. 
8.3 
Pharmacokinetics Assessment 
Nivatrotamab serum concentration will be measured in all patients dosed in both phase 1 and 
phase 2. Such measurements will occur at baseline (predose) and at regular intervals during the 
treatment period (see section 3). During the inpatient period, samples will be taken prior to 
                                                 
 
2 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 


 
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treatment start (baseline) and at defined time points after IMP administration (see Table 8-1). 
The time window for these samples are also shown in Table 8-1. It is important that the actual 
time of sampling is documented precisely in the eCRF. For further details, see the laboratory 
manual. 
Table 8-1 
Pharmacokinetics assessment time points  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Abbreviations: PK = pharmacokinetics 
8.4 
Assessment of GD2 Expression (optional) 
Collection of tumor specimens from archival paraffin embedded tissue (minimum 5 to 10 slides) 
will be done for immunohistochemical analysis of GD2 expression. This will be done for 
patients with available tissue and who have provided a separate consent for this procedure. 
Please refer to the laboratory manual for further details. 


 
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9 
ADVERSE EVENTS 
9.1 
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 that 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. 
A pre-existing condition (i.e., a disorder present before the AE reporting period started, which is 
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. 
9.2 
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 should be classified as serious: 
• It is fatal or life-threatening.3 
                                                 
3 The term “life-threatening” in the definition of “serious” refers to an event in which the patient, in view of either 
the Investigator or the 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. 
 


 
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• It requires inpatient hospitalization or prolongation of existing hospitalization.4 
• It results in persistent or significant disability/incapacity. 
• It is a congenital anomaly/birth defect. 
• It is a medically important event.5 
9.3 
Definition of Non-serious Adverse Events 
A non-serious AE is any AE that does not fulfil the definition of an SAE. 
9.4 
Definition of Predefined Adverse Events of Special Interest 
The following AEs (serious and non-serious) graded according to CTCAE v5.0 Revised CRS 
Criteria according to Lee et al.27 for CRS are selected as adverse events of special interest 
(AESIs) in this trial: 
• CRS grade 2 or higher 
• Hypotension grade 3 or higher not in connection with CRS 
• Neuralgia grade 3 or higher 
• Peripheral neuropathy grade 3 or higher  
 
 
 
                                                 
4 Hospitalization is defined as admission to a hospital/inpatient stay (irrespective of the duration of the physical 
stay) or no admission to a hospital/no inpatient stay but stay at the hospital for treatment or observation for more 
than 24 h. Events leading to hospitalizations for the following reasons should not be reported as SAEs: 
• 
Trial-related purposes not associated with any deterioration in the 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. 
5 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 SAE 
definition above. 


 
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9.5 
Adverse Event Reporting Period 
The AE reporting period is shown in Figure 9-1. 
Figure 9-1 
Adverse event reporting 
 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; IMP = investigational medicinal 
product; SAE = serious adverse event 
 
9.5.1 
Non-serious Adverse Events Reporting 
Non-serious AEs (including non-serious AESIs) should be reported from signing informed 
consent until 30 days after the last IMP administration.  
9.5.2 
Serious Adverse Events Reporting 
Serious AEs should be reported from signing the informed consent until 30 days after the last 
IMP administration.  
9.5.3 
Adverse Events During Follow-Up 
During the follow-up period, SAEs at least possibly related to nivatrotamab or to the study 
procedures and new onset of secondary malignancies regardless of causality, should be reported 
the until end of the trial. 
9.5.4 
Adverse Events with Onset After End-of-trial 
If the Investigator becomes aware of an SAE after the end of the trial with a suspected causal 
relationship to the IMPs, it should immediately be reported to the Sponsor. 
9.6 
Recording of Adverse Events 
All events meeting the definition of an AE must be collected and reported in the eCRF. SAEs, 
DLTs, and AESIs (whether serious or non-serious) should be reported both in the eCRF and on 
the clinical AE report form. 


 
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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 the patient, must be reported by the Investigator and evaluated unless specifically 
excluded (see section 9.6.4). 
9.6.1 
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. 
Further instructions on the recording of CRS and neurological AEs are provided below. 
9.6.1.1 
Cytokine release syndrome 
AEs that are considered to be consistent with CRS should be recorded as “cytokine release 
syndrome” on the AE page of the eCRF. Associated signs and symptoms should be recorded on 
the dedicated CRS eCRF. Cytokine Release Syndrome grade 2 or higher should also be reported 
as an AESI and CRS grade 3 or higher should be reported as a DLT. 
The severity grading of AEs of CRS should be performed in accordance with the CRS grading 
scheme presented in Table 7-2 in section 7. 
9.6.1.2 
Neurological Adverse Events 
Neurological AEs (e.g., seizures) should be assessed and graded as per CTCAE version 5.0.  The 
Investigator should indicate in the eCRF if the event is considered to be a symptom of ICANS. 
ICANS grade 3 or higher should also be reported as a DLT. 
 
9.6.2 
Onset Date and Time 
Start date for an (S)AE is the date of occurrence of the first symptom. 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 h. 
9.6.3 
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 should be entered, i.e., if the event starts on a dosing day or if the duration of the event is 
less than 24 h. 
9.6.4 
Signs and Symptoms of the Cancer Disease 
Signs and symptoms which, according to the Investigator, are expected and well-known 
consequences of the indication both in intensity and frequency, should not be reported as AEs or 
SAEs except for events with a fatal outcome. Any unexpected change in the intensity or 
frequency should be reported as an AE or SAE as applicable. In addition, all deaths (including 
death caused by PD and secondary cancers) must be reported as SAE. 


 
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9.6.5 
Severity 
The Investigator will use CTCAE version 5.0 to describe the severity of the AE apart from AEs 
of CRS (see section 9.6.1.1). 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. For 
grading of CRS and neurological AEs please see section 7.2.4. 
9.6.6 
Outcome 
The Investigator must judge the outcome of an AE by the following terms 
• Recovered 
• Recovered with sequelae (description of the sequelae should be provided) 
• Not recovered 
• Fatal 
• Unknown* 
*Should only be used if the patient is lost to follow-up 
9.6.7 
Relationship to Investigational Medicinal Product 
The Investigator must assess whether the event is related to the IMP. 
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 
• 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 the IMP. 
Probably Related 


 
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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 
9.6.8 
Action Taken with the Investigational Medicinal Product 
The action taken with the IMP should be noted as: 
• Dose decreased 
• Drug postponed 
• Drug discontinued 
• None 
• Not Applicable* 
• Unknown 
* Should be used if the AE occurs before the first treatment, IMP has been discontinued for other reasons, or after 
the EOT 
9.7 
Events Requiring Immediate Reporting 
The following events (for reporting periods, see Figure 9-1) require reporting to the Sponsor 
within 24 h of knowledge (for details, see section 9.5): 
• SAE 
• AESI 
• DLT 
• Pregnancy 
9.7.1 
Pregnancy 
Any pregnancy, including partner pregnancy, that occurs during trial participation must be 
reported to the Sponsor within 24 h of knowledge using the pregnancy form. Pregnant trial 
patients must be discontinued from IMP treatment immediately (see section 6.3.3). The 
pregnancy must be followed up to determine the outcome and status of the mother and the child. 
The child must be followed at least to the age of 1 month. Pregnancy complications and elective 


 
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terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must 
be reported as an SAE. 
9.8 
Initial Reporting of Adverse Events 
SAEs/AESIs/DLTs 
• The paper clinical AE report form must be reported from the site to the Sponsor within 
24 h 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 (see 
section 14.1.2). 
The eCRF completion instructions for reporting of AEs should be followed. 
9.8.1 
Contact Details for Adverse Event 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 +0045 7879 6060 
9.9 
Follow Up on Adverse Events 
SAEs/AESIs/DLTs 
• New follow-up information available at the site must be reported within 24 h of 
knowledge. 
• Follow-up information requested from the Sponsor must be replied to within 3 working 
days. The eCRF AE form should be updated in accordance to agreed data entry timelines 
(see section 14.1.2). 
• If an ongoing SAE/AESI 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 h of the change in assessment. 
• Grade 3 or higher non-serious AEs that are considered treatment related and all SAEs, 
AESIs, and DLTs should be followed on a regular basis, according to the Investigator’s 


 
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clinical judgment, until the event has been resolved or until the Investigator can assess it 
as chronic or stable. This includes follow-up after EOT. 
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. 
9.9.1 
Reporting of SUSARs 
The Sponsor will ensure that all relevant information about suspected unexpected serious 
adverse reactions (SUSARs) is reported to the regulatory authorities in accordance with 
regulatory requirements. 
The contract research organization (CRO) appointed by the Sponsor will notify the Investigators 
of SUSARs in accordance with local requirements. Furthermore, the Investigators will be 
informed of any trial-related SAEs that may warrant a change in any trial procedure. The CRO 
appointed by the Sponsor will inform the institutional review boards (IRBs)/independent ethics 
committees (IECs) of SUSARs in accordance with local requirement, unless locally this is an 
obligation of the Investigator. 
The Sponsor’s assessment of expectedness for nivatrotamab will be performed according to the 
current version of the IB. 
9.9.2 
Communication of significant safety issues 
In the event of any significant safety-related issues, the Sponsor will decide upon immediate 
action to be taken, including prompt notification of the DMC, and will communicate to the 
regulatory authorities, Investigators, IECs/IRB, and patients, as needed, within regulatory 
timelines. 
9.9.3 
Data Monitoring Committee 
An external DMC will be established to assure patient safety and will function independently of 
all other individuals associated with the conduct of the trial, including the site Investigators 
participating in the trial. The DMC will consist of a minimum of 2 physicians whose expertise 
covers relevant specialties. 
During the conduct of phase 1 of the trial, after completion of the DLT evaluation period 
(2 treatment cycles/28 days) for the last patient in each dose level, the DMC will evaluate the 
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 dose level. 
During phase 1 and until the DMC meeting in phase 2, the Sponsor will share with the DMC all 
SAEs occurring during the trial, and an unplanned DMC meeting can be held at the request of 
either the DMC or the Sponsor safety committee. 


 
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During the conduct of phase 2, an additional DMC meeting will be held when the 10th patient 
across cohorts has completed Cycle 1 to evaluate whether the trial should be modified, stopped, 
or continue unchanged. 
The Sponsor safety committee will evaluate the recommendations provided by 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 IRB/IEC as 
appropriate, and to the sites. 
Responsibilities, procedures, content of the DMC packages, and workflow of the DMC are 
specified in the DMC charter. 


 
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10 LABORATORIES 
Laboratory assessments are outlined in detail in section 8. 
10.1 
Clinical Laboratory Assessments  
See section 8.1.9 
10.2 
Pharmacokinetic Assessments 
See section 8.3. 
10.3 
Immunogenicity 
See section 8.1.13. 
 


 
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11 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
11.1 
General Overview 
The data will be summarized in tables, as appropriate, showing the number of patients with 
non-missing data (n), mean, standard deviation, median, minimum, and maximum for continuous 
data and counts and percentages for categorical data. Data will also be listed as deemed 
appropriate. All statistical analyses will be performed and data appendices created by using 
SASTM version 9.4 or later. 
Any statistical tests will be 2-sided with an α (significance) level of 0.05. 
Data from patients who were screened but never started treatment will be listed. Screening 
failures will not be included in any of the analyses and summary tables. 
The results will be presented by groups and total. In the dose escalation phase of the trial, groups 
will be defined by dose-levels, and in the dose expansion phase, groups will be defined by 
sensitivity/resistance to previous platinum therapy. 
Patients in the dose escalation phase, for whom major inclusion/exclusion criteria and dose 
regimen are the same as for the patients in the dose expansion phase, may be included in the 
analyses and presentations of the dose expansion results. 
For the sake of the statistical analyses and summaries, the baseline value is defined as the value 
collected at the time closest to, but prior to, the start of the first nivatrotamab administration. 
Measurements made on the same day as the first nivatrotamab administration are assumed to 
have been performed pre-treatment, unless recorded, or by this trial protocol stipulated, 
otherwise. 
The statistical analysis plan (SAP) will describe in further detail the analyses presented below. 
Furthermore, handling and presentation of data, including demographics, baseline data, and other 
trial assessments, will be described in more detail in the SAP. 
11.2 
Sample Size 
Up to 39 patients may be included in the dose escalation phase. This number is based on the 
operational characteristics in Appendix 1, including the up to10 additional patients who may be 
added to any dose-level as described in section 6.2.1.4. 
The impact of sample size on the detectability of AEs during dose escalation (when N=3, 6, or 
9 patients at a dose level) and during dose expansion (when N=30) is shown in Table 11-1. 


 
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Table 11-1 
Probabilities of observing adverse events 
Probability of an 
event 
Probability of making at least 1 observation of an event in N patients 
 
N=3 
N=6 
N=9 
N=30 
30% 
66% 
88% 
96% 
100% 
10% 
27% 
47% 
61% 
96% 
5% 
14% 
26% 
37% 
79% 
2% 
6% 
11% 
17% 
45% 
1% 
3% 
6% 
9% 
26% 
0.1% 
0% 
1% 
1% 
3% 
 
11.3 
Analysis Populations of Interest 
11.3.1 
Full Analysis Set 
The full analysis set (FAS) will include all patients enrolled in the trial who received at least 1 
dose of nivatrotamab. Patients who do not fulfil relevant inclusion criteria (e.g., no baseline 
measurable disease) but still receive the study drug, may be excluded from the FAS. 
11.3.2 
Safety Analysis Set 
The safety analysis set (SAF) will include all enrolled patients who receive at least 1 dose of 
nivatrotamab. 
Unless stated otherwise, the SAF will be used for the analyses related to the primary objective. 
11.3.3 
DLT Evaluable Analysis Set 
The DLT evaluable analysis set (DAS) is a subset of the SAF. This analysis population will 
include patients in the dose escalation phase who receive at least 80% of the planned doses on 
each of the 4 administrations in the DLT evaluation period and who had sufficient safety 
evaluations, or who had a DLT during the DLT evaluation period. 
11.3.4 
PK Analysis Set 
The PK analysis set (PKAS) consists of all patients who receive at least 1 dose of nivatrotamab 
and have at least 1 evaluable concentration measurement of nivatrotamab. Patients will be 
removed from the estimation of certain PK parameters on an individual basis due to, for 
example, missing PK samples or inadequate dosing such that the PK parameters cannot be 
appropriately derived or summarized. These patients will be identified at the time of the analyses 
along with the reason for their removal. 


 
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11.4 
Statistical Analysis 
11.4.1 
Dose-limiting Toxicities 
DLTs observed during the DLT evaluation period will be listed and summarized in a table by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT). The information from the DLTs will be used to guide the escalation and de-
escalation rules as per the mBOIN-design and ultimately determine the MTD. The evaluation of 
DLTs will be based on the DAS. 
Patients with and without DLTs will be plotted in a graph with dose level on the vertical axis and 
patient number on the horizontal axis. 
11.4.2 
Maximum Tolerated Dose 
Upon completion of the mBOIN-design, the MTD is preliminarily estimated as the dose for 
which the isotonic estimate of the DLT rate is closest to the target toxicity level. If there are ties, 
either the highest dose level when the estimate of the DLT rate is smaller than the target or the 
lowest dose level when the estimate of the DLT rate is greater than the target, will be selected 
from the ties. 
This MTD will be estimated using the select.mtd()-function in the BOIN-package for the R 
software (R software package ‘BOIN’ v 2.7.0 or later 36). 
11.4.3 
Adverse Events 
The overall observation period for AEs will be divided into 3 parts: 
• Pre-treatment period: From the day of the patient’s informed consent to the day before the 
first dose of nivatrotamab 
• On-treatment period: From the day of the first dose of nivatrotamab to 30 days after the 
last dose of nivatrotamab 
• Post-treatment period: From 31 days after the last dose of nivatrotamab and thereafter 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, the respective data will be assigned to the on-treatment period. 
Additional analyses and presentations will be included in the SAP. 
AEs will be presented descriptively in summary tables and listings. 
AEs will be regarded as Treatment-emergent AEs (TEAEs) if they occur after the start of the 
first IMP administration.  
A TEAE is defined as an AE that emerges during treatment having been absent pre-treatment 
(i.e., has onset on or after the first dose of study treatment). 


 
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AEs with onset during the pre- and post-treatment periods will be listed. AEs with onset during 
the on-treatment period will be summarized as follows: 
• Summaries of AEs by MedDRA SOC and PT will be presented for all TEAEs, related 
TEAEs, CTCAE grade 3 or higher TEAEs, related CTCAE grade 3 or higher TEAEs, 
injection-related TEAEs, SAEs, related SAEs, CTCAE grade 3 or higher SAEs, related 
CTCAE grade 3 or higher SAEs, TEAEs leading to treatment discontinuation, and AEs 
leading to death. 
11.4.4 
Safety Laboratory Parameters 
Descriptive statistics will be presented for baseline values, absolute values, and changes from 
baseline in safety laboratory parameters. Laboratory data will be summarized in tables and 
presented in figures by the type of laboratory test. 
11.4.5 
Vital Signs 
Vital signs will be listed. 
11.4.6 
Electrocardiogram 
Abnormal ECG-observations will be listed and summarized. The ECG data will be summarized 
for the SAF. 
11.4.7 
Analyses of Anti-tumor Activity 
The efficacy analyses will be based on the FAS. 
11.4.7.1 
Imaging Data 
All imaging data will be listed. Reduction in tumor sizes will be analyzed by summarizing the 
measures of the target lesions, including the relative change (%) from baseline. Graphs of the 
individual patient profiles over time of the (i) sum of measures and (ii) relative change in the 
sum of measures from baseline will be presented. 
The best relative change from baseline will be presented in a waterfall plot. 
11.4.7.2 
Response Evaluation 
The responses will be evaluated according to both RECIST 1.1 and iRECIST. 
RECIST 1.1 
The OR is the best timepoint response recorded from the start of the study treatment until the 
EOT. Patients who obtain CR and PR are considered responders. Both confirmed and 
unconfirmed responses will be presented. Patients are considered non-responders if they obtain 
SD, PD, or “Not evaluable” as OR. 
SD requires that post-baseline measurements have met the SD criteria at least once and for a 
minimum period of 4 weeks (± 7 days). 


 
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The OR rate will be presented including corresponding, for binomial distribution, exact 95% 
confidence intervals. 
The DCR as well as proportions of patients in disease control at 4, 8, 16, and 24 weeks (± 7 days 
for each of the timepoints) will be analyzed and presented in the same way as OR. 
iRECIST 
Responses assigned using iRECIST have a prefix of “i” (immune): iCR, iPR, iSD, iUPD, or 
iCPD to differentiate them from responses assigned using RECIST 1.1. Patients who obtain iCR 
and iPR are considered responders. Patients are considered non-responders if they obtain iSD, 
iUPD, iCPD or Not Evaluable as iOR. For iDCR, patients are considered to be in disease control 
if the corresponding response is iCR, iPR, or iSD. iSD requires that post-baseline measurements 
have met the iSD criteria at least once and for the same time-period as SD. 
The iRECIST response endpoints are analyzed using the same statistical methodology and the 
results presented in the same way as for the corresponding RECIST 1.1 endpoints. 
11.4.7.3 
Progression-free Survival 
PFS and iPFS are derived as the time from the first dose administration until progression or 
death, whichever occurs first.  
The progression date to be used for calculation of iPFS should be the first date at which 
progression criteria are met (i.e, the date of iUPD) provided that iCPD is confirmed at the next 
assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that iUPD date 
should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, the iUPD date 
should still be used if:  
• the patient stops protocol treatment because they were not judged to be clinically stable, or 
• no further response assessments are done (because of patient refusal, protocol non-
compliance, or patient death), or 
• the next timepoint responses are all iUPD, and iCPD never occurs, or  
• the patient dies from their cancer. 
PFS and iPFS will be derived for all patients and presented graphically as well as summarized 
using survival analysis methods: distribution functions will be estimated using the Kaplan-Meier 
technique and plotted. The corresponding Kaplan-Meier quartile estimates including 2-sided 
95% confidence intervals will be presented. 
PFS and iPFS will be censored on the date of the last adequately evaluable tumor assessment for 
patients who do not have an event (progression or death), for patients who start new anti-cancer 


 
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treatment prior to an event, or for patients with an event after 2 or more consecutive missing 
tumor assessments. 
Patients who do not have a baseline tumor assessment or who do not have any post-baseline 
tumor assessments will be censored on the date of the first treatment unless death occurred on or 
before the time of the second planned tumor assessment, in which case the death will be 
considered an event. 
11.4.7.4 
Duration of Response 
The DoR and iDoR are calculated, censored, and presented in the same way as PFS and iPFS, 
respectively, above with the following differences: 
• DoR and iDoR are derived for responders only 
• DoR and iDoR begin at the timepoint when the criteria for response are first met. 
11.4.8 
Overall Survival 
OS is defined as the time from the first dose administration until death. OS will be analyzed 
using the same Kaplan-Meier methodology as for PFS above, except that in the absence of an 
observed event, OS is censored on the latest day that the patient is known to be alive as per 
assessment or contact. 
11.4.9 
PK Analysis 
The PK information will be summarized for the PKAS. 
All PK-concentrations and PK-parameters will be presented in listings. 
Individual curves of nivatrotamab concentrations, including information on actual dose, will be 
presented for all patients. All available data will be shown in these figures. Both actual as well as 
ln (log)-transformed values will be presented. In the graphical presentations, values below the 
lower level of quantification (LLOQ) will be set to LLOQ/2 and marked with a “<LLOQ.” Any 
values above the upper level of quantification (ULOQ) will be marked with a “>ULOQ.” 
PK parameters (Table 11-2) will be calculated based on non-compartmental methods. 


 
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Table 11-2 
List of PK parameters 
Parameter 
Description 
Cmax 
The maximum (peak) observed drug concentration after a single dose administration  
Tmax 
The time to reach maximum (peak) drug concentration in serum after a single dose 
administration. 
AUC0–T 
The area under the serum concentration–time curve from time zero to the last quantifiable 
timepoint (T). 
AUC0–∞ 
The area under the serum concentration–time curve from time zero to infinity 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi-logarithmic 
concentration–time curve. 
CL 
The total body clearance of drug from serum. 
Vd 
Volume of distribution 
 
The relation between derived PK parameters and covariates such as actual dose, weight, and 
selected parameters will be evaluated graphically. 
If deemed applicable, compartmental modeling approaches to parameter estimation will be 
applied. 
The PK-parameters will be presented in summary tables where AUC and Cmax will be 
summarized using the geometric mean and the coefficient of variation (CV) that is based on a 
log-normal distribution: CV(%)=100 ∙√𝑒𝜎𝑙𝑛
2 −1.  
The half-life will be summarized using the harmonic mean. 
In support of the RP2D-selection, analyses of a relation between exposure and response will be 
performed: 
• Exposure after Cycle 1 
o Cmax  
o AUC0–∞  
• Response 
o Efficacy at weeks 4 and 8 
▪ Disease control [RECIST & iRECIST] (yes/no) 
▪ Reduction in tumor size (Section 11.4.7.1) 
o Safety after Cycle 1, 2 and 4 
▪ CRS (yes/no) 
▪ Highest grade of CRS 
▪ SAE (yes/no) 


 
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by means of logistic regressions (with ordinal response variable for highest grade of CRS, as 
appropriate) or linear regression for Reduction in tumor size. Non-linear PK/PD-modelling of the 
above will be considered. 
Further details of the analyses and results presentations will be presented in a separate plan. 
11.4.10 
Analysis of Anti-Drug Antibody Formation 
Immunogenicity data will be listed and positive/negative host immune response to nivatrotamab 
and presence of binding antibodies will be summarized (positive/negative). 
The immunogenicity information will be summarized for the SAF. 
11.4.11 
Exploratory Objectives 
GD2 expression from tumor tissue will be summarized and presented graphically. 
The results from these exploratory analyses may be presented in a separate report. 
11.4.12 
Interim Analysis 
No formal interim analyses are planned. Ad-hoc interim analyses may be performed in relation 
to health authority interactions. 
11.4.13 
Subgroup Analyses 
No subgroups beyond the sensitivity/resistance to previous platinum therapy strata in phase 2 are 
defined. 
11.4.14 
Handling of Missing Data 
Missing safety data will in general not be imputed. In the analyses of OR, patients with evaluable 
disease at baseline but who cannot be evaluated for response will be considered as 
non-responders. 
11.5 
Reporting of Trial Results 
The results from this trial will be presented in a clinical trial report (CTR) after the last patient in 
the dose expansion has reached the end of the trial. 


 
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12 ETHICS 
12.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This protocol and any accompanying material to be provided to the patient (such as patient 
information sheets and/or descriptions of the trial used to obtain informed consent) will be 
submitted by the Investigator to an IRB/IEC. Approval from the IRB/IEC must be obtained 
before starting the trial and should be documented in a letter to the Investigator. 
It is the responsibility of the Investigator or his/her representative to obtain approval from the 
IRB/IEC before enrollment of any patient into the trial for the trial protocol/protocol 
amendments, advertisements, the patient information and the Informed Consent, including any 
written material to be given to the patient. 
12.2 
Ethical Conduct of the Trial 
The trial will be conducted in accordance with the protocol, applicable regulatory requirements, 
International Council on Harmonisation (ICH) Good Clinical Practice (37) (GCP) and the ethical 
principles of the Declaration of Helsinki (38) as adopted by the 18th World Medical Assembly in 
Helsinki, Finland, in 1964 and sub-sequent versions. 
The trial will be conducted according to FDA regulations relating to GCP and clinical trials, 
Protection of Human Subjects (21 CFR Part 50) and as per Ethical Considerations for Clinical 
Trials on Medicinal Products Conducted with the Pediatric Population (recommendations of the 
ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating 
to GCP in the conduct of clinical trials on medicinal products for human use). The guideline is 
referenced on internet address http://ec.europa.eu/health/files/eudralex/vol-
10/ethical_considerations_en.pdf. 
12.3 
Patient Information and Informed Consent 
The Investigator or his/her designee must obtain the written informed consent from each patient, 
before any trial related procedures are performed as applicable to local regulations. The written 
patient information must not be changed without prior discussion with the Sponsor and approval 
by the IRB/IEC.  
Patient must receive full trial information, both verbally and written, before consent is given.  
The patient information will contain full and adequate verbal and written information regarding 
the objective and procedures of the trial and the possible benefits and risks involved. This will 
include any information of possible transfer of biological materials, imaging and other needed 
for central analysis. 
Before signing the ICF, the patient must be given sufficient time to consider the possible 
participation. Further, each patient must be informed about their right to with-draw from the trial 
at any time. The patients will also be informed that research participation is voluntary but if they 
withdraw from the trial, their data will still be used. When the informed consent form has been 


 
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signed, the patient receives a copy of the signed form and the original is retained in the 
Investigator site file. A second copy may be kept in the patient’s medical notes. The informed 
consent forms must be signed and dated both by the signee and by the person providing the 
information to the patient. It is recommended to notify the patient’s family doctor of the patient’s 
consent to participate in the trial. 
12.4 
Confidentiality 
The Investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties according to local requirements. The 
Investigator must keep a screening log showing codes, names, and addresses for all patients 
screened and for all patients enrolled in the trial. The patient will be identified only by a subject 
ID number. 
The Investigator agrees that the IMPs and all information received from Sponsor including but 
not limited to the IB, this protocol, data, eCRFs, and other trial information, remain the sole and 
exclusive property of Sponsor during the conduct of the trial and thereafter. This information is 
not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the trial or as required by law) without prior written consent from Sponsor. The 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the trial site to any third party or otherwise into the public domain. 


 
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13 MONITORING AND QUALITY ASSURANCE 
13.1 
Compliance with Good Clinical Practice 
The Investigator will ensure that this trial is conducted in accordance with the principles of the 
Declaration of Helsinki 38 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, Washington, 
Seoul, and South Africa), International Council for Harmonisation (ICH) guideline 37, or with the 
laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the trial patient. 
13.2 
Protocol Compliance 
The Investigator is responsible for ensuring the trial is conducted in accordance with the 
procedures and evaluations described in this protocol. Deviations from the protocol should not 
occur. If deviations do occur, the Investigator has to inform the CRA for discussion and decision 
on required action(s). Deviations should be documented in writing including an explanation. 
Documentation of deviations will be filed in the Investigator’s site file and a copy in the 
Sponsor’s file. Depending on the nature of the deviation, this may be reported to the appropriate 
regulatory authority. 
13.3 
Changes to the Protocol 
Protocol modifications, except those intended to reduce immediate risk to trial patients, may 
only be made by Sponsor. Protocol modifications will follow local requirements for 
submission to the regulatory authorities and IRB/IECs. Approval must be obtained before 
changes can be implemented. 
13.4 
Training of Personnel 
Training of personnel will be conducted during the site initiation visit. If change of personnel 
occurs, it is the responsibility of the Principal Investigator to train new personnel and it should be 
documented by e.g. completion of training log form. If the protocol or any trial specific 
procedures are updated, it is the responsibility of the CRA and Principal Investigator to ensure 
documented training of all personnel. 
13.5 
Monitoring 
In accordance with the principles of ICH GCP and the Sponsor or its designee’s standard 
operating procedures, monitoring of the trial will be arranged. During the trial, the CRA will 
have regular contacts with the trial site, including visits to ensure that the trial is conducted and 
documented properly in compliance with the protocol, ICH GCP, and applicable local 
regulations. The extent of monitoring will be based on a risk assessment and will be described in 
a monitoring plan. 
The CRA will ensure that accountability of IMPs is performed and will review source documents 
for verification of consistency with the data entered in the eCRFs (source data verification). The 
CRA will also provide information and support to the investigational sites.  


 
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In order to assure quality standards, the trial sites may be audited by the Sponsor or its designee 
as well as inspected by a Regulatory Authority. The Investigator and other responsible personnel 
must be available during the monitoring visits, audits and inspections and should devote 
sufficient time to these processes. 
The Investigator should provide a curriculum vitae or equivalent documentation of suitability to 
be responsible for the trial including valid GCP training (i.e. within the previous 2 years), a copy 
of current licensure, and should sign a financial disclosure on conflict of interests. All 
Investigators and other responsible personnel should be listed together with their function in the 
trial on the signature and delegation list to be filed in the Investigator site file. 
During these contacts, the monitoring activities will include: 
• Drug accountability 
• AE identification/review 
• Checking and assessing the progress of the trial  
• Reviewing trial data collected to date for completeness and accuracy 
• Conducting source document verification by reviewing each patient’s eCRF against source 
documents (e.g. medical records, ICF, laboratory result reports, raw data collection forms)  
• Identifying any issues and addressing resolutions 
These activities will be done in order to verify that the: 
• Data are attributable, legible, contemporaneous, original, and accurate 
• Safety and rights of the patients are being protected  
• Trial is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements 
The Investigator will allow the CRA direct access to all relevant documents and allocate ample 
time and the time of the personnel to the CRA to discuss findings and any relevant issues.  
In addition to contacts during the trial, the CRA will contact the site prior to the start of the trial 
to discuss the protocol and data collection procedures with the site personnel. 
13.5.1 
Monitoring of Pharmacies 
If a pharmacy is needed to be involved at the site, then monitoring of the records kept here will 
be described in the monitoring plan. 


 
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13.6 
Source Data Verification 
13.6.1 
Source Data 
All digital or paper hospital records regarding the treatment of the patient included in the trial 
are considered source data. The following minimum amount of information should be reported 
in the hospital records: 
• Clinical trial identification 
• Patient identification 
• Date when patient information was given and when the signed informed consent was obtained 
• Diagnosis 
• Fulfilment of eligibility criteria 
• Specification of treatment with IMP 
• Specification of visit dates, concomitant medications and any (S)AEs 
• Specification of the patient’s cessation in the trial (e.g. premature withdrawal) 
• Specification of the patient’s outcome in the trial 
13.6.2 
Direct Access to Source Data/Documents 
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, review and 
regulatory inspection(s), access to source data/hospital records. The CRA verifies that each 
patient has consented in writing to direct access to the original source data/hospital records by 
the use of written patient information and signed informed consent. 
13.6.3 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the CRA must have direct access to the Investigator’s 
source documentation in order to verify the data entered in the eCRFs for consistency. The CRA 
is responsible for routine review of the eCRFs at regular intervals throughout the trial to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered into the eCRF. The CRA should have access to any patient records needed to verify the 
entries on the eCRFs. The Investigator agrees to cooperate with the CRA to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
13.6.4 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Sponsor may conduct inspections or audits of the 
clinical trial. If the Investigator is notified of an inspection by a regulatory authority, the 
Investigator agrees to notify the CRA immediately. The Investigator agrees to provide to 
representatives of a regulatory authority or Sponsor direct access to source documentation, 
facilities, and personnel for the effective conduct of any inspection or audit. 


 
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13.6.5 
Quality Assurance 
At its discretion, the Sponsor (or designee) may conduct a quality assurance audit of this trial. 
Auditing procedures of the Sponsor (or designee) will be followed in order to comply with GCP 
guidelines and ensure acceptability of the trial data for registration purposes. If such an audit 
occurs, the Investigator will give the auditor direct access to all source documents, will provide a 
guided tour of the facilities and will allocate ample time and the time of the personnel to the 
auditor as may be required to have interviews and discuss findings and potential issues. 
 


 
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14 DATA HANDLING AND RECORD KEEPING 
14.1 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the Investigator. This also 
applies to records for those patients who fail to complete the trial. If a patient withdraws from the 
trial, the reason must be noted in the eCRF. If a patient is withdrawn from the trial because of an 
AE, thorough efforts should be made to clearly document the outcome. For screening failure 
patients, the date of informed consent and reason for failure to enroll demographic data and any 
SAE must be captured in the eCRF. 
eCRF 
An eCRF will be established to collect data in a validated and effective way and in compliance 
with ICH guidelines including audit trail and a query module. The patient’s identity must always 
remain confidential. All information in the eCRFs should be in English.  
The completed eCRF data should not be made available in any form to third parties (except for 
authorized representatives of appropriate regulatory authorities) without written permission 
from the Sponsor. 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data entered in the eCRFs. 
14.1.1 
Corrections to Data 
Corrections to the eCRF data can be made by the Investigator or the Investigator’s delegated 
staff. The eCRF will contain an audit trail capturing as a minimum: the original and 
corrected/changed data, identification of the person correcting/changing the data, date and time 
of the correction/change and reason for the correction. 
If corrections are made by the Investigator’s delegated staff after the date the Investigator has 
signed the eCRF, the Investigator must re-sign the eCRF. 
14.1.2 
Data Entry Timelines 
The Investigator must ensure that data is entered in the eCRF as soon as possible after the trial 
visit and no later than 5 working days after the trial visit. Detailed requirements for data entry 
will be specified in the eCRF completion guideline. Timeliness of data entries are monitored in 
the eCRF system. Data entry later than 5 days after the trial visit does not qualify as protocol 
non-compliance (section 13.2) and does not need to be documented by the Investigator; however, 
the CRA will address lateness during monitoring visits. 
14.2 
Trial Documents at Site and Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the trial 
to be fully documented and the trial data to be subsequently verified. These documents should be 
classified into at least the following 2 categories: (1) Investigator’s site file, and (2) patient 
clinical source documents. The Investigator’s site file will contain the protocol/amendments, and 


 
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IRB/IEC approval with correspondence, informed consent, drug records, personnel curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. The 
Investigator is required to complete a source data list, defining where the specific source data can 
be found (patient record/trial specific patient record). 
During the trial, the Investigator will have full access to the eCRF. After the trial is completed, 
the Investigator will receive a copy of the eCRF on CD-ROM or other appropriate electronic 
storage device. 
All clinical trial documents must be retained by the Investigator until at least 25 years after the 
clinical trial. Investigators may be required to retain documents longer if required by applicable 
regulatory requirements, by local regulations, or by an agreement with Sponsor. The Investigator 
must notify Sponsor before destroying any clinical trial records. Should the Investigator wish to 
assign the trial records to another party or move them to another location, Sponsor must be 
notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the trial site for any or all of the 
documents, special arrangements must be made between the Investigator and Sponsor to store 
these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in case of a regulatory inspection. 
When source documents are required for the continued care of the patient, appropriate copies 
should be made for storage outside of the site. 
Biological samples (for ADA, PK and tumor tissue assessments) will be discarded after the 
analysis has been completed and no later than at the finalization of the full Clinical Trial Report. 
If requested by the local sites, the tumor tissue material may be returned before End of Trial. 
14.3 
Data Management 
All data, except IL-6, ADA, PK and tumor tissue data, will be collected using an eCRF 
compliant with 21 CFR Part 11 regulation. IL-6, ADA, PK and tumor tissue data centrally 
collected will be transferred to data management facility for inclusion in the clinical database. 
Data management will be performed in accordance with applicable standards and data cleaning 
procedures. Only authorized access to the eCRF will be possible using encrypted username and 
password. Roles in the system are given according to functions. All tasks performed in the eCRF 
are logged in an audit trail. The eCRF will contain validation checks to maintain an ongoing 
quality check of data entered. The Investigator will approve the data using an electronic 
signature and thereby confirm the accuracy of the data entry. Medical history and AEs will be 
coded using the MedDRA dictionary. Concomitant medication will be coded using the World 
Health Organization (WHO) Drug dictionary. 
 


 
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15 PREMATURE TERMINATION OF THE TRIAL 
15.1 
Sponsor Criteria for Pausing Patient Enrolment 
Enrolment will be paused if one of the following criteria is met: 
• One or more patients experience unexpected, sudden death during the treatment period 
• SAEs or frequency of AEs that, in the judgement of the Sponsor, are deemed to warrant 
immediate review by the DMC. 
• One or more patients experience treatment-related death before EOT visit 
If an above-mentioned criterion is met, the DMC will review the safety results and determine 
how to proceed as described in section 9.9.3. 
Patients already included at the time of clinical trial pause, will continue in the clinical trial but 
further dosing will be postponed until a decision has been reached by the DMC. 
15.2 
Criteria for Termination of the Trial 
 The Sponsor reserves the right to close a trial site or terminate the trial at any time for the 
reasons below at the sole discretion of the Sponsor. If the trial is suspended or terminated, the 
Investigator must inform the patients promptly and ensure that adequate considerations is given 
to the protection of the patient’s interest. The Sponsor must promptly inform the regulatory 
authorities and provide a detailed explanation of the termination. Furthermore, the Investigator 
or Sponsor will inform IECs/IRBs. 
Trial site(s) will be closed upon completion. A trial site is considered closed when it has been 
verified that all eCRFs have been completed as far as possible, that all required documents are 
filed as required and that the IMP have been destroyed and a trial site closure visit has been 
performed. 
The Investigator may initiate trial site closure at any time, provided there is a reasonable cause 
and sufficient notice in advance of the intended termination. 
The trial could be prematurely discontinued in the following situations (examples): 
• New findings about the IMPs that is considered significantly to worsen the benefit/risk 
ratio 
• Compliance with the trial protocol proves difficult 
• Recruitment of eligible patients is far too low or slow 
• Level of Investigator, Sponsor or patient compliance becomes unacceptable 
• Critical changes are observed in Sponsor or trial site personnel, administrative or scientific 
standards 


 
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• The DMC recommends discontinuation 
 


 
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16 REPORTING AND COMMUNICATION OF RESULTS 
16.1 
Publication 
The data collected in this trial are the property of the Sponsor. Sponsor commits to communicate 
and make available for public disclosure, the results of the clinical trial regardless of outcome, in 
accordance with applicable regulatory requirements. Public disclosure implies publication in 
scientific journals, abstract submission for scientific meetings and other types of disclosure (e.g., 
via ClinicalTrials.gov). Co-authorship from Investigators will be in accordance with 
International Committee of Medical Journal Editors 39 (ICMJE) rules: 
• Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
• Drafting the work or revising it critically for important intellectual content; AND 
• Final approval of the version to be published; AND 
• Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
A predefined publication committee will follow the entire process; decide on publication, 
manuscript authorship for the entire clinical trial and authorship of potential additional 
manuscripts based on sub- studies. All manuscripts relating to sub-studies will state that they are 
sub-studies and cite the main publication. The publication committee will also decide on which 
journal(s) to submit to. 
16.2 
Use of Information 
Sponsor will make 1 main publication from the clinical trial and all other publications should 
come afterwards and refer to the main clinical trial publication. 
All information not previously published concerning the IMPs, including patent applications, 
manufacturing processes, basic scientific data, clinical trial data and results, etc., is considered 
confidential and remains the sole property of the Sponsor. The Investigator agrees to use this 
information only in connection with this trial and will not use it for other purposes without 
written permission from the Sponsor. 
No such communication, presentation, or publication will include Sponsor’s confidential 
information. All presentation and publications will be governed by the publication committee. 
Proposed publication(s) or presentation(s) along with the respective scientific journal or 
presentation forum should be provided to the Sponsor at least 30 days prior to submission of the 
publication or presentation. Publication authors will comply with Sponsor’s request to delete 
references to its confidential information (other than the trial results) in any paper or presentation 
and agrees to withhold publication or presentation for an additional 60 days in order to obtain 
patent protection if deemed necessary. 


 
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17 INSURANCE 
Insurance and liability will be in accordance with applicable local laws and regulations and GCP. 


 
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18 REFERENCES 
 
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19 APPENDICES 
Appendix 1 
Statistical properties of the modified BOIN-design 
The BOIN design is described in statistical detail in 40 as well as in clinical application in 28. It 
can be considered as a generalization of the 3+3, accelerated titration and 3+3+3 designs and is 
quite similar to these designs 28). 
Let 𝑝̂ denote the observed DLT-rate (number of patients with DLT/number of patients treated) at 
the current dose level. 
The BOIN design shares the simplicity of the 3+3 design, which makes the decision of dose 
escalation/de-escalation by comparing 𝑝̂ with 0/3, 1/3, 2/3, 0/6, 1/6, and 2/6. In the BOIN design 
this decision is based on a comparison of 𝑝̂ with 2 pre-determined fixed boundaries, 𝜆𝑒 and 𝜆𝑑.  
In this study, the target toxicity level, i.e. the target DLT rate, is 28%% and the boundaries 
𝝀𝒆=0.229 and 𝝀𝒅=0.334. This choice gives the design escalation and de-escalation rules that are 
similar to the 3+3 and 3+3+3 designs, e.g, note the similarities in how 2 DLTs in 6 or 9 patients 
are addressed in Table 6-3. While not directly comparable, in a standard 3+3 design the DLT rate 
of the MTD is <33%. 
The 𝜆𝑒=0.229 and 𝜆𝑑=0.334 are based on: 
• 𝑝𝑠𝑎𝑓= 0.65 × 28% = 18% (the highest toxicity probability that is deemed subtherapeutic 
[i.e., below the MTD] such that dose escalation should be undertaken) 
• 𝑝𝑡𝑜𝑥= 1.4 × 28% =39% (the lowest toxicity probability that is deemed overly toxic such 
that de-escalation is required) 
 
In this trial, the BOIN has been modified in 2 ways: 
• The single-patient cohorts in the initial accelerated stage allocates fewer patients to low 
dose-levels with low chance of therapeutic effect. 
• A declaration of the MTD on a dose-level based on ≤1 DLT in 6 patients in a situation 
where a higher dose-level has been evaluated and the number of DLTs on that higher 
dose-level lead to a de-escalation. 
For operational simplicity, the rules based on the comparisons of the DLT-rate 𝑝̂ with the rate-
boundaries, 𝜆𝑒 and 𝜆𝑑 have been translated into number of patients and patients with DLTs and 
presented in Figure 19-1 below. While the disallowing of dose-levels is not described in 28, it is 
described in the implementation of BOIN in R provided by Yuan and (R package ‘BOIN’ v 
2.7.0, Yuan Y and Liu S, 2020).  
 


 
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When a large number of patients have been assigned to a dose-level (here 9 seems to be an 
appropriate number, the dose-finding algorithm has approximately converged, and one can stop 
early and select the MTD). 
Figure 19-1 Flow-chart of the BOIN-design 
 
 
 
Nmax,Total :maximum total number of patients in the dose-escalation (39). 
Nmax, Dose-level: maximum number of patients on a dose-level (9). 
If either Nmax,Total is reached or Nmax, Dose-level is reached (*** and the decision rule recommends to remain on 
the same dose-level), the trial dose escalation should stop and the MTD be selected. 
 
 
 


 
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The remainder of this section investigates the operational characteristics of the mBOIN design 
implemented in R (v 3.6.0) including the BOIN package 36 with the accelerated titration design 
option set to true (Titration=True) , based on 20000 simulations. The simulation results have the 
following limitations, reflecting the limitations and available features of the BOIN package 
v2.7.0: 
• The number of dose-levels in the accelerated titration part are not limited 
• The probability of the first grade>=2 toxicity is the same as for a DLT 
 
The operating characteristics are estimated based on simulations under 4 different scenarios. 
Figure 19-2 Dose-toxicity scenarios used for assessment of operating characteristics 
 
A brief description of the dose-toxicity relationships in the 4 scenarios: 
All 7 dose-levels under investigation are safe and the probability of DLT is very low (≤7%) 
on all of them.  
A linear-like dose-tox ranging from 5% to 35%. The true MTD comes “late”: on the sixth 
dose-level. 
A sigmoid-like dose-toxicity relationship, where the true MTD is on the fourth dose-level. 
Toxicity is seen early and most dose-levels are quite toxic. 


 
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Figure 19-3 Main Operating Characteristics for BOIN and accelerated BOIN designs 
The expected total number of patients ranges between 18 and 23 patients. The actual sample size 
may vary: it may be lower or higher, depending on the real trial data.  
 
 


 
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Figure 19-4 Expected number of patients per dose-level 
The expected number of patients per dose-level reflects the assumptions for dose-toxicity-
relationship in the different scenarios. Approximately half of the expected number of patients are 
allocated to dose-levels near the MTD. 


 
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Figure 19-5 Expected number of patients with DLTs per dose-level 
The expected number of patients with DLTs per dose-level reflects the assumptions for dose-
toxicity-relationship in the different scenarios. Fewer patients with DLTs are observed on dose-
levels with toxicity rates above the MTD: the trial design stops the escalation in due time. 
 
 


 
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Appendix 2 
Protocol amendment summary of key changes 
 
Version  
Date 
Description of document 
1.0 
04-Dec-2020 
Final Protocol 
2.0 
07-Jan-2021 
Final Protocol -FDA requested amendment during IND 
evaluation 
3.0 
12-Jan-2021 
Final Protocol -FDA requested amendment during IND 
evaluation 
4.0 
14-Jan-2021 
Final Protocol -FDA requested amendment during IND 
evaluation 
5.0 
15-Jan-2021 
Final Protocol -FDA requested amendment during IND 
evaluation 
6.0 
09-Feb-2021 
Protocol amendment to introduce the Current concepts in 
the diagnosis and management of cytokine release 
syndrome, to introduce pre-medication and management 
of pain and to introduce temporary withdrawal of 
antihypertensive medication. Furthermore, minor changes 
are included to clarify ambiguous wording and ensure 
consistency across protocol sections.  
7.0 
23-Jun -2021 
FDA requested amendment to replace the Current 
concepts in the diagnosis and management of cytokine 
release syndrome with ASTCT CRS consensus grading 
system. Furthermore, to remove section regarding 
temporary withdrawal of antihypertensive medication. In 
addition, minor changes are included to clarify ambiguous 
wording and ensure consistency across protocol sections. 
8.0 
20-Jan-2022 
Exclusion criteria #12 updated according to 
recommendations from American Society of Clinical 
Oncology.  
Frequency of CRS grading and ICE-scoring/neurotoxicity 
assessments updated in flow chart, section 3. 
 


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