Clinical trial NCT02761915
Conditions: Relapsed or Refractory Neuroblastoma
Keywords: Neuroblastoma Immunotherapy 1RG-CART Cyclophosphamide Fludarabine CAR T-cells Anti-GD2 GD2 CAR Chimeric Antigen Receptor Cytokine Release Syndrome
Sponsor: Cancer Research UK
Start date: 2016-02-29; Completion date: 2020-12-16
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this first in human study is to determine the safety and feasibility of 1RG-CART therapy in patients with relapsed or refractory neuroblastoma. 1RG-CART therapy is a novel immunotherapy under investigation in which patients have their T-cells (a type of white blood cell) collected and modified in the laboratory, before they are given back to the patient. The T-cells are modified to express a chimeric antigen receptor (CAR) which targets disialoganglioside (GD2), a marker expressed on the surface of neuroblastoma cells.

Detailed description:
The purpose of this trial is to explore the safety and feasibility of deploying autologous anti-GD2 CAR T-cells for the immunotherapy of neuroblastoma. The CAR T-cell trials employing second generation receptors and lymphodepleting conditioning regimes have produced objective clinical responses in patients with relapsed leukaemias. The trial aims to evaluate similar CAR T-cells but directed against the antigen GD2. Neuroblastoma is well suited to this form of targeted therapy because of the homogeneous and almost universal expression of GD2 on the surface of neuroblastoma cells, and because of the poor prognosis of eligible patients.

1RG-CART will be administered intravenously. As the CAR T-cells are designed to survive and proliferate on encountering antigen, no direct relationship is anticipated between cell dose and either efficacy or toxicity. Rather, clinical benefit is more likely to be observed in those patients in whom in vivo expansion successfully occurs. A possible key determinant of expansion will be prior lymphodepletion of the patients. For this reason this trial is designed to evaluate a phased introduction of lymphodepletion in successive patient cohorts, rather than T-cell dose escalation. Only if there is insufficient expansion of T-cells following full lymphodepletion will the T-cell dose be escalated. Rituximab (MabThera®) will be used as a rescue medication only when necessary, and will be considered a non-investigational medicinal product (NIMP) in this trial.

Arms: arm 1: Patients in Dose Level 1 will receive 1x10\^7 1RG-CART/m\^2 intravenously (IV) on Day 0. arm 2: Patients in Dose Level 2 will receive 300 mg/m\^2/day of cyclophosphamide for four days (Days -4 to -1) followed by 1x10\^7 1RG-CART/m\^2 IV on Day 0. arm 3: Patients in Dose Level 3 will receive 300 mg/m\^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m\^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10\^7 1RG-CART/m\^2 IV on Day 0. arm 4: Patients in Dose Level 4 will receive 300 mg/m\^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m\^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10\^8 1RG-CART/m\^2 IV on Day 0. arm 5: If the required level of 1RG-CART survival is not reached, a further cohort of patients (Dose Level 5) will receive 300 mg/m\^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m\^2/day of fludarabine for five days (Days -8 to -4), followed by 5-10x10\^8 1RG-CART/m\^2 IV which could be be split over two days (Day 0 and Day 1). arm 6: Patients who were enrolled and underwent leukapheresis but who did not receive any IMP.
Interventions: intervention 1: Leukapheresis intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: 1RG-CART
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov  
Document Cover Page 
 
NCT No.: NCT02761915 
 
14 June 2021 
Protocol No.: CRUKD/15/001 
 
 
 
ClinicalTrials.gov Upload Document Cover Page 
NCT Number 
NCT02761915 
EudraCT Number 
2013-004554-17 
Sponsor Protocol Number CRUKD/15/001 
Official Title 
A Cancer Research UK Phase I trial of anti-GD2 chimeric 
antigen receptor (CAR) transduced T-cells (1RG-CART) in 
patients with relapsed or refractory neuroblastoma. 
 
 
Documents, Version & 
Date 
Protocol Version 8.0, dated 18 October 2019 
 


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CANCER RESEARCH UK 
Centre for Drug Development 
 
A Cancer Research UK Phase I trial of anti-GD2 chimeric 
antigen receptor (CAR) transduced T-cells (1RG-CART) in 
patients with relapsed or refractory neuroblastoma. 
 
Sponsor protocol number: CRUKD/15/001 
EudraCT number: 2013-004554-17 
 
Chief Investigator: 
Professor John Anderson 
 
UCL Institute of Child Health & Great Ormond Street Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Cancer Research UK 
 
Centre for Drug Development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PARTICIPATING INVESTIGATORS AND CENTRES: 
 
Details of Principal Investigators and Investigational Sites are recorded on the Participating Investigators 
and Centres list in the Sponsor’s Trial Master File. 
 
VERSION HISTORY: 
Version No. 
Date of issue 
Reason for update 
1.0 
15Apr2015 
Version submitted to the MHRA for approval  
2.0 
06Jun2015 
Version resubmitted to the MHRA after being revised to address their 
comments and submitted to GTAC.  
3.0 
23Dec2015 
Substantial amendment to change the cryopreservation media for 
1RG-CART and revise main trial exclusion criteria 1; plus other 
non-substantial changes. 
4.0 
08Dec2016 
Substantial amendment to allow for single patient cohorts (where 
appropriate); revise the regimens used in dose escalation; revise the time 
window and criteria for patients receiving a second dose after a failed first 
dose; correct the definition of persistence of 1RG-CART in the blood; 
revise main trial exclusion criterion 4; amend the timing of the Day 18 
visit; plus other non-substantial changes.  Not approved by GTAC and 
MHRA. 
5.0 
31Jan2017 
A revised version of the previous amendment incorporating all changes 
above but reinstating a 21 day observation period after the first patient in 
each dose level as requested by the MHRA. 
6.0 
24May2017 
Non-substantial changes to: the pharmaceutical section to clarify that 
1RG-CART may be stored in cryobags as well as vials; wording of 
Sponsor and Investigator signature pages updated. 
7.0 
25Apr2018 
To expand the second dose criteria and to allow a second manufacture 
for patients in Dose Level 1 who have insufficient stored 1RG-CART for a 
second dose in the currently recruiting dose level; plus other 
non-substantial changes. 
8.0 
18Oct2019 
Non-substantial changes: change of Sponsor address; 
 
 
 
 
restructuring of Section 8 to align with 
objectives/endpoints; correction of starting point for measurement of 
overall survival and progression-free survival; 
 
other minor clarifications/corrections.  
 


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TABLE OF CONTENTS 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SUMMARY ........................................................................................ 12 
1.1 
Full Title....................................................................................................................................................... 12 
1.1.1 
Short Title ................................................................................................................................................... 12 
1.2 
Clinical Trial Objectives and Endpoints ........................................................................................................ 12 
1.3 
Design ......................................................................................................................................................... 12 
1.4 
Administration Schedule ............................................................................................................................. 12 
1.5 
Treatment Group ......................................................................................................................................... 13 
1.6 
Expected Accrural ........................................................................................................................................ 13 
2 
INTRODUCTION .................................................................................................... 14 
2.1 
Background ................................................................................................................................................. 14 
2.1.1 
Background on Neuroblastoma ................................................................................................................. 14 
2.1.1.1 
Disialoganglioside Expression and Rationale for Targeting in Neuroblastoma ...................................... 15 
2.2 
Chimeric Antigen Receptor T-cell Therapy ................................................................................................... 15 
2.3 
1RG-CART Therapy ...................................................................................................................................... 16 
2.3.1 
Lymphodepletion as a Preparative Regimen for 1RG-CART Therapy ........................................................ 17 
2.3.2 
Safety of 1RG-CART Therapy ...................................................................................................................... 18 
2.3.2.1 
Toxicities Associated with GD2-targeted Antibodies and their Derivatives ........................................... 18 
2.3.2.2 
Toxicities Associated with Genetically Modified CAR T-cells ................................................................. 19 
2.3.2.3 
Expected Safety Profile for 1RG-CART Therapy ..................................................................................... 21 
2.4 
Rationale for the Proposed Trial .................................................................................................................. 22 
2.5 
Selection of the Phase I Starting Dose and Schedule ................................................................................... 22 
3 
TRIAL DESIGN ...................................................................................................... 24 
3.1 
Clinical Trial Objectives and Endpoints ........................................................................................................ 24 
3.1.1 
Primary Objectives and Endpoints ............................................................................................................. 24 
3.1.2 
Secondary Objectives and Endpoints ......................................................................................................... 24 
3.1.3 
 24 
3.2 
Design of the Clinical Trial ........................................................................................................................... 25 
3.3 
Patient Treatment Group ............................................................................................................................ 26 
3.4 
Definition of Dose Limiting Toxicity ............................................................................................................. 26 
3.5 
Criteria for Administration of Rituximab ..................................................................................................... 26 
3.6 
Trial Steering Committee ............................................................................................................................. 27 
3.7 
Definition of Recommended Phase II Regimen ............................................................................................ 27 
3.8 
Patient Evaluability ..................................................................................................................................... 27 
4 
PATIENT SELECTION ........................................................................................... 29 
4.1 
Eligibility Criteria ......................................................................................................................................... 29 
4.1.1 
Eligibility Criteria for Leukapheresis/Venepuncture .................................................................................. 29 
4.1.1.1 
Inclusion Criteria .................................................................................................................................... 29 
4.1.1.2 
Exclusion Criteria .................................................................................................................................... 29 
4.1.2 
Eligibility Criteria for the Main Trial ........................................................................................................... 29 
4.1.2.1 
Inclusion Criteria: ................................................................................................................................... 29 
4.1.2.2 
Exclusion Criteria: ................................................................................................................................... 30 
4.2 
Patient Enrolment ....................................................................................................................................... 31 
5 
TREATMENT ......................................................................................................... 32 
5.1 
Dosing Schedule/Treatment Schedule ......................................................................................................... 32 
5.1.1 
Leukapheresis/Venepuncture .................................................................................................................... 32 


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5.1.2 
Lymphodepletion ....................................................................................................................................... 32 
5.1.3 
Administration of 1RG-CART ...................................................................................................................... 32 
5.2 
Dose Escalation Scheme .............................................................................................................................. 33 
5.2.1 
Intra-patient Dose Escalations ................................................................................................................... 35 
5.2.2 
Expansion of Dose Level(s) ......................................................................................................................... 35 
5.3 
Dose Modifications...................................................................................................................................... 35 
5.3.1 
Dose Reductions ......................................................................................................................................... 35 
5.3.1.1 
1RG-CART ............................................................................................................................................... 35 
5.3.1.2 
Lymphodepleting Regimen .................................................................................................................... 35 
5.3.2 
Dose Delays ................................................................................................................................................ 36 
5.3.3 
Dose Interruptions ..................................................................................................................................... 36 
5.4 
Duration of Treatment ................................................................................................................................ 36 
5.4.1 
Retreatment of Patients ............................................................................................................................. 36 
5.4.1.1 
Patients who have received ineffective therapy (a ‘failed’ first dose) ................................................... 37 
5.4.1.2 
Patients who benefited from the first dose (a ‘successful’ first dose) ................................................... 38 
5.4.1.3 
Patients not having a ‘Failed’ or 'Successful’ First Dose ......................................................................... 38 
5.4.2 
Replacement of Patients ............................................................................................................................ 39 
5.5 
Concomitant Medication and Treatment ..................................................................................................... 39 
6 
PHARMACEUTICAL INFORMATION .................................................................... 41 
6.1 
1RG-CART .................................................................................................................................................... 41 
6.1.1 
Supply of 1RG-CART ................................................................................................................................... 41 
6.1.2 
Pharmaceutical Data .................................................................................................................................. 41 
6.1.2.1 
Formulation of 1RG-CART ...................................................................................................................... 41 
6.1.2.2 
Storage Conditions ................................................................................................................................. 42 
6.1.2.3 
Method of Thawing ................................................................................................................................ 42 
6.1.2.4 
1RG-CART Administration ...................................................................................................................... 42 
6.1.2.5 
Accidental Spillages ................................................................................................................................ 42 
6.1.3 
1RG-CART Accountability ........................................................................................................................... 42 
6.2 
Cyclophosphamide and Fludarabine ............................................................................................................ 42 
6.2.1 
Supply of Cyclophosphamide and Fludarabine .......................................................................................... 42 
6.2.2 
Cyclophosphamide ..................................................................................................................................... 43 
6.2.2.1 
Formulation of Cyclophosphamide ........................................................................................................ 43 
6.2.2.2 
Cyclophosphamide Storage Conditions and Stability ............................................................................. 43 
6.2.2.3 
Cyclophosphamide Reconstitution, Stability and Administration .......................................................... 43 
6.2.3 
Fludarabine ................................................................................................................................................ 43 
6.2.3.1 
Formulation of Fludarabine.................................................................................................................... 43 
6.2.3.2 
Fludarabine Storage Conditions and Stability ........................................................................................ 44 
6.2.3.3 
Fludarabine Dilution, Stability and Administration ................................................................................ 44 
6.2.4 
Cyclophosphamide and Fludarabine Accountability .................................................................................. 44 
6.3 
Rituximab (MabThera®) .............................................................................................................................. 44 
6.3.1 
Supply of Rituximab (MabThera®) ............................................................................................................. 44 
6.3.2 
Formulation of Rituximab (MabThera®) .................................................................................................... 44 
6.3.3 
Rituximab (MabThera®) Storage Conditions and Stability ......................................................................... 45 
6.3.4 
Rituximab (MabThera®) Dilution, Stability and Administration ................................................................. 45 
6.3.5 
Rituximab (MabThera®) Accountability ..................................................................................................... 45 
7 
INVESTIGATIONS SCHEDULE ............................................................................. 46 
7.1 
Pre-treatment Evaluations .......................................................................................................................... 48 
7.1.1 
Obtaining Written Informed Consent ........................................................................................................ 48 
7.1.2 
Evaluations at Baseline/Pre-Trial ............................................................................................................... 50 


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7.1.2.1 
Within 14 days Prior to Leukapheresis/Venepuncture .......................................................................... 50 
7.1.2.2 
Prior to Planned 1RG-CART Infusion (Day -21 to Day -1 for Dose Level 1) or Commencement of 
Lymphodepletion (Day -25 to Day -5 for Dose Level 2 or Day -29 to Day -9 for Dose Levels 3 to 5) ..................... 50 
7.2 
Evaluations During Lymphodepleting Regimen (Day -4 to Day -1 for Dose Level 2 or Day -8 to Day -4 for 
Dose Levels 3 to 5) ....................................................................................................................................... 52 
7.3 
Evaluations on Day 0 (1RG-CART Administration) ....................................................................................... 52 
7.4 
Evaluations from Day 1 to Day 14 (Daily Assessments) & Day 18† ............................................................... 53 
7.5 
Evaluations on Days 21, 28, 35 and Day 42† (‘End of Treatment Assessment’) ............................................. 54 
7.6 
Follow-Up Visits† (2 months to 2 years from Day 0) ..................................................................................... 55 
7.7 
Follow-Up Visits (>2 years until the End of Trial) ......................................................................................... 56 
7.8 
Patients Undergoing a Second Treatment with 1RG-CART ........................................................................... 57 
7.9 
Schedule of Events ...................................................................................................................................... 59 
7.9.1 
Baseline/Pre-Trial Evaluations ................................................................................................................... 59 
7.9.2 
Evaluations During Treatment Phase and up to Day 18* ........................................................................... 62 
7.9.3 
Evaluations During Follow-Up (Day 21 to End of the Trial) ........................................................................ 64 
8 
PHARMACODYNAMIC ASSESSMENTS .............................................................. 66 
8.1 
Secondary Assessments ............................................................................................................................... 66 
8.1.1 
Estimation of 1RG-CART Counts in Peripheral Blood (Flow Cytometry) .................................................... 66 
8.2 
Tertiary/Research Assessments ................................................................................................................... 66 
8.2.1 
 
8.2.2 
 
8.2.3 
 
8.2.4 
 
8.2.5 
 
8.3 
Additional Research Assays for Safety / Eligibility / Disease Monitoring ..................................................... 68 
8.3.1 
Serum Cytokine Profiles (Safety Monitoring) ............................................................................................. 68 
8.3.2 
GD2 Expression in Tumour Biopsies / Bone Marrow (Eligibility & Disease Monitoring)............................ 68 
9 
ASSESSMENT OF SAFETY .................................................................................. 69 
9.1 
Investigator Responsibilities ........................................................................................................................ 69 
9.1.1 
Medical Cover ............................................................................................................................................ 69 
9.2 
Adverse Event Definitions ........................................................................................................................... 69 
9.2.1 
Adverse Event ............................................................................................................................................ 69 
9.2.2 
Serious Adverse Events .............................................................................................................................. 70 
9.2.3 
Suspected, Unexpected, Serious Adverse Reactions ................................................................................. 70 
9.2.4 
Expectedness .............................................................................................................................................. 71 
9.3 
Collection of Safety Information .................................................................................................................. 72 
9.3.1 
Screening Failures ...................................................................................................................................... 72 
9.3.2 
Eligible Patients .......................................................................................................................................... 72 
9.3.3 
Follow-Up of AEs and SAEs ......................................................................................................................... 72 
9.4 
Reporting of SAEs to the Sponsor’s Pharmacovigilance Department ........................................................... 72 
9.4.1 
Events Exempt from being Reported as SAEs to the Pharmacovigilance Department .............................. 73 
9.5 
Recording of Adverse Events and Serious Adverse Events in eCRFs ............................................................. 73 
9.6 
Urgent Safety Measures .............................................................................................................................. 73 
9.7 
Pregnancy .................................................................................................................................................... 74 
10 
ASSESSMENT OF EFFICACY .............................................................................. 75 
10.1 Measurement of Disease ............................................................................................................................. 75 
10.2 Timing and Type of Tumour Assessments .................................................................................................... 76 
10.2.1 
Baseline Evaluations ................................................................................................................................... 76 
10.2.2 
Evaluations During and at ‘Off-Study’ ........................................................................................................ 77 


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10.3 Tumour Response ........................................................................................................................................ 77 
10.3.1 
Recording of Response in the eCRF ............................................................................................................ 77 
10.4 Overall Survival and Progression-Free Survival ............................................................................................ 77 
10.4.1 
Overall Survival........................................................................................................................................... 77 
10.4.2 
Progression-Free Survival ........................................................................................................................... 77 
11 
PATIENT WITHDRAWAL BEFORE THE END OF THE TRIAL ............................ 79 
12 
DEFINING THE END OF TRIAL ............................................................................ 80 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................ 81 
13.1 Presentation of Data ................................................................................................................................... 81 
13.2 Feasibility of 1RG-CART Therapy ................................................................................................................. 81 
13.3 Safety .......................................................................................................................................................... 81 
13.4 Pharmacodynamics ..................................................................................................................................... 82 
13.4.1 
Flow Cytometry Assay for Detection and Enumeration of 1RG-CART in Peripheral Blood ........................ 82 
13.4.2 
 
13.4.3 
 
13.4.4 
 
13.4.5 
 
13.4.6 
 
13.4.7 
 
13.4.8 
 
13.5 Anti-Tumour Activity ................................................................................................................................... 83 
13.6 Overall Survival and Progression-Free Survival ............................................................................................ 83 
13.6.1 
Overall Survival........................................................................................................................................... 83 
13.6.2 
Progression-Free Survival ........................................................................................................................... 84 
14 
ADMINISTRATION................................................................................................. 85 
14.1 Protocol Deviations and Amendments ........................................................................................................ 85 
14.2 Completion of the Electronic Case Report Form .......................................................................................... 85 
14.3 Trial Performance and Monitoring .............................................................................................................. 86 
14.4 Source Document Verification ..................................................................................................................... 86 
14.5 Clinical Study Report ................................................................................................................................... 86 
14.6 Record Retention ........................................................................................................................................ 86 
14.7 Ethical Considerations ................................................................................................................................. 87 
14.8 Indemnity .................................................................................................................................................... 87 
14.9 Publication Policy and Press Releases .......................................................................................................... 87 
15 
REFERENCES ....................................................................................................... 88 
16 
APPENDICES ........................................................................................................ 93 
16.1 APPENDIX 1: CYTOKINE RELEASE SYNDROME REVISED GRADING SYSTEM .................................................. 93 
16.2 APPENDIX 2: INDICATORS AND MANAGEMENT OF SEVERE CYTOKINE RELEASE SYNDROME (DERIVED FROM 
DAVILA ET AL, 2014 [38]) ............................................................................................................................. 94 
16.3 APPENDIX 3: LANSKY PLAY PERFORMANCE SCALE....................................................................................... 95 
16.4 APPENDIX 4: KARNOFSKY PERFORMANCE SCALE ........................................................................................ 96 
16.5 APPENDIX 5: DECLARATION OF HELSINKI .................................................................................................... 97 
16.6 APPENDIX 6: ASSESSMENT OF RESPONSE USING RECIST 1.1 CRITERIA ...................................................... 101 
16.7 APPENDIX 7:  ASSESSMENT OF RESPONSE USING IMMUNE-RELATED RESPONSE CRITERIA (irRC) ............. 107 
16.8 APPENDIX 8: ASSESSMENT OF RESPONSE USING INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA 
(INRC) ........................................................................................................................................................ 110 
16.9 APPENDIX 9:  ASSESSMENT AND MANAGEMENT OF PAIN ........................................................................ 112 
16.10 APPENDIX 10: ESTIMATION OF BODY SURFACE AREA IN INFANTS AND CHILDREN .................................... 113 
16.11 APPENDIX 11: TOXICITY TIMELINE SCHEME ............................................................................................... 114 
 
 








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PROTOCOL SIGNATURES 
 
Sponsor Signature: 
The Sponsor has read and agrees to the protocol, as detailed in this document.  I am aware of my 
responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of Good Clinical 
Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of UK law and the trial protocol.  
The Sponsor agrees to conduct the trial according to these regulations and guidelines and to appropriately 
direct and assist sponsor’s staff who will be involved in the trial, and ensure that all staff members are 
aware of their clinical trial responsibilities. 
 
Name: 
 
 
 
Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6(R1): Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, adopted by 
CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 


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Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities as an 
Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice (GCP)2, the 
Declaration of Helsinki3, the applicable regulations of the relevant NHS Trusts and the trial protocol.  I 
agree to conduct the trial according to these regulations and guidelines and to appropriately direct and 
assist the staff under my control, who will be involved in the trial, and ensure that all staff members are 
aware of their clinical trial responsibilities. 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________ 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, adopted by 
CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 




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The fourth cohort of patients will be given the same conditioning regimen as for Dose Level 3, followed by 
1x108 1RG-CART/m2 on Day 0 (Dose Level 4). 
If 1RG-CART survival is not considered optimal in earlier dose levels and improved efficacy seems likely 
with a higher 1RG-CART dose, a fifth dose level may be explored. Patients in this cohort will be given the 
same conditioning regimen as for Dose Levels 3 and 4, followed by 5-10x108 1RG-CART/m2 on Day 0 
(Dose Level 5). 
In most patients, it is expected that 1RG-CART will only be given once. However, patients may receive a 
second dose of 1RG-CART as described in Section 5.4.1. 
If adequate 1RG-CART survival and anti-tumour efficacy is achieved in a cohort, then subsequent dose 
levels may be omitted and the expansion phase of the trial may commence. Persistence of transduced 
T-cells (defined as ≥0.02x109/L transduced T-cells in peripheral blood) for at least 2 weeks after infusion in 
the majority of patients in a cohort is considered an indicator of successful engraftment. 
In the expansion phase, additional patients will be recruited to the most favourable cohort (to give a total of 
nine patients treated at this dose level) to further evaluate safety, 1RG-CART engraftment and survival, 
and anti-tumour efficacy. 
See Section 5.1 for further details. 
1.5 
Treatment Group 
Patients with relapsed or refractory neuroblastoma. It is expected that all patients will be in the paediatric 
age range, although there is no upper age limit for the trial.    
1.6 
Expected Accrural 
It is expected that between 15 and 27 patients will be required to complete this trial, the final number 
depending on the number of patients evaluated at each dose level and the number of dose levels explored.   


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2 
INTRODUCTION 
2.1 
Background 
The investigational medicinal product (IMP), 1RG-CART, used in this trial is classed as an advanced 
therapy investigational medicinal product (ATIMP). The cyclophosphamide and fludarabine used for the 
conditioning regimen are also considered investigational medicinal products (IMPs). Rituximab is 
considered a non-investigational medicinal product (NIMP) in this trial as it will only be used as a rescue 
medication when necessary. Cyclophosphamide, fludarabine and rituximab (MabThera®) will all be used 
outside of their licensed indications. All patients will also receive a dose of antihistamine prior to 
administration of the 1RG-CART, and this will also be considered a NIMP. Generic drugs can be used and 
the dose and use of the antihistamine will be in line with its licensed indication. 
2.1.1 
Background on Neuroblastoma 
Neuroblastoma is a rare embryonal tumour of the sympathetic nervous system, which occurs almost 
exclusively in children. It is the most common extracranial solid tumour in childhood and the most common 
malignant tumour in infants (i.e. children aged <1 year) [2, 3]. There are approximately 1,385 new cases 
per year in Europe [4], including approximately 100 cases per year in the UK [5]. Overall, 5-year survival for 
neuroblastoma has improved in recent decades, especially in infants. In Europe the 5-year overall survival 
between 1993-1997 was 66% compared with 37% between 1978-1982 [5].  
Neuroblastoma is a very heterogeneous disease in terms of clinical presentation and prognosis.  Important 
prognostic factors include age, stage, MYCN status, histopathological classification, and the presence or 
absence of segmental chromosomal aberrations. These clinical and biological variables have been 
combined into risk stratification systems. Approximately a third of patients fall into the high risk group, 
which is defined by the International Society of Paediatric Oncology European Neuroblastoma (SIOPEN) 
Group as including patients older than 1.5 years with Stage 4 tumours, and patients with MYCN-amplified 
tumours. Patients in the International Neuroblastoma Risk Group (INRG) high risk group have 5-year 
event-free survival rates of <50%, compared with >85% for patients in the very low risk group [6].  
For patients with high risk neuroblastoma, standard first-line therapy consists of intensive chemotherapy 
(generally with platinum agents, etoposide, vincristine and cyclophosphamide), followed by myeloablative 
chemotherapy with autologous haematopoietic stem cell rescue (ASCT), radiotherapy to the primary 
tumour site and maintenance therapy with 13-cis retinoic acid (isotretinoin) and the monoclonal antibody 
(mAb), ch14.18 (within the context of a clinical trial for patients in the UK). Patients in the UK with relapsed 
or refractory high risk neuroblastoma are generally entered into clinical trials of salvage therapy where 
possible.  
Survival after relapse is poor with only 20% of patients still alive after five years [7].  For patients with 
relapsed high risk disease, the prognosis is worse. For example, a retrospective review was conducted of 
patients entered into three consecutive national trials of salvage therapy in Germany from 1990–2007 [8]. 
Four hundred and fifty-one patients aged at least one year, who received ASCT during first-line treatment 
for high risk disease, were identified. Of these patients, 253 relapsed (56%) and 158 received salvage 
chemotherapy (35%), including 23 patients (5%) who underwent a second ASCT and 21 patients who 
underwent an allogeneic or haploidentical stem cell transplant (SCT). The 23 patients who underwent a 
second ASCT demonstrated a better median survival (2.08 years) and 3-year survival rate (43.5%) than the 
74 patients who had no second chemotherapy (median survival 0.24 years, 3-year survival rate 4.0±2.6%) 
and the 135 patients who underwent second-line chemotherapy but did not undergo second ASCT (median 
survival of 0.89 years, 3-year survival rate 9.6%). However, by February 2010, only three of the 23 patients 
who had undergone a second ASCT were in complete remission (CR), three were in very good partial 
remission (VGPR), and one was in partial remission (PR). Fourteen of the 23 patients had died of disease 
and two had died of complications due to the second ASCT. These results illustrate the very poor 
prognosis of patients with relapsed high risk neuroblastoma and the need for effective new therapies for 
these patients. 


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2.1.1.1 
Disialoganglioside Expression and Rationale for Targeting in Neuroblastoma 
Disialoganglioside (GD2) is a sialic acid-containing glycosphingolipid expressed primarily on the cell 
surface. It is thought to play an important role in the attachment of tumour cells to extracellular matrix 
proteins [9]. GD2 is densely, homogenously and almost universally expressed on neuroblastomas [10, 11]. 
In normal tissues, GD2 expression is largely limited to skin melanocytes, and peripheral pain fibre myelin 
sheaths [12]. Within the central nervous system (CNS), GD2 appears to be an embryonic antigen [13] but 
is expressed at low levels on oligodendrocytes and within the posterior pituitary [12]. GD2 is also 
expressed on other cancers including medulloblastomas, melanomas, soft-tissue sarcomas, 
osteosarcomas, Ewing sarcomas and small-cell lung cancers [14]. Importantly, GD2 expression appears to 
persist after anti-GD2-directed antibody therapy in the great majority of patients with neuroblastoma [15, 
16, 17]. 
The safety and efficacy of targeting GD2 has been demonstrated in trials involving the GD2 targeted 
antibodies, ch14.18 and 3F8 and their derivatives. The ch14.18 and 3F8 antibodies were found to produce 
clinical responses in patients with advanced refractory neuroblastoma in early Phase I and Phase II trials 
[18]. Ch14.18 also improved outcomes in a randomised Phase III trial in children with high-risk 
neuroblastoma who had achieved radiological remission after initial therapy [19]. When given in 
combination with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-2, 
concurrently with standard isotretinoin therapy after induction therapy and ASCT, ch14.18 significantly 
improved event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% 
at 2 years, P=0.02 without adjustment for interim analyses). Randomisation within the trial was stopped 
early on the basis of positive interim results, and ch14.18 was offered to participants in the control arm who 
were progression-free [20]. The trial continues to recruit (according to National Institutes of Health Clinical 
trials database April 2014, trial identifier NCT01704716) but now all patients receive ch14.18. A form of 
ch14.18, manufactured from SP2/0 cells, was licensed in the United States and the European Union (EU) 
for the treatment of neuroblastoma (generic name dinutuximab, Brand name Unituxin™) in 2015. 
2.2 
Chimeric Antigen Receptor T-cell Therapy 
The principle underlying CAR T-cell therapy is the generation of large numbers of autologous peripheral 
T-cells, which recognise a surface antigen expressed on malignant cells. This is achieved by ex vivo 
transduction of the patient’s peripheral blood T-cells with a gene encoding a CAR. CARs are generated by 
grafting the antigen-binding region of a mAb to intracellular T-cell signalling domains. Introduction of genes 
encoding CARs into T-cells enables the T-cells to recognise and respond to antigen-bearing cells, without 
major histocompatibility complex (MHC) restriction. On binding to the target antigen, the T-cells become 
activated and cause tumour destruction via a number of mechanisms, including the release of perforins, 
granzymes, cytokines (such as interferon-gamma [IFN-] and tumour necrosis factor alpha [TNF-α]), T-cell 
surface ligands (such as FAS ligand and TNF-related apoptosis-inducing ligand [TRAIL]) and by activating 
other components of the immune system. 
CAR T-cell therapy has been most extensively evaluated in B-cell malignancies, and encouraging results 
have been reported for patients with chronic lymphocytic leukaemia (CLL) and acute lymphoblastic 
leukaemia (ALL) using CD19-directed CAR T-cells [21, 22, 23, 24, 25]. Two trials of CAR T-cell therapy 
have been conducted in patients with neuroblastoma, including one trial in which the CAR was directed 
against GD2, as described in the next paragraphs.  
In 2006, a neuroblastoma Phase I trial was reported in which T-cells were targeted against CD171, a cell 
surface adhesion molecule [26]. In this trial, expression of the CAR was achieved by electroporation of a 
coding plasmid. Stable expressing clones were expanded to enable doses ranging from 108/m2 up to 
109/m2 and six patients were treated. Transduced T-cells were detected by polymerase chain reaction 
(PCR) in peripheral blood for up to 56 days after infusion. No treatment-related toxicity or anti-tumour 
efficacy was noted in this trial. 
In a second neuroblastoma clinical trial, the CAR was directed against GD2 and was introduced to 
autologous T-cells by transduction using a retroviral vector [27, 28]. In this trial, the CAR was expressed in 
activated T-cells and also in Epstein-Barr virus-specific cytotoxic T-cells (EBV-CTL). The CAR-encoding 
vector was identical in each case except for a non-coding sequence, allowing researchers to determine 
whether CAR-expressing T-cells identified in vivo arose from activated T-cells or EBV-CTL. Transduced 


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T-cells from both sources were mixed in equal proportions and administered IV at total doses of 2 to 
20x107/m2. Nineteen patients were treated (with 44 infusions) without any severe or dose limiting toxicities 
(DLTs). CAR-engrafted EBV-CTLs reached higher levels in vivo than CAR-engrafted activated T-cells but 
at 6 weeks both populations were low or undetectable. However, low-level persistence was detected 
beyond 6 weeks (for up to 96 weeks for CAR-expressing EBV-CTLs and for up to 192 weeks for 
CAR-expressing activated T-cells). Three of 11 patients with active disease at the time of the GD2 CAR 
T-cell infusion achieved a CR and two of these CRs were durable out to >21 and >60 months respectively. 
All three patients had persistent CAR T-cells at 6 weeks. 
For further details on these and other CAR T-cell trials, please see the 1RG-CART Investigator’s Brochure 
(IB).  
2.3 
1RG-CART Therapy 
A major limitation of the first generation CARs used in the previous trials in patients with neuroblastoma 
was their failure to trigger proliferation or cytokine secretion in response to recognition of tumour target 
antigen. Physiological T-cell activation requires both engagement of the T-cell receptor (TCR) with its 
antigen as well as a co-stimulatory signal. However, tumour cells rarely express co-stimulatory molecules. 
Combining intracellular components of co-stimulatory molecules within the CAR construct circumvents this 
problem. Engagement of such second-generation CARs with their antigen-expressing targets results not 
only in lysis of the tumour cell but also T-cell proliferation in vitro. Typically, CD28 or 4-1BB have been used 
as the co-stimulatory endodomain. Simultaneous administration of CD19-CAR T-cells containing either a 
CD3 (CD3-zeta) or a fused CD28-CD3 endodomain to patients with CD19-expressing lymphoma, 
resulted in preferential expansion and persistence of CAR T-cells containing CD28-CD3 [29]. Third 
generation CARs have also been described which contain tri-partite endodomains including both a TNF 
family receptor endodomain (OX40 or 41BB), as well as CD28.  
In this trial, transduction of autologous T-cells will be achieved using the retrovirus, 
 (referred to as MP10413 retrovirus hereafter). 
This retrovirus encodes two different transgenes: 
• 
The CAR itself, 
(referred to hereafter as GD2 
CAR). 
 
 
 
 
 
 
 
 
 
• 
A sort-suicide gene, which is called RQR8. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  




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infused T-cells to expand, to promote availability of essential cytokines, and to deplete regulatory T-cells. 
The cyclophosphamide and fludarabine lymphodepletion regimen planned for this clinical trial uses similar 
doses to those used as part of a minimal intensity conditioning regimen for stem cell transplantation in 
children with immunodeficiencies. The regimen was well tolerated in this group of children despite their 
high vulnerability to treatment-related morbidity due to their underlying condition [30]. The combination of 
cyclophosphamide and fludarabine has also been used to condition paediatric neuroblastoma patients prior 
to reduced-intensity allogeneic SCT [31, 32]. The same two lymphodepleting cytotoxic agents were also 
used in the Cancer Research UK (CRUK) sponsored trial of MFEz T-cells (Protocol No. PH1/105, EudraCT 
No. 2005-004085-16, 
) and in several other trials in patients receiving CAR T-cell 
and other adoptive T-cell therapies. For further details on the lymphodepleting agents, please refer to the 
Cyclophosphamide and Fludarabine (1RG-CART Conditioning Regimen) IB. 
2.3.2 
Safety of 1RG-CART Therapy 
2.3.2.1 
Toxicities Associated with GD2-targeted Antibodies and their Derivatives 
Although the mechanism of action of GD2 CAR T-cell therapy and mAbs targeting GD2 are different, some 
similarities in the safety profile would be expected, notably those specifically associated with 
GD2-targeting. Table 1 summarises common Grade 3-4 toxicities shared by ch14.18, 3F8, and the 
IL-2-conjugated antibody derivative, hu14.18-IL-2 (from Parsons et al., 2013 [18]). Pain is the most 
common toxicity associated with these agents and this appears to be increased by concomitant IL-2 but 
controlled by opioid premedication and concurrent opioid infusion. The pain is typically abdominal and/or 
pelvic in distribution. Hypersensitivity and fever are other common toxicities associated with 
anti-GD2-targeted antibody infusions (also increased by concomitant IL-2). Other notable toxicities include 
urticaria, hypertension, nausea, vomiting, diarrhoea, transient visual changes (mydriasis and 
accommodation defects), hypokalaemia, hyponatraemia and elevated liver transaminase levels. Decreases 
in platelets, leukocytes, neutrophils and haemoglobin have also been reported with hu14.18-IL-2 
immunocytokine, and are likely to be due to the IL-2 component. The toxicities associated with these 
antibodies/derivatives (including pain) typically resolve within a few hours of completion of the infusion and 
3F8 is commonly administered as an outpatient treatment. Infusion-related pain, in particular, may be 
related to complement activation or other mechanisms. Importantly, pain was not observed in the previous 
GD2 CAR T-cell trial by Pule et al. (2008) [27]. Accordingly, infusion-related pain would not be anticipated 
to occur with 1RG-CART infusions.  
Some toxicities described for GD2-directed mAbs are typical of mAb infusions in general, and are seen 
(especially with the first infusion of mAbs) regardless of the antigen targeted (e.g. rituximab, alemtuzumab, 
trastuzumab). Therefore, such toxicities may not occur with 1RG-CART therapy, although the infusion of 
autologous cells is also associated with infusion reactions. 


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Table 1. Incidence of Grade 3-4 Toxicities Seen with 3F8, ch14.18 and hu14-18-IL-2 (from Parsons et 
al., 2013 [18]) 
Toxicity 
3F8 + GM-CSF + 
isotretinoin 1 
(n=85) 
Ch14.18 + GM-CSF + 
IL-2 + isotretinoin 2 
(n=299) 
Hu14.18-IL-2 3 
(n=38) 
Pain 
1% 
52% 
31% 
Urticaria 
0 
13% 
5% 
Rash 
nr 
nr 
5% 
Hypertension 
2% 
nr 
0 
Hypotension 
0 
18% 
16% 
Fever 
5% 
39% 
40% 
Capillary leak/oedema 
0 
23% 
32% 
Anaphylaxis/respiratory distress 
3-4% 
13-25% 
11% 
Serum sickness 
0 
1% 
0 
Nausea/vomiting 
2% 
3% 
0 
Diarrhoea 
4% 
13% 
0 
Abnormal liver enzymes 
4-8% 
10-23% 
23% 
Neutropenia 
nr 
nr 
34% 
Hyperbilirubinaemia 
nr 
nr 
21% 
Thrombocytopenia 
nr 
nr 
42% 
Anaemia 
nr 
nr 
24% 
Hypokalaemia 
11% 
35% 
10.5% 
Hyponatraemia 
0 
23% 
5% 
1 Cheung et al., 2012 [33] 
2 Yu et al., 2010 [19] 
3 Shusterman et al., 2010 [34] 
Abbreviations: nr = not reported, GM-CSF = granulocyte-macrophage colony stimulating factor, IL-2 = interleukin-2 
2.3.2.2 
Toxicities Associated with Genetically Modified CAR T-cells 
Previously identified safety concerns with genetically modified T-cells include the following (reviewed in 
Maher, 2012 [35] and Heslop, 2010 [36]): 
• 
Immediate infusion-related events:  Fever and chills have been commonly described in patients 
with haematological malignancies receiving CD19 or CD20-directed CAR T-cells [35, 57]. In 
addition, the rapid onset of severe pulmonary symptoms has also been described. A patient with 
metastatic colon cancer received 1x1010 T-cells modified with a third generation CAR targeting 
HER2 and containing 4-1BB and CD28 co-stimulatory moieties, after intensive lymphodepletion 
[37]. The patient developed pulmonary toxicity within 15 minutes of the T-cell infusion, followed by 
cardiac arrest and subsequently died 4 days later. The events were associated with very high 
cytokine levels and may have been due to targeting of low levels of HER2 on pulmonary 
endothelium by very high numbers of transgenic T-cells leading to local cytokine hypersecretion 
and pulmonary leukostasis (i.e. an “on-target but off-tumour” effect – see below). Anaphylaxis has 
also been reported in a patient receiving CAR T-cells directed against mesothelin (see fourth bullet 
point below). 
• 
Toxicities due to immune activation and cytokine storm:  Immune activation and cytokine 
storms have been described in adult and paediatric patients with haematological malignancies 
treated with CD19-and CD20-targeted T-cell therapy [25, 38, 39, 57]. As would be expected from 
the mechanism of action of CAR T-cells, at least some level of cytokine release appears to be 
necessary for CAR T-cells to have efficacy, and the severity of cytokine release correlates with 
tumour bulk as well as anti-tumour activity. In one child who experienced a severe cytokine storm, 
cytokine blockade with etanercept and tocilizumab (in addition to glucocorticoids) was effective in 
reversing the syndrome and did not appear to inhibit the expansion or anti-leukaemic efficacy of the 
transduced T-cells [23]. Glucocorticoids were also used to treat CRS caused by anti-CD20 CAR 


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T-cells without eliminating the CAR T-cells [57]. However, in adult patients with sCSR, 
glucocorticoids (but not tocilizumab) also eliminated the anti-CD19 CAR T-cells and this appeared 
to lead to loss of anti-leukaemic efficacy. Of interest, CRS has been reported in a patient who 
received genetically unmodified T-cells with native receptors directed against tumour antigens [58]. 
The patient, who had bulky refractory Epstein-Barr virus (EBV)-associated lymphoma, developed 
the syndrome two weeks after receiving donor-derived, ex vivo expanded T-cells directed against 
EBV antigens through their native receptors. Cytokine release syndrome has also been reported 
after natural and bispecific antibodies and derivatives, especially those targeting CD3 (OKT3), 
CD52 (alemtuzumab) and CD20 (rituximab), and the CD28 super-agonist, TGN1412 (reviewed in 
Lee et al, 2014 [56]). Guidelines have been devised for monitoring patients receiving CAR T-cell 
therapy and for diagnosing and managing severe CRS in these patients (see Appendix 1 for 
grading of CRS according to Lee et al. (2014) [56] and Appendix 2 for indicators and management 
of severe CRS derived from Davila et al. (2014) [38]. 
• 
“On-target but off-tumour” effects:  When allogeneic T-cells specific for minor histocompatibility 
antigens were given to treat leukaemic relapse, severe toxicity resulted from the unexpected 
presence of the target antigens on lung tissue [40]. Similarly, T-cells genetically modified with 
MART-1-specific T-cell receptors (which recognise a melanoma associated antigen) were 
associated with toxicities related to melanin-expressing cells in the inner ear and the retina 
(causing uveitis and hearing loss) [41]. T-cells directed against a MAGE-A3 epitope (another 
melanoma associated antigen) have also cross reacted with a related cardiac muscle protein 
resulting in fatal cardiac toxicity [42] and fatal neurotoxicity [68]. A CAR targeting carbonic 
anhydrase IX (CAIX) expressed by renal carcinoma cells produced liver toxicity because the target 
antigen was also expressed on bile duct epithelium [43]. This toxicity could be prevented by prior 
administration of a mAb to CAIX. CD19 is a specific antigen of B-cell lineage, which is expressed 
on the surface of malignant B-cells as well as normal B-lymphocytes. Therefore, B-cell aplasia is 
one of the complications of CD19 CAR T-cell therapy [69]. Finally, CAR T-cell therapy targeting 
carcinoembryonic antigen (CEA) caused severe dose-limiting colitis in patients with colorectal 
cancer [44]. 
• 
Toxicities due to immune responses against the CAR or vector-associated proteins:  In a 
trial of CAR T-cells targeting CAIX in renal cell carcinoma, the majority of patients developed 
humoral and/or cellular immune responses to the CAR and/or viral vector [45]. Although this did not 
result in any apparent toxicity, it did appear to limit the duration of transduced T-cell survival in the 
circulation. Of note, patients in this study were not lymphodepleted prior to CAR T-cell infusion and 
they received multiple infusions, which may have increased the immunogenicity of the CAR T-cell 
treatment. Anaphylaxis has been described in a patient receiving a third dose of CAR T-cells 
directed against mesothelin [46, 47]. The patient experienced a cardiac arrest but was resuscitated 
and made a complete recovery. This event was thought to be due to IgE antibodies to the CAR 
itself, which included a scFv component derived originally from a murine antibody. The authors felt 
that the schedule of infusions was critical in this patient (3 infusions given over 49 days) because it 
allowed Ig switching (to IgE) to occur. As a result of this case, they modified their schedule for 
future patients so that the gap between infusions was no more than 10 days and all infusions had 
to be given within 21 days. Of note, the scFv targeting GD2 in the CAR expressed in 1RG-CART is 
fully humanised, and all other components of the receptor are human. These features are intended 
to minimise the risk of cross reactivity and possible host rejection and will also reduce the chance 
of anaphylaxis. The CAR expressed by 1RG-CART targets a different antigen (GD2), and 
1RG-CART are intended to persist in the circulation and expand. In contrast, the CAR T-cells given 
to the patient who experienced anaphylaxis target the antigen mesothelin and the CAR expression 
is intended to be transient, lasting a few days only. These differences may also be important in the 
relative immunogenicity of the two CAR T-cell therapies. Importantly, all infusions of 1RG-CART 
will take place in a hospital environment with immediate facilities available to manage 
infusion-related reactions including anaphylaxis.  
• 
Normal tissue ‘bystander’ damage:  Damage to normal tissue surrounding tumour sites has 
been described. These effects are probably due to inflammation and/or necrosis of the normal 
tissue following CAR T-cell mediated tumour lysis. Symptoms/signs include GI haemorrhage in 
patients with lymphoma involving the GI tract, serous effusion and pulmonary consolidation with 
dyspnoea and respiratory distress in patients with lung parenchymal involvement with lymphoma 
[57]. 


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2.3.2.3 
Expected Safety Profile for 1RG-CART Therapy 
Based on clinical experience with GD2-targeted mAbs, previous GD2 CAR T-cell therapy and other CAR 
T-cell therapies, potential toxicities of 1RG-CART therapy in patients with neuroblastoma include the 
following: 
• 
Side effects of lymphodepleting chemotherapy (if given), notably infections related to neutropenia 
and/or lymphopenia. These are considered readily manageable in the context of advanced, 
relapsed neuroblastoma and the planned in-patient setting. 
• 
Acute (occurring on the day of administration) non-specific or specific reactions to T-cell infusions, 
which could include allergic-type reactions to the T-cells, traces of culture-related products or the 
transgene, and/or exposure to dimethyl sulfoxide (DMSO) or human albumin solution (HAS). 
Anaphylaxis could potentially occur in patients given a second dose of 1RG-CART. Respiratory 
distress syndrome due to pulmonary leukostasis is also possible (although considered unlikely 
since patients will only be given low doses of T-cells and GD2 is not expressed in pulmonary 
endothelium). Symptoms could include rash, fever, rigors, bronchospasm, and hypotension. 
Infusion-related reactions are considered readily manageable in the context of advanced, relapsed 
neuroblastoma and the planned in-patient setting. All patients will receive supportive care including 
pre-medication with an antihistamine (see Section 5.1.3). Should acute infusion-related 
neuropathic pain occur (as seen with GD2-targeted mAb infusions), patients will be treated with 
analgesia regimens known to be effective in managing ch14.18-related pain (see Appendix 9).   
• 
Toxicity from intense immune activation, including cytokine storm and/or macrophage activation 
syndrome (overlapping syndromes – see Rosado & Kim, 2013 [48]). This is considered the most 
important and most likely toxicity of 1RG-CART therapy in patients with neuroblastoma. Apart from 
general supportive care measures (including fluid administration, oxygen, ventilatory support, 
antiepileptics and inotropes if needed), potential treatments include cytokine antagonists, such as 
tocilizumab or a TNF antagonist (e.g. etanercept) or corticosteroids. Administration of rituximab (to 
activate the suicide gene product, RQR8, and trigger apoptosis of 1RG-CART) is considered 
unlikely to be necessary and could potentially exacerbate symptoms due to rituximab 
infusion-related cytokine release. However, rituximab administration would be considered if other 
methods failed to control the symptoms. 
• 
Direct effects of CAR activity, notably neuropathic pain and/or peripheral neuropathy (due to GD2 
expression on myelin sheathes), tumour lysis syndrome (generally extremely rare in 
neuroblastoma), and/or local inflammation at sites of disease. GD2 expression in the CNS and/or 
posterior pituitary could potentially lead to adverse CNS effects, including neurological disorders of 
the eyes (such as blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve 
disorder, eyelid ptosis and papilledema) or syndrome of inappropriate antidiuretic hormone 
secretion (SIADH). GD2 expression in melanocytes could potentially lead to pigment disorders, 
such as vitiligo, or increased susceptibility to sunburn. Rituximab (to activate the suicide gene) may 
be indicated for severe or progressive neuropathic pain that cannot be controlled with conventional 
analgesics (see Appendix 9) or for CNS effects, unless they are mild or transient. Patients with 
bulky disease at anatomic locations which could be hazardous, if acutely inflamed (notably where it 
might threaten an airway), will be excluded from the trial. Photophobia may be managed with 
supportive measures such as dimming the lights or the closing curtains. Patients/parents will be 
advised to take appropriate precautionary measures regarding sun exposure. 
• 
Immunogenicity such as human anti-CAR antibody formation (HACARA) or formation of antibodies 
to RQR8 or other components of the transgene or vector. Given the unique expression of RQR8 
and the GD2 CAR in transduced T-cells, antibody- or cell-mediated immunity against these 
products is likely to result in elimination of transduced T-cells (and therefore loss of efficacy) rather 
than unwanted immunological effects.  
• 
Effects of integrating vectors, including insertional mutagenesis-driven T-cell lymphoproliferation 
and germ-line transmission of vector. Uncontrolled lymphoproliferation due to continued antigenic 
stimulation of 1RG-CART by GD2 expressed on normal cells after elimination of neuroblastoma 
could also occur. However, these toxicities are purely theoretical, and have never been observed in 
an engineered T-cell trial. First line treatment would be rituximab to activate the suicide gene. 
 
The timing and management of potential toxicities of 1RG-CART therapy are illustrated schematically in 
Appendix 11 (note that timings should be regarded as uncertain and approximate). Section 3.5 provides 
detailed information on the potential use of rituximab in this trial (for further details on rituximab please refer 
to the Rituximab (1RG-CART Rescue Therapy) IB. 


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2.4 
Rationale for the Proposed Trial 
The purpose of this trial is to explore the feasibility of deploying autologous anti-GD2 CAR T-cells for the 
immunotherapy of neuroblastoma. The CAR T-cell trials employing second generation receptors and 
lymphodepleting conditioning regimes have produced objective clinical responses in patients with relapsed 
leukaemias. The current trial aims to evaluate similar CAR T-cells but directed against the antigen GD2. 
Neuroblastoma is well suited to this form of targeted therapy because of the homogeneous and almost 
universal expression of GD2 on the surface of neuroblastoma cells, and because of the poor prognosis of 
eligible patients. A successful outcome in this trial could pave the way for the development of the GD2 CAR 
T-cell therapy for additional GD2-positive malignancies.  
1RG-CART will be administered by IV injection/infusion as is standard for T-cell adoptive transfer trials. As 
the CAR T-cells are designed to survive and proliferate on encountering antigen, no direct relationship is 
anticipated between cell dose and either efficacy or toxicity. Rather, clinical benefit is more likely to be 
observed in those patients in whom in vivo expansion successfully occurs. A likely key determinant of 
expansion will be prior lymphodepletion of the patients. For this reason this trial is designed to initially 
evaluate a phased introduction of lymphodepletion in successive patient cohorts. Only if there is insufficient 
expansion of T-cells following full lymphodepletion will the T-cell dose be escalated. Initially, a very modest 
dose of T-cells is planned to reduce the possibility of immediate adverse reactions, such as pulmonary 
leukostasis or severe cytokine storms induced by infused cells. The T-cell doses proposed for this clinical 
trial are based on those of the Phase I GD2 CAR T-cell trial performed in a similar patient group in the 
Texas Children’s Hospital [27] and previous adoptive transfer T-cell trials in Epstein Barr Virus-positive 
malignancies [49, 50]. 
2.5 
Selection of the Phase I Starting Dose and Schedule 
1RG-CART will be administered to patients as a slow IV injection or infusion (with a maximal infusion rate 
of 20 mL/m2/min) on Day 0. The starting dose (and the dose for Dose Levels 2 and 3) will be 1x107 
1RG-CART/m2, based on prior clinical experience with CAR T-cell therapy (pre-clinical studies have not 
been conducted since no suitable animal model exists). This is at the lower end of the dose of CAR T-cells 
infused in previous CAR T-cell trials, in which a second generation CAR construct was used (Table 2). The 
starting dose of CAR T-cells in this CRUK trial is also lower than that given in the first anti-GD2 CAR T-cell 
trial, in which a first generation CAR was used. The dose in that trial was 2 to 20x107 cells/m2 [27]. 
In this trial, it is expected that most patients will only receive a single dose of 1RG-CART. However, 
patients may receive a second dose of 1RG-CART as described in Section 5.4.1. Most CAR T-cell trials 
have involved administration of more than one dose of CAR T-cells. As many as 10 doses have been given 
to individual patients with no reports of adverse consequences associated with repeat dosing, other than 
anaphylaxis in one patient (see Section 2.3.2.2 for details of this case and the 1RG-CART IB for details of 
other CAR T-cell trials). 


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Table 2 Dose of Relevant Second Generation CAR T-cells (CD28-CD3ζ construct) Used in Published 
CAR T-cell Clinical Trials 
Target 
Patientsd 
Doses 
Dose range 
Disease 
Reference 
CD19 
1 
2 
a4x108 
b1.4x108 cells/m2 
B-NHL 
[51] 
CD19 
8 
2 
0.3 to 3x107 cells/kg 
b0.75 to 7.5x108 cells/m2 
B-NHL 
[52] 
CD19 
10 
1 
1 – 10x106/kg (allogeneic 
T-cells) 
B-cell 
malignancies 
[61] 
CD19 
6 
1-2 
0.2-8x108 cells/m2 per dose 
Non-Hodgkin’s 
lymphoma 
[29] 
CD19 
9 
1  
(split in 
some 
cases) 
a1.8x108 to 2.5x109 
b6.4x107 to 8.9x108 cells/m2 
CLL/ALL 
[24] 
CD19 
5 
1 
1.5x106 to 3x106 cells/kg 
b5.6x105 to 1.1x106 cells/m2 
ALL 
[25] 
CD19 
16 
1 
3x106/kg 
B-ALL 
[38] 
CD19 
15 
1 
1x106 
CAR-positive T/kgc 
B-cell 
malignancies 
[62] 
CD19 
21 
1 
1x106 to 3x106/kg 
ALL & NHL 
[63] 
CD19 
7 
1 
3x106 to 3x107/kg 
CLL 
[64] 
CD19 
6 
1 
0.2 to 2x108 cells/m2 
B-cell 
malignancies 
[65] 
PSMA 
7 
1 
1 to 3x107/kg 
Prostate cancer 
[66] 
LeY 
antigen 
4 
1 
1.5 to 9.2x106/kg 
AML 
[67] 
 
a When whole body dose given a body weight of 70 kg was assumed to convert dose to m2. 
b Cell dose in mg/kg converted to dose in mg/m2 using an allometric scaling factor of 25 based on a child bodyweight of 
20kg. 
c Dose reduced from 5x10 CART/kg during the study due to toxicity. 
d Some patients are included in more than one publication (see 1RG-CART IB for more details). 
Abbreviations:  ALL=acute lymphoblastic leukaemia; AML=acute myeloid leukaemia; B-NHL=B-cell non-Hodgkin’s 
lymphoma; CLL=chronic lymphocytic leukaemia; PSMA = prostate specific membrane antigen. 
The rationale for the starting doses of cyclophosphamide and fludarabine can be found in the 
Cyclophosphamide and Fludarabine (1RG-CART Conditioning Regimen) IB. 




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3.2 
Design of the Clinical Trial 
This is a two centre, Phase I, first-in-human, open label, dose escalation and expansion trial in patients with 
relapsed or refractory neuroblastoma. The dose escalation phase of the trial will employ cohorts of at least 
one patient until evidence of 1RG-CART engraftment, 1RG-CART-related toxicity (other than minor 
non-specific side effects, e.g. Grade 1-2 infusion-related reactions), and/or anti-tumour efficacy is seen. 
It is expected that between 15 and 27 patients will be required to complete this trial, the final number 
depending on the number of dose levels explored. Approximately 9 to 24 patients will be entered into the 
dose escalation part of the trial. Further patients will be recruited into the dose expansion part of the trial, to 
give a total of nine patients treated at the expanded dose level.  
Each cohort of one or more patients will receive 1RG-CART given as a slow IV injection or infusion (with a 
maximal infusion rate of 20 mL/m2/min) on Day 0.  See Table 3 in Section 5.2 for a summary of the planned 
dose escalation scheme.  
The first cohort of patients will receive 1x107 1RG-CART/m2 on Day 0 without any preparative 
lymphodepleting regimen (Dose Level 1). The second cohort of patients will be given 300 mg/m2/day of 
cyclophosphamide on each of Days -4 to -1 (total of four doses), followed by 1x107 1RG-CART/m2 on 
Day 0 (Dose Level 2). 
The third cohort of patients will be given 300 mg/m2/day of cyclophosphamide each day on Days -7 to -4 
(total of four doses) and 25 mg/m2/day of fludarabine each day on Days -8 to -4 (total of five doses), 
followed by 1x107 1RG-CART/m2 on Day 0 (Dose Level 3). 
The fourth cohort of patients will be given the same conditioning regimen as for Dose Level 3, followed by 
1x108 1RG-CART/m2 on Day 0 (Dose Level 4). 
If 1RG-CART survival is not considered optimal in earlier dose levels and improved efficacy seems likely 
with a higher 1RG-CART dose, a fifth dose level may be explored. Patients in this cohort will be given the 
same conditioning regimen as for Dose Levels 3 and 4, followed by 5-10x108 1RG-CART/m2 on Day 0 
(Dose Level 5). 
If adequate 1RG-CART survival and anti-tumour efficacy is achieved then subsequent dose levels may be 
omitted and the expansion phase of the trial may commence. Persistence of transduced T-cells (defined as 
≥0.02x109/L transduced T-cells in peripheral blood) for at least 2 weeks after infusion in the majority of 
patients in a cohort is considered an indicator of successful engraftment. 
In most patients, it is expected that 1RG-CART will only be given once. However, patients may receive a 
second dose of 1RG-CART as described in Section 5.4.1. 
In the expansion phase, additional patients will be recruited to the most favourable cohort (to give a total of 
nine patients treated at this dose level) to further evaluate safety, 1RG-CART engraftment and survival, 
and anti-tumour efficacy. 
After administration of the 1RG-CART on Day 0, patients will be monitored daily for the first 14 days, then 
weekly until Day 42. Follow-up visits will be performed at 2, 3, 4, 5, 6, 9, 12 and 24 months from Day 0 and 
then annually until the end of the trial.   
The End of Trial will be declared once all patients have either withdrawn from the trial or the last patient to 
receive an infusion of 1RG-CART has completed the 24 month follow-up visit (following their last 
administration of the 1RG-CART). Once the End of Trial is declared, any patients remaining on study will 


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be consented and re-enrolled to a follow-on protocol in which they will be followed up for at least 15 years 
after their last dose of 1RG-CART (see Section 12). 
3.3 
Patient Treatment Group 
Patients with relapsed or refractory neuroblastoma and who fulfil the eligibility criteria will be eligible for the 
trial. It is expected that all patients will be in the paediatric age range, although there is no upper age limit 
for the trial.    
3.4 
Definition of Dose Limiting Toxicity 
Toxicity will be graded according to the NCI CTCAE Version 4.02 or trial-specific grading scheme for CRS 
(Appendix 1).   
A DLT is defined as any of the following when considered highly probably or probably treatment-related 
following the first dose of 1RG-CART: 
• 
Uncontrollable pain attributable to 1RG-CART requiring suicide gene activation in the first two 
weeks after receiving 1RG-CART. 
• 
Progressive central neurological deficit attributable to 1RG-CART. 
• 
Severe immunological activation syndrome requiring ventilatory or prolonged inotropic support. 
• 
Any other reason for activation of the suicide gene within the first two weeks after receiving 
1RG-CART. 
• 
Any other fatal event (Grade 5) or life-threatening event (Grade 4) that cannot be managed with 
conventional supportive measures or which in the opinion of the Trial Steering Committee (TSC) 
(see Section 3.6) necessitates dose reduction or other modification to trial treatment to avoid a 
similar hazard in future patients.  
 
Reporting requirements 
• 
All DLTs must be reported as serious adverse events (SAEs) within 24 hours of site staff becoming 
aware of them (see Section 9). All DLTs will be notified to the TSC by the Sponsor. 
• 
Although not necessarily considered a DLT, a decision to activate the suicide gene by 
administration of rituximab at any time should be reported as an SAE to the Sponsor. The TSC will 
also be informed by the Sponsor (see Section 3.6). 
Please note that the definition of DLT is not based on NCI CTCAE criteria alone since Grade 3/4 toxicities 
are anticipated in relation to immune activation and cytokine release but these events are expected to be 
manageable and reversible. 
For patients receiving a second dose, all significant toxicities (including any event which meets the 
definition of a DLT) will be taken into account for making dose escalation decisions and in determining the 
recommended Phase II regimen. 
If a change is made to the grade or causality of an adverse event during the trial, the event should be 
reconsidered against the DLT definitions above. Any change which causes an adverse event to be 
considered a DLT when it was not previously considered a DLT, or vice versa, should be notified to the 
Sponsor immediately as this may affect dose escalation decisions.  
3.5 
Criteria for Administration of Rituximab 
In the event that unmanageable toxicity attributable to the 1RG-CART is observed, rituximab can be used 
to eliminate the cells and ameliorate the toxicity. A single dose of 375 mg/m2 should be administered. This 
may be repeated if the first dose produces insufficient depletion of 1RG-CART to control toxicity.   
It should be noted that rituximab infusions are associated with reactions that are thought to be due to 
cytokine release. Moreover, rituximab causes B-cell depletion and could therefore exacerbate or prolong 
the immune suppression caused by fludarabine and cyclophosphamide lymphodepletion.  Finally, depletion 


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of 1RG-CART by rituximab might lead to loss of tumouricidal benefit. The decision to use rituximab should 
therefore not be made lightly.  
The following toxicities are considered reasonable indications for suicide gene activation: 
• 
Pain syndrome not controllable by maximal analgesia (see Appendix 9). 
• 
Severe (Grade 3-4) progressive CNS deficit attributable to 1RG-CART. 
• 
Severe (Grade 3-4) immunological activation syndrome, which cannot be managed with steroids 
and/or cytokine inhibitors such as tocilizumab or etanercept. 
• 
Progressive pathological clonal T-cell lymphoproliferative disorders. 
• 
Any other severe, unexpected toxicities attributable to 1RG-CART that cannot be managed with 
conventional measures. 
A decision to activate the suicide mechanism by administration of rituximab at any time should be reported 
as an SAE to the Sponsor. The TSC will also be informed by the Sponsor (see Section 3.6). The 
Investigator’s reasons/justification for rituximab use will also be collected in the electronic case report form 
(eCRF). 
3.6 
Trial Steering Committee 
A TSC will be convened to review safety and efficacy data from the trial on an ongoing basis, in 
consultation with the Chief Investigator (CI) and representatives from the Sponsor (including the Medical 
Advisor). The TSC will provide independent expert advice in the event of any concerns around toxicity and 
will review safety and efficacy data prior to initiation of a new cohort, in consultation with the CI and 
Sponsor. The committee will include one member of CRUK’s Protocol and Safety Review Board (PSRB) 
and at least two independent experts with expertise in CAR T-cell therapy and/or other relevant intensive 
therapies for paediatric patients with advanced malignancy. The PSRB will be informed of the TSC’s 
recommendations. 
Amongst other possible scenarios, the TSC will consider late (>2 weeks after administration of 1RG-CART) 
activation of the suicide mechanism using rituximab and whether this should be considered a DLT or not 
(see Section 3.4). If it is not considered a DLT, the TSC will make recommendations to modify the protocol 
or continue unchanged, as appropriate. They will also make recommendations on cohort expansion or 
dose de-escalation following the occurrence of DLTs of any kind (including DLTs based on activation of the 
suicide mechanisms using rituximab) (see Section 5.2). Where required, the TSC will make 
recommendations regarding whether patients should receive a second dose of 1RG-CART and (where 
applicable) what regimen these patients should receive (see Section 5.4.1). Finally, the TSC will be 
responsible for recommending early termination of the trial for safety or efficacy reasons.  
3.7 
Definition of Recommended Phase II Regimen 
The recommended Phase II regimen (RP2R) will be based primarily on safety data and on the frequency, 
persistence and phenotype of 1RG-CART in the peripheral blood. Persistence of transduced T-cells 
(defined as ≥0.02x109/L transduced T-cells in peripheral blood) for at least 2 weeks after infusion in the 
majority of patients in a cohort will be considered an indicator of successful engraftment. Evidence of 
anti-tumour efficacy will also be of relevance in defining a Phase II regimen. 
3.8 
Patient Evaluability 
1RG-CART survival  
All patients who complete their assigned treatment regimen (first administration of 1RG-CART with/without 
lymphodepletion*) and provide at least one post-treatment blood sample on or after Day 14 for 1RG-CART 
analysis, will be evaluable for 1RG-CART survival.  
*Patients who do not receive the full target number of 1RG-CART (1x107 cells/m2 at Dose Levels 1-3, 1x108 
cells/m2 at Dose Level 4, and ≥5x108 cells/m2 at Dose Level 5 [see Section 5.2 for minimum target number 
criteria]) and patients who have some or all of their assigned lymphodepleting regimen omitted because of 
lymphopenia, pancytopenia, infection or similar reason (see Section 5.3.1) will still be evaluable for 
1RG-CART survival.   


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Feasibility of 1RG-CART administration 
All patients entered into the trial (i.e. enrolled for leukapheresis/venepuncture) will be evaluable for 
feasibility of using 1RG-CART to treat patients with relapsed or refractory neuroblastoma. This includes two 
main components: the feasibility of T-cell transduction with the MP10413 retrovirus, and the feasibility of 
treating the patients.  
Safety and dose escalation 
All patients who are given 1RG-CART or one dose of the lymphodepleting regimen will be evaluable for 
safety and dose escalation decisions.  
Tumour response 
All patients who are given one dose of 1RG-CART and who complete a baseline and at least one 
post-treatment disease assessment will be evaluable for tumour response. Patients who are given one 
dose of 1RG-CART and experience clear disease progression without a formal post-treatment disease 
assessment will be considered non-responders.  
Overall survival 
All patients who receive 1RG-CART will be evaluable for overall survival, regardless of whether they 
subsequently receive other anti-cancer treatments. 
Progression-free survival 
All patients who receive 1RG-CART and complete a baseline and at least one post-treatment disease 
assessment (or experience clear disease progression without a formal post-treatment disease assessment) 
will be evaluable for progression-free survival, regardless of whether they subsequently receive other 
anti-cancer treatments.  


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4 
PATIENT SELECTION 
4.1 
Eligibility Criteria 
Patients must fulfil the eligibility criteria listed in Sections 4.1.1 and 4.1.2. 
4.1.1 
Eligibility Criteria for Leukapheresis/Venepuncture 
4.1.1.1 
Inclusion Criteria 
1. 
Written informed consent* for leukapheresis/venepuncture and transduction of T-cells. 
2. 
Suitability for leukapheresis/venepuncture defined as: 
• 
Negative for human immunodeficiency virus (HIV), human T-cell lymphotropic virus 
(HTLV) 1, HTLV 2, syphilis and hepatitis B 
• 
Minimum T-lymphocyte count of 0.25x109/L  
3. 
Relapsed or refractory neuroblastoma (the patient must have evidence of active disease even if 
they do not currently require active treatment).  
4. 
Patients must have at least one lesion that can be evaluated for response by imaging and/or 
diffuse bone marrow infiltration. 
5. 
Adequate renal function, defined as a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m2 
(corrected). 
6. 
Karnofsky score ≥60% if ≥16 years old (Appendix 4) or Lansky performance score of ≥60% if 
<16 years old (Appendix 3).  
*Informed consent from the patient’s parent or legal guardian is required for all patients under 16 years of 
age. Patients under 16 years of age may also provide written assent to take part in the trial. 
4.1.1.2 
Exclusion Criteria 
Patients should not meet (or be anticipated to meet) any of the exclusion criteria for the main trial, see 
Section 4.1.2.2. 
4.1.2 
Eligibility Criteria for the Main Trial 
4.1.2.1 
Inclusion Criteria: 
1. 
Histologically proven neuroblastoma, which is relapsed or refractory to conventional treatment.   
2. 
Patients must have at least one lesion that can be evaluated for response by imaging and/or 
diffuse bone marrow infiltration. 
3. 
Aged ≥12 months at the time written consent is given for the dose escalation phase or aged 
≥6 months at the time written consent is given for the dose expansion phase of the trial. 
4. 
Life expectancy of at least two months. 
5. 
Karnofsky score ≥60% if ≥16 years old (Appendix 4) or Lansky performance score of ≥60% if 
<16 years old (Appendix 3). 
6. 
Adequate renal function, defined as a GFR of ≥30 mL/min/1.73m2 (corrected).   
7. 
Written (signed and dated) informed consent to the main trial* and be capable of co-operating 
with treatment and follow-up. 
*Informed consent from the patient’s parent or legal guardian is required for all patients under 16 years of 
age. Patients under 16 years of age may also provide written assent to take part in the trial. 


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Note:  
• 
Evaluation of GD2 expression prior to trial entry is desirable in all patients. Therefore, whenever 
possible GD2 expression should be checked prior to study entry on a tumour sample taken after 
relapse/progression. However, as expression of this ganglioside is ubiquitous in neuroblastoma 
and is not down-regulated in response to therapy [59, 60], re-biopsy is not mandatory for patients 
with inaccessible tumour sites or in whom GD2 assessment would not be feasible (for example, 
patients with bone-only disease). GD2 expression will also be assessed in any tumour tissue 
obtained during the trial (e.g. in patients undergoing bone marrow assessment). 
• 
There are no haematological or biochemical entry requirements for this trial (other than the 
minimum lymphocyte count required for leukapheresis) since these parameters are frequently 
deranged in patients with advanced neuroblastoma and would not prevent a patient receiving 
1RG-CART. All patients will receive full supportive care, including transfusion of blood products to 
maintain adequate haematological parameters. 
4.1.2.2 
Exclusion Criteria: 
1. 
Patients who have received anti-GD2 antibody treatment within the previous 2 weeks (based on 
the half life of ch14.18 antibody being 1-3 days in children); patients who have received 
dinutuximab or other anti-GD2-directed antibody may need a longer wash-out period. 
2. 
Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or any 
other reason. 
3. 
Patients must have recovered from the acute reversible effects of any previous therapy before 
infusion of the 1RG-CART. 
4. 
Current CNS involvement (including intradural meningeal involvement). Patients who previously 
had CNS involvement but have been surgically treated and disease free for ≥2 months are 
eligible. 
5. 
Co-existing chronic progressive neurological disease. 
6. 
Airway compromise by direct tumoural invasion or compression. 
7. 
Patients with active autoimmune disease requiring systemic treatment.   
8. 
Patients who are taking or likely to require high dose systemic corticosteroids or other 
immunosuppressive therapy (patients on steroid replacement therapy are eligible). 
9. 
Patients at high medical risk because of non-malignant systemic disease including active 
uncontrolled infection. 
10. Major surgery from which the patient has not yet recovered. 
11. Female patients who are able to become pregnant (or already pregnant or lactating). However, 
those patients who have a negative serum or urine pregnancy test before enrolment and agree 
to use two highly effective forms of contraception (oral; injected or implanted hormonal 
contraception and condom; have an intra-uterine device and condom; diaphragm with 
spermicidal gel and condom) effective at the first administration of the lymphodepleting regimen 
or at administration of the 1RG-CART (whichever comes first), throughout the trial and for six 
months afterwards are considered eligible. Note that for female patients who receive 
cyclophosphamide or rituximab, the contraceptive period should be extended to 12 months after 
cyclophosphamide/rituximab administration.   
12. Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using one form of highly effective contraception [condom plus spermicide] 
effective at the first administration of the lymphodepleting regimen or at administration of the 
1RG-CART [whichever comes first], throughout the trial and for six months afterwards). Men with 
pregnant or lactating partners must be advised to use barrier method contraception (for example: 
condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 
13. Known to be serologically positive for hepatitis B, hepatitis C or HIV. 
14. Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical trial. 
15. Is a participant in another clinical trial of an investigational medicinal product (CTIMP). 
Participation in an observational trial or in the follow-up phase of a CTIMP would be acceptable. 


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4.2 
Patient Enrolment 
Informed consent from the patient’s parent or guardian is required for all patients under 16 years old. 
Written or verbal assent will be sought from all patients under 16 years old where appropriate. Informed 
consent is required for all patients aged 16 or older. All patients who provide informed consent or for whom 
informed consent has been provided and are eligible for leukapheresis/venepuncture must be added to the 
electronic data capture (EDC) system by the site staff. Screen failure patients who do not go on to be 
enrolled for leukapheresis/venepuncture should not be added to the EDC system; their details must be 
added to the screening log.  
Before enrolling the patient in the trial, the Investigator or designated representative should determine the 
eligibility of the patient during the trial screening period. Please ensure that the Sponsor is notified of any 
eligibility concerns at least four working days before leukapheresis/venepuncture or treatment is planned. 
Eligible patients must be enrolled in the EDC system by site staff and then registered by the Sponsor 
before they undergo leukapheresis/venepuncture and again before they start trial treatment. If the patient is 
eligible a patient number will be allocated by the EDC system during the initial enrolment process. This 
patient number will be kept throughout the trial.  The Sponsor will send confirmation of the patient 
registration to the Investigator following enrolment of the patient at each stage. Once the patient’s eligibility 
for the main trial is confirmed, the Sponsor will send confirmation of the patient’s assigned dose regimen. 


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5 
TREATMENT 
5.1 
Dosing Schedule/Treatment Schedule 
5.1.1 
Leukapheresis/Venepuncture 
Patients who meet the eligibility criteria for leukapheresis/venepuncture (see Section 4.1.1) and consent to 
leukapheresis/venepuncture will have their T-cells collected, transduced and the transduced cells frozen for 
use in the main trial.   
A non-mobilised, steady state, two blood volume apheresis will be performed according to standard local 
practice to harvest sufficient peripheral blood T-cells for transduction. Alternatively, if feasible, peripheral 
blood T-cells will be extracted from a sample of whole blood obtained by venepuncture. It is expected that 
each patient will only undergo a single leukapheresis/venepuncture. However, it is possible a second 
leukapheresis/venepuncture might need to be conducted in case of poor yield or failure of 1RG-CART 
manufacture. In addition, a second leukapheresis and manufacture may be performed for patients in Dose 
Level 1 who had a ‘failed’ first dose, if they meet the criteria for a second dose but have insufficient stored 
1RG-CART to administer the dose required for the currently enrolling dose level. 
Those patients who then meet the eligibility criteria for the trial (see Section 4.1.2) and consent to 
participate in the main trial will be enrolled and treated as described in Sections 5.1.2 and 5.1.3.   
5.1.2 
Lymphodepletion 
Patients treated at Dose Levels 2 to 5 will be given a lymphodepleting regimen prior to administration of the 
1RG-CART, as follows: 
• 
Dose Level 2 patients will be given 300 mg/m2/day of cyclophosphamide on each of Days -4 to -1 
(total of four doses), followed by 1RG-CART on Day 0.   
• 
Dose Levels 3 to 5: patients will be given 300 mg/m2/day of cyclophosphamide on each of Days -7 
to -4 (total of four doses) and 25 mg/m2/day of fludarabine on each of Days -8 to -4 (total of five 
doses), followed by 1RG-CART on Day 0 (or on Day 0 and Day 1, for patients requiring a split 
dose).   
For patients receiving cyclophosphamide, it will be given by IV infusion with: 
• 
2 hours pre hydration of glucose 2.5%/sodium chloride 0.45% at 125 mL/m2/hr with mesna equal to 
20% of cyclophosphamide dose 
• 
6 hours post hydration of glucose 2.5%/sodium chloride 0.45% at 125 mL/m2/hr with mesna equal 
to 100% of cyclophosphamide dose.  
Fludarabine will be given by IV infusion over 30 minutes in sodium chloride 0.9%. For patients with renal 
impairment (GFR 30-60 mL/min/1.73m2 [corrected]), the dose of fludarabine should be reduced according 
to routine clinical practice (generally by 25%). On days when patients receive both cyclophosphamide and 
fludarabine, the fludarabine will be given first.   
5.1.3 
Administration of 1RG-CART 
If the 1RG-CART manufacture is successful and sufficient transduced T-cells are obtained, they will be 
given as a slow IV injection or infusion (with a maximal infusion rate of 20 mL/m2/min) on Day 0.  
If 1RG-CART survival is not considered optimal in Dose Levels 1 to 4 and improved efficacy seems likely 
with a higher 1RG-CART dose, a fifth dose level may be explored. Patients at Dose Level 5 will receive a 
higher dose of 1RG-CART (5-10x108 1RG-CART/m2) combined with the same preparative regimen used in 
Dose Levels 3 and 4. In order to administer higher doses of 1RG-CART, it may be necessary to split the 
dose over two consecutive days (Day 0 and Day 1) to comply with the daily limits on DMSO administration.      
If adequate 1RG-CART survival and anti-tumour activity is achieved at any dose level, then subsequent 
dose levels may be omitted and the expansion phase of the trial may commence. Persistence of 


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transduced T-cells (defined as ≥0.02x109/L transduced T-cells in peripheral blood) for at least 2 weeks after 
infusion in the majority of patients in a cohort is considered an indicator of successful engraftment. 
In the expansion phase, additional patients will be recruited to the most favourable cohort (to give a total of 
nine patients treated at this dose level) to further evaluate safety, 1RG-CART engraftment and survival, 
and anti-tumour efficacy. The most favourable dose level will be determined after a review of all the 
available data by the TSC, CI and Sponsor. 
All patients will receive full supportive care, including pre-medication with antihistamine (doses in 
accordance with product licence) 30 minutes before T-cell infusion, and IV fluids (125 mL/m2/hour) from 
6 hours prior to the T-cell infusion until 24 hours post infusion. Transfusions of blood products, antibiotics, 
analgesics, and intensive care (including ventilation, dialysis and other intensive supportive care measures) 
will also be provided as clinically indicated. Prophylaxis for tumour lysis syndrome is not planned for 
patients in this trial since tumour lysis syndrome rarely occurs in patients with neuroblastoma. However, 
urate levels will be monitored and treatment started if indicated. 
In most patients, it is expected that 1RG-CART will only be given once. However, patients may receive a 
second dose of 1RG-CART as described in Section 5.4.1. 
5.2 
Dose Escalation Scheme 
The dose escalation phase of the trial will employ a modified rolling six design [1]. However, cohorts of at 
least one patient are allowed until there is evidence of 1RG-CART engraftment, 1RG-CART-related toxicity 
(other than minor non-specific side effects such as Grade 1-2 infusion-related reactions), and/or 
anti-tumour efficacy is seen. As soon as evidence of 1RG-CART engraftment, 1RG-CART-related toxicity 
(other than minor non-specific side effects such as Grade 1-2 infusion-related reactions), and/or 
anti-tumour efficacy is seen, the trial will revert to a minimum cohort size of three patients (expanding to six 
patients if needed to further evaluate the safety profile, see Section 5.2.2). In case of uncertainty (such as 
treatment of a single patient with very high or very low disease burden at baseline, or transient low-level 
1RG-CART survival and proliferation), one or more additional patients will be enrolled in a cohort. Up to six 
evaluable patients will be entered at any dose level to determine the safety and feasibility of 1RG-CART 
therapy before further dose escalation or initiation of the dose expansion phase of the trial.  
Although described as ‘dose escalation’, the dose of 1RG-CART will not be escalated in Dose Levels 1 to 
3. Instead, it is the conditioning regimen (cyclophosphamide ± fludarabine) which is escalated. At Dose 
Levels 4 and 5, the conditioning regimen remains the same as for Dose Level 3 whilst the dose of 
1RG-CART is escalated. 
The dose escalation scheme is summarised in Table 3 (more detailed information on the dosing schedule 
can be found in Section 5.1). Note that a range is provided for the 1RG-CART cell dose in Dose Level 5. 
The exact dose of 1RG-CART within this range will be decided based on emerging data from the previous 
cohorts, and the availability of sufficient cells for each patient. For example, if no engraftment is seen at 
Dose Levels 1-4, a higher dose of 1RG-CART (10 x108 cells/m2, i.e. 1 x109 cells/m2) might be considered 
appropriate for patients at Dose Level 5. Conversely, if some engraftment is seen at Dose Level 4 but the 
extent or duration of engraftment is considered suboptimal, a dose of 5 x108/m2 may be considered 
sufficient for patients treated at Dose Level 5. 
Table 3: Planned Dose Escalations 
 
 
Conditioning regimen 
Dose 
Level 
Dose of 1RG-CART* 
(Day 0) 
Cyclophosphamide  
(300 mg/m2/day) 
Fludarabine 
(25 mg/m2/day) 
1 
1x107 cells/m2 
None 
None 
2 
1x107 cells/m2 
Day -4 to Day -1  
(total of four doses) 
None 
3 
1x107 cells/m2 
Day -7 to Day -4  
(total of four doses) 
Day -8 to Day -4 
(total of five doses) 


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4 
1x108 cells/m2 
 Day -7 to Day -4  
(total of four doses) 
Day -8 to Day -4 
(total of five doses) 
5 
5-10x108 cells/m2 
Day -7 to Day -4  
(total of four doses) 
Day -8 to Day -4 
(total of five doses) 
*Target cell numbers for transduced cells. Actual number may differ and will be recorded in the electronic case report 
form (eCRF). 
The first patient at any dose level will be observed for toxicity for at least 21 days from Day 0 before a 
second patient can begin treatment or a decision can be made to dose escalate (or not). If a third patient is 
to be treated at a dose level, the previous patient must be observed for toxicity for 14 days from Day 0 
before they can begin treatment. If further patients are recruited into a cohort, they should not be dosed on 
the same day and should ideally be dosed at least four days apart. If patients show evidence of 
engraftment and/or 1RG-CART-related toxicity, a longer period of observation may be necessary before 
the next patient can begin treatment.  
In certain circumstances, dose escalation can be considered after one patient has been followed for at 
least 21 days after administration of 1RG-CART.  However, as dose escalation proceeds and evidence of 
engraftment is detected, at least three patients will be required at each dose level. The use of single patient 
cohorts is intended to reduce the number of patients potentially exposed to ineffective regimens.  Decisions 
will be based on the number of DLTs (and any other drug-related AEs) observed at the current dose level, 
the number of patients enrolled who are at risk of developing a DLT (see Section 3.4), and evidence of 
1RG-CART engraftment and activity.  When sufficient data are available to assess these, dose escalation 
may be considered as follows: 
• 
SINGLE-PATIENT COHORTS: If data are only available for one new* patient at a dose level, dose 
escalation may take place if this patient has received the planned regimen+ and been followed for 
at least 21 days without evidence of 1RG-CART engraftment (1RG-CART <0.02x109/L at Day 14 
with no evidence of increasing peripheral blood CAR T-cell numbers within the first 14 days), 
1RG-CART-related toxicity (other than minor non-specific side effects such as Grade 1-2 
infusion-related reactions), or anti-tumour efficacy. The patient must also be considered a 
reasonable candidate for 1RG-CART engraftment (patients with very low disease burden at 
baseline may not be ideal for assessing engraftment, for example). In case of uncertainty, one or 
more additional patients must be enrolled. The data from the current cohort must be reviewed by 
the TSC before the next dose level can open.   
• 
THREE PATIENT COHORTS: If data are available from a minimum of three new* patients treated 
at a dose level, who have received the planned regimen+, and no DLTs have been observed at that 
dose level, then dose escalation can be considered. Of those three patients, two patients in the 
cohort must have been treated and followed for at least six weeks and all other patients must have 
been treated and followed for at least two weeks.  
*Patients undergoing a second infusion of 1RG-CART for any reason cannot be the first patient 
treated at a new dose level. They will also not count as a ‘new’ patient for any dose level which 
requires three patients (they will be considered an ‘additional’ patient in that cohort).   
+Patients at Dose Levels 1, 2 and 3 must have received at least 5x106 1RG-CART/m2 to be 
considered to have received the planned regimen. Patients at Dose Level 4 must have received at 
least 5x107 1RG-CART/m2 to be considered to have received the planned regimen. Patients at 
Dose Level 5 must have received at least 2.5x108 1RG-CART/m2 to be considered to have 
received the planned regimen (or at least 5x108 1RG-CART/m2 if the planned regimen is 1x109 
1RG-CART/m2). At Dose Levels 2 to 5, if a patient does not complete the lymphodepleting regimen 
due to lymphopenia, pancytopenia, infection or similar reason (see Section 5.3.1), then additional 
patients will be recruited as necessary to ensure sufficient patients have completed the planned 
regimen for that cohort before dose escalation can occur. Patients who receive a reduced dose of 
fludarabine due to renal impairment will be considered to have completed the conditioning regimen 
as planned. If there is uncertainty about whether an additional patient needs to be recruited the 
TSC will be consulted.  
• 
If DLT occurs (see Section 3.4), recruitment into that cohort will cease pending discussion by the 
TSC. If it is agreed that recruitment to the cohort can continue then it will be expanded to include 
up to six patients. For less severe toxicity or in the case of uncertainty, the cohort may be 


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expanded up to six patients to better assess the safety profile.  Cohort expansion up to six patients 
may also be appropriate to better assess engraftment and anti-tumour efficacy. 
• 
If it is too soon to take a decision on dose escalation but an eligible patient has been identified who 
needs to start treatment without further delay, the patient may be enrolled in the current cohort. Up 
to three additional patients may be enrolled in a cohort (i.e. a total of six patients in a cohort that 
does not require expansion for toxicity). 
Prior to any escalation of the dose level, a dose decision meeting will be held. If possible, the TSC will be 
present at the same meeting. If this is not possible, the TSC will review the data prior to a dose decision 
meeting and provide their recommendation. The final decision will be made by the Sponsor and CI in 
consultation. At the meeting the following data will be reviewed: 
o 
Demographic data. 
o 
Administration data for all IMPs. 
o 
All safety data for patient(s) in the current cohort as described above.  
o 
All available safety data from any patient treated (i.e. data from previous cohorts, and any 
patients who receive a second dose).  
o 
Any available engraftment and serum cytokine data. 
5.2.1 
Intra-patient Dose Escalations  
Intra-patient dose escalation is not planned in the trial protocol as in general, patients will only receive a 
single dose of 1RG-CART. However, intra-patient dose escalation may occur in selected patients receiving 
a second dose of 1RG-CART (see Section 5.4.1). 
5.2.2 
Expansion of Dose Level(s) 
If DLT (as defined in Section 3.4) occurs, recruitment into that cohort will cease pending discussion by the 
TSC. If it is agreed that recruitment can continue, the cohort will be expanded up to six patients.  For less 
severe toxicity, or in the case of uncertainty, the cohort may be expanded to six patients to better assess 
the safety profile.  
Additional patients will be recruited to the most favourable cohort in the dose expansion phase of the trial, 
to give a total of nine patients treated at that level. 
5.3 
Dose Modifications  
5.3.1 
Dose Reductions 
5.3.1.1 
1RG-CART 
Dose reductions to the 1RG-CART are not allowed, although it is acknowledged that there is a possibility 
that exact T-cell numbers may fall short of the protocol-described target level. However, if the dose is less 
than 1x106 1RG-CART/m2 administration will not proceed. The dose given to each patient will be 
documented.   
5.3.1.2 
Lymphodepleting Regimen 
For patients with a low GFR (30-60 mL/min/1.73m2 [corrected]) the fludarabine dose should be reduced 
according to routine clinical practice (generally by 25%). Patients who have their fludarabine dose reduced 
due to low GFR (and have no other dose reductions) will be considered to have completed the planned 
regimen and will not be replaced (see Section 5.4.2). 
Other dose reductions to the conditioning regimen are not planned but may be clinically indicated, for 
example in the context of lymphopenia, pancytopenia or infection. In this situation, some or all of the 
lymphodepleting regimen may be omitted as clinically indicated. Any treatment-related toxicities will be 


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managed with conventional supportive measures. If a patient does not complete the lymphodepleting 
regimen due to lymphopenia, pancytopenia, infection or similar reason, then they will be replaced (see 
Sections 5.2 and 5.4.2). 
5.3.2 
Dose Delays 
In the event that the lymphodepleting regimen is interrupted for intercurrent illness or other reason, the 
patient may complete or recommence the preparative regimen after recovery, according to the Chief 
Investigator’s judgment after consultation with the Sponsor.   
If the patient has completed lymphodepleting therapy but is unable to receive the 1RG-CART on Day 0 for 
any reason, clinical judgement will be used as to whether it is appropriate to delay the administration of 
1RG-CART, or whether to wait for the patient’s blood counts to recover sufficiently before repeating the 
lymphodepleting regimen and administering the 1RG-CART. If the patient is deemed unsuitable to receive 
the 1RG-CART, they will be withdrawn from the trial (see Section 11) and replaced.  Similarly, clinical 
judgment will be used to decide on the best course of action (to omit or administer the dose late) for a 
patient scheduled to receive a split dose, who is unable to receive the planned dose on Day 1. 
In case of uncertainty, individual cases should be discussed with the Sponsor. 
5.3.3 
Dose Interruptions 
In the event of severe infusion reactions the cyclophosphamide/fludarabine/1RG-CART infusion should be 
stopped and the patient treated as clinically indicated. When the patient has recovered the infusion may be 
restarted. For severe life-threatening toxicity, as determined by the clinical judgement of the Investigator, 
the infusion will be permanently discontinued and there will be no rechallenge. For less severe toxicity, the 
infusion will be restarted on recovery and given at a reduced rate following administration of hydrocortisone 
and chlorpheniramine, in accordance with local practice.   
If an infusion is interrupted for mechanical, technical or any other reason, then this should be dealt with 
according to local practice and the infusion restarted as soon as possible. 
5.4 
Duration of Treatment 
In most patients, it is expected that 1RG-CART will only be given once. However, patients may receive a 
second dose of 1RG-CART as described in Section 5.4.1. The conditioning regimen and/or 1RG-CART 
dose for these patients may differ from the first dose depending on the patients’ circumstances (see 
Section 5.4.1 for details).  
Patients at Dose Level 2 will receive cyclophosphamide once daily for four days prior to administration of 
the 1RG-CART.   
Patients at Dose Levels 3 to 5 will receive cyclophosphamide once daily for four days and fludarabine once 
daily for five days prior to administration of the 1RG-CART.  
In the event that the patient is lymphopenic or pancytopenic at trial entry or becomes excessively 
lymphodepleted before completing their assigned lymphodepletion regimen, the Investigator may omit 
some or all of the lymphodepleting regimen, as clinically indicated (see Section 5.3.1.2).   
After administration of the 1RG-CART on Day 0, patients will be monitored daily for the first 14 days, then 
weekly until Day 42. Follow-up visits will then be performed at 2, 3, 4, 5, 6, 9, 12 and 24 months from 
Day 0. Patients will then be assessed annually until the End of Trial is declared, at which time any patients 
still on study will be consented and re-enrolled to a follow-on protocol (see Section 12). 
5.4.1 
Retreatment of Patients  
It is expected that most patients will receive a single infusion of 1RG-CART. However, patients may receive 
a second dose as follows: 


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• 
After a ‘failed’ first dose; i.e. patients who show evidence of minimal 1RG-CART survival and 
function (manifest as transient or no 1RG-CART detectable in the peripheral blood with no 
evidence of anti-tumour efficacy and minimal toxicity). These patients are likely to have received 
ineffective therapy and if they meet the criteria in Section 5.4.1.1, they may receive a second dose 
of 1RG-CART with a different conditioning regimen and/or a higher dose of 1RG-CART (as for the 
currently enrolling cohort). 
• 
After a ‘successful’ first dose; i.e. patients who tolerated the first dose of 1RG-CART and 
showed evidence of 1RG-CART survival with evidence of anti-tumour activity (for at least 8 weeks) 
but who subsequently show progressive disease in association with declining 1RG-CART levels. 
These patients may receive a second dose if they meet the criteria in Section 5.4.1.2. They will 
generally receive the same 1RG-CART dose and conditioning regimen as originally given, unless 
there is clear evidence from other completed cohorts that superior results are expected with a 
different dose/regimen (which could be a lower or higher cohort than the patient originally entered). 
• 
Patients who do not fall into either of the first two categories but meet the criteria in Section 5.4.1.3 
and whom, in the opinion of the Investigator, may benefit from another dose will be reviewed by the 
TSC, CI, PI (where applicable) and the Sponsor. These patients will only receive a second dose if it 
is agreed by the TSC, CI, PI (where applicable) and the Sponsor that it is in the patient’s best 
interest. The conditioning regimen and dose of 1RG-CART the patient will receive will be agreed by 
the TSC, CI, PI (where applicable) and Sponsor.  
5.4.1.1 
Patients who have received ineffective therapy (a ‘failed’ first dose) 
It is anticipated that survival and function of 1RG-CART may be inadequate in some patients (a ‘failed’ first 
dose) and that in these patients it may be appropriate to administer a second dose of 1RG-CART with a 
different conditioning regimen and/or higher dose of cells. Accordingly, a second dose of 1RG-CART may 
be given if the patient meets the following criteria: 
• 
The patient has adequate cryopreserved 1RG-CART available for a second dose of 1RG-CART. 
Except for patients enrolled in Dose Level 1, for these patients a second manufacture may be 
performed if they have insufficient cryopreserved 1RG-CART to be treated in the currently enrolling 
dose level. 
• 
The patient still fulfils the trial entry criteria for Lansky/Karnofsky performance status and renal 
function required to tolerate another infusion. 
• 
There are no alternative therapies available that are considered more likely to benefit the patient. 
• 
The patient tolerated the first infusion with minimal toxicity during a follow-up period of six weeks. 
• 
The patient has low levels (<0.02x109/L) or undetectable circulating 1RG-CART at or after Day 14 
and for at least 3 weeks prior to the second infusion. 
• 
There was no clinical evidence of anti-tumour activity following the first 1RG-CART infusion. 
For patients in Dose Level 1 requiring a second leukapheresis and manufacture to receive a second dose 
in the currently enrolling dose level, the patient must also meet the following eligibility criteria for 
leukapheresis/venepuncture: 
• 
The patient is negative for HIV, HTLV1, HTLV2, syphilis and hepatitis B. 
• 
The patient has a minimum T-lymphocyte count of 0.25x109/L. 
• 
The patient has no detectable circulating 1RG-CART prior to leukapheresis/venepuncture.  
Patients fulfilling these criteria at the Day 42 (‘End of treatment’) assessment may receive a second dose of 
1RG-CART according to the currently enrolling cohort/dose level. They will be considered “additional” 
patients in that dose level and cannot be the first patient treated at that dose level. The second dose should 
be given at least 6 weeks after the first dose (i.e. on or after Day 42). If there is uncertainty about whether a 
patient is eligible for a second dose, the TSC will be consulted. Patients may receive palliative anti-cancer 
therapy at the investigator’s discretion, while awaiting a decision or timeslot for administration of a second 
dose. 


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5.4.1.2 
Patients who benefited from the first dose (a ‘successful’ first dose) 
Patients who tolerated the first dose of 1RG-CART and showed evidence of 1RG-CART survival with 
evidence of anti-tumour activity for at least 8 weeks may receive a second dose if they fulfil the following 
requirements: 
• 
The patient has adequate cryopreserved 1RG-CART available for a second dose of 1RG-CART. 
• 
The patient tolerated the first infusion without dose-limiting or other severe or unmanageable 
toxicity for a follow-up period of at least six weeks. 
• 
The patient still fulfils the trial entry criteria for Lansky/Karnofsky performance status and renal 
function required to tolerate another infusion. 
• 
There are no alternative therapies available that are considered more likely to benefit the patient.  
• 
There was objective clinical evidence of anti-tumour activity following the previous 1RG-CART 
infusion, i.e. a CR, PR, tumour shrinkage, or stable disease for at least 8 weeks. 
• 
The patient now has evidence of progressive disease in the context of declining 1RG-CART. 
Levels of circulating 1RG-CART must be low (<0.02x109/L) or undetectable for at least 3 weeks 
prior to the second infusion. 
• 
The patient has not received any alternative systemic anti-cancer therapy since the first 
1RG-CART infusion (palliative radiotherapy and/or corticosteroids for symptom control are 
allowed).  
Patients undergoing a second 1RG-CART infusion should receive the same conditioning regimen (or lack 
of) and dose of 1RG-CART as in their first treatment cycle, unless data from subsequent completed dose 
levels clearly indicates that improved outcomes are likely with a different regimen. If they are treated with 
any regimen other than their original regimen, they will be considered “additional” patients in that dose 
level. The dose level they enter for their second dose should be complete (i.e. the required number of 
patients must have completed the required observation period following treatment and the data from the 
cohort must have been reviewed by the TSC). 
The decision to re-treat a patient, and whether the patient should receive a different lymphodepletion 
regimen and/or dose of 1RG-CART or not, will be made by the CI and Sponsor in consultation with the 
TSC.  
5.4.1.3 
Patients not having a ‘Failed’ or 'Successful’ First Dose 
Some patients may not meet the criteria for a ‘failed’ (Section 5.4.1.1) or ‘successful’ (Section 5.4.1.2) first 
dose if there are manageable signs of toxicity suggestive of engraftment, some low level engraftment 
(<0.02x109 1RG-CART/L) or a short lived clinical response (<8 weeks in duration). The PI/CI may, 
however, consider it to be in the patient’s best interest for a second dose to be given.  
In these circumstances, if the patient has sufficient transduced T-cells leftover from their first manufacture, 
the PI/CI may request the patient receive a second dose. Such patients may receive a second infusion of 
their own stored 1RG-CART if the TSC, CI, PI (where applicable) and Sponsor agree it is in the patient’s 
best interest and they fulfil the following requirements: 
• 
The patient has adequate cryopreserved 1RG-CART available for a second dose of 1RG-CART. 
• 
The patient tolerated the first infusion without dose-limiting or other severe or unmanageable 
toxicity for a follow-up period of at least six weeks. 
• 
The patient still fulfils the trial entry criteria for Lansky/Karnofsky performance status and renal 
function required to tolerate another infusion. 
• 
There are no alternative therapies available that are considered more likely to benefit the patient.  
• 
The patient has low levels (<0.02x109/L) or undetectable circulating 1RG-CART prior to the second 
infusion. 
The following data will be reviewed: medical history, diagnosis, demographic data, adverse events 
(including serious adverse events), IMP administration, cytokine and engraftment data, and results of any 


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disease assessments (bone marrow, scan results). Other data may also be reviewed as required on a case 
by case basis.   
The conditioning regimen and dose of 1RG-CART for these patients will be agreed by the TSC, CI, PI 
(where applicable) and Sponsor on a case by case basis. If they are treated with any regimen other than 
their original regimen, they will be considered “additional” patients in that dose level and cannot be the first 
patient treated at that dose level.  
5.4.2 
Replacement of Patients 
Any patient meeting the following criteria will be replaced by another patient treated at the same dose level: 
• 
Withdrawal from the trial before two weeks from first administration of 1RG-CART for reasons other 
than treatment-related toxicity. 
• 
Failure to complete the assigned treatment regimen (first administration of 1RG-CART with/without 
lymphodepletion). Patients who receive a reduced dose of fludarabine due to low GFR (and have 
no other dose reductions) are considered to have completed the assigned regimen and do not 
need to be replaced. Patients who have a dose reduction due to lymphopenia, pancytopenia, 
infection or similar reason will be replaced to ensure that sufficient patients in the cohort have 
completed the assigned lymphodepleting regimen prior to dose escalation (see Section 5.2).  
• 
Treatment with significantly fewer 1RG-CART than the target cell number for that cohort (patients 
at Dose Levels 1, 2 and 3 must have received at least 5x106 1RG-CART/m2 to be considered to 
have received the planned regimen; patients at Dose Level 4 must have received at least 5x107 
1RG-CART/m2 to be considered to have received the planned regimen; and patients at Dose Level 
5 must have received at least 2.5x108 1RG-CART/m2 [or at least 5x108 1RG-CART/m2 if the 
planned regimen is at least 1x109 1RG-CART/m2] to be considered to have completed the planned 
regimen).  
5.5 
Concomitant Medication and Treatment 
Concomitant medication may be given as medically indicated. Details (including start and stop dates) of the 
concomitant medication/treatment given must be recorded in the patient’s medical records and details 
entered into the electronic case report form (eCRF). 
Standard drugs required by the patient may be administered alongside the trial protocol.   
No herbal, homeopathic agents or food supplements will be allowed between Day -10 and Day 20 following 
T-cell infusion, unless recommended by the Principal Investigator (PI). 
All patients will receive full supportive care, including pre-medication with antihistamine (dose in 
accordance with product licence) 30 minutes before T-cell infusion, and IV fluids (125 mL/m2/hour) from 
6 hours prior to the T-cell infusion until 24 hours post infusion. Transfusions of blood products, antibiotics, 
analgesics, antiepileptics and intensive care (including ventilation, dialysis and other intensive supportive 
care measures) will also be provided as clinically indicated. Details of these should be recorded in the 
eCRF. CRS will be managed according to local policy. A scheme for managing severe cytokine release 
syndrome is provided in Appendix 2. This should be considered only as a guide and deviations from this 
scheme are allowed according to the Investigator’s judgement. 
The use of immunosupressants, such as high dose corticosteroids, should be avoided where possible as 
these are likely to influence the efficacy and possibly safety of 1RG-CART. Patients on low dose 
corticosteroids, for example for asthma, should ideally be weaned off them before entering the trial 
(corticosteroids for adrenal replacement therapy are allowed and should be continued).  
Radiotherapy may be given concomitantly for the palliative control of pain. Irradiated lesions will not be 
evaluable for response.   


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In general, patients should not receive other anti-cancer therapy (including radiotherapy except as above) 
or investigational drugs for the first six weeks after administration of the 1RG-CART. However, patients with 
clear failure of engraftment may receive palliative anti-cancer therapy at the Investigator’s discretion, while 
awaiting a decision or timeslot for administration of a second dose of 1RG-CART. Administration of other 
systemic anti-cancer therapy at any time will be considered an indicator of treatment failure (progressive 
disease). However, palliative radiotherapy will be allowed for symptom control without necessarily 
indicating progressive disease.  
Patients who have been administered 1RG-CART and subsequently require alternative anti-cancer therapy 
of any kind should remain on trial (it is not a reason for withdrawal – see Section 11) and continue to be 
monitored as described in Section 7. Details of the anti-cancer therapy must be recorded in the patient’s 
medical records and details entered into the eCRF.   


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6 
PHARMACEUTICAL INFORMATION 
1RG-CART is an autologous genetically modified cell therapy. T-cells to be used in the manufacture of 
1RG-CART will be sourced from each patient at GOSH
 as part of the trial procedures.   
GOSH
shall establish and maintain a system for patient and product traceability. All patient 
identifiers need to match those issued by CRUK following patient registration. Upon receipt of the bag 
containing whole blood or leukapheresate, a unique batch number will be assigned which will link the 
derived cell product with the Batch Manufacturing Record and to the initial patient donation. This enables 
tracking of the patient and 1RG-CART as required under the ATMP regulations. 
6.1 
1RG-CART 
6.1.1 
Supply of 1RG-CART 
A complete certificate of analysis and a Qualified Person (QP) certification must be provided to CRUK with 
each batch of the advanced therapy investigational medicinal product (ATIMP) 1RG-CART and copies be 
retained in the 
 
 
 
  
1RG-CART will be manufactured to EU Good Manufacturing Practice and supplied by: 
Cellular Therapies 
Great Ormond Street Hospital for Children NHS Foundation Trust 
 
 
 
 
 
 
 
 
 
 
must send a copy of the IMP Despatch Request Form to the CSM/CRA on 
despatch of the 1RG-CART. 
The primary and, where applicable, the secondary packaging for the 1RG-CART will be labelled according 
to Eudralex Volume 4: Annex 13 ‘Investigational Medicinal Products’ of the European Union Guide to Good 
Manufacturing Practice.   
An example of the label(s) can be found in the Trial Master File (TMF). 
6.1.2 
Pharmaceutical Data 
6.1.2.1 
Formulation of 1RG-CART 
1RG-CART are autologous, patient-derived MP10413 retrovirus transduced T-cells cryopreserved in one or 
several aliquots 
 
 
 
 


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6.1.2.2 
Storage Conditions 
All supplies must be stored in a secure, limited access storage area. 
1RG-CART will be stored in the vapour phase of liquid nitrogen until required for use whereupon they will 
be thawed, brought to a temperature of 37C, and administered within 30 minutes of thawing to the patient.  
6.1.2.3 
Method of Thawing 
Frozen 1RG-CART will be thawed at the patients’ bedside in accordance with local procedures for infusion 
of donor lymphocytes. 
6.1.2.4 
1RG-CART Administration 
Good aseptic practice must be employed when preparing 1RG-CART for IV injection/infusion.   
Once the patient has been prepared for 1RG-CART administration, the 1RG-CART will be thawed and 
brought to 37ºC. They must be administered within 30 minutes of thawing as a slow IV injection or infusion 
(with a maximal infusion rate of 20 mL/m2/min) through a central venous line. If needed and to avoid 
exceeding the maximum daily volume that can be administered, the dose may be split and given over two 
consecutive days. 
6.1.2.5 
Accidental Spillages 
1RG-CART should be treated as a blood product and any spillages should be cleaned up as per local 
hospital policy. 
6.1.3 
1RG-CART Accountability 
Accurate records of shipment, dispensing and returns for the ATIMP 1RG-CART for intravenous 
administration must be maintained by 
. This inventory record must be available 
for inspection at any time by CRA or CSM of the Sponsor. ATIMP supplies are to be used only in 
accordance with this protocol and under the supervision of the Investigator. 
The Investigator undertakes not to destroy any unused or returned ATIMP unless authorised to do so by 
the Sponsor. Any dispensed ATIMP which is unused must be destroyed according to hospital procedures 
and properly accounted for using the ATIMP Destruction Form and also on the ATIMP Accountability 
Record. During the course of the trial the CRA will check the numbers of vials/bags of 1RG-CART 
dispensed, the number used and the number destroyed or returned. GOSH Cellular Therapies will give an 
account of any discrepancy. 
6.2 
Cyclophosphamide and Fludarabine 
6.2.1 
Supply of Cyclophosphamide and Fludarabine 
Cyclophosphamide and fludarabine will be used outside their licensed indications in this trial and are 
therefore considered IMPs. Both drugs are available commercially. The Investigators will be responsible for 


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their own supply of cyclophosphamide and fludarabine. Dispensed cyclophosphamide and fludarabine will 
be labelled by the Pharmacy according to Eudralex Volume 4: Annex 13 ‘Investigational Medicinal 
Products’ of the EU Guide to Good Manufacturing Practice. The dispensed label applied by Pharmacy will 
be approved by CRUK and an example of the labels will be filed in the Pharmacy Folder. Sufficient 
quantities of either cyclophosphamide, fludarabine or both cyclophosphamide and fludarabine will be 
dispensed to cover the prescribed dose (as per Section 5.1). 
Cyclophosphamide and fludarabine are cytotoxics and must be handled with care in accordance with local 
policy. 
Good aseptic practice must be employed when preparing cyclophosphamide and fludarabine solutions for 
infusion. 
6.2.2 
Cyclophosphamide 
6.2.2.1 
Formulation of Cyclophosphamide 
Each vial of cyclophosphamide powder for solution for injection contains cyclophosphamide monohydrate 
as a white crystalline powder equivalent to either 500 mg, 1000 mg or 2000 mg anhydrous 
cyclophosphamide in type I or III clear glass injection vials with butyl rubber closures and aluminium caps. 
Please also refer to the latest Summary of Product Characteristics (SmPC) for the current approved 
pharmaceutical information. 
6.2.2.2 
Cyclophosphamide Storage Conditions and Stability 
Unopened vials of cyclophosphamide are stable for 36 months from the date of manufacture (refer to expiry 
date stated on the vial label) when stored at or below 25°C. 
6.2.2.3 
Cyclophosphamide Reconstitution, Stability and Administration 
Cyclophosphamide will only be given intravenously (IV) in this trial; oral administration is not allowed. 
Each vial of cyclophosphamide should be dissolved with either water for injection or 0.9% (w/v) aqueous 
sodium chloride to a concentration of 20 mg/mL. Please refer to CRUK supplied approved Pharmacy 
Guidelines.  
After reconstitution for intravenous (IV) administration, store at 2 to 8°C in accordance with local practice 
(but for no more than 7 days) and protect from light. 
Cyclophosphamide solution for IV administration will be prepared as per CRUK supplied approved 
Pharmacy Guidelines.  
Patients at Dose Level 2 will receive 300 mg/m2/day of cyclophosphamide by IV infusion on Days -4 to -1 
prior to receiving 1RG-CART on Day 0 (see Section 5.1). Patients at Dose Levels 3 to 5 will receive 
300 mg/m2/day of cyclophosphamide by IV infusion on Days -7 to -4 prior to receiving 1RG-CART on Day 0 
(see Section 5.1). 
Each vial of cyclophosphamide is for single use only. Any unused contents and/or vials dispensed for 
patient use must be destroyed as per local policies and accounted for as described in Section 6.2.4. 
6.2.3 
Fludarabine 
6.2.3.1 
Formulation of Fludarabine 
Fludarabine will only be given intravenously (IV) in this trial; oral administration is not allowed. 


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Fludarabine is available in two formulations for IV use: 25 mg/mL concentrate for solution for injection or 
infusion and 50 mg powder for solution for injection or infusion; both product formulations contain 50 mg 
fludarabine phosphate per vial.  For example, the solution (25 mg/mL) for injection is presented as a sterile 
2 mL fill in a 5 mL type I glass vial with bromobutylic rubber stopper and metallic cap (aluminium) with a 
polypropylene disk. For a list of excipients present in the solution formulation please refer to the applicable 
Summary of Product Characteristics (SmPC).  
Please also refer to the latest SmPC for the current approved pharmaceutical information for the relevant 
fludarabine formulation. 
6.2.3.2 
Fludarabine Storage Conditions and Stability 
Unopened vials of fludarabine stored at 2 to 8°C are stable for 2 years. Please refer to the vial label for the 
expiry date of the product. 
6.2.3.3 
Fludarabine Dilution, Stability and Administration 
Please also refer to the latest SmPC for the current approved pharmaceutical information. 
Fludarabine solution for administration will be prepared as per CRUK supplied approved Pharmacy 
Guidelines.   
Fludarabine diluted in 0.9% (w/v) saline is stable for up to 28 days. However, from a microbiological point of 
view it should be used within 24 hours of being prepared when stored at 2 to 8°C. 
Patients at Dose Levels 3 to 5 will receive 25 mg/m2/day of fludarabine by IV infusion over 30 minutes on 
Days -8 to -4 prior to receiving 1RG-CART on Day 0 (see Section 5.1). 
Each vial of fludarabine is for single use only. Any unused contents and/or vials dispensed for patient use 
must be destroyed as per local policies and accounted for as described below. 
6.2.4 
Cyclophosphamide and Fludarabine Accountability 
Pharmacy records should be kept of the cyclophosphamide and fludarabine dispensed to trial patients, the 
expiry date and batch number used should be recorded as well as vials dispensed and returned (if 
applicable). These records must be available for inspection by CRAs or CSMs of the Sponsor at any time. 
6.3 
Rituximab (MabThera®) 
6.3.1 
Supply of Rituximab (MabThera®) 
Rituximab (MabThera®) will be used a rescue medication (when necessary) but will be used outside of its 
licensed indication; it is considered a NIMP in the trial. Rituximab (MabThera®) is available commercially 
and the Investigators will be responsible for their own supply of rituximab (MabThera®). Dispensed 
rituximab (MabThera®) will be labelled according to local practice.   
6.3.2 
Formulation of Rituximab (MabThera®) 
Rituximab (MabThera®) concentrate solution for infusion (100 mg/vial or 500 mg/vial) is presented in either 
a 10 mL or 50 mL type I glass vial with butyl rubber stopper and metallic cap. Excipients present in the 
formulation are sodium citrate, Polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water 
for injection.  


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6.3.3 
Rituximab (MabThera®) Storage Conditions and Stability 
Please refer to the vial label for the expiry date of the product. 
Unopened vials of rituximab (MabThera®) stored at 2 to 8°C protected from light are chemically stable for 
30 months from date of manufacture.   
6.3.4 
Rituximab (MabThera®) Dilution, Stability and Administration 
Good aseptic practice must be used when preparing rituximab (MabThera®) concentrate solution for 
infusion. 
Please also refer to the latest SmPC for the current approved pharmaceutical information. 
Rituximab (MabThera®) solution for administration will be prepared as per local procedures.   
The prepared infusion solution of rituximab (MabThera®) is physically and chemically stable for 24 hours at 
2 to 8°C and subsequently 12 hours at room temperature. 
From a microbiological point of view, the prepared infusion solution should be used immediately. If not used 
immediately, in use storage times and conditions prior to use are the responsibility of the user and would 
normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and 
validated aseptic conditions.   
If required, patients will receive a single dose of 375 mg/m2 of rituximab (MabThera®) administered by slow 
infusion according to guidance in the SmPC for rituximab (MabThera®) and CRUK supplied approved 
Pharmacy Guidelines. At the Investigator’s discretion, this dose may be repeated if there is insufficient 
depletion of 1RG-CART and the patient’s symptoms fail to resolve or improve sufficiently. 
Each vial of rituximab (MabThera®) is for single use only. Any unused contents and/or vials dispensed for 
patient use must be destroyed as per local policies and accounted for as described below. 
6.3.5 
Rituximab (MabThera®) Accountability 
Pharmacy records should be kept of the rituximab (MabThera®) dispensed to trial patients, the expiry date 
and batch number used should be recorded as well as vials dispensed and returned (if applicable). These 
records must be available for inspection by CRAs or CSMs of the Sponsor at any time. 


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7 
INVESTIGATIONS SCHEDULE 
In cases where a patient has investigations at a different hospital, for example weekly blood samples, 
scans and other investigations as appropriate, then it is the Investigator’s responsibility to ensure he/she 
receives and reviews the reported results. These results must be available for source data verification. 
Laboratory reference ranges, including effective dates, and evidence of laboratory accreditation must be 
obtained from all laboratories used. For scan results, the original images and reports must be available for 
comparison to any scan performed at the investigator site and be in a format that is suitable for 
comparison. For all other investigations, apart from the results, any supporting data must also be made 
available for source data verification or review. 
The Investigator or delegate must inform the Sponsor of any changes to their laboratory normal ranges or 
to any laboratory accreditation and provide any new documentation. 
Blood volumes  
European Medicines Agency recommendations for trial related blood loss in paediatric populations are that 
no more than 3% of total blood volume should be taken during a four week period and not more than 1% of 
total blood volume at a single time-point. With a total blood volume estimated to be 80 to 90 mL per 
kilogram (kg) body weight, this equates to 2.4 mL to 2.7 mL blood per kg body weight during a four week 
period, or 0.8 mL to 0.9 mL blood per kg at any one time. Table 4 shows the total volume of blood by 
patient weight and the corresponding 1% and 3% blood volumes. 
These recommended volumes are likely to be exceeded in this trial in all but the heaviest patients. The 
relatively high blood volumes required for investigations in this trial are because of the possible toxicities 
associated with this novel trial treatment, which may be severe, and the need to monitor all patients closely 
for at least two weeks for evidence of immune activation, cytokine release, and resulting organ dysfunction. 
Where possible smaller volumes of blood will be taken and all patients will be monitored for anaemia and 
actively treated as needed.   
A number of different samples are taken in this study. The following routine samples are taken to monitor 
patient safety: 
 
Volume collected per sample in patients: 
Sample type 
≤ 12 years old 
13 years and older 
Haematology 
0.5 mL 
4.0 mL 
Biochemistry 
1.0 mL 
5.0 mL 
Coagulation profile 
1.4 mL 
4.5 mL 
CRP / lactate dehydrogenase (LDH)* 
1.0 mL 
5.0 mL 
 *Additional volume per sample at time points where no biochemistry sample is taken, otherwise these will be 
assessed using the sample collected for biochemistry. 
The following samples are taken for research purposes (volumes not affected by age): 
• 
 
• 
Sample for 1RG-CART quantification (5.0 mL per sample) 
• 
 
• 
Cytokine samples (2.0 mL per sample) – research specific safety samples 


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Total study-related blood loss for this study for a child ≤12 years old is estimated as follows: 
Time period 
Volume of blood for 
safety assessments 
Volume of blood for 
research assessments 
Total volume of blood for 
time period 
Day -1 to Day 27* 
35.4 mL 
99.0 mL 
134.4 mL 
Day 28, Day 35, 
Day 42 and 2 month 
follow-up* 
10.2 mL 
27.0 mL 
37.2 mL 
Monthly follow-up (at 
3, 4, 5, 6, and 9 
months)* 
1.5 mL per visit 
0.0 to 7.0 mL per visit 
1.5 to 8.5 mL per visit 
Long term follow-up 
(at 12 and 24 months) 
1.5 mL per visit 
5.0 mL per visit 
6.5 mL per visit 
Long term follow-up 
(annual visits) 
Not applicable 
5.0 mL 
5.0 mL 
*Approximately 4 week period 
Over a four week period, the largest total volume collected for a child up to 12 years old will be 134.4 mL. 
This would be 3% of a total blood volume of 4675 mL, which at 85 mL per kg would be expected for a 55 kg 
child. 106.5 mL of this 134.4 mL will be collected during the first two weeks of the trial (Day -1 to Day 14) 
when the patient is hospitalised and being intensely monitored. These volumes do not include blood loss 
from venepuncture or leukapheresis to obtain T-cells for 1RG-CART production. 
Total study-related blood loss for this study for a child 13 years or older is estimated as follows: 
Time period 
Volume of blood for 
safety assessments 
Volume of blood for 
research assessments 
Total volume of blood for 
time period 
Day -1 to Day 27* 
186.0 mL 
99.0 mL 
285.0 mL 
Day 28, Day 35, 
Day 42 and 2 month 
follow-up* 
49.5 mL 
27.0 mL 
76.5 mL 
Monthly follow-up (at 
3, 4, 5, 6, and 9 
months)* 
9.0 mL per visit 
0.0 to 7.0 mL per visit 
9.0 to 16.0 mL per visit 
Long term follow-up 
(at 12 and 24 months) 
9.0 mL per visit 
5.0 mL per visit 
14.0 mL per visit 
Long term follow-up 
(annual visits) 
Not applicable 
5.0 mL 
5.0 mL 
*Approximately 4 week period 


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Over a four week period, the largest total volume collected for a child of 13 years or older will be 285.0 mL. 
This would be 3% of a total blood volume of 4675 mL, which at 85 mL per kg would be expected for >80 kg 
child. 242.5 mL of this 285.0 mL will be collected during the first two weeks of the trial (Day -1 to Day 14) 
when the patient is hospitalised and being intensely monitored. These volumes do not include blood loss 
from venepuncture or leukapheresis to obtain T-cells for 1RG-CART production. All patients will have 
frequent blood counts and top-up transfusions as needed (see Section 5.5). 
Table 4: Total Blood Volume, 1% and 3% of Total Blood Volume by Weight Assuming 85 mL per kg 
Total Blood Volume 
Weight  
(kg) 
Total Blood Volume 
(mL) 
1% Blood Volume 
(mL)* 
3% Blood Volume (mL)* 
5 
425 
4 
12 
10 
850 
8 
24 
15 
1275 
12 
36 
20 
1700 
17 
51 
25 
2125 
21 
63 
30 
2550 
25 
75 
35 
2975 
29 
87 
40 
3400 
34 
102 
45 
3825 
38 
114 
50 
4250 
42 
126 
55 
4675 
46 
138 
60 
5100 
51 
153 
65 
5525 
55 
165 
70 
5950 
59 
177 
75 
6375 
63 
186 
80 
6800 
68 
204 
* all blood volumes have been rounded down 
Time-points for the pharmacodynamic assays have been aligned in order to minimise invasiveness and 
reduce the volume of dead space blood that is removed from the patient. Where possible, blood for 
haematology and biochemistry analysis will be taken at the same times as other samples for the same 
reasons. Investigators must discuss with the Sponsor any concerns regarding the volume of study-related 
blood loss for a particular patient.  
7.1 
Pre-treatment Evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records so that the eCRF can be checked against the source 
data. 
Please also refer to the tabulated Schedule of Assessments in Section 7.9.1. 
7.1.1 
Obtaining Written Informed Consent 
Patients of 16 years of age or older must provide written informed consent for the trial. Parents or 
guardians of patients under 16 years of age must provide written informed consent. Written or verbal 
assent will be sought from patients under 16 years of age where appropriate. Information sheets and 
consent / assent forms will be provided as follows: 
• Patients 16 years of age or older (information sheet and consent form) 
• Parents/legal guardians of patients under 16 years of age (information sheet and consent form) 
• Patients below 16 years of age (information sheet and assent form): 


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o Patients 13-15 years of age 
o Patients 8-12 years of age 
o Patients <8 years of age 
Written informed consent / assent must be obtained from the patient and / or the patient’s parent or 
guardian before any protocol-specific procedures are carried out. Patients who move from one age bracket 
to another during the course of the trial will be re-consented / re-assented using the appropriate information 
sheet and consent/assent form in accordance with local practice.   
Consent to evaluate GD2 expression in tumour samples collected prior to study entry (using biopsies taken 
at the time of disease relapse/progression) will be obtained where possible. Consent for leukapheresis and 
T-cell transduction will be obtained within 28 days before leukapheresis. The main trial consent will be 
obtained before any screening investigations for the main trial are carried out. If there are more than 28 
days between main trial informed consent and the start of dosing (with whichever IMP [1RG-CART / 
fludarabine / cyclophosphamide] is given first), then the Investigator should consider whether repeat 
consent should be obtained from the patient and/or patient’s parent or guardian. The patient / patient’s 
parents or guardian must be given adequate time to think about their commitment to the trial. 
Only the PI and those Sub-Investigator(s) delegated responsibility by the PI, and who have signed the 
Delegation Log, are permitted to obtain informed consent from patients or the patient’s parent/guardian and 
sign the consent form. All signatures must be obtained before any medical intervention required by the 
protocol (ICH GCP 4.8.8 and 8.3.1.2). The date of the signatures of both the patient and/or, patient’s 
parent/guardian, and the PI/Sub-Investigator should be the same. 
The PI or the Sub-Investigator must inform the patient and/or their parent/guardian about the background 
to, and present knowledge of the normal management of their disease and 1RG-CART, and must also 
ensure that the patient is aware of the following points:  
• 
That the use of 1RG-CART is new and that the exact degree of activity is at present unknown, but 
that treating him/her will contribute to further knowledge. 
• 
The expected toxicity of 1RG-CART and the possibility of experiencing side-effects. 
• 
The known toxicity of fludarabine and / or cyclophosphamide (where applicable) and the possibility 
of experiencing side-effects. 
• 
That long-term follow-up is required because it is an ATIMP and this may require enrolment in a 
subsequent follow-up trial. 
• 
If appropriate, the potential dangers of becoming pregnant (or the patient’s partner becoming 
pregnant) and that he/she has been given information about appropriate medically approved 
contraception (refer to Section 9.7). 
• 
That he/she may refuse treatment either before or at any time during the trial and that refusal to 
participate will involve no penalty or loss of benefits to which they are otherwise entitled. 
• 
Who to contact for answers to pertinent questions about the research and their rights, and also 
who to contact in the event of a research-related injury. 
A copy of the informed consent documents (ICD) must be given to the patient and/or their parent/guardian 
to keep and the original ICD, must be filed in the Investigator Trial File (ITF) (unless otherwise agreed that 
the original document will be filed in the medical records and copies kept in the ITF) and a copy placed in 
the patient’s medical records. 


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7.1.2 
Evaluations at Baseline/Pre-Trial 
7.1.2.1 
Within 14 days Prior to Leukapheresis/Venepuncture 
The patient should consent to leukapheresis/venepuncture within 28 days before leukapheresis. Their 
eligibility (as defined in Section 4.1.1) should be confirmed before having their T-cells collected and 
transduced. The following must therefore be performed/obtained within 14 days before leukapheresis: 
• 
Blood sample to assess suitability for leukapheresis/venepuncture, defined as: 
o 
Negative for HIV, HTLV 1, HTLV 2, syphilis and hepatitis B. 
o 
Minimum T-lymphocyte count of 0.25x109/L. 
• 
Confirmation the patient has relapsed or refractory neuroblastoma. 
• 
Confirmation of GD2 expression in a tumour biopsy taken after relapse/progression, if available. 
Alternatively, confirmatory GD2 assessment may be carried out on optional pre-treatment biopsies 
or bone marrow (in those with bone marrow involvement) (see Section 7.1.2.2). 
• 
Demographic details. 
• 
Medical history including prior diagnosis, prior treatment, concomitant conditions/diseases and 
baseline signs and symptoms, concomitant treatment. Note that, to undergo 
leukapheresis/venepuncture for the trial, patients must have evidence of active disease even if they 
do not currently require active treatment. 
• 
GFR (e.g. serum creatinine). 
• 
Karnofsky performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if 
<16 years old, see Appendix 3). 
• 
Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable). This test should be 
repeated if clinically indicated within 7 days prior to commencement of lymphodepletion (Dose 
Level 2 onwards) or T-cell infusion (Dose Level 1). 
Adverse events and concomitant medications:  All patients should be assessed for AEs at every visit 
from the time of written informed consent for leukapheresis/venepuncture by the Investigator, Research 
Nurse or suitably qualified member of the Investigator’s team. All AEs must be graded according to 
NCI CTCAE Version 4.02 or trial specific grading scheme for CRS (Appendix 1). Any concomitant 
treatment must also be recorded in the medical records and eCRF (see Section 9 for further details 
regarding AE reporting requirements). 
Note: The leukapheresis/venepuncture may be conducted ahead of planned entry into the trial and the 
transduced T-cells will be frozen until required (in accordance with the approved shelf-life).  
7.1.2.2 
Prior to Planned 1RG-CART Infusion (Day -21 to Day -1 for Dose Level 1) or 
Commencement of Lymphodepletion (Day -25 to Day -5 for Dose Level 2 or Day -29 to 
Day -9 for Dose Levels 3 to 5) 
The following baseline investigations should be carried out after written informed consent to the main trial† 
and within 3 weeks prior to 1RG-CART infusion for Dose Level 1, or prior to commencement of the 
lymphodepleting regimen for Dose Level 2 onwards.  
†If more than 28 days have passed between informed consent and the start of dosing (with whichever IMP 
[1RG-CART/fludarabine/cyclophosphamide] is given first), then the Investigator should consider whether 
repeat consent should be obtained from the patient and/or patient’s parent or guardian.   


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• 
Disease assessments may be performed up to 3 weeks* prior to 1RG-CART infusion for Dose 
Level 1, or up to 3 weeks* prior to commencement of lymphodepleting regimen for Dose Level 2 
onwards. These will include at a minimum: 
o 
Cross sectional imaging (magnetic resonance imaging [MRI] or computerised tomography 
[CT]) and ultrasound. 
o 
[123I]MIBG scintigraphy SPECT-CT.  For patients with [123I]MIBG non-avid tumours, 
consider use of [86Ga]dotatate PET-CT, [18F]FDG-PET-CT or technetium-99 (99mTc) bone 
scan. (Please see ‘List of abbreviations and definition of terms’ for explanation of 
abbreviations for imaging techniques.)  
o 
Bone marrow aspirate and trephine biopsy (mandatory for all patients); samples taken at 
the time of leukapheresis/venepuncture and falling outside of the 3 week window, do not 
need to be repeated (unless clinically indicated). 
 
  
*Disease assessments performed as part of the patient’s routine care prior to the patient’s 
provision of informed consent may be used for the trial if they were performed within the 4 weeks 
prior to 1RG-CART infusion for Dose Level 1, or commencement of lymphodepleting regimen for 
Dose Level 2 onwards. 
• 
Urine sample for assessment of catecholamines (homovallinic acid [HVA] and vanillylmandelic acid 
[VMA] to creatinine ratios). 
• 
Complete physical examination (including neurological, ophthalmological and dermatological 
examination). 
• 
For patients aged ≤18 years: weight and body surface area (BSA) using Children’s Cancer and 
Leukaemia Group (CCLG) standard tables in Appendix 10. For patients aged >18 years (or 
patients aged ≥13 years who are obese): weight, height and BSA (calculated using the Dubois & 
Dubois formula).  
• 
Blood samples for laboratory tests (on the day prior to T-cell infusion for Dose Level 1 or 
within 3 days prior to commencement of lymphodepleting regimen for Dose Levels 2 and 
above): 
o 
Haematology - haemoglobin (Hb), white blood cells (WBC) with a two point differential 
count (neutrophils and lymphocytes) and platelets. 
o 
Coagulation profile - activated partial thromboplastin time (aPTT), prothrombin time (PT), 
thrombin time (TT) and fibrinogen. 
o 
Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
creatine kinase, amylase and lipase. 
• 
Urinalysis by stick test: glucose, protein and blood. 
• 
Tumour biopsy (optional and only in patients with amenable extramedullary sites of disease). To be 
performed at the same time as the bone marrow biopsy if considered to be of insignificant 
additional risk and there is a high probability of obtaining representative tissues (samples taken at 
the time of leukapheresis/venepuncture and falling outside of the 3 week window, do not need to 
be repeated). Several needle cores of tumour should be biopsied in accordance with normal 
institutional diagnostic procedures. 
The following assessments should only to be reassessed if previous assessment was before 
Day -21 for Dose Level 1, or Day -25 for Dose Level 2, or Day -29 for Dose Levels 3 to 5: 


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• 
Estimated GFR. 
• 
Karnofsky performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if 
<16 years old, see Appendix 3). 
Adverse events and concomitant treatments: All patients should be assessed for AEs at every visit by 
the Investigator, Research Nurse or suitably qualified member of the Investigator’s team. The start and stop 
dates of the AE must be recorded in the medical records. All AEs must be graded according to NCI CTCAE 
Version 4.02 or trial specific grading scheme for CRS (Appendix 1). Any concomitant treatment must also 
be recorded in the medical records and eCRF (see Section 9 for further details regarding AE reporting 
requirements). 
7.2 
Evaluations During Lymphodepleting Regimen (Day -4 to Day -1 for Dose Level 2 or 
Day -8 to Day -4 for Dose Levels 3 to 5) 
• Physical examination: When clinically indicated, a symptom-directed physical examination 
(including neurological, ophthalmological and dermatological examination as clinically indicated) 
will be performed before administration of chemotherapy on each day (Day -4, Day -3, Day -2 and 
Day -1 for Dose Level 2; Day -8, Day -7, Day -6, Day -5 and Day -4 for Dose Level 3 onwards). 
• Vital signs: Temperature, pulse rate and blood pressure (BP) will be measured before 
administration of chemotherapy on each day. 
• Adverse events and concomitant treatments: Before each chemotherapy administration, an 
assessment of any AE experienced since the previous visit must be made. The start and stop 
dates of the AE together with the relationship of the event to the chemotherapy agent(s) must be 
recorded in the medical records. All AEs must be graded according to NCI CTCAE Version 4.02 or 
Appendix 1 for CRS. Any concomitant medications must also be recorded in the medical records 
and eCRF (see Section 9 for further details regarding AE reporting requirements). 
Please also refer to the tabulated Schedule of Assessments in Section 7.9.2. 
7.3 
Evaluations on Day 0 (1RG-CART Administration) 
• Physical examination: When clinically indicated, a symptom-directed physical examination 
(including neurological, ophthalmological and dermatological examination as clinically indicated) 
will be performed before 1RG-CART administration.  
• Vital signs: Temperature, pulse rate and BP will be measured prior to 1RG-CART administration 
and thereafter as clinically indicated but at least hourly until 12 hours post infusion. 
• Pain score (see Appendix 9): To be assessed prior to 1RG-CART administration. 
• Adverse events and concomitant treatments: To be assessed prior to 1RG-CART 
administration as detailed in Section 7.2. 
• Blood sample for quantification of 1RG-CART: before the 1RG-CART administration and 
4 hours post infusion. 
• Blood sample for measurement of HACARA: before the 1RG-CART administration. 
• Blood sample for safety monitoring (cytokines): before the 1RG-CART administration and 
4 hours post infusion: 
o 
2 mL serum blood sample for cytokines (including but not limited to TNF-α, IFN- and 
IL-6). Serum may be stored or run daily depending on the patient’s symptoms. In the 
event of fever or suspected cytokine storm the cytokine profile will be determined 


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immediately on a fresh serum sample and additional measurements will be taken as 
clinically indicated. 
o 
CRP. 
o 
LDH. 
o 
Urate. 
*Note: the timing of immune stimulation/cytokine release is not known and may occur after Day 14 
(or before Day 1). If so, assessments of cytokine release, and intensive monitoring of vital signs will 
start then.   
Please also refer to the tabulated Schedule of Assessments in Section 7.9.2. 
7.4 
Evaluations from Day 1 to Day 14 (Daily Assessments) & Day 18† 
Patients will be in-patients for the first 14 days after 1RG-CART infusion or resident within the vicinity of the 
hospital. During this time the patient will be monitored closely, at least daily. If a patient is given a split dose 
of 1RG-CART, the second part will be administered on Day 1 and all visits will be timed from administration 
of the first part of the dose on Day 0. The following minimum assessments will be performed (additional 
assessments should be performed as clinically indicated): 
• 
Physical examination: a symptom-directed physical examination (including neurological, 
ophthalmological and dermatological examination as clinically indicated) daily until Day 14.  If the 
1RG-CART dose is being split over two days, then the physical examination on Day 1 should be 
carried out before the second part of the 1RG-CART dose is given. 
• 
Vital signs*: Temperature, BP and pulse rate 24 hours after 1RG-CART administration (Day 1) 
and then daily until Day 14. If the 1RG-CART dose is being split over two days the:  
o 
Day 1 vital signs should be taken before 1RG-CART administration (this will be considered 
to be the 24 hour post Day 0 administration measurement) and thereafter as clinically 
indicated but at least hourly until 12 hours post infusion.  
o 
Day 2 vital signs should be taken 24 hours after 1RG-CART administration on Day 1. 
• 
Pain score (see Appendix 9): daily until Day 14. Thereafter as clinically indicated. If the 
1RG-CART dose is being split over two days, then the pain score on Day 1 should be assessed 
before the second part of the 1RG-CART dose is given. 
• 
Blood samples for haematology and biochemistry (see Section 7.1.2.2): 24 hours after 
1RG-CART administration (Day 1) and then daily until Day 14. At the Investigator’s discretion daily 
bloods may be omitted on two occasions during this period (but not on consecutive days) in 
patients who are clinically well and whose blood results are stable. 
• 
Urinalysis by stick test: daily until Day 14.  If the 1RG-CART dose is being split over two days, 
then the urinalysis on Day 1 should be carried out before the second part of the 1RG-CART dose is 
given. 
• 
Blood samples for coagulation profile (see Section 7.1.2.2): on Days 3, 7, 10 and 14. 
• 
Blood samples for safety monitoring (cytokines)*: to be taken on Days 1, 2 and 3, then at least 
on Days 5, 7, 10, 14 and 18†  or more frequently if clinically indicated (e.g. at the onset of fever or 
other clinical symptom suggesting possible immune activation/cytokine release): 
o 
2 mL serum blood sample for cytokines (including but not limited to TNF-α, IFN- and IL-6). 
Serum may be stored or run daily depending on the patient’s symptoms. In the event of 


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fever or suspected cytokine storm the cytokine profile will be determined immediately on a 
fresh serum sample and additional measurements will be taken as clinically indicated. 
o 
CRP. 
o 
LDH. 
o 
Urate. 
*Note: the timing of immune stimulation/cytokine release is not known and may occur after Day 14 
(or before Day 1). If so, scheduling for assessments of cytokine release, and intensive monitoring 
of vital signs will be appropriately adjusted.   
• 
Blood sample for quantification of 1RG-CART: at 24 hours post 1RG-CART administration 
(Day 1), then Days 2, 3, 5, 7, 10 and 14. If the 1RG-CART dose is being split over two days, then 
the sample on Day 1 should be taken before the second part of the 1RG-CART dose is given. 
• 
 
 
 
 
• 
Urine sample: for assessment of catecholamines on Day 14 only. 
• Adverse events and concomitant treatments: All patients should be assessed for AEs at every 
visit. The start and stop dates of the AE together with the relationship of the event to the 
chemotherapy agent(s) and / or 1RG-CART infusion (and rituximab where administered) must be 
recorded in the medical records. All AEs must be graded according to NCI CTCAE Version 4.02 or 
trial specific grading scheme for CRS (Appendix 1). Any concomitant medications must also be 
recorded in the medical records and eCRF. Cytokine release syndrome (CRS) events Grade 3 to 5 
should be reported as SAEs (see Section 9.2.2). Individual components of CRS (e.g. hypotension, 
rash, fever) do not need to be reported as SAEs, unless there is uncertainty about whether they are 
part of the CRS, but should be recorded as AEs in the eCRF and reported as being part of CRS. 
Significant sequelae of CRS (e.g. renal failure, cardiac failure, sepsis) should be reported as 
separate SAEs (see Section 9.2.2).   
 
  
Please also refer to the tabulated Schedule of Assessments in Section 7.9.2. 
7.5 
Evaluations on Days 21, 28, 35 and Day 42† (‘End of Treatment Assessment’) 
Patients will be monitored on Day 21 and then weekly until the ‘end of treatment visit’ on Day 42. The 
following minimum assessments will be performed at each visit (the patient may remain an in-patient and 
additional assessments may be performed as clinically indicated): 
• 
Physical examination: a symptom-directed physical examination (including neurological, 
ophthalmological and dermatological examination as clinically indicated).  
• 
Vital signs*: Temperature, BP and pulse rate. 
• 
Pain score (see Appendix 9): If clinically indicated. 
• 
Blood samples for haematology and biochemistry (see Section 7.1.2.2). 
• 
Urinalysis by stick test: as clinically indicated. 
• 
Blood samples for clotting (see Section 7.1.2.2). 


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• 
Blood samples for safety monitoring (cytokines)*: to be taken at least on Day 21 or more 
frequently if clinically indicated (e.g. at the onset of fever or other clinical symptom suggesting 
possible immune activation/cytokine release): 
o 
2 mL serum blood sample for cytokines (including but not limited to TNF-α, IFN- and IL-6). 
Serum may be stored or run daily depending on the patient’s symptoms. In the event of 
fever or suspected cytokine storm the cytokine profile will be determined immediately on a 
fresh serum sample and additional measurements will be taken as clinically indicated. 
o 
CRP. 
o 
LDH. 
o 
Urate. 
*Note: the timing of immune stimulation/cytokine release is not known and may occur after Day 21. 
If so, assessments of cytokine release, and intensive monitoring of vital signs will start then.   
• 
Blood sample for quantification of 1RG-CART. 
• 
 
• 
Urine sample: for assessment of catecholamines on Days 28 and 42 only. 
• 
Disease assessment: Bone marrow aspirate and trephine biopsy (mandatory for all patients), 
tumour dimensions (assessed using the same methods as at baseline) on Day 28 (±6 days) only. 
Samples of bone marrow may be stored and used for future exploratory assessment of MRD. 
• 
 
 
 
 
 
• 
 
• Adverse events and concomitant treatments: as detailed in Section 7.4. 
†Patients who commence the lymphodepleting regimen but do not go on to receive the 1RG-CART should 
be followed up until Day 42 (‘end of treatment visit’) or until resolution of any reversible toxicities; no 
follow-up visits are required thereafter. 
Please also refer to the tabulated Schedule of Assessments in Section 7.9.3. 
7.6 
Follow-Up Visits† (2 months to 2 years from Day 0) 
Follow-up visits will be performed at the following time points from administration of the 1RG-CART 
(Day 0):  2, 3, 4, 5 and 6 months, then 9, 12 and 24 months. The following assessments will be performed 
as indicated: 
• 
Physical examination: a symptom-directed physical examination including Karnofsky 
performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if <16 years 
old, see Appendix 3), and weight at each visit and including neurological, ophthalmological and 
dermatological examination as clinically indicated.  
• Blood sample for quantification of 1RG-CART:  at 2, 3, 4, 5, 6, 12 and 24 months. 
• 
 
 


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• 
 
 
 
• Blood samples for haematology and biochemistry (reduced set): at every visit. 
o 
Haematology – Hb, WBC with a two point differential count (neutrophils and lymphocytes), 
platelets 
o 
Biochemistry – sodium, potassium, urea, creatinine, bilirubin, ALP, ALT. 
• Disease assessment – imaging (using the same methods as at baseline): at 2 months, 
4 months, 12 and 24 months (or as clinically indicated). For patients who undergo surgical excision 
of residual disease, a response assessment should be documented in the eCRF before and after 
surgery.  
• Adverse events: assessment of any new or ongoing AEs considered possibly related to 
chemotherapy, 1RG-CART or rituximab (if given) will be performed at each visit. For patients with 
no evidence of residual circulating transduced T-cells who start a new anticancer therapy, 
collection of new AEs may cease. However, SAEs considered possibly related to trial therapy are 
always reportable regardless of the time elapsed. 
• Concomitant medications: assessment of concomitant treatments related to the AEs (see 
above). Assessment of concomitant medications may cease if collection of AEs stops (see above). 
Details of any new anti-cancer treatment started since the previous visit should be recorded. 
Note: the timing of immune stimulation/cytokine release is not known and may occur after the Day 42 (‘end 
of treatment visit’). If so, assessments of cytokine release and intensive monitoring of vital signs (as 
described in Sections 7.4 and 7.5) will start then. In the event of fever or suspected cytokine storm the 
cytokine profile will be determined immediately on a fresh serum sample and additional measurements will 
be taken as clinically indicated. 
†Patients who commence the lymphodepleting regimen but do not go on to receive the 1RG-CART should 
be followed up until Day 42 (‘end of treatment visit’) or until resolution of any reversible toxicities; no 
follow-up visits are required thereafter. 
Please also refer to the tabulated Schedule of Assessments in Section 7.9.3. 
7.7 
Follow-Up Visits (>2 years until the End of Trial) 
Follow-up visits will be performed annually (from administration of the 1RG-CART on Day 0).   
The following assessments will be performed as indicated: 
• 
Physical examination: a symptom-directed physical examination including Karnofsky 
performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if <16 years 
old, see Appendix 3) and including neurological, ophthalmological and dermatological examination 
as clinically indicated.  
• Blood sample for quantification of 1RG-CART. 
• Disease status: survival status, and if patient has progressed, date of progression. 
• Adverse events: assessment of any new or ongoing AEs considered possibly related to the 
1RG-CART or rituximab (if given). For patients with no evidence of residual circulating transduced 
T-cells who start a new anticancer therapy, collection of new AEs may cease. However, SAEs 
considered possibly related to trial therapy are always reportable regardless of the time elapsed. 
Please also refer to the tabulated Schedule of Assessments in Section 7.9.3. 


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7.8 
Patients Undergoing a Second Treatment with 1RG-CART 
Patients receiving a second treatment with 1RG-CART will undergo the assessments listed below and then 
repeat the assessments in Sections 7.2 to 7.7 according to their assigned treatment regimen. Patients 
having a second dose after a failed first dose must meet the criteria as detailed in Section 5.4.1.1. Patients 
having a second dose after a successful first dose must meet the criteria as detailed in Section 5.4.1.2. 
Patients having a second dose under other circumstances must meet the criteria as detailed in Section 
5.4.1.3. 
Within 14 days Prior to Leukapheresis/Venepuncture (only for patients in Dose Level 1 requiring a 
second manufacture):  
• 
Written informed consent for leukapheresis/venepuncture (this maybe done up to 28 days before 
leukapheresis).  
• 
Blood sample to assess suitability for leukapheresis/venepuncture, defined as: 
o 
Negative for HIV, HTLV 1, HTLV 2, syphilis and hepatitis B. 
o 
Minimum T-lymphocyte count of 0.25x109/L. 
o 
No detectable circulating 1RG-CART. 
• 
GFR (e.g. serum creatinine). 
• 
Karnofsky performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if 
<16 years old, see Appendix 3). 
• 
Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable). This test should be 
repeated if clinically indicated within 7 days prior to commencement of lymphodepletion. 
Within 21 days prior to planned 1RG-CART infusion (if no lymphodepletion is given) or 
commencement of lymphodepletion (ALL patients): 
• 
Written informed consent (patients must sign the main study consent form again; this may be done 
up to 28 days before the second dose is administered). 
• 
Complete physical examination (including neurological, ophthalmological and dermatological 
examination). 
• 
For patients aged ≤18 years: weight and BSA using CCLG standard tables in Appendix 10. For 
patients aged >18 years (or patients aged ≥13 years who are obese): weight, height and BSA 
(calculated using the Dubois & Dubois formula).  
• 
Karnofsky performance score (if ≥16 years old, see Appendix 4) or Lansky performance score (if 
<16 years old, see Appendix 3). 
• 
GFR (e.g. serum creatinine). 
• 
Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable) within 7 days prior to 
planned 1RG-CART infusion (if no lymphodepletion is given) or commencement of 
lymphodepletion.   
• 
Blood samples for laboratory tests: 
o 
Haematology – Hb, WBC with a two point differential count (neutrophils and lymphocytes) 
and platelets. 


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o 
Coagulation profile - aPTT, PT, TT and fibrinogen. 
o 
Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, creatinine, total 
protein, albumin, bilirubin, ALP, ALT, creatine kinase, amylase and lipase. 
• 
Urinalysis by stick test: glucose, protein and blood. 
• 
Urine sample for assessment of catecholamines (homovallinic acid [HVA] and vanillylmandelic acid 
[VMA] to creatinine ratios), unless these have been performed in the previous 4 weeks. 
• 
Adverse events: All patients should be assessed for AEs. All AEs must be graded according to 
NCI CTCAE Version 4.02 or Appendix 1 for CRS. Any concomitant medications must also be 
recorded in the medical records and eCRF. 
Ideally all patients receiving a second dose should also undergo a full disease assessment (including 
bone marrow aspirate and biopsy [optional]) to re-establish baseline measurements, unless these 
have been performed in the previous 4 weeks.  






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- Haematology – Hb, WBC with differential count (neutrophils and lymphocytes), platelets. 
- Coagulation profile - aPTT, PT, TT and fibrinogen. 
 
- Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, creatinine, total protein albumin, bilirubin, ALP, ALT, creatine kinase, amylase and lipase. 
(j)  Tumour biopsy: This is optional but should be performed wherever possible in patients with amenable extramedullary sites of disease. A biopsy should only be performed 
at the same time as the bone marrow biopsy if considered to be of insignificant additional risk and a high probability of obtaining representative tissues. Several needle cores 
of tumour should be biopsied in accordance with normal institutional diagnostic procedures. Confirmation of GD2 expression in the optional tumour biopsy or bone marrow 
sample (if involved with neuroblastoma) are alternatives to confirmation in a specimen taken at relapse/progression. 
(k)  Estimated GFR & Performance status:  Only to be reassessed if previous assessments were more than three weeks prior to commencing the 1RG-CART infusion for 
Dose Level 1 (i.e. before Day -21) or the lymphodepleting regimen for Dose Level 2 onwards (i.e. before Day -25 for Dose Level 2, Day -29 for Dose Levels 3 to 5). 




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(l)  Physical examination: a symptom directed physical examination (including neurological, ophthalmological and dermatological examination as clinically indicated) to be 
performed as clinically indicated prior to each administration of chemotherapy, i.e. on Days -4 to -1 for Dose Level 2, Days -8 to -4 for Dose Level 3 onwards. Then for all 
cohorts: prior to administration of 1RG-CART on Day 0, and daily until Day 14. If 1RG-CART is being given as a split dose, the physical examination on Day 1 should be 
performed prior to the second administration of 1RG-CART. 
(m) Vital signs:  Temperature, pulse rate and blood pressure (BP) will be performed prior to each administration of chemotherapy, i.e. on Days -4 to -1 for Dose Level 2, 
Days -8 to -4 for Dose Level 3 onwards. Then for all cohorts: prior to administration of 1RG-CART on Day 0 and then at least hourly (or more frequently if clinically indicated) 
until 12 hours post dose, then daily until Day 14. If the 1RG-CART is being given as a split dose: Day 1 vital signs should be taken before the second 1RG-CART 
administration and thereafter as clinically indicated but at least hourly until 12 hours post infusion. Day 2 vital signs should then be taken 24 hours after 1RG-CART 
administration on Day 1.  The timing of immune stimulation / cytokine release is not known, in the event of symptoms suggestive of cytokine release syndrome intensive vital 
signs monitoring will commence and continue as clinically indicated. 
(n) Pain score: to be performed prior to administration of 1RG-CART on Day 0 and daily until Day 14 (thereafter as clinically indicated). See Appendix 9. If 1RG-CART is 
being given as a split dose, the pain score on Day 1 should be performed prior to the second administration of 1RG-CART. 
(o)  Adverse events: Cytokine release syndrome (CRS) events Grade 3 to 5 should be reported as SAEs (see Section 9.2.2). Individual components of CRS (e.g. 
hypotension, rash, fever) do not need to be reported as SAEs unless there is uncertainty about whether they are part of CRS, but should be recorded as AEs in the eCRF 
and reported as being part of CRS. Significant sequelae of CRS (e.g. renal failure, cardiac failure, sepsis) should be reported as separate SAEs (see Section 9.2.2). 
(p)  Bloods for safety monitoring (cytokines, CRP, LDH and urate) will be taken at least on Day 0 (prior to 1RG-CART infusion and 4 hours post infusion), 1, 2, 3, 5, 7, 10, 14 
and 18†. The timing of immune stimulation / cytokine release is not known, in the event of symptoms suggestive of cytokine release syndrome blood samples for assessment 
of cytokines, CRP, LDH and urate will be taken as clinically indicated. 
(q)  Bloods for quantification of 1RG-CART:  To be performed on Day 0 prior to 1RG-CART and 4 hours post infusion, then 24 hours post infusion (Day 1), and on Days 2 
(±12 h), 3 (±12 h), 5, 7, 10 and 14 (±1 day).  If 1RG-CART is being given as a split dose, the sample on Day 1 should be taken prior to the second administration of 
1RG-CART. 
 
(s)  ATIMP/IMPs to be given as follows (dosing for expansion cohort to be defined during the dose escalation part of the trial): 
- Cyclophosphamide:  To be given on Days -4 to -1 for Dose Level 2 and Days -8 to -4 for Dose Level 3 onwards. 
- Fludarabine:  To be given on Days -8 to -4 for Dose Level 3 onwards. (Fludarabine to be given first on days when given with cyclophosphamide.) 
- 1RG-CART:  To be given on Day 0 for all cohorts. In order to administer the higher doses of 1RG-CART in Dose Level 5, it may be necessary to split the dose 
over two consecutive days (Day 0 and Day 1).      
*Patients receiving a second dose of 1RG-CART will repeat the assessments tabulated in Section 7.9.2 (and described in Sections 7.2 to 7.7) according to the 
treatment regimen assigned. 




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(t)  Physical examination: a symptom directed physical examination (including neurological, ophthalmological and dermatological examination as clinically indicated) to be 
performed on Days 21, 28, 35 and 42, then at 2, 3, 4, 5, 6, 9, 12 and 24 months and then annually until the End of the Trial.   
(u) Vital signs:  Temperature, pulse rate and blood pressure (BP) will be performed on Days 21, 28, 35 and 42. The timing of immune stimulation / cytokine release is not 
known, in the event of symptoms suggestive of cytokine release syndrome intensive vital monitoring will commence and continue as clinically indicated. 
(v)  Adverse events / concomitant medications: Once the patient is in follow-up (from 2 months until the End of the Trial) only new or ongoing adverse events considered 
possibly, probably or definitely related to chemotherapy or 1RG-CART need to be assessed. For patients with no evidence of residual circulating transduced T-cells who start 
a new anti-cancer therapy, collection of new AEs may cease. However, SAEs considered related to trial therapy are always reportable regardless of the time elapsed. Only 
concomitant medications related to the AEs which require reporting (see above) and details of any new anti-cancer treatment (up until the 2 year follow-up visit) should be 
recorded. 
Cytokine release syndrome (CRS) events Grade 3 to 5 should be reported as SAEs (see Section 9.2.2). Individual components of CRS (e.g. hypotension, rash, fever) do not 
need to be reported as SAEs unless there is uncertainty about whether they are part of CRS, but should be recorded as AEs in the eCRF and reported as being part of CRS. 
Significant sequelae of CRS (e.g. renal failure, cardiac failure, sepsis) should be reported as separate SAEs (see Section 9.2.2). 
(w)  Bloods for safety monitoring (cytokines, CRP, LDH and urate) will be taken at least on Day 21. The timing of immune stimulation / cytokine release is not known, in the 
event of symptoms suggestive of cytokine release syndrome blood samples for assessment of cytokines, CRP, LDH and urate will be taken as clinically indicated. 
(x)   Bloods for quantification of 1RG-CART: To be performed: 
 
- on Days 21, 28, 35 and 42 (±2 days). 
 
- at 2, 3, 4, 5, 6 and 12 months (±1 week). 
 
- at 24 months (±2 weeks). 
 
- annually until the End of the Trial (±2 weeks). 
(y)  Bloods for haematology and biochemistry:  Only a reduced set of bloods is required at 2, 3, 4, 5, 6, 9, 12 and 24 months as follows: 
 
Haematology – Hb, WBC with differential (neutrophils and lymphocytes), platelets. 
 
Biochemistry – sodium, potassium, urea, creatinine, bilirubin, ALP, ALT. 
(z)  Bone marrow aspirate and biopsy / tumour assessment (imaging):  
Bone marrow aspirate and biopsy - To be performed on Day 28 (±6 days), then at 2 and 4 months (only for patients with evidence of disease or 1RG-CART in the 
bone marrow on previous assessment). 
 
Disease assessment (imaging – using the same methods as at baseline) - To be performed on Day 28 (±6 days), then at 2, 4, 12 and 24 months from Day 0 (or as 
clinically indicated). 
Patients who undergo surgical excision of residual disease require a response assessment eCRF page to be completed before and after surgery. 
 
 


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8 
PHARMACODYNAMIC ASSESSMENTS  
Please refer to the 1RG-CART Laboratory Manual for detailed instructions. 
Sample collection schemes may be revised during the trial upon collection of more pharmacodynamic 
data. 
8.1 
Secondary Assessments 
8.1.1 
Estimation of 1RG-CART Counts in Peripheral Blood (Flow Cytometry) 
Circulating transduced T-cells will be measured by flow cytometry using whole blood, according to 
agreed SOPs and validated methods. 
5 mL of blood will be collected into ethylenediaminetetraacetic acid (EDTA) tubes from all patients at 
the following time points: 
• 
Day 0 (pre-infusion and 4 hours post end of infusion) 
• 
Day 1 (24 hours post end of infusion) 
• 
Days 2, 3 (±12 h) 
• 
Days 5, 7, 10, 14 (±1 day) 
• 
Days 21, 28, 35 and 42 (±2 days) 
• 
At 2, 3, 4, 5, 6, 12 (±1 week) and 24 months (±2 weeks)   
• 
Annually until the End of the Trial (±2 weeks) 
The approximate total volume of blood withdrawn from each patient (in the first two years of the trial) 
for these samples will be 100 mL. 
The fluorescence activated cell sorting (FACS) assay generates data in terms of percentage of 
transduced cells per mL of whole blood. 
Please refer to the 1RG-CART Laboratory Manual for handling and storage of samples. 
8.2 
Tertiary/Research Assessments 
8.2.1 
 
 
 
 
  
 
 
 


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8.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3 
 
 
 
  
 
 
   
8.2.4 
 
 
 
 
 
  
 
 
 


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8.2.5 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
8.3 
Additional Research Assays for Safety / Eligibility / Disease Monitoring 
8.3.1 
Serum Cytokine Profiles (Safety Monitoring) 
Serum cytokine profile (minimum dataset of TNF-α, IFN-, and IL-6) will be measured in 2 mL of 
serum using cytokine bead array (Becton Dickinson). Serum samples will be frozen for cytokine 
measurements as follows: 
• 
Day 0 (pre-infusion and 4 hours post end of infusion),  
• 
Day 1 (24 hours post end of infusion) and then 
• 
Days 2, 3, 5, 7, 10, 14, 18 (timing of this sample may vary depending on when 1RG-CART 
levels in the blood peak) and 21.  
Samples will be analysed as a single test set. In the event of fever or suspected cytokine storm the 
cytokine profile will be determined immediately on a fresh serum sample and additional measurements 
will be taken as clinically indicated. 
The minimum approximate total volume of blood withdrawn from each patient for these samples will 
be 22 mL. However, in the event of fever or suspected cytokine storm additional samples will be 
collected as required to ensure the safety of the patient. 
Please refer to the 1RG-CART Laboratory Manual for handling and storage of samples. 
8.3.2 
GD2 Expression in Tumour Biopsies / Bone Marrow (Eligibility & Disease Monitoring) 
GD2 expression will be evaluated by immunohistochemistry performed on tissue from existing tumour 
samples (collected as part of routine care at the time of disease relapse/progression) and the optional 
tumour biopsies taken as part of the study at pre-treatment and on Day 28 (±6 days), for the 
estimation of 1RG-CART as detailed in Section 8.2.4.  
Alternatively, GD2 expression will be assessed on tumour detected in bone marrow trephines taken as 
part of routine clinical assessment. GD2 expression will be evaluated by immunohistochemistry or 
other techniques according to agreed SOPs and methods. 


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9 
ASSESSMENT OF SAFETY 
9.1 
Investigator Responsibilities 
The Investigator is responsible for monitoring the safety of patients who have enrolled in the trial and 
for accurately documenting and reporting information as described in the following sections.   
9.1.1 
Medical Cover 
The CI/PI is responsible for ensuring patients have access to 24 hour advice and/or care. Patients will 
be provided with the necessary contact numbers for both normal working and out of hours care. A 
copy of the protocol must be made available out of hours to ward staff and clinicians on call so that the 
appropriate advice may be given to the patient, the patient’s relative or other care giver (for example 
GP). The CI/PI must ensure that should the on call clinician or ward staff require more advice than is 
in this protocol, that they have access to the Investigator or delegated members of the investigator’s 
team who can answer any questions.   
9.2 
Adverse Event Definitions 
9.2.1 
Adverse Event 
An AE is any untoward, undesired or unplanned occurrence in a patient administered an IMP, a 
comparator product or an approved drug.   
An AE can be a sign, symptom, disease, and/or laboratory or physiological observation that may or 
may not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition. This includes conditions that may 
resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious or if the Investigator suspects that the IMP has contributed to 
disease progression. 
Other reportable events that must be treated as AEs are listed below:   
• 
Pregnancy exposure to the IMP. Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration (12 
months for female patients who become pregnant after receiving cyclophosphamide or 
rituximab), must be reported to the Pharmacovigilance Department (PV) in the same timelines 
as an SAE. These should be reported even if the patient is withdrawn from the trial. 
• 
Overdose with or without an AE (any dose above that specified in the protocol, not necessarily 
intentional). 
• 
Medication error (any unintentional error in the dispensing or administration of an IMP). 
• 
Occupational exposure / accidental exposure (to a person other than the patient, for example 
spilling of IMP on hands of nurse or splashing in the eye). 
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct 
of the trial. 
Any occurrence of these events should be reported in the same manner as SAEs (see Section 9.4). 


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9.2.2 
Serious Adverse Events 
A SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening^; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – e.g. hospital admissions planned prior to the 
patient entering the trial; overnight stays for planned procedures such a blood transfusions 
(Section 9.4.1); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event.* 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather 
than reporting death as the SAE term.  When available the autopsy report will be provided to the 
Sponsor. 
^ A life-threatening event is defined as an event when the patient was at substantial risk of dying at the 
time of the adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient. 
*A medically important event is defined as any event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above.  Examples include allergic bronchospasm (a 
serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias 
(blood disorders) or seizures/convulsions that do not result in hospitalisation. The development of drug 
dependence or drug abuse would also be examples of important medical events. 
Trial–specific medically important events 
For this trial any event which meets the definition of a DLT (as defined in Section 3.4) or requires the 
administration of rituximab should be reported as a SAE.   
Grade 3 to 5 CRS events should be reported as medically important events, if they do not satisfy the 
other criteria for an SAE. Individual components (e.g. hypotension, rash, fever), should not be reported 
as individual SAEs, unless there is uncertainty about whether they are part of the CRS. However, 
significant sequelae (e.g. renal failure, cardiac failure, sepsis) should be reported as separate SAEs.  
If during the course of the study, additional medically important events are identified, these will be 
communicated to site and the protocol will be updated to reflect this. 
9.2.3 
Suspected, Unexpected, Serious Adverse Reactions 
A SUSAR is a suspected, unexpected, serious adverse reaction. All AEs and SAEs will be assessed 
by the Sponsor for seriousness, causality and expectedness. The Sponsor’s PV Department will 
expedite all SUSARs to the relevant Competent Authority/Authorities and the relevant Ethics 
Committee(s) within the timelines specified in legislation (SI 2004/1031 as amended).  


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Determining Adverse Event Causality 
The relationship of an AE to the IMPs (1RG-CART/cyclophosphamide/fludarabine) and/or NIMPs 
(rituximab/antihistamine) is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not likely 
to have had an association with the observed effect. 
Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc) and must provide his/her opinion of the causal 
relationship between each AE and IMP. This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking 
a further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the 
IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
IMP blood levels and evidence, if any, of overdose. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to 
the adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
9.2.4 
Expectedness 
Assessment of expectedness for 1RG-CART will be made by the PV Department against the current 
version of the 1RG-CART IB. Expectedness for cyclophosphamide, fludarabine, rituximab and the 
antihistamine will be made against their respective SmPCs. 


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9.3 
Collection of Safety Information 
9.3.1 
Screening Failures 
For patients who fail screening (for leukapheresis or the main study), SAEs must be reported to the 
PV Department from the date of first consent until the date the patient is confirmed as ineligible. 
9.3.2 
Eligible Patients 
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient 
gives their written consent to undergo trial-specific leukapheresis.  
For patients who receive 1RG-CART, monitoring will continue until they withdraw from the trial or the 
trial ends (whichever comes first).  However, once patients enter the follow up phase of the study (2 
months to 2 years from 1RG-CART administration) only new and ongoing AEs considered related 
(possible, probable or highly probable) to chemotherapy, 1RG-CART or rituximab (if given) will be 
collected.  Once a patient has completed the 24 month visit, only AEs related to 1RG-CART (or 
rituximab, if given) will be collected.  For patients with no evidence of residual circulating transduced 
T-cells who start a new anticancer therapy, collection of new AEs may cease. 
For patients who commence the lymphodepleting regimen but do not go on to receive 1RG-CART, 
monitoring will continue until the Day 42 ‘end of treatment visit’ or until resolution of any reversible 
toxicities.   
Should an Investigator become aware of any drug-related SAEs after the patient has completed the 
protocol-mandated follow-up period (as specified above), these must also be reported to the Sponsor 
within the expedited timelines in Section 9.4. 
9.3.3 
Follow-Up of AEs and SAEs 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve or stabilise.   
The Sponsor’s PV Department will make requests for further information on SAEs to the trial site at 
regular intervals. Requested follow-up information should be reported to the PV Department in a timely 
manner and as soon as possible after receipt of the follow-up request. For fatal or life-threatening 
cases, follow-up information must be reported to the PV Department as soon as possible. 
9.4 
Reporting of SAEs to the Sponsor’s Pharmacovigilance Department 
All SAEs, regardless of causality, must be reported to the PV Department in an expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided.  
The SAE report form should be emailed to Pharmacovigilance Department within 24 hours of 
site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form. The NCI CTCAE 
Version 4.02 (or Appendix 1 for CRS) must be used to grade each SAE, and the worst grade 
recorded. If new or amended information on a previously reported SAE becomes available, the 
Investigator should report this to the PV Department on a new SAE report form.  
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
to the form when sending the SAE report to the PV Department. 
Should the investigator become aware of any drug-related SAEs after the patient has withdrawn from 
the study, these must also be reported to the PV Department within the timelines specified above. 


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9.4.1 
Events Exempt from being Reported as SAEs to the Pharmacovigilance Department 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed. The events must still be recorded 
in the appropriate section of the eCRF. 
Elective admissions – Elective admissions to hospital for planned procedures or for primarily social 
reasons or convenience are not SAEs, and do not require SAE reporting. Hospitalisation for 
administration of the IMP according to the trial protocol is also exempt from being reported as an SAE. 
However, if during hospitalisation for IMP administration the patient experiences an adverse event that 
would normally qualify as an SAE, this event should still be reported as an SAE. 
Death due to disease progression – cases of death due to disease progression do not require SAE 
reporting, unless considered related to an IMP. 
9.5 
Recording of Adverse Events and Serious Adverse Events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients. This includes AEs/SAEs 
attributable to 1RG-CART, cyclophosphamide, fludarabine or rituximab. All concomitant medications, 
including herbal medications and supplements must be recorded (herbal, homeopathic agents or food 
supplements are not allowed between Day -10 and Day 20 unless recommended by the PI). Any 
therapy used to treat the event must be recorded. The eCRF will be reconciled with the safety 
database during and at the end of the trial. Therefore, the sites should ensure the data entered on the 
SAE report form and the data entered into the eCRF are consistent. The Sponsor’s Medical Advisor 
and the Investigator(s) will regularly review the safety data from both the safety and the clinical 
database. 
9.6 
Urgent Safety Measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety. This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulatory Agency (MHRA) and the main Research Ethics 
Committee (REC) must be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
 
 
 
 
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the REC within three days of USM initiation.   


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9.7 
Pregnancy 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for six months after the last IMP 
administration. For female patients who receive cyclophosphamide or rituximab, the contraceptive 
period should be extended to 12 months after cyclophosphamide/rituximab administration.  Where 
appropriate, this should be done as part of the consent process by explaining clearly to the patient 
and/or their parent or guardian the potential dangers of becoming pregnant and also providing each 
patient with information about appropriate medically approved contraception. Where appropriate, two 
forms of medically approved contraception should be used, such as:   
• 
oral contraceptives and condom; 
• 
intra-uterine device and condom; 
• 
diaphragms with spermicidal gel and condom. 
Contraception should be effective before the patient is enrolled on the trial, throughout the trial and for 
six months after the last IMP administration (in female patients receiving cyclophosphamide or 
rituximab it should be extended to 12 months after cyclophosphamide/rituximab administration). 
Where appropriate, it should be explained to the patient and/or patient’s parent or guardian that if his 
partner is pregnant or breast-feeding when he is enrolled on the trial, the patient should use barrier 
method contraception (condom plus spermicidal gel) to prevent the unborn baby or the baby being 
exposed to the trial treatment.  
However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within six months of last IMP administration (or 12 months from last administration of 
cyclophosphamide or rituximab for female patients) must be reported to the PV Department within 
24 hours of the site staff becoming aware of it using a Pregnancy Form. It is the Investigator’s 
responsibility to obtain consent for follow-up from the patient or patient’s partner and/or their parent or 
guardian. In addition, the Investigator must be made aware of the need to obtain contact details for the 
patient’s partner’s General Practitioner.  The PV Department will follow-up all pregnancies for the 
pregnancy outcome via the Investigator, using a Pregnancy Form.  
The Investigator must ensure that all patients and/or the patient’s parent or guardian are aware at the 
start of a clinical trial of the importance of reporting all pregnancies (in themselves and their partners) 
that occur whilst being treated with the IMP and occurring up to six months after the last IMP 
administration (or 12 months from last administration of cyclophosphamide or rituximab for female 
patients). The Investigator should offer counselling to the patient and/or the partner, and discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the patient 
or partner should continue until the conclusion of the pregnancy, if the patient or patient’s partner (or 
their parent or guardian) has consented to this. Monitoring of the baby should continue until 12 months 
after birth, if the patient or patient’s partner (or their parent or guardian) has consented to this.  


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10 
ASSESSMENT OF EFFICACY 
In this trial, response will be assessed using RECIST 1.1 criteria ([53]; see Appendix 6), 
immune-related Response Criteria (irRC) ([54], 2009; see Appendix 7), and International 
Neuroblastoma Response Criteria (INRC) ([55]; see Appendix 8).In order to satisfy the requirements 
of all three response criteria, please follow the guidelines outlined in the sections below and in 
Appendices 6, 7 and 8. 
10.1 Measurement of Disease 
Key features of the three sets of response criteria (as published) are summarised in the table below. 
 
RECIST 1.1 
irRC 
INRC 
Key reference 
[53] 
[54] 
[55] 
Types of lesions 
identified at baseline 
Target & non-target 
Index and non-index 
Primary and metastases 
Measurements of 
measurable lesions 
One dimension (longest 
diameter) 
Two dimensions 
(longest perpendicular 
diameters) 
Three dimensions 
(volume, not otherwise 
specified) 
Number of lesions 
measured at baseline 
Maximum of 5 (maximum 
of 2 lesions per organ) 
5 lesions per organ, up to 
10 visceral lesions total 
and 5 cutaneous lesions 
Not specified 
Minimum size of 
measurable lesion at 
baseline 
10 mm (15 mm for lymph 
nodes, 20 mm for CXR) 
Not specified (but 
presumed to be 
≥5x5 mm)  
Not specified 
New lesions 
Considered progressive 
disease 
If measurable (≥5x5 mm) 
added to tumour burden; 
up to 5 new lesions per 
organ; 5 new cutaneous 
lesions ,and 10 visceral 
lesions 
Considered progressive disease 
Response categories 
CR, PR, SD and PD 
CR, PR, SD and PD 
CR, VGPR, PR, MR, NR and 
PD 
Key differences in PR 
criteria: 
Requires 30% reduction 
in sum of diameters of 
target lesions, confirmed 
>4 weeks later 
Requires decrease in 
tumour burden ≥50% 
relative to baseline, 
confirmed >4 weeks later 
Two categories of PR based on 
separate measurements of 
primary tumour and individual 
metastases 
Key differences in SD 
criteria: 
Neither PR nor PD by 
RECIST 1.1 
Neither PR nor PD by 
irRC 
Divided into MR and NR; some 
MRs would be PR by 
RECIST 1.1 or irRC 
Key differences in PD 
criteria 
Requires a 20% increase 
in the sum of diameters 
of target lesions or any 
new lesion (no 
confirmation required) 
Requires increase in 
tumour burden ≥25% 
relative to nadir, 
confirmed >4 weeks later 
Requires an increase in any 
measurable lesion by >25% or 
any new lesion or a positive 
bone marrow after a previous 
negative marrow. Progression 
within 4 months = PD 
regardless of interim PR/CR 
and no confirmation required 
Other differences in 
response criteria 
Bone marrow and 
catecholamines not 
specifically covered 
Bone marrow and 
catecholamines not 
specifically covered 
Bone marrow and 
catecholamines specifically 
included in response criteria 
Abbreviations: CR=complete response; CXR= chest x-ray; MR=mixed response; NR= no response; 
PD=progressive disease; PR=partial response; SD=stable disease; VGPR= very good partial response 


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In this trial, in order to simplify data collection and verification, and to facilitate data analysis: 
• 
Bidimensional lesion measurements will be collected for all lesions that are bidimensionally 
measurable according to irRC criteria at baseline (i.e. ≥5x5 mm). Measurements will be 
collected for a maximum of 5 lesions per organ, including up to 10 visceral lesions in total, and 
5 cutaneous lesions (index lesions). 
• 
Bidimensional lesion measurements will be collected for all measurable new lesions (i.e. those 
measuring i.e. ≥5x5 mm). 
• 
Bidimensional lesion measurements (including baseline/index and new lesion measurements) 
will be used to calculate response and progression according to irRC criteria. 
• 
Bidimensional lesion measurements of baseline/index lesions will be used to calculate 
response and progression according to INRC criteria. 
• 
Target lesions will be selected from the index lesions based on RECIST 1.1 criteria. A 
maximum of 5 lesions (2 per organ) will be selected based on the longest diameter measured 
and other RECIST 1.1 criteria (see Appendix 6). 
• 
Target lesion diameters will be used to assess response according to RECIST 1.1 criteria. 
• 
Bone marrow and catecholamine data will be used in the assessment of CR, PR and PD 
according to INRC, and bone marrow and catecholamine data will be used in the assessment 
of CR according to RECIST 1.1 and irRC.  
• 
Whenever possible, patients with progressive disease (by any criteria) should have a 
confirmatory assessment at least 4 weeks later. 
• 
Patients with a PR or CR should have a confirmatory assessment at least 4 weeks later. 
10.2 Timing and Type of Tumour Assessments 
A thorough clinical and radiological evaluation of malignancy, as judged appropriate by the 
Investigator, and in line with the protocol, must be performed before a patient receives their first dose 
of 1RG-CART or lymphodepleting regimen (whichever comes first).   
Whenever possible, the same methods of lesion assessment at baseline must be used to follow these 
lesions throughout the trial. To ensure compatibility, the radiological assessments used to assess 
response must be performed using identical techniques. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the anti-tumour 
effect of a treatment. 
All baseline radiological assessments must be performed within three weeks before receiving 
1RG-CART or lymphodepleting regimen (whichever comes first), unless they were performed as part 
of the patient’s routine care, in which case they may be performed within four weeks before 
commencing treatment.   
All clinical measurements to assess response must be performed within one week before the patient’s 
first dose of 1RG-CART or lymphodepleting regimen (whichever comes first). 
Copies of the scans must be available for external independent review if requested by the Sponsor. 
10.2.1 Baseline Evaluations 
These must include radiological measurements and as indicated chest computerised tomography (CT) 
scan or magnetic resonance imaging (MRI), abdominal CT scan or MRI, bone scan and/or clinical 
measurements as appropriate. All areas of disease present must be documented (even if specific 
lesions are not going to be followed for response) and the measurements of all measurable lesions 
must be recorded clearly on the scan reports. Any non-measurable lesions must be stated as being 
present. For clinical measurements, documentation by colour photography including a ruler to 
estimate the size of the lesion is strongly recommended, as this aids external independent review of 
responses.  


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10.2.2 Evaluations During and at ‘Off-Study’ 
Tumour assessments must be repeated on Day 28 (±6 days) and at 2, 4, 12 and 24 months post 
1RG-CART administration or more frequently, when clinically indicated. All lesions measured at 
baseline must be measured at every subsequent disease assessment, and recorded clearly on the 
scan reports. All non-measurable lesions noted at baseline must be noted on the scan report as 
present or absent. 
All patients, who are removed from the trial for reasons other than progressive disease, must be 
re-evaluated at the time of treatment discontinuation, unless a tumour assessment were performed 
within the previous four weeks. 
It is the responsibility of the PI to ensure that the radiologists are aware of the requirement to follow-up 
and measure every measurable/index/target lesion mentioned at baseline and comment on the other 
lesions in accordance with RECIST 1.1, irRC and INRC criteria. 
10.3 Tumour Response 
All patients who receive at least one dose of 1RG-CART and who have a baseline and at least one 
post-treatment assessment of disease will be evaluable for response. Patients who experience clear 
disease progression without a formal post-treatment disease assessment will be considered 
non-responders. To be assigned a status of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once and at least six weeks after the initial dose of the 1RG-CART is 
given. 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it 
under another response category, for example, when baseline and/or follow-up assessment is not 
performed or not performed appropriately.  
Expert reviewers appointed by the Sponsor may undertake an independent review of the Investigator’s 
assessed objective responses (CR and PR). The expert reviewers will include at least one specialist 
who is not an Investigator in the trial. In case of disagreement between the Investigator’s and the 
expert reviewers’ assessment, the Sponsor’s assessment will be used to make any decisions with 
regard to recruitment etc. The independent reviewer’s assessment will also be documented in the final 
clinical study report (CSR) along with the original assessment made by the Investigator. The eCRF will 
reflect the Investigator’s opinion. 
10.3.1 Recording of Response in the eCRF 
The applicable overall response category (for RECIST, irRC and INRC) for each visit that includes 
disease assessment must be recorded in the eCRF. The overall response category for RECIST (see 
Appendix 6), irRC (see Appendix 7) and INRC (see Appendix 8) should also be documented in the 
eCRF. 
10.4 Overall Survival and Progression-Free Survival 
10.4.1 Overall Survival 
All patients who receive 1RG-CART will be evaluable for overall survival, regardless of whether they 
subsequently receive other anti-cancer treatments. Overall survival will be measured from the date of 
administration of the first dose of 1RG-CART. Since only limited follow-up (until Day 42) is planned for 
patients who receive the lymphodepleting regimen only, these patients will not be included in analyses 
of overall survival unless the patient’s death is considered primarily due to the lymphodepleting 
regimen.   
10.4.2 Progression-Free Survival 
All patients who receive 1RG-CART and who complete a baseline and at least one post-treatment 
disease assessment (or experience clear disease progression without a formal post-treatment disease 


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assessment) will be evaluable for progression-free survival, regardless of whether they subsequently 
receive other anti-cancer treatments. This will be assessed according to all three tumour response 
criteria (RECIST 1.1, irRC and INRC). Progression-free survival will be measured from the date of 
administration of the first dose of 1RG-CART. Since only limited follow-up (until Day 42) is planned for 
patients who receive the lymphodepleting regimen only, these patients will not be included in analyses 
of progression-free survival unless there is clear evidence of disease progression in the 42-day 
follow-up period or the patient’s death is considered primarily due to the lymphodepleting regimen. 


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PATIENT WITHDRAWAL BEFORE THE END OF THE TRIAL 
Due to the possibility that the 1RG-CART may persist for many years, patients who are given the 
transduced T-cells should remain on the trial until the End of Trial is declared, at which time they will 
be re-enrolled and consented to a follow-on protocol (see Section 12). The Investigator must make 
every reasonable effort to keep each patient given 1RG-CART on the trial in order to collect long-term 
safety data. The main justifiable reasons for a patient to be withdrawn from the trial after 
administration of 1RG-CART are: 
• 
Withdrawal of consent;  
• 
Loss to follow-up; 
However, patients with progressive disease necessitating alternative anti-cancer treatment may be 
withdrawn from the trial (and long-term follow-up) if there are no detectable transduced T-cells in the 
peripheral blood and maintaining follow-up is difficult. 
Patients who commence the lymphodepleting regimen but do not go on to receive the 1RG-CART 
should be assessed as clinically indicated (including weekly haematology and biochemistry samples) 
until Day 42 (‘end of treatment’ visit) or until resolution of any reversible toxicities; no follow-up visits 
are required thereafter. The results of the evaluations and observations, treatment for AEs/SAEs and 
a description of the reasons for stopping study treatment, should be recorded in the medical records 
and eCRF. 
Patients who do not commence the lymphodepleting regimen and do not receive the 1RG-CART 
infusion will be followed at the Investigator’s discretion according to routine clinical practice until 
resolution/stabilisation of any AEs related to trial-related procedures. 


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12 
DEFINING THE END OF TRIAL  
The ‘End of Trial’ is defined as the date when all patients have either withdrawn (see Section 11) from 
the trial or died, or the last patient to receive an infusion of 1RG-CART has completed the 24 month 
follow-up visit (following their last administration of 1RG-CART).   
Patients remaining on trial at the time the End of Trial is declared will be re-enrolled and consented to 
a follow-on protocol which will continue to follow-up patients annually for at least 15 years after their 
last dose of 1RG-CART. This protocol will be independently submitted for MHRA and REC approval 
as required, at an appropriate time to ensure a seamless opening and transfer of patients following 
closure of the current trial. 
It is the responsibility of the Sponsor to inform the MHRA and the Main REC within 90 days of the ‘End 
of the Trial’ that the trial has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the 
Sponsor, the Sponsor will notify the MHRA and the Main REC within 15 days of the decision and a 
detailed, written explanation for the termination/halt will be given. 
The entire trial will be stopped when: 
• 
The drug is considered too toxic to continue treatment before the required number of patients 
have been recruited. Examples of unacceptable toxicity that could lead to premature 
termination of the trial include the following: 
➢ 
One fatal DLT in Dose Level 1; 
➢ 
Non-fatal DLTs in one or more patients in Dose Level 1; 
➢ 
Major toxicities (but not amounting to DLTs) in all or most patients in Dose Levels 1 to 
5 without evidence of engraftment or anti-tumour efficacy.    
• 
Failure of engraftment with no evidence of anti-tumour efficacy in Dose Levels 1 to 5 (i.e. 
expansion phase will not commence) 
• 
The stated number of patients to be recruited is reached and the stated objectives of the trial 
are achieved or all patients have died. 
Regardless of the reason for termination, all data available for the patient at the time of discontinuation 
of follow-up must be recorded in the eCRF. All reasons for discontinuation of treatment must be 
documented.   
In terminating the trial, the Sponsor and the Investigator(s) must ensure that adequate consideration is 
given to the protection of the patient’s interest. 


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DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The final analysis will be conducted after one of the following conditions is met. 
• 
The trial is terminated early (for example, due to toxicity). 
• 
All patients have either withdrawn from the trial (see Section 11) or the last patient to receive 
an infusion of 1RG-CART has completed their 24 month follow-up visit (following their last 
administration of 1RG-CART). 
Once one of the above conditions is met, a data cut-off date will be established. All patient visits 
occurring on or before this date will be analysed and summarised in the final CSR. Any data collected 
after this date will be summarised in supplemental reports. 
13.1 Presentation of Data 
Data will be presented in a descriptive fashion. Variables will be analysed to determine whether the 
criteria for the trial conduct are met. This will include a description of patients who did not meet all the 
eligibility criteria, an assessment of protocol violations, IMP accountability and other data that impact 
on the general conduct of the trial. 
Baseline characteristics will be summarised for all enrolled patients. Patients who died or withdrew 
before treatment started or did not complete the required safety observations will be described and 
evaluated separately. 
Treatment administration will be described for all patients who receive at least one dose of 
lymphodepleting treatment and/or 1RG-CART. Dose administration, dose modifications or delays and 
the duration of therapy will be described. 
13.2 Feasibility of 1RG-CART Therapy 
One of the primary objectives of the study is to assess the feasibility of 1RG-CART therapy in patients 
with relapsed or refractory neuroblastoma. This will be assessed as the percentage of patients 
entering the study (i.e. enrolled for leukapheresis / venepuncture) who undergo evaluation of 
1RG-CART survival on or after Day 14. For 1RG-CART therapy to be considered feasible, it is 
proposed that at least 50% of patients must be assessed for 1RG-CART at this time point or later. 
This is a composite endpoint and failure to reach this assessment could be due to a number of factors, 
including but not limited to: failure of viral transduction, lack of viable transduced cells after the 
thawing, toxicity due to the conditioning regimen, early death or rapid disease progression. 
For every patient who enters the trial (defined as enrolling for leukapheresis/venepuncture and 
modification of T-cells) and fails to undergo evaluation of 1RG-CART survival on or after Day 14, the 
reason for failure will be collected in the eCRF. The reasons will be collected as tick boxes (for the 
most likely reasons - disease progression, death, inadequate T-cell harvest etc) and free text.    
13.3 Safety 
Safety data will be collected from the date of first written consent. Safety variables will be summarised 
by descriptive statistics. Laboratory variables will be described using the NCI CTCAE Version 4.02. 
Adverse events will be reported for each dose level and presented as tables of frequency of AEs by 
body system and by worse severity grade observed. Tables should indicate related and unrelated 
events.   


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13.4 Pharmacodynamics 
13.4.1 Flow Cytometry Assay for Detection and Enumeration of 1RG-CART in Peripheral 
Blood 
With this technique (see Section 8.1.1), the percentage of 1RG-CART present in each sample will be 
determined by flow cytometry gating on CD3+ cells that are additionally positive for QBEND10. 
Results will be expressed as % transduced T-cells present and/or absolute cell number. 
All eligible patients who receive 1RG-CART and have at least one post-treatment blood sample taken 
on or after Day 14 will be included in the analysis. 
13.4.2 
 
 
 
 
   
 
 
 
 
 
 
 
 
13.4.3 
 
 
 
 
 
 
 
 
 
 
  
 
 
13.4.4 
 
 
 
 
  
 
 
 
 
13.4.5 
 
 
 
  
 
 


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13.4.6 
 
 
 
 
 
  
13.4.7 
 
 
 
 
 
 
 
 
 
 
 
13.4.8 
 
 
 
 
 
 
  
13.5 Anti-Tumour Activity 
Documenting anti-tumour activity is a secondary objective of this trial. Patients must have received 
1RG-CART and completed a baseline and at least one post-treatment disease assessment to be 
evaluable for response. Patients who experience clear disease progression without a formal 
post-treatment disease assessment will be included and considered non-responders. Objective 
responses, the best tumour response achieved by each patient while on trial (according to each of the 
three response criteria) and the time to progression will be presented in the data listings.  
13.6 Overall Survival and Progression-Free Survival 
13.6.1 Overall Survival 
All patients who receive 1RG-CART will be evaluable for overall survival, regardless of whether they 
subsequently receive other anti-cancer treatments. Overall survival will be measured from the date of 
administration of the first dose of 1RG-CART. Subgroup analyses of per protocol patients may be 
performed.  


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13.6.2 Progression-Free Survival 
All patients who receive 1RG-CART and who complete a baseline and at least one post-treatment 
disease assessment (or experience clear disease progression without a formal post-treatment disease 
assessment) will be evaluable for progression-free survival, regardless of whether they subsequently 
receive other anti-cancer treatments. Progression-free survival will be measured from the date of 
administration of the first dose of 1RG-CART. This will be assessed according to all three tumour 
response criteria (RECIST 1.1, irRC and INRC). Since only limited follow-up (until Day 42) is planned 
for patients who receive the lymphodepleting regimen only, these patients will not be included in 
analyses of progression-free survival unless there is clear evidence of disease progression in the 
42-day follow-up period or the patient’s death is considered primarily due to the lymphodepleting 
regimen. Subgroup analyses of per protocol patients may be performed. 


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14 
ADMINISTRATION 
This trial is conducted under a clinical trial authorisation (CTA) and approval from the MHRA and the 
relevant REC(s) will be obtained before the start of this trial. This trial is sponsored and monitored by 
the Cancer Research UK, Centre for Drug Development. Applicable regulatory requirements are 
described in this section. 
14.1 Protocol Deviations and Amendments 
The protocol should be adhered to throughout the conduct of the trial, if a situation arises where the 
conduct of the trial may not be in line with the protocol, then site should contact the Sponsor to discuss 
this. 
Amendments to the protocol may only be made with the approval of the Sponsor. A protocol 
amendment may be subject to review by the assigned Ethics Committee, Health Research Authority 
(HRA) and the MHRA. Written documentation of the Ethics Committee and HRA (and if appropriate 
the MHRA) ‘favourable opinion’ (i.e. approval) must be received before the amendment can be 
implemented and incorporated into the protocol if necessary. 
14.2 Completion of the Electronic Case Report Form 
Electronic case report forms (eCRFs) approved by the Sponsor will be used to collect the data. The 
Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the data 
reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Delegation Log provided by the 
Sponsor and have been authorised by the Investigator should enter or change data in the eCRFs. 
Authorised users will be included on a User Management Tool (UMT) in order to be provided access 
to the eCRF. All protocol required investigations, with the exception of the pharmacodynamic assays, 
must be reported in the eCRF. The Investigators must retain all original reports, traces and images 
from these investigations for future reference.   
The collection and processing of personal data from the patients enrolled in this clinical trial will be 
limited to those data that are necessary to investigate the efficacy, safety, quality and usefulness of 
the study drug used in this trial.  The data must be collected and processed with adequate precautions 
to ensure patient confidentiality and compliance with applicable data privacy protection according to 
the applicable regulations.  The data collected will comply with Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data. 
Data will be entered directly into electronic screens by authorised site personnel. Amendments to 
eCRF data will be made directly to the system and the system audit trail will retain details of the 
original value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks. Queries will be issued electronically to the site. Authorised personnel must answer 
the queries by making relevant amendments to data or providing a response. Answered queries will 
be closed or reissued as appropriate. 
Once the patient has completed or withdrawn from the trial and the eCRF has been fully completed, 
the Investigator must provide an electronic signature to authorise the complete subject casebook. 
At the end of the trial all eCRFs are retained and archived by the Sponsor and a PDF copy provided to 
the Investigator who is responsible for archiving at site. 


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14.3 Trial Performance and Monitoring 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the trial centre. The Sponsor must be informed immediately of 
any change in the personnel involved in the conduct of the trial. 
During the trial the Sponsor’s CRA will be responsible for monitoring data quality in accordance with 
the Sponsor’s SOPs. A strategic monitoring approach, including targeted source data verification, will 
be implemented where appropriate.  
Before the trial start, the Investigator will be advised of the anticipated frequency of the monitoring 
visits. The Investigator will receive reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacodynamic samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
It is the responsibility of the Sponsor to inform the MHRA and the main REC within 90 days of the ‘End 
of the Trial’ that the trial has closed (See definition in Section 12). 
14.4 Source Document Verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data. 
Therefore, it is the Investigator’s responsibility to ensure that both he/she and his/her trial team 
records all relevant data in the medical records. The Investigator must allow the CRA direct access to 
relevant source documentation for verification of data entered into the eCRF, taking into account data 
protection regulations. Entries in the eCRF will be compared with patients’ medical records and the 
verification will be recorded in the eCRF.   
Some source data may exist only electronically and be entered, or loaded directly into the eCRF. The 
patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the Sponsor appointed to audit the trial, and by regulatory authorities. 
Details will remain confidential and patients’ names will not be recorded outside the hospital. 
14.5 Clinical Study Report 
At appropriate intervals, interim data listings will be prepared to give the Investigator the possibility to 
review the data and check the completeness of information collected. All clinical data will be presented 
at the end of the trial on final data listings. The Sponsor will prepare a CSR based on the final data 
listings. The report will be submitted to the Investigator(s) for review and confirmation it accurately 
represents the data collected during the course of the trial. A summary of the final clinical report must 
be provided by the Sponsor to the MHRA and to the REC. 
14.6 Record Retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be 
evaluated and verified. These essential documents (as detailed in Chapter V of Volume 10 [Clinical 
Trials] of The Rules Governing Medicinal Products in the European Union based upon Section 8 of the 


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ICH GCP Guidelines), including source documents such as scans, trial related documents and copies 
of the eCRFs, associated audit trail and SAE report forms, shall show whether the Investigator has 
complied with the principles and guidelines of Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by the Sponsor. Records must 
not be destroyed without prior written approval from the Sponsor. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
14.7 Ethical Considerations 
Before starting the trial, the protocol, patient ICDs must go through the Sponsor’s external review process, 
and be approved by the PSRB and receive the favourable opinion of the assigned REC. 
It is the CI/PI’s responsibility to update patients (or their authorised representatives, if applicable) 
whenever new information (in nature or severity) becomes available that might affect the patient’s 
willingness to continue in the trial. The CI/PI must ensure this is documented in the patient’s medical 
notes and the patient is re-consented. 
The Sponsor and CI/PI must ensure that the trial is carried out in accordance with the GCP principles 
and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 2006/1928 as amended), 
the ICH GCP guidelines and the Declaration of Helsinki (Appendix 5). 
14.8 Indemnity 
This trial is being carried out under the auspices of Cancer Research UK and therefore injury to a 
patient caused by the compounds under trial will not carry with it the right to seek compensation from 
the pharmaceutical industry. Cancer Research UK will provide patients with compensation for adverse 
side effects, in accordance with the principles set out in the Association of the British Pharmaceutical 
Industry (ABPI) guidelines on compensation for medicine-induced injury. 
14.9 Publication Policy and Press Releases 
Results of this trial must be submitted for publication. The Sponsor must be involved in reviewing all 
drafts of the manuscripts, abstracts, press releases and any other publications. Manuscripts must be 
submitted to the Sponsor at least 40 days in advance of being submitted for publication to allow time 
for the Sponsor to schedule a review and resolve any outstanding issues. Abstracts and press 
releases must also be submitted to the Sponsor at least 35 days in advance of being released.   
Authors must acknowledge that the trial was sponsored by and performed with the support of the 
Sponsor. 
The contribution of the Sponsor must be recognised by at least one member of staff being included as 
a co-author on each publication arising from the trial.   


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15 
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Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the 
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Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
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Detailed guidance on the application format and documentation to be submitted in an application for 
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Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
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37. Morgan RA et al., 'Case Report of a Serious Adverse Event Following the Administration of T 
Cells Transduced with a Chimeric Antigen Receptor Recognizing Erbb2', Mol Ther, 18 (2010), 
843-51. 
38. Davila ML et al., ‘Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell 
acute lymphoblastic leukemia.’  Sci Transl Med (2014); 6, 224ra25: 1-10. 
39. Brentjens R, Yeh R, Bernal Y, Riviere I, and Sadelain M, 'Treatment of Chronic Lymphocytic 
Leukemia with Genetically Targeted Autologous T Cells: Case Report of an Unforeseen 
Adverse Event in a Phase I Clinical Trial', Mol Ther, 18 (2010), 666-8. 
40. Warren EH et al., 'Therapy of Relapsed Leukemia after Allogeneic Hematopoietic Cell 
Transplantation with T Cells Specific for Minor Histocompatibility Antigens', Blood, 115 (2010), 
3869-78. 
41. Johnson LA et al., 'Gene Therapy with Human and Mouse T-Cell Receptors Mediates Cancer 
Regression and Targets Normal Tissues Expressing Cognate Antigen', Blood, 114 (2009), 
535-46. 
42. Cameron BJ et al., 'Identification of a Titin-Derived Hla-A1-Presented Peptide as a 
Cross-Reactive Target for Engineered Mage A3-Directed T Cells', Sci Transl Med, 5 (2013), 
197ra03. 


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43. Lamers CH et al., 'Treatment of Metastatic Renal Cell Carcinoma with Caix Car-Engineered T 
Cells: Clinical Evaluation and Management of on-Target Toxicity', Mol Ther, 21 (2013), 
904-12. 
44. Parkhurst, MR, et al., ‘T cells targeting carcinoembryonic antigen can mediate regression of 
metastatic colorectal cancer but induce severe transient colitis’, Mol Ther, 2011. 19(3): p. 
620-6. 
45. Lamers CH et al., 'Immune Responses to Transgene and Retroviral Vector in Patients Treated 
with Ex Vivo-Engineered T Cells', Blood, 117 (2011), 72-82. 
46. Maus VM et al., ‘T cells expressing chimeric antigen receptors can cause anaphylaxis in 
humans’.  Cancer Immunol Res (2013), 1, 26-31. 
47. Beatty GL et al., ‘Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T cells 
Induce Antitumor Activity in Solid Malignancies’, Cancer Immunol Res (2014), 2 (2), 112-20. 
48. Rosado FG, and Kim AS, 'Hemophagocytic Lymphohistiocytosis: An Update on Diagnosis and 
Pathogenesis', Am J Clin Pathol, 139 (2013), 713-27. 
49. Straathof KCM et al., ‘Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific 
T lymphocytes’. Blood, (2005),105 (5), 1898–1904. 
50. Bollard CM et al., ‘Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin’s disease’, 
J. Exp. Med. (2004), 200 (12), 1623–1633. 
51. Kochenderfer JN et al., ‘Eradication of B-lineage cells and regression of lymphoma in a patient 
treated with autologus T cells genetically engineered to recognize CD19’, Blood, 116 (2010), 
581-7. 
52. Kochenderfer JN et al., ‘B-cell depletion and remissions of malignancy along with 
cytokine-associated toxicity in a clinical trial of anti-CD19 
chimeric-antigen-receptor-transduced T cells’, Blood, 119 (2012), p2709-20. 
53. Eisenhauer EA et al., ‘New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1.)’, European Journal of Cancer (2009), 45:2, 228-247. 
54. Wolchok JD et al., ‘Guidelines for the Evaluation of Immune Therapy Activity in Solid 
Tumours: Immune-Related Response Criteria’, Clin Cancer Res (2009), 15, 7412-7420. 
55. Brodeur GM et al., ‘Revisions of the International Criteria for Neuroblastoma Diagnosis, 
Staging and Response to Treatment’, J Clin Oncol, 11 (1993), 1466-1477. 
56. Lee DW et al.,  ‘Current concepts in the diagnosis and management of cytokine release 
syndrome’, Blood 10 July 2014 Vol 124 (2): 188-195. 
57. Wang Y, et al., ‘Effective response and delayed toxicities of refractory advanced diffuse large 
B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells’, Clin 
Immunol, 2014. 155(2): p. 160-75. 
58. Papadopoulou A, et al., ‘Systemic inflammatory response syndrome after administration of 
unmodified T lymphocytes’, Mol Ther, 2014. 22(6): p. 1134-8. 
59. Wu ZL, et al., ‘Expression of GD2 ganglioside by untreated primary human neuroblastomas’, 
Cancer Res, 1986. 46(1): p. 440-3. 
60. Schengrund CL and Shochat SJ, ‘Gangliosides in neuroblastomas’, Neurochem Pathol, 1988. 
8(3): p. 189-202. 


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61. Kochenderfer JN et al., ‘Donor-derived CD19-targeted T cells cause regression of malignancy 
persisting after allogeneic hematopoietic stem cell transplantation.’ Blood, 2013. 
62. Kochenderfer JN et al., ‘Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and 
Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing 
an Anti-CD19 Chimeric Antigen Receptor.’ J Clin Oncol, 2014. 
63. Heslop HE et al., ‘Long-term outcome of EBV-specific T-cell infusions to prevent or treat 
EBV-related lymphoproliferative disease in transplant recipients.’ Blood, 2010. 115(5): p. 
925-35 
64. Park JH, et al., ‘Phase I trial of autologous CD19-targeted CAR-modified t cells as 
consolidation after purine analog-based first-line therapy in patients with previously untreated 
CLL.’ J Clin Oncol 2014. 32(5s): p. abstr 7020. 
65. Ramos CA et al., ‘Effect of a costimulatory endodomain on the performance of T cells 
expressing CD19-directed chimeric antigen receptors (CARs) in subjects with 
relapsed/refractory B-cell malignancies.’ J Clin Oncol 2011. 29(abstract 2541). 
66. Slovin S et al., ‘Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific 
membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC).’ 
J Clin Oncol 2013. suppl6(abstract 72). 
67. Ritchie, D.S., et al., ‘Persistence and efficacy of second generation CAR T cell against the 
LeY antigen in acute myeloid leukemia.’ Mol Ther, 2013. 21(11): p. 2122-9. 
68. Morgan RA et al., ‘Cancer regression and neurological toxicity following anti-MAGE-A3 TCR 
gene therapy.’ J Immunother, 2013. 36(2): p. 133-51. 
69. Maude S et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl 
J Med. 2014. 371: 1507-1517. 




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16.2 APPENDIX 2: INDICATORS AND MANAGEMENT OF SEVERE CYTOKINE 
RELEASE SYNDROME (DERIVED FROM DAVILA ET AL, 2014 [38]) 
 
Indicators of severe cytokine release secondary to CD19-directed CAR T-cells in ALL 
 
 
• 
Fever for at least three consecutive days. 
• 
2 cytokines increase at least 75-fold over baseline or one cytokine increases at 
least 250-fold. 
• 
At least one clinical sign of toxicity such as  
o 
Hypotension requiring at least one intravenous vasopressor; 
o 
Hypoxia (pO2 <90%); 
o 
Neurological disorders (such as mental status changes, obtundation or 
seizures). 
 
 
 
Suggested management algorithm for patients receiving 1RG-CART 
 
 
Fever for at least 3 days
CRP > 20 mg/dL
•Inform chief investigator
•Inform PICU
•Increase monitoring
•Consider clonazepam or 
other anti-epileptic 
Consider tocilizumab
4mg/kg (repeat once if 
needed)
Consider dexamethasone 
0.2mg/kg bd
Consider rituximab
and/or
Clinical deterioration
No improvement
No improvement
 


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16.3 APPENDIX 3: LANSKY PLAY PERFORMANCE SCALE 
 
This performance scale is recommended for children aged <16 years: 
Fully active and normal 
100 
Minor restrictions in physically strenuous activity 
90 
Active, but tires more easily 
80 
Both greater restriction of, and less time spent in, active play 
70 
Up and around, but minimal active play; keeps busy with quieter activities 
60 
Gets dressed, but lies around much of the day; no active play; able to participate 
in all quiet play and activities 
50 
Mostly in bed; participates in quiet activities 
40 
In bed; needs assistance even for quiet play 
30 
Often sleeping; play entirely limited to very passive activities 
20 
No play; does not get out of bed 
10 
Unresponsive 
0 


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16.4 APPENDIX 4: KARNOFSKY PERFORMANCE SCALE 
This performance scale is recommended for children aged ≥16 years: 
Normal, no complaints, no signs of disease 
100 
Capable of normal activity, few symptoms or signs of disease 
90 
Normal activity with some difficulty, some symptoms or signs 
80 
Caring for self, not capable of normal activity or work 
70 
Requiring some help, can take care of most personal requirements 
60 
Requires help often, requires frequent medical care 
50 
Disabled, requires special care and help 
40 
Severely disabled, hospital admission indicated but no risk of death 
30 
Very ill, urgently requiring admission, requires supportive measures or treatment 
20 
Moribund, rapidly progressing fatal disease processes 
10 
Death  
0 


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16.5 APPENDIX 5: DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. 
Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. 
It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are dedicated 
to the fulfilment of this duty. 
4. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
5. 
Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. 
In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 
7. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
8. 
In medical practice and in medical research, most interventions involve risks and burdens. 
9. 
Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. 


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12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for treating 
and/or compensating subjects who are harmed as a consequence of participation in the research 
study. The protocol should describe arrangements for post-study access by study subjects to 
interventions identified as beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. The committee 
must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No 
change to the protocol may be made without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional.  The responsibility for the protection of research subjects must always rest with the 
physician or other health care professional and never the research subjects, even though they 
have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands to 
benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by 
the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the 
first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no competent 
individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information and to minimize the impact of the study on their physical, mental and 
social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, and any other relevant aspects of the study. The potential 


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subject must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver the 
information. After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where consent 
would be impossible or impractical to obtain for such research or would pose a threat to the 
validity of the research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a research 
study that has no likelihood of benefit for them unless it is intended to promote the health of the 
population represented by the potential subject, the research cannot instead be performed with 
competent persons, and the research entails only minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to decisions 
about participation in research, the physician must seek that assent in addition to the consent of 
the legally authorized representative. The potential subject’s dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In such 
circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research should be obtained as soon as possible from the subject or a legally 
authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the 
results of research. Authors have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their reports. They 
should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest should be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
32. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the physician 
has good reason to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects. 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best current proven intervention, except in the following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
• Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 


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patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
34. At the conclusion of the study, patients entered into the study are entitled to be informed about 
the outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
35. The physician must fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the 
study must never interfere with the patient-physician relationship. 
36. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgement it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly available. 


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16.6 APPENDIX 6: ASSESSMENT OF RESPONSE USING RECIST 1.1 CRITERIA 
The following guidelines are based on the publication by E.A. Eisenhauer et al. (European Journal of 
Cancer 2009, 45: 228-247) [53]. Please refer to the full publication for further details. 
1. 
Measurability of Tumour at Baseline 
1.1. 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
1.1.1. Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan or MRI (CT scan slice thickness no greater than 5 mm). 
• 
10 mm calliper measurement by clinical exam (lesions which cannot be accurately measured 
with callipers should be recorded as non-measurable). 
• 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15mm in the short axis when assessed by CT scan or MRI (CT scan slice thickness 
recommended to be no greater than 5 mm). Nodes that have a short axis <10 mm are considered 
non-pathological and should not be recorded or followed. At baseline and in follow-up, only the short 
axis will be measured and followed. 
1.1.2. Non-Measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 


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• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable.  
1.2. Specifications by Methods of Measurements 
1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using callipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start. 
1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up, wherever possible. Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Ultrasound:  
Ultrasound is not considered useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.   
Tumour markers (urinary catecholamines):  
Tumour markers (i.e. urinary catecholamines) alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must normalise for a 
patient to be considered in complete response.   
Cytology, histology:  
Bone marrow examination can be used to differentiate between a PR and CR in patients with no 
residual macroscopic disease elsewhere.   
2. Tumour Response Evaluation 
2.1 Assessment of Overall Tumour Burden and Measurable Disease 
To assess objective response or progression, it is necessary to estimate the overall tumour burden at 
baseline and use this as a comparator for subsequent measurements. Measurable disease is defined 
by the presence of at least one measurable lesion (as detailed above in Section 1).   
2.2. Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should be 
identified as target lesions (this means in instances where patients have only one or two organ sites 
involved a maximum of two and four lesions respectively will be included in RECIST response 
assessment). Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.   
For RECIST 1.1 response assessment, the sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 


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diameters. If lymph nodes are to be included in the sum, then, only the short axis is added into the 
sum. All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions. These lesions should be followed as ‘present’, ‘absent’, or as ‘unequivocal 
progression’. Multiple non-target lesions involving the same organ may be considered a single item for 
RECIST response assessment (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
2.3. Response Criteria 
2.3.1. Evaluation of Target Lesions 
• 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes.  
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of <10 mm.   
Target lesions that become ‘too small to measure’. 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on imaging that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being ‘too small to measure’. When this occurs it is important that a value be recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned.   
Lesions that split or coalesce on treatment: 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3. Evaluation of Non-Target Lesions 
• 
Complete Response (CR): Disappearance of all non-target lesions and normalisation of 
tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 






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2.4.2. Duration of Stable Disease 
Stable disease is measured from the start of the treatment (i.e. infusion of 1RG-CART) until the criteria 
for progression are met, taking as reference the smallest sum on study (if the baseline sum is the 
smallest, this is the reference for calculation of PD).   


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16.7 APPENDIX 7:  ASSESSMENT OF RESPONSE USING IMMUNE-RELATED 
RESPONSE CRITERIA (irRC) 
The following guidelines are based on the publication by JD Wolchok et al. (Clin Cancer Res. 2009 
Dec 1;15(23):7412-20) [54]. Please refer to the full publication for further details. 
Assessment of tumour burden 
Immune-related response criteria are based on WHO criteria in that bidimensional measurements are 
required (unlike RECIST criteria, which involve unidimensional measurements only). For irRC, only 
index and measurable new lesions are taken into account (in contrast to RECIST criteria, which do not 
require the measurement of new lesions, nor do they include new lesion measurements in the 
characterisation of evolving tumour burden). At the baseline tumour assessment, the sum of the 
products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, 
up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumour 
assessment, the SPD of the index lesions and of new, measurable lesions (≥5 x 5 mm; up to 5 new 
lesions per organ; 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the 
total tumour burden: 
Tumour burden = SPDindex lesions + SPDnew, measurable lesions  
In irRC, new measurable lesions (i.e. ≥5 x 5mm) are incorporated into tumour burden, whereas 
according to RECIST criteria new measurable lesions (i.e. longest diameter ≥ 10 mm) always 
represent PD. In irRC, new non-measurable lesions (i.e. ≤5 x 5mm) do not define progression (but 
preclude irCR), whereas according to RECIST criteria new non-measurable lesions (i.e. longest 
diameter <10 mm) always represent PD. Although not specified in the irRC described by Wolchok et 
al., for this trial it is recommended that to be considered an index lesion (i.e. a measurable lesion at 
baseline), a lesion must measure at least 5 x 5mm. 
Time-point response assessment using irRC 
Percentage changes in tumour burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumour 
assessment, the response in target and new, measurable lesions is defined based on the change in 
tumour burden (after ruling out irPD). Decreases in tumour burden must be assessed relative to 
baseline measurements (i.e. the SPD of all index lesions at screening). 
Whereas RECIST criteria has separate definitions of tumour response for target lesion and non-target 
lesions, irRC defines tumour response for tumour burden (index and new measurable lesions 
together). The irRC tumour response definitions for any time point are as follows: 
Time Point Response 
IrRC definition 
CR 
Disappearance of all lesions and no new lesions 
PR 
≥50% decrease in tumour burden compared with baseline 
SD 
50% decrease in tumour burden compared with baseline cannot be 
established nor 25% increase compared with nadir 
PD 
At least 25% increase in tumour burden compared with nadir 


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Overall response using the irRC 
The overall response according to the irRC is derived from time-point response assessments (based 
on tumour burden) as follows: 
• 
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions); 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented. 
• 
irPR, decrease in tumour burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation. 
• 
irSD, not meeting criteria for irCR or irPR, in absence of irPD. 
• 
irPD, increase in tumour burden ≥25% relative to nadir (minimum recorded tumour burden); 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented. 
Derivation of irRC overall responses: 
Measurable response 
Non-measurable response 
Overall 
response 
Index and new, measurable 
lesions (tumour burden), *% 
Non-index lesions 
New, non-measurable lesions 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal 
progression 
Any 
irPR† 
↓≥50 
Absent / stable 
Any 
irPR† 
↓≥50 
Unequivocal 
progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent / stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal 
progression 
Any 
irSD 
≥25? 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline, including measurable lesions only (>5 × 5 mm).  
†Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second, consecutive assessment 
at least 4 wk apart. Note that for this trial, to achieve an irRC overall response of CR, a patient must have a 
documented disease-free bone marrow post-baseline unless the bone marrow was clear at baseline 
Note that, according to irRC, patients are considered to have irPR or irSD even if new lesions are 
present, as long as they meet the respective thresholds of response as described above. Furthermore, 
patients are not considered to have irPD if new lesions are present but the tumour burden of all 
lesions does not increase by ≥25%. In contrast to irCR, irPR, and irPD, a response of irSD does not 
require confirmation. It is important to note that irCR, irPR, and irSD include all patients with CR, PR, 
or SD by WHO criteria (many of whom would also have CR, PR or SD by RECIST criteria) as well as 
some patients with WHO-determined or RECIST-determined PD. Patients with irSD according to irRC, 
particularly those with slow-declining tumour burden ≥25% from baseline at the last tumour 
assessment, may be considered clinically meaningful because they show an objectively measurable 
reduction in tumour burden without reaching the 50% threshold that defines irPR.  
Confirmation of progression 
Note that unlike RECIST and WHO criteria, if a patient is classified as having irPD at a post-baseline 
tumour assessment, then confirmation of irPD by a second scan in the absence of rapid clinical 
deterioration is required. Confirmation of progression requires an increase in tumour burden ≥25% 


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compared with the nadir at two consecutive time points at least 4 weeks apart. It is recommended that 
this be done at the discretion of the investigator because follow-up with observation alone may not be 
appropriate for patients with a rapid decline in performance status. 


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16.8 APPENDIX 8: ASSESSMENT OF RESPONSE USING INTERNATIONAL 
NEUROBLASTOMA RESPONSE CRITERIA (INRC) 
The following guidelines are based on the publication by GM Brodeur et al. (J Clin Oncol 1993, 
11:1466-1477) [55]. Please refer to the full publication for further details. 
The response definitions of the INRC are summarised in the bullet points and Table below. Note that 
the INRC recommends that the volume of the primary tumour and large metastases be determined to 
the best approximation (i.e. using 3-dimensional measurements), and that the volume should be used 
to determine response. This differs significantly from irRC criteria (in which the sum of products of 
bidimensional lesions is used) and RECIST criteria (in which the sum of unidimensional 
measurements is used). In this trial, in order to simplify data entry and verification, and to facilitate 
data analysis, only bidimensional lesion measurements will be used in assessing response according 
to INRC. No recommendations are made in the INRC criteria regarding minimum size, number of 
lesions to measure, lesion location etc. Therefore, in this trial, in order to simplify data entry and 
verification, and to facilitate data analysis, the same lesions and lesion measurements will be for 
assessing INRC response as used for assessing irRC response. 
• 
A complete response (CR) indicates complete disappearance of all primary and metastatic 
disease, and the normalisation of catecholamines and metabolites (if they were increased at 
diagnosis).  
• 
A very good partial response (VGPR) indicates a 90% to 99% volume reduction in the primary 
tumour, with clearing of all measurable metastatic disease and normalisation of 
catecholamines. The only exception to this would be residual abnormalities on technetium 
bone scan attributable to incomplete healing of the bone. The MIBG scan (if performed) 
should be negative at all metastatic sites.  
• 
A partial response (PR) indicates a greater than 50% volume reduction of the primary tumour 
and a greater than 50% reduction of all measurable metastatic sites (but not satisfying criteria 
for CR or VGPR). Residual positive marrow aspirate or biopsy (one site) is permitted if this 
reflects a decrease from the number of sites of involvement at the time of diagnosis (e.g., two 
to four sites positive initially). MIBG scans may allow residual tumour to be distinguished, but if 
this is not available, there should be no new bone lesions, and the pre-existing lesions should 
be improving. Note that this definition is somewhat more stringent than World Health 
Organisation (WHO), RECIST and irRC definitions of PR. 
• 
The term mixed response (MR) is used to indicate a greater than 50% response at one or 
more sites and a less than 50% reduction at one or more other sites. This might occur, for 
instance, if metastatic disease responded, but the primary tumour size did not change. In such 
a case, the histology of the tumour could have changed from neuroblastoma either to 
ganglioneuroma or to predominantly scar tissue and necrosis. In this situation, a surgical 
procedure could convert such a patient status to PR, VGPR, or even CR. Note that at least 
some cases of mixed response (MR) according to INRC would likely to be categorised as 
partial response (PR) according to other response criteria. 
• 
No response (NR) indicates a less than 50% reduction of some or all measurable lesions, but 
no increase of greater than 25% in these lesions and no new lesions. This definition 
corresponds to the definition of SD according to WHO and irRC criteria. 
• 
Progressive disease (PD) indicates a greater than 25% increase in any pre-existing lesion or 
any new lesion. 
According to INRC, determination of overall response is based on the response of the primary tumour 
and all metastatic sites. Thus, complete disappearance of all metastatic disease, but only a PR at the 
primary site would represent a PR overall. However, if all residual tumour tissue had become mature 
ganglioneuroma or was resectable, the chemotherapy response would be a PR, but the response to 
combined therapy would be a CR. For this trial, a response to 1RG-CART that results in residual 


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mature ganglioneuroma or residual disease that is subsequently surgically resected, will be 
considered a PR or VGPR and not a CR. 
Response 
Primary Tumour 
Metastatic Sites* 
Complete Response (CR) 
No Tumour 
- 
No tumour 
- 
Catecholamines normal 
Very Good Partial 
Response (VGPR) 
Decrease by 90 - 99% 
- 
No tumour 
- 
Residual bone changes allowed 
Partial Response (PR) 
Decreased by >50% 
- 
All measurable sites decreased by > 50% 
- 
Bones and bone marrow: number of positive 
sites decreased by > 50%; no more than one 
positive bone marrow site allowed* 
Mixed Response (MR) 
- 
No new lesions 
- 
>50% reduction of any measurable lesion (primary or metastases) with ≤50% 
reduction in any other 
- 
<25% increase in any existing lesion 
No response (NR) 
- 
No new lesions 
- 
≤50% reduction but <25% increase in any existing lesion 
Progressive Disease (PD) 
- 
Any new lesion 
- 
increase of any measurable lesion by ≥25% 
- 
Previous negative marrow biopsy for tumour. 
*One positive marrow aspirate or biopsy allowed for PR if this represents a decrease from the number of positive 
sites at diagnosis. 
Duration of response 
According to INRC, tumours that respond initially (e.g. after 2 months) but grow back by 4 months 
would be considered to have an overall response of PD. However, for this trial, in which a novel 
experimental therapy is being evaluated, transient responses are still of clinical interest. Therefore, to 
be considered an INRC response (CR, VGPR, PR) in this trial, response only has to be sustained for 
at least 4 weeks. 


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16.9 APPENDIX 9:  ASSESSMENT AND MANAGEMENT OF PAIN 
Neuropathic-type pain has been regularly reported in children receiving GD2-targeted antibodies, so it 
is possible that similar pain could be experienced following 1RG-CART infusion or during the T-cell 
expansion phase in the weeks following 1RG-CART infusion. The following measures should be in 
place to detect and manage pain: 
• A daily age-appropriate pain score will be recorded from Day 0 to Day 14. Thereafter a pain 
score (Wong-Baker FACES® Pain Rating Scale) will be recorded as clinically indicated.  
• In the event of worsening pain, if it appears likely to be unrelated to infused 1RG-CART, 
escalate through standard pain management as per local Haemato/Oncology supportive care 
guidelines.   
• If the pain is suspected to be related to the infused 1RG-CART: 
1. Start gabapentin 10 mg/kg (Day 1: 10 mg/kg once daily, Day 2: 10 mg/kg twice daily, 
Day 3: 10 mg/kg three times daily, per oral/nasogastric tube) and continue  
2. Alert the Pain Team  
3. For mild pain, treat initially with paracetamol or codeine phosphate   
4. For severe pain consider a morphine infusion and titrate rate against response. 
 


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16.10 APPENDIX 10: ESTIMATION OF BODY SURFACE AREA IN INFANTS AND CHILDREN 
 


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16.11 APPENDIX 11: TOXICITY TIMELINE SCHEME