A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity Of AUTO3, a CAR T Cell Treatment Targeting CD19 And CD22 in Paediatric And Young Adult Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia
Phase: PHASE1
Conditions: B Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia, B-cell Acute Lymphoblastic Leukemia
Sponsor: Autolus Limited

AUTOLUS LTD 
 
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Clinical Study Protocol 
CONFIDENTIAL 
 
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CLINICAL STUDY PROTOCOL 
A 
SINGLE-ARM, 
OPEN-LABEL, 
MULTI-CENTRE, 
PHASE 
I/II 
STUDY 
EVALUATING THE SAFETY AND CLINICAL ACTIVITY OF AUTO3, A CAR 
T CELL TREATMENT TARGETING CD19 AND CD22 IN PAEDIATRIC AND 
ADULT PATIENTS WITH RELAPSED OR REFRACTORY B CELL ACUTE 
LYMPHOBLASTIC LEUKAEMIA. 
 
Short Study Title: 
AMELIA 
Protocol Number: 
AUTO3-PA1 
Study Product: 
AUTO3 for i.v. infusion 
Development Phase: 
I/II 
Sponsor: 
 
 
 
 
 
Protocol Version:
Version 8.0 
EudraCT Number: 
2016-004680-39 
IND Number: 
18431 
Protocol Date: 
10 May 2019 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council on 
Harmonisation), ethical principles that have their origin in the 
Declaration of Helsinki and all applicable national and local 
regulations.  
This protocol includes information and data that contain trade secrets and privileged or 
confidential information that is the property of the Sponsor (Autolus Limited). This 
information must not be made public without written permission from Autolus Limited. 
These restrictions on disclosure will apply equally to all future information supplied to you. 
This material may be disclosed to and used by your staff and associates as may be necessary 
to conduct the clinical study. 

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ADMINISTRATIVE AND CONTACT INFORMATION  
Sponsor: 
Autolus Limited 
 
 
 
 
 
Tel: 
 
Contact List 
The List of Service Providers for the study will be maintained separately by Autolus Limited 
and maintained in the Trial Master File. 
Chief Investigator:  
 
 
 
 
 
Tel: 
 
Email: 
 
Sponsor’s Medical Monitor: 
 
 
 
  
Tel: 
 
Mobile:
 
Email: 
   
Sponsor’s Project Manager: 
  
Tel: 
 
Email: 
 
Notification of SAEs: 
SAE Fax number: 
 
Email: 
 
24 Hour Safety Hotline: 
 
 
 
Tel: 
 
 
 

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SPONSOR SIGNATURE PAGE 
Study Title: A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the 
Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 
in Paediatric and Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic 
Leukaemia. 
Short Study Title: 
AMELIA 
Protocol Number: 
AUTO3-PA1 
Version Number:  
Version 8.0 
Version Date:  
10 May 2019 
I have read the protocol AUTO3-PA1 titled “A Single-Arm, Open-Label, Multi-Centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell 
Treatment Targeting CD19 and CD22 in Paediatric and Adult Patients with Relapsed 
Refractory B Cell Acute Lymphoblastic Leukaemia” and confirm that, to the best of my 
knowledge, the protocol accurately describes the design and conduct of the study.  
 
 
 
Date 
(DD MMM YYYY) 
 
 
 
 
 

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INVESTIGATOR SIGNATURE PAGE 
Study Title: A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the 
Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 
in Paediatric and Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic 
Leukaemia. 
Short Study Title: 
AMELIA 
Protocol Number: 
AUTO3-PA1 
Version Number:  
Version 8.0 
Version Date:  
10 May 2019 
I have read the protocol AUTO3-PA1 titled “A Single-Arm, Open-Label, Multi-Centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell 
Treatment Targeting CD19 and CD22 in Paediatric and Adult Patients with Relapsed 
Refractory B Cell Acute Lymphoblastic Leukaemia”. By signing this protocol, I agree to 
conduct the clinical study, after approval by an Institutional Review Board or Independent 
Ethics Committee (as appropriate), in accordance with the protocol, the principles of the 
Declaration of Helsinki (2008), the standards of Good Clinical Practice (as defined by the 
International Council on Harmonisation) and applicable regulatory requirements.  
Changes to the protocol will only be implemented after written approval is received from 
Autolus Limited and the Institutional Review Board or Independent Ethics Committee (as 
appropriate), with the exception of medical emergencies. I will ensure that study staff fully 
understand and follow the protocol. 
 
 
 
Signature 
Name and address: 
 
 
 
 
 
 
 
Date  
(DD MMM YYYY) 
 

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PROTOCOL SYNOPSIS 
Title 
A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the 
Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment 
Targeting CD19 and CD22 in Paediatric and Adult Patients with Relapsed 
or Refractory B Cell Acute Lymphoblastic Leukaemia 
Short Study 
Title  
AMELIA 
Protocol 
Number 
AUTO3-PA1 
Sponsor 
Autolus Limited 
Phase 
I/II 
Study Product 
AUTO3, an Advanced Therapy Investigational Medicinal Product, 
comprising of autologous enriched T cells retrovirally transduced to 
express two Chimeric Antigen Receptors (CAR), targeting cluster of 
differentiation (CD) 19 and CD22.   
Study 
Population 
Paediatric and adult patients aged ≥1 year with B cell acute lymphoblastic 
leukaemia (ALL) who have relapsed or refractory disease. 
Study Duration 
The study will take approximately 5 years from recruitment to the last 
patient’s last 24-month follow-up visit. The end of the trial will be 
24 months after the last patient has received an AUTO3 infusion or the 
last patient last visit if this occurs earlier due to patient death or 
withdrawal. 
Overview 
A single-arm, open-label, multi-centre, Phase I/II dose-escalation and 
expansion study to determine the safety and clinical activity of AUTO3 
administered intravenously (i.v.) in paediatric and adult patients with 
relapsed or refractory B cell acute lymphoblastic leukaemia (ALL).   
AUTO3 is an autologous T cell product transduced to express two CARs 
targeting CD19 and CD22 using a retroviral vector. The CAR construct 
expresses endodomains of OX40 and CD3-ζ on CD19 CAR, and 41BB-ζ 
and CD3-ζ on CD22 CAR. This first-in-human (FIH) study will assess the 
safety of AUTO3, evaluate the dose and determine dosing schedule for 
Phase II of the study, and evaluate the preliminary efficacy of the AUTO3 
in paediatric and adult patients with relapsed or refractory B cell ALL.  

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Primary 
Objective(s) 
and Endpoints 
The primary objectives of the study are as follows:  
Objectives 
Endpoints 
Phase I 
To assess the overall safety and 
tolerability of AUTO3 administration.  
Incidence of Grade 3-5 toxicity 
occurring within the dose limiting 
toxicity (DLT) period (30 days after 
last dose) of AUTO3 infusion.  
To confirm and evaluate the 
recommended Phase II dose (RP2D) 
and dosing schedule, and confirm 
maximum tolerated dose (MTD), if an 
MTD exists, of AUTO3 in both 
paediatric and adult patients. 
Frequency of DLT of AUTO3. 
Phase II 
To evaluate the anti-leukaemic effect 
of AUTO3 in paediatric and young 
adult patients (aged 1-24 years). 
Proportion of patients achieving 
morphological remission (complete 
response [CR] or complete response 
with incomplete recovery of counts 
[CRi]) and minimal residual disease 
(MRD) negative response in bone 
marrow (BM) within 30 (±3) days 
post first AUTO3 infusion  
 
In patients with isolated central 
nervous system (CNS) disease, anti-
tumour effect will be assessed by 
whether patients clear their 
cerebrospinal fluid disease with 
ongoing BM CR, within 
30 (±3) days post first AUTO3 
infusion. 
Study Design 
This is a Phase I/II, open-label, multi-centre study to characterise the 
safety and clinical activity of AUTO3 when administered to paediatric 
and adult patients with relapsed or refractory B cell ALL. The study will 
consist of two parts: a Phase I, dose escalation in paediatric (>1 years) 
and adult patients followed by a Phase II, expansion in only paediatric 
and young adult patients (≥1-24 years). Both parts of the study will 
involve patients going through the following five sequential stages: 
screening, leukapheresis, pre-conditioning, treatment, and follow-up.  
Phase I (Dose Escalation): To identify the optimal dose schedule (based 
on safety, tolerability, and anti-leukaemic activity) of AUTO3 based on 
disease burden, 36-60 patients with ALL will be treated in the dose 
escalation phase starting at 1.0 x 106/kg CD19/CD22 CAR-positive 
T cells administered as a single or split dose based on disease burden. 
Then escalating to 3 x 106/kg, and 5 x 106/kg CD19/CD22 CAR-positive 

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T cells administered in a similar manner.  
Patients ≥25 years of age will enroll onto adult ALL dose cohorts. Adult 
ALL dose escalation may start at the highest paediatric dose considered 
safe after dosing 3 patients. Dosing will be based on a fixed dose which is 
equivalent to a dose in a 70 kg person. 
Phase II (Dose Expansion): To further characterise the safety and assess 
the efficacy of AUTO3 at the recommended dose schedule confirmed in 
Phase I; up to 24 paediatric and young adult patients will be treated in 
Phase II.  
Biomarkers relating to the CAR T cells and tumours will be evaluated in 
all patients. All patients enrolled in Phases I and II of the study will attend 
clinic visits for up to 24 months post AUTO3 infusion for study-specific 
assessments including adverse event (AE) assessments, physical 
examination, and laboratory and immunology tests. 
After completion of the 24-month follow-up period, or following AUTO3 
treatment and early withdrawal from this study, all patients will be 
eligible to be followed until death or for up to 15 years from the first 
AUTO3 infusion under a separate long-term follow-up study protocol. 
Number of 
Patients 
Up to 100 patients in total are expected to be enrolled into Phase I and 
Phase II of the study and up to 84 patients in total are anticipated to be 
treated with AUTO3. 
• 
Phase I (Escalation): Up to 33-46 patients in total (up to 3-6 patients 
per cohort)  
o 24-36 patients in the paediatric / young adult patient 
cohorts (age 1-24 years) 
o 12-24 patients in the adult patient cohorts (≥25 years) 
• 
Phase II (Expansion): Dose expansion: up to 24 evaluable patients 
(aged 1-24 years) in total, using a Simon’s 2-stage optimal design. 
Simon's 2-stage design (Simon 1989) will be used for Phase II. The null 
hypothesis that the true response rate is 25% will be tested against a 
1-sided alternative. In the first stage, nine patients will be accrued. If there 
are two or fewer responses in these nine patients, the study will be 
stopped. Otherwise, 15 additional patients will be accrued for a total of 
24. The null hypothesis will be rejected if 10 or more responses are 
observed in 24 patients. This design yields a 1-sided type I error rate of 
5% and 80% power when the true response rate is 50%. 

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Criteria for 
Eligibility 
Only patients whose leukapheresate sample has been successful in 
generating AUTO3 in adequate quantity will be treated. The key criteria 
for patient eligibility are summarised as follows: 
INCLUSION CRITERIA  
PAEDIATRIC AND YOUNG ADULT PATIENTS 
1. Male or female paediatric and young adult patients (aged 1-24 years) 
with high risk (HR) relapsed or refractory B-lineage ALL and 
a. 
Any BM relapse or CNS relapse with detectable BM disease 
(>10-4) by flow cytometry/molecular MRD after allogeneic stem 
cell transplant (SCT) and must be ≥6 months from SCT at the 
time of AUTO3 infusion, OR 
b. High Risk first relapse (as per International Study for Treatment 
of Childhood Relapsed ALL criteria Appendix 6), OR 
c. 
Standard risk relapse patients with HR cytogenetics (HR defined 
as mixed linkage leukaemia gene rearrangement (KMT2A), intra-
chromosomal amplification of chromosome 21 amplification, 
near-triploidy 
(60-78 
chromosomes) 
or 
near-haploidy 
(<30 chromosomes) and low hypodiploidy (30-39 chromosomes), 
OR 
d. Second or greater relapse, OR 
e. 
Bone marrow MRD ≥10-3 prior to planned SCT, OR 
f. 
Any on-treatment relapse in patients aged 16-24 years 
Phase II Only (Criteria in addition to those described above) 
g. Primary refractory disease defined as MRD ≥5% blasts in the BM 
by flow cytometry or molecular assay following frontline 
induction therapy. For good risk cytogenetics, MRD >0.1% at 
Week 9 of consolidation chemotherapy is also required (Note: 
For patients with good risk cytogenetics the leukapheresis may 
be done before starting consolidation therapy but manufacturing 
and AUTO3 infusion will only occur if MRD is >0.1% at Week 9 
of consolidation), OR 
h. Patients with Philadelphia chromosome-positive ALL are eligible 
if they are intolerant to or have failed 2 lines of tyrosine kinase 
inhibitor therapy, or if tyrosine kinase inhibitor therapy is 
contraindicated OR 
i. 
Isolated CNS relapse (post-SCT or pre-SCT if high risk, age 
16-24 years on therapy relapse or ≥2nd relapse) but with ≤CNS 
Grade 2 disease at time of enrolment. 
2. Documentation of CD19 and or CD22 expression on leukaemic blasts 
in the BM, peripheral blood, or cerebrospinal fluid by flow cytometry 
within 3 months of screening. 

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3. Detectable disease in the BM at a level ≥10-4 by molecular or flow 
cytometry based methods (Phase I only) at enrolment (patients 
developing ≤10-4 BM disease due to bridging therapy may continue to 
receive AUTO3). 
4. Absolute lymphocyte count ≥0.5 x 109/L at enrolment. 
5. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
- 
Serum creatinine based on age/gender ≤1.5x upper limit of 
normal (ULN). 
- 
Serum alanine aminotransferase/aspartate amino-transferase 
≤5x ULN. 
- 
Total bilirubin ≤2x ULN, except in subjects with Gilbert's 
syndrome. 
- 
Left ventricular shortening fraction ≥28% confirmed by 
echocardiogram, or left ventricular ejection fraction ≥45% 
confirmed by echocardiogram. 
- 
Baseline oxygen saturation >92% on room air. 
6. Karnofsky (age 10-24 years) or Lansky (age <10 years) score ≥50%. 
7. Willing and able to give written, informed consent to the current 
study (patient and/or parent or legal guardian). 
INCLUSION CRITERIA  
ADULT PATIENTS 
1. Age 25 or older. 
2. Eastern cooperative oncology group (ECOG) performance status of 0 
or 1. 
3. Relapsed or refractory B-precursor ALL defined as one of the 
following: 
a. 
Primary refractory disease 
b. First relapse if first remission ≤12 months 
c. 
Relapsed or refractory disease after 2 or more lines of systemic 
therapy 
d. Relapsed or refractory disease after allogeneic transplant 
provided individual is at least 6 months from stem cell transplant 
at the time of infusion. 
4. Patients with Philadelphia chromosome-positive ALL are eligible if 
they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor 
therapy, or if tyrosine kinase inhibitor therapy is contraindicated,  
5. Documentation of CD19 and/or CD22 expression on leukaemic blasts 
in the BM, peripheral blood, or CSF by flow cytometry within 
3 months of screening. 
6. For females of childbearing potential (defined as <24 months after 

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last menstruation or not surgically sterile), a negative serum or urine 
pregnancy test must be documented at screening, prior to pre-
conditioning and confirmed before receiving the first dose of study 
treatment.  
For females who are not postmenopausal (<24 months of amenorrhea) 
or who are not surgically sterile (absence of ovaries and/or uterus), 
two methods of contraception comprising of one highly effective 
method of contraception together with a barrier method must be used 
during the treatment period and for at least 12 months after the last 
dose of study treatment. They must agree not to donate eggs (ova, 
oocytes) for the purposes of assisted reproduction during the study 
and for 12 months after receiving the last dose of study drug (please 
refer to Appendix 5). 
7. For males, it must be agreed that two acceptable methods of 
contraception are used (one by the patient – usually a barrier method, 
and one highly effective method by the patient’s partner as defined in 
Appendix 5) during the treatment period and for at least 12 months 
after the last dose of study treatment and that sperm will not be 
donated during the treatment period and for at least 12 months after 
the last dose of study treatment.  
8. Absolute lymphocyte count ≥0.5 x 109/L at enrolment 
9. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a. 
Serum 
alanine 
aminotransferase/aspartate 
aminotransferase 
≤2.5 x ULN. 
b. Creatinine clearance (as estimated by Cockcroft Gault) 
≥60 cc/min. 
c. 
Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's 
syndrome. 
d. Left ventricular ejection fraction (LVEF) ≥45% confirmed by 
ECHO or multigated acquisition (MUGA). 
e. 
Baseline oxygen saturation >92% on room air. 
EXCLUSION CRITERIA  
Patients meeting any of the following exclusion criteria must not be 
enrolled into the study: 
PAEDIATRIC AND YOUNG ADULT PATIENTS 
1. Isolated extra-medullary disease relapse (In Phase II of the study, 
patients with isolated CNS relapse post-SCT or pre-SCT if high risk, 
age 16-24 years on therapy relapse or ≥2nd relapse with ≤CNS 
Grade 2 disease at time of enrolment are eligible). 
2. Active CNS involvement of ALL, defined by CNS Grade 3 per 
National Comprehensive Cancer Network guidelines.  Patients 

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developing CNS Grade 3 disease at any time after enrolment will also 
be excluded. 
3. Active infectious bacterial or viral disease (hepatitis B virus, hepatitis 
C virus, human immunodeficiency virus, human T-lymphotropic 
virus, syphilis, West Nile (US only) or Zika viruses (US only)) 
requiring i.v. anti-microbials for treatment. 
4. Females who are pregnant or lactating. 
5. Females of child-bearing potential (defined as all females 
physiologically capable of becoming pregnant) and post-pubertal 
male participants who are unwilling to use highly effective methods 
of contraception during the treatment period and for a period of 1 year 
after the AUTO3 infusion. Note: Examples of highly effective 
contraception methods are described in Appendix 5. 
6. Inability to tolerate leukapheresis. 
7. Prior CD19 or CD22 targeted therapy with Grade 4 toxicity (except 
for haematological toxicity) or ≥Grade 3 cytokine release syndrome 
(CRS) or ≥Grade 3 drug-related CNS toxicity.  CD22 targeted therapy 
such as inotuzumab ozogamicin in patients that are CD19 negative 
(unless it is demonstrated that this therapy had no effect on CD22 
target expression). In Phase II, patients with prior CAR therapy will 
be excluded. 
8. Pre-existing significant neurological disorder (other than CNS 
involvement of underlying haematological malignancy).  
9. Stem Cell Transplant patients only: active significant (overall Grade 
≥2, Seattle criteria) acute graft versus host disease (GVHD) or 
moderate/severe chronic GVHD (National Institutes of Health 
consensus 
criteria) 
requiring 
systemic 
steroids 
or 
other 
immunosuppressant within 4 weeks of enrolment. 
10. The following medications are excluded: 
a. 
Steroids: Therapeutic doses of steroids must be stopped 
>72 hours prior to AUTO3 infusion and leukapheresis. However, 
physiological replacement doses of steroids are allowed: 
<12 mg/m2/day hydrocortisone or equivalent. 
b. Allogeneic cellular therapy: Any donor lymphocyte infusions 
must be completed >6 weeks prior to AUTO3 infusion. 
c. 
Graft versus host disease therapies: Any drug used for GVHD 
must be stopped >4 weeks prior to AUTO3 infusion.  
d. Chemotherapy: Should be stopped 1 week prior to leukapheresis 
and 2 days prior to starting pre-conditioning chemotherapy.  
e. 
Intrathecal therapy: Methotrexate within 4 weeks and other 
intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to 

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starting pre-conditioning chemotherapy. 
f. 
Live vaccine ≤4 weeks prior to enrolment. 
11. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or 
fludarabine. 
12. Any other condition which in the Investigator’s opinion would 
prevent the patient from undergoing protocol-based therapy. 
EXCLUSION CRITERIA 
ADULT PATIENTS 
1. Isolated extramedullary disease 
2. Diagnosis of Burkitt's leukaemia/lymphoma according to World 
Health Organization (WHO) classification or chronic myelogenous 
leukaemia lymphoid blast crisis 
3. Females who are pregnant or lactating. 
4. History or presence of clinically relevant (CNS) pathology such as 
epilepsy, paresis, aphasia, stroke within 3 months prior to enrolment, 
severe brain injuries, dementia, Parkinson’s disease, cerebellar 
disease, organic brain syndrome, uncontrolled mental illness, or 
psychosis.  
5. Presence of CNS-3 disease or CNS-2 disease with neurological 
changes. Patients developing CNS Grade 3 disease or symptomatic 
CNS-2 disease at any time after enrolment will also be excluded. 
6. Clinically significant, uncontrolled heart disease (New York Heart 
Association Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, sick-sinus syndrome, or 
electrocardiographic evidence of acute ischaemia or Grade 3 
conduction system abnormalities unless the patient has a pacemaker) 
or a recent (within 12 months) cardiac event. 
a. 
Uncontrolled cardiac arrhythmia (patients with rate-controlled 
atrial fibrillation are not excluded). 
b. 
Evidence of pericardial effusion. 
7. Patients with a history (within 3 months) or evidence of pulmonary 
embolism requiring ongoing therapeutic anticoagulation at the time of 
pre-conditioning. 
8. Patients with active gastrointestinal (GI) bleeding. 
9. Patients with any major surgical intervention in the last 3 months. 
10. Active infectious bacterial or viral disease or fungal (hepatitis B virus, 
hepatitis C virus, HIV, HTLV, syphilis, West Nile virus [US only] or 
Zika virus [US only]) requiring treatment with i.v. antimicrobials. 
11. History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, 
systemic lupus) resulting in end organ injury or requiring systemic 

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immunosuppression/systemic disease modifying agents within the last 
24 months. Any autoimmune disease with CNS involvement. 
12. History of other malignant neoplasms unless disease free for at least 
24 months (carcinoma in situ, non-melanoma skin cancer, breast or 
prostate cancer on hormonal therapy allowed). 
13. History of concomitant genetic syndrome such as Fanconi anemia, 
Shwachman-Diamond syndrome, Kostmann syndrome or any other 
known BM failure syndrome. 
14. Stem cell transplant patients only: Active significant (overall Grade 
≥II, Seattle criteria) acute GVHD or moderate/severe chronic GVHD 
(NIH consensus criteria) requiring systemic steroids or other 
immunosuppressants within 4 weeks of enrolment. 
15. Prior CD19 or CD22 targeted therapy other than blinatumomab and 
inotuzumab ozogamicin. 
16. The following medications are excluded: 
a. 
Steroids: Therapeutic doses of corticosteroids within 7 days of 
leukapheresis or 72 hours prior to AUTO3 administration. 
However, physiological replacement, topical, and inhaled 
steroids are permitted. 
b. 
Immunosuppression: Immunosuppressive medication must be 
stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion 
c. 
Allogeneic cellular therapy: Any donor lymphocyte infusions 
must be completed >6 weeks prior to AUTO3 infusion. 
d. 
Graft versus host disease therapies: Any drug used for GVHD 
must be stopped >4 weeks prior to AUTO3 infusion.  
e. 
Chemotherapy 
including 
TKIs 
for 
Philadelphia 
chromosome-positive ALL: Should be stopped 1 week prior to 
leukapheresis or 2 days prior to starting pre-conditioning 
chemotherapy. 
f. 
Treatment with alemtuzumab within 6 months prior to 
leukapheresis, or treatment with clofarabine or cladribine within 
3 months prior to leukapheresis. 
g. 
Live vaccine ≤4 weeks prior to enrolment. 
h. 
Intrathecal therapy: Methotrexate within 4 weeks and other 
intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to 
starting pre-conditioning chemotherapy. 
i. 
Systemic inhibitory/stimulatory immune checkpoint - At least 
2 half-lives must have elapsed from any prior systemic 
inhibitory/stimulatory immune checkpoint molecule therapy 
prior to enrolment. 
17. Presence of any indwelling line or drain (e.g., percutaneous 

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nephrostomy tube, indwelling Foley catheter, biliary drain, or 
pleural/peritoneal/pericardial catheter). Ommaya reservoirs and 
dedicated central venous access catheters such as a Port-a-Cath or 
Hickman catheter are permitted. 
18. Research participants receiving any other investigational agents, or 
concurrent biological, chemotherapy, or radiation therapy. 
19. Inability to tolerate leukapheresis. 
20. Patients, who in the opinion of the Investigator, may not be able to 
understand or comply with the safety monitoring requirements of the 
study or unlikely to complete all protocol-required study visits or 
procedures, including follow-up visits. 
Note: Patients failing any of the eligibility criteria, after leukapheresis or 
AUTO3 product manufacture, such as those with progressive CNS 
disease and are discontinued may re-enter the study when they are 
considered to be eligible again. If AUTO3 product has been manufactured 
they can be treated at the current dose using the original product if it 
continues to meet release criteria. 
For Pre-conditioning or AUTO3 Infusion: Patients meeting any of the 
following exclusion criteria must not be given pre-conditioning or treated 
with AUTO3 or treatment should be delayed until they no longer meet 
these criteria:  
1. Severe intercurrent infection at the time of, or within 14 days of, 
scheduled AUTO3 infusion.  
2. Requirement for supplementary oxygen at the time of scheduled 
pre-conditioning or AUTO3 infusion.  
3. Allogeneic transplant recipients with active significant acute GVHD 
overall Grade ≥II or moderate/severe chronic GVHD requiring 
systemic steroids at the time of scheduled pre-conditioning or 
AUTO3 infusion.  
Note: Such patients will be excluded until the patient is GVHD free and 
off steroids. 
4. Significant deterioration of renal or hepatic function (Serum 
creatinine ≥1.8 x ULN,   Serum alanine aminotransferase or aspartate 
aminotransferase ≥6 x ULN, Total bilirubin ≥3 x ULN, except in 
subjects with Gilbert's syndrome) prior to pre-conditioning.  
Note: Patient with ≥Grade 3 CRS, ≥Grade 2 neurotoxicity or a DLT 
following the first split dose should not receive the second split dose.  

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Study Product 
Dose, Dosing 
Regimen, and 
Administration  
Eligible patients will receive a single or split dose i.v. infusion of AUTO3 
following pre-conditioning treatment. The AUTO3 product contains both 
transduced (CD19/CD22 CAR-positive) and non-transduced cells. The 
dose is expressed as the number of CD19/CD22 CAR-positive T cells. 
The following dose levels are planned in Phase I: 
Paediatric and Young Adult Doses  
• 
Dose Level 1: 1.0 x 106/kg CD19/CD22 CAR-positive T cells 
• 
Dose Level 2: 3.0 x 106/kg CD19/CD22 CAR-positive T cells 
• 
Dose Level 3: 5.0 x 106/kg CD19/CD22 CAR-positive T cells 
• 
Dose Level 4: 10.0 x 106/kg CD19/CD22 CAR-positive T cells 
Adult Doses  
• 350 x 106 CD19/CD22 CAR-positive T cells 
• 700 x 106 CD19/CD22 CAR-positive T cells 
Each dose level (both age groups) will have 2 cohorts: one for patients 
with <25% blasts who will receive a single dose and another for patients 
with ≥25% blasts (on Day -7) who will receive a split dose (approx. 1/3rd, 
2/3rd split), second dose given between Days 3-10. 
Pre-
conditioning 
Treatment 
All patients will receive a pre-conditioning regimen using fludarabine 
30 mg/m2 i.v. over 30 minutes immediately followed by 
cyclophosphamide 500 mg/m2 i.v. over 30 minutes. Fludarabine will be 
given on Days -6, -5, -4, and -3 (total dose 120 mg/m2) and 
cyclophosphamide will be given on Days -6 and -5  (total dose 
1000 mg/m2) before AUTO3 infusion.  
Safety 
Evaluation 
Safety will be assessed by physical examination, vital signs, laboratory 
tests, AE and serious AE monitoring, and concomitant medication usage. 
The severity of AEs will be assessed using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (version 5.0), with the 
exception of CRS and CAR associated neurotoxicity, which will be 
graded according to the CRS grading. 
Efficacy 
Evaluation 
Efficacy will be evaluated by determining the proportion of patients 
achieving morphological CR, or CRi  and/ or MRD-negative response in 
bone marrow (BM) within 30 (±3) days post first AUTO3 infusion. 
Biomarker 
Evaluation 
Biomarker evaluation will include the following: 
• 
Expansion and persistence of AUTO3 as determined by quantitative 
polymerase chain reaction and/or flow cytometry on the peripheral 
blood and BM. 
• 
 

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Special Study 
Procedures 
All patients will undergo an unstimulated leukapheresis for AUTO3 
generation. 
Statistical 
Analysis 
The data will be summarised using descriptive statistics. Continuous 
variables will be summarised using the number of observations, mean, 
standard deviation, median, and range as appropriate. Categorical values 
will be summarised using the number of observations and percentages as 
appropriate. Time-to-event endpoints will be estimated using 
Kaplan-Meier methodology.  
Data from all treated patients (safety analysis set) will be used for safety 
analyses and will be summarised by dose level. All treated patients 
(efficacy analysis set) and other subsets will be defined for the efficacy 
analyses. 
Interim 
Analyses 
An interim analysis on safety and preliminary efficacy will be performed 
when all Phase I patients have been followed for a minimum of 3 months.  
In Phase II of the study, an interim analysis will be performed when 
9 patients have been evaluated for response.  The study will be terminated 
if less than 3 responses are observed in 9 patients. 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................ 5 
 
TABLE OF CONTENTS ...................................................................................................... 23 
LIST OF APPENDICES ....................................................................................................... 27 
LIST OF TABLES ................................................................................................................. 28 
LIST OF FIGURES ............................................................................................................... 29 
1 
 
1.1 
 
1.2 
 
1.3 
 
 
1.4 
 
1.5 
 
 
 
1.6 
 
1.7 
 
2 
OBJECTIVES AND ENDPOINTS .............................................................................. 47 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS ................................................... 47 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS ............................................. 48 
2.3 
 
3 
STUDY DESIGN ........................................................................................................... 49 
3.1 
STUDY OVERVIEW ........................................................................................... 49 
3.2 
PHASE I DOSE ESCALATION .......................................................................... 50 
3.3 
PLANNED DOSE LEVELS ................................................................................. 53 
3.4 
PHASE II DOSE EXPANSION ........................................................................... 54 
3.5 
DOSE LIMITING TOXICITY ............................................................................. 54 
3.6 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL ...................... 55 
3.7 
STUDY DURATION ........................................................................................... 56 
3.8 
NUMBER OF PATIENTS.................................................................................... 56 
4 
SCIENTIFIC RATIONALE FOR STUDY ................................................................ 57 
4.1 
DESIGN RATIONALE ........................................................................................ 57 
4.2 
STUDY POPULATION RATIONALE ............................................................... 57 
4.3 
CYCLOPHOSPHAMIDE AND FLUDARABINE PRE-CONDITIONING 
RATIONALE ........................................................................................................ 58 
4.4 
STARTING DOSE RATIONALE........................................................................ 60 
4.5 
DOSING SCHEDULE RATIONALE .................................................................. 62 
4.6 
 

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5 
RISKS AND MITIGATION STRATEGY .................................................................. 64 
6 
PATIENT POPULATION ............................................................................................ 69 
6.1 
INCLUSION CRITERIA ...................................................................................... 69 
6.1.1 Paediatric and Young Adult Patients ......................................................... 69 
6.1.2 Adult Patients............................................................................................. 70 
6.2 
EXCLUSION CRITERIA..................................................................................... 71 
6.2.1 Paediatric and Young Adult Patients ......................................................... 71 
6.2.2 Adult Patients............................................................................................. 72 
7 
 
7.1 
 
7.2 
 
7.3 
 
7.4 
 
7.5 
 
8 
STUDY PROCEDURES AND TREATMENT .......................................................... 77 
8.1 
CONSENT, SCREENING, AND REGISTRATION ........................................... 77 
8.2 
LEUKAPHERESIS ............................................................................................... 79 
8.3 
PRE-CONDITIONING CHEMOTHERAPY ....................................................... 80 
8.3.1 Pre-conditioning Chemotherapy Dose and Regimen ................................ 81 
8.3.2 Supply of Cyclophosphamide and Fludarabine ......................................... 81 
8.3.3 Accountability of Cyclophosphamide and Fludarabine ............................ 82 
8.4 
AUTO3 TREATMENT AND PATIENT MONITORING .................................. 82 
8.4.1 Assessment Prior to AUTO3 Infusion ....................................................... 82 
8.4.2 AUTO3 Administration ............................................................................. 82 
8.4.3 Monitoring During and After AUTO3 Administration ............................. 83 
8.4.4 Dose Delay................................................................................................. 84 
8.4.5 Interruption of Infusion.............................................................................. 84 
8.4.6 Duration of Treatment ............................................................................... 84 
8.4.7 Re-treatment of Patients ............................................................................ 84 
8.5 
FOLLOW-UP PHASE .......................................................................................... 85 
8.6 
LONG-TERM FOLLOW-UP ............................................................................... 86 
9 
STUDY ASSESSMENTS .............................................................................................. 87 
9.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS....................................... 87 
9.1.1 Demographic Data and Baseline Variables ............................................... 87 
9.1.2 Medical/Leukaemia History ...................................................................... 87 
9.1.3 Pregnancy Test........................................................................................... 87 
9.2 
SAFETY EVALUATIONS .................................................................................. 87 
9.2.1 Adverse Events and Toxicity ..................................................................... 87 
9.2.2 Clinical Laboratory Tests .......................................................................... 88 
9.2.3 12-lead Electrocardiogram......................................................................... 88 

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9.2.4 Echocardiogram and Multigated Acquisition ............................................ 89 
9.2.5 Vital Signs ................................................................................................. 89 
9.2.6 Physical Examination ................................................................................ 89 
9.2.7 Karnofsky or Lansky or ECOG Performance Status ................................. 89 
9.3 
PHARMACODYNAMICS AND BIOMARKER EVALUATION ..................... 89 
9.3.1 Evaluation of AUTO3 Persistence in Peripheral Blood ............................ 89 
9.3.2 Evaluation of RCR in Peripheral Blood .................................................... 90 
9.3.3 Insertional Mutagenesis ............................................................................. 90 
9.3.4 
 
9.3.5 
 
9.4 
EFFICACY EVALUATION ................................................................................ 91 
9.4.1 Bone Marrow Aspiration and Biopsy ........................................................ 91 
9.4.2 Treatment Response................................................................................... 92 
9.4.3 Documentation of CNS/Extramedullary Disease ...................................... 92 
9.5 
PATIENT REPORTED OUTCOMES ................................................................. 93 
9.6 
BLOOD VOLUME COLLECTIONS .................................................................. 93 
10 
GUIDELINES FOR PREVENTION, MONITORING, AND MANAGEMENT 
OF ADVERSE EVENTS .............................................................................................. 94 
10.1 GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY .............................................................. 94 
10.2 PRE- AND POST-INFUSION SUPPORTIVE THERAPY ................................. 95 
10.3 TREATMENT OF INFUSION RELATED REACTIONS .................................. 96 
10.4 GRADING AND MANAGEMENT OF CYTOKINE RELEASE 
SYNDROME ........................................................................................................ 98 
10.5 MANAGEMENT OF TUMOUR LYSIS SYNDROME .................................... 102 
10.6 GRADING AND MANAGEMENT OF NEUROTOXICITY (ICANS) ........... 103 
10.7 HYPOGAMMAGLOBULINAEMIA ................................................................ 108 
10.8 MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS DUE TO 
ON-TARGET BUT OFF-TUMOUR TOXICITY .............................................. 109 
11 
CONCOMITANT MEDICATIONS AND THERAPIES ........................................ 110 
11.1 ALLOWED CONCOMITANT MEDICATIONS/THERAPIES ....................... 110 
11.2 PROHIBITED AND CAUTIONARY THERAPIES ......................................... 110 
11.3 BRIDGING THERAPY ...................................................................................... 111 
11.4 OVER-DOSAGE ................................................................................................ 111 
11.5 DIETARY AND LIFESTYLE RESTRICTIONS .............................................. 111 
12 
SAFETY AND PHARMACOVIGILANCE ............................................................. 112 
12.1 DEFINITIONS .................................................................................................... 112 
12.1.1 Definition of an Adverse Event ............................................................... 112 
12.1.2 Definition of an Adverse Reaction .......................................................... 112 
12.1.3 Definition of a Serious Adverse Event .................................................... 112 
12.1.4 Suspected Unexpected Serious Adverse Reactions ................................. 113 

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12.1.5 Adverse Events of Special Interest .......................................................... 114 
12.2 ASSESSMENT OF ADVERSE EVENTS ......................................................... 114 
12.2.1 Severity of Adverse Events ..................................................................... 114 
12.2.2 Relationship of Adverse Events to Treatment ......................................... 114 
12.3 REPORTING PROCEDURES ........................................................................... 115 
12.3.1 All Adverse Events .................................................................................. 115 
12.3.2 Serious Adverse Event Reporting ............................................................ 116 
12.3.3 Suspected Unexpected Serious Adverse Reaction Reporting ................. 118 
12.3.4 Adverse Events of Special Interests Reporting ....................................... 118 
12.3.5 Pregnancy Reporting and Management ................................................... 118 
12.3.6 Overdose Reporting and Dosing Errors ................................................... 119 
13 
OVERSIGHT COMMITTEES .................................................................................. 121 
13.1 SAFETY EVALUATION COMMITTEE .......................................................... 121 
13.2 INDEPENDENT DATA MONITORING COMMITTEE ................................. 121 
14 
STATISTICS ............................................................................................................... 123 
14.1 SAMPLE SIZE ESTIMATION .......................................................................... 123 
14.2 DESCRIPTION OF ANALYSIS DATASETS .................................................. 123 
14.2.1 Full Analysis Set ...................................................................................... 123 
14.2.2 Safety Analysis Set for the Study and for Study Treatment .................... 123 
14.2.3 Efficacy Analysis Set ............................................................................... 123 
14.3 STATISTICAL ANALYSES AND METHODS ............................................... 124 
14.4 PRIMARY ENDPOINTS ................................................................................... 124 
14.4.1 Phase I: Safety ......................................................................................... 124 
14.4.2 Phase I: Recommended Phase II Dose and Maximum Tolerated Dose .. 125 
14.4.3 Phase II: Anti-Leukaemic Effect ............................................................. 125 
14.5 SECONDARY ENDPOINTS ............................................................................. 125 
14.6 
 
14.7 
 
14.8 PHARMACOKINETICS .................................................................................... 127 
14.9 OTHER ANALYSES ......................................................................................... 127 
14.10 INTERIM ANALYSIS ....................................................................................... 127 
15 
STUDY COMPLETION/DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS ................................................................................................................... 128 
15.1 COMPLETION ................................................................................................... 128 
15.2 DISCONTINUATION IN STUDY .................................................................... 128 
15.3 PATIENT WITHDRAWAL FROM THE STUDY............................................ 129 
15.3.1 Procedures for Handling Withdrawals..................................................... 129 
15.4 REPLACEMENT POLICY ................................................................................ 130 

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16 
END OF TRIAL/TERMINATION ............................................................................ 131 
17 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 132 
17.1 ETHICS COMMITTEE REVIEW AND APRROVAL ..................................... 132 
17.2 REGULATORY AUTHORITY REVIEW AND APPROVAL ......................... 132 
17.3 INVESTIGATOR RESPONSIBILITIES ........................................................... 132 
17.3.1 Overall Responsibilities ........................................................................... 132 
17.3.2 Site Review .............................................................................................. 132 
17.3.3 Informed Consent .................................................................................... 133 
17.3.4 Delegation of Investigator Duties ............................................................ 133 
17.3.5 Communication with Independent Ethics Committee/Institutional 
Review Board .......................................................................................... 133 
17.3.6 Confidentiality of Trial Documents and Patient Records ........................ 134 
17.4 LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE 
RESEARCH ........................................................................................................ 134 
18 
ADMINSTRATIVE REQUIREMENTS ................................................................... 135 
18.1 DATA QUALITY CONTROL AND ASSURANCE ........................................ 135 
18.1.1 Compliance with the Protocol and Protocol Revisions ........................... 135 
18.1.2 Protocol Violations and Deviations ......................................................... 135 
18.1.3 Monitoring ............................................................................................... 135 
18.1.4 Audits and Site Inspections ..................................................................... 136 
18.2 DATA HANDLING AND RECORD KEEPING .............................................. 136 
18.2.1 Data Management .................................................................................... 136 
18.2.2 Study Documentation and Retention of Records..................................... 137 
18.3 CLINICAL TRIAL AGREEMENT, FINANCE AND INSURANCE ............... 137 
19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS.......... 138 
20 
REFERENCES ............................................................................................................ 139 
21 
APPENDICES ............................................................................................................. 149 
 
LIST OF APPENDICES 
Appendix 1:  Response Criteria for Acute Lymphoblastic Leukaemia (National 
Comprehensive Cancer Network Guidelines) ................................................ 149 
Appendix 2:  Karnofsky Score ............................................................................................. 150 
Appendix 3: Lansky Score .................................................................................................. 151 
Appendix 4: Eastern Cooperative Oncology Group Performance Status Score ................. 152 
Appendix 5:  Highly Effective Methods of Birth Control ................................................... 153 
Appendix 6:  International Study for Treatment of Childhood Relapsed Acute 
Lymphoblastic Leukaemia Definition of Risk Groups in Relapsed 
Paediatric Acute Lymphoblastic Leukaemia .................................................. 155 
 

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LIST OF TABLES 
Table 1: 
Summary of CD19 CAR Constructs in Clinical Trials in Paediatric and 
Adult ALL ........................................................................................................ 39 
Table 2:  
Phase I Primary Objectives and Endpoints ...................................................... 47 
Table 3:  
Phase II Primary Objectives and Endpoints ..................................................... 47 
Table 4:  
Secondary Objectives and Endpoints ............................................................... 48 
Table 5: 
Rolling 6 Dose Escalation Decision Rules ....................................................... 52 
Table 6: 
AUTO3 Treatment Cohorts & Schedules ........................................................ 53 
Table 7: 
Leukapheresis – Risks and Mitigation Strategy ............................................... 64 
Table 8: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy ................... 65 
Table 9: 
AUTO3 Infusion – Risks and Mitigation Strategy ........................................... 66 
Table 10: 
Infectious Disease Screening ........................................................................... 78 
Table 11: 
Clinical Laboratory Tests ................................................................................. 88 
Table 12:  
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy ............................................................................................................. 94 
Table 13: 
Pre- and Post-infusion Medications (Dose Adjusted as Age Appropriate) ...... 96 
Table 14: 
Guidelines for the Management of Infusion-related Reactions (Dose 
Adjusted as Age Appropriate) .......................................................................... 97 
Table 15A: 
Severity Grading of Cytokine Release Syndrome (ASBMT CRS Consensus 
Grading) ........................................................................................................... 99 
Table 15B: 
Management of Cytokine Release Syndrome (Dose Adjusted as Age 
Appropriate) ................................................................................................... 100 
Table 16:  
Definitions and Doses of Vasopressors (Dose Adjusted as Age Appropriate)101 
Table 17:  
Pharmacologic Management of CRS/MAS (Dose Adjusted as Age 
Appropriate) ................................................................................................... 102 
Table 18:  
Assessment & Grading of Neurological AEs (ASBMT ICANS Consensus 
Grading for Adults (Lee et al. 2018) ............................................................. 104 
Table 18A: 
Management and Follow-up of Neurological AEs and CRES ....................... 106 
Table 18B: 
Recommendations for the Management of Status Epilepticus After CAR T 
Cell Therapy ................................................................................................... 107 
Table 18C: 
Recommendation for Management of Raised Intracranial Pressure (ICP) 
After CAR T Cell Therapy ............................................................................. 108 
Table 19: 
Severity Grading of AEs Not Listed on the NCI CTCAE Grading System .. 114 
Table 20: 
Reporting Period for All AEs ......................................................................... 116 

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LIST OF FIGURES 
Figure 1: 
Schematic Representation of the CD19 and CD22 CAR Protein Structure 
Expressed on AUTO3 Cells ............................................................................. 43 
Figure 2: 
CD19/CD22 CAR-T Expansion by qPCR ....................................................... 46 
Figure 3: 
Dose Escalation and Dose Expansions Phases ................................................. 49 
Figure 4: 
Overview of the Stages of the Study ................................................................ 50 
Figure 5: 
CRS Management Overview .......................................................................... 101 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACD-A 
Anticoagulant citrate dextrose solution A 
AE 
Adverse event  
ALL 
Acute lymphoblastic leukaemia 
BM 
Bone marrow 
CAPD 
Cornell Assessment of Pediatric Delirium 
CAR 
Chimeric antigen receptor 
CD3-ζ, -19, -20, -28, -134, 
-137 
Cluster of differentiation 3, 19, 20, 28, 134, 137 
CNS 
Central nervous system 
CR 
Complete response 
CRES 
CAR-T-Cell-Related Encephalopathy Syndrome 
CRi 
Complete response with incomplete recovery of counts 
CRS 
Cytokine release syndrome 
CSF 
Cerebrospinal fluid 
CT 
Computerised tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CY 
Cyclophosphamide 
DFS 
Disease-free survival 
DIC 
Disseminated intravascular coagulation 
DLT 
Dose limiting toxicity 
DMSO 
Dimethyl sulfoxide 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EFS 
Event-free survival 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
First-in-human 

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Abbreviation 
Definition 
FLU 
Fludarabine  
FLU-CY 
Fludarabine and cyclophosphamide 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVHD 
Graft versus host disease 
HIV 
Human immunodeficiency virus 
HR 
High risk 
HRQOL 
Health-related quality of life 
HSCT 
Haematopoietic stem cell transplantation 
HTLV 
Human T-cell lymphotropic virus 
i.v. 
Intravenous(ly) 
IB 
Investigator’s Brochure 
ICANS 
Immune effector Cell-Associated Neurotoxicity Syndrome 
ICE 
Immune effector Cell-associated Encephalopathy 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICP 
Intracranial Pressure 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IHC 
Immunohistochemical 
IL 
Interleukin 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
KM 
Kaplan-Meier 
LAIP 
Leukaemia-associated immunophenotype 
LFS 
Leukaemia-free survival 
LVEF 
Left ventricular ejection fraction 
MAS 
Macrophage activation syndrome 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 

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Abbreviation 
Definition 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OS 
Overall survival 
OX40 
Tumour necrosis factor receptor superfamily 4 [TNFRSF4] 
and cluster of differentiation 134 [CD134]) endodomain 
PBMCs 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PedsQL 
Pediatric Quality of Life Inventory 
PFS 
Progression-free survival 
PIS 
Patient Information Sheet 
PTT 
Partial thromboplastin time 
qPCR 
Quantitative polymerase chain reaction 
RCR 
Replication competent retrovirus 
RFS 
Relapse free survival 
RP2D 
Recommended Phase II dose 
SAE 
Serious adverse event 
ScFv 
Single chain variable fragment 
SCT 
Stem cell transplant 
SEC 
Safety Evaluation Committee 
SR 
Standard risk 
SST 
Serum separator tube 
SUSAR 
Suspected unexpected serious adverse reaction 
TLS 
Tumour lysis syndrome 
TNF 
Tumour necrosis factor 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UPENN 
University of Pennsylvania 
WBC 
White blood cell 
 

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2 
OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS 
Primary objectives and endpoints for Phase I and Phase II of the study are presented in 
Table 2 and Table 3, respectively. 
Table 2:  
Phase I Primary Objectives and Endpoints 
Objectives 
Endpoints 
To assess the overall safety and tolerability of 
AUTO3 administration.  
Incidence of Grade 3-5 toxicity occurring within the dose 
limiting toxicity (DLT) period (30 days after last dose) of 
AUTO3 infusion. 
To confirm and evaluate the RP2D and dosing 
schedule, and confirm maximum tolerated dose 
(MTD, if an MTD exists, of AUTO3 in both 
paediatric and adult patients. 
Frequency of DLT of AUTO3. 
DLT = dose limiting toxicity; MTD = maximum tolerated dose; RP2D = recommended Phase II dose. 
Table 3:  
Phase II Primary Objectives and Endpoints 
Objectives 
Endpoints 
To evaluate the anti-leukaemic effect of 
AUTO3 in paediatric and young adult patients 
(aged 1-24 years). 
Proportion of patients achieving morphological remission 
(CR or complete response with incomplete recovery of 
counts [CRi]) and MRD-negative response in bone 
marrow (BM) within 30 (-3/+5) days post first AUTO3 
infusion. 
In patients with isolated CNS disease, anti-tumour effect 
will be assessed by whether patients clear their 
cerebrospinal fluid (CSF) of disease with ongoing BM CR, 
within 30 (±3) days post first AUTO3 infusion. 
BM = bone marrow; CNS = central nervous system; CR = complete response; CRi = complete response with incomplete 
recovery of counts; CSF = cerebrospinal fluid; MRD = minimal residual disease. 

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2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives and endpoints are presented in Table 4. 
Table 4:  
Secondary Objectives and Endpoints 
Objectives 
Endpoints 
To assess the safety and tolerability of 
AUTO3  
Frequency and severity of adverse events (AEs) and serious adverse 
events (SAEs)  
Incidence and duration of severe hypogammaglobulinaemia 
To evaluate the feasibility of 
generating AUTO3 
Proportion of patients for whom an AUTO3 product can be 
generated (feasibility) 
To evaluate the clinical efficacy of 
AUTO3 
Proportion of patients (all and prior CD19 CAR T treatment naïve) 
achieving morphological remission (CR or CRi) and/or MRD-
negative complete response in bone marrow (BM) within 30 
(±3) days post first AUTO3 infusion by qPCR and/or flow 
cytometry. 
Relapse Free Survival (RFS), Event Free Survival (EFS), 
Progression-Free Survival (PFS) and Overall Survival (OS) 
following first treatment with AUTO3 
Proportion of patients in molecular remission without further 
therapy at 6 months, 1 & 2 years following treatment with AUTO3 
Incidence of CD19 and/or CD22-negative relapse 
To determine the expansion and 
persistence of AUTO3 following 
adoptive transfer 
Quantitative polymerase chain reaction (qPCR) and/or flow 
cytometry at a range of time points in the peripheral blood and BM 
Duration of B-cell aplasia 
Depletion of circulating B cells assessed by flow cytometry at a 
range of time points in the peripheral blood 
AE = adverse event; CD = cluster of differentiation; CR = complete response; CRi = complete response with incomplete 
recovery of counts; MRD = minimal residual disease; OS = overall survival; PFS = progression-free survival; 
qPCR = quantitative polymerase chain reaction; SAE = serious adverse event. 
2.3 
 
 
• 
 
• 
 
 
• 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 

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3
STUDY DESIGN  
3.1
STUDY OVERVIEW 
This multi-centre, single-arm study will consist of two parts, a Phase I/dose escalation phase 
and a Phase II/expansion phase:  
• 
Phase I: Dose escalation
o 
To evaluate the optimal dose and schedule of AUTO3 in paediatric and young adults 
(age 1-24 years), starting at 1.0 x 106/kg CD19/CD22 CAR-positive T cells and then 
escalated to 3, 5 and 10 x 106/kg CD19/CD22 CAR-positive T cells as a single or 
split dose based on disease burden). 
o 
Adult ALL (≥25 years) dose escalation may start at the highest paediatric/young 
adult dose declared safe. Dosing will be based on a fixed dose which is equivalent to 
a dose in a 70 kg patient. 
• 
Phase II: Dose expansion to further assess safety and anti-leukaemic activity at the 
RP2D and dose schedule in paediatric and young adult patients only.  
An overview of the study design is presented in Figure 3 below.  
Figure 3: 
Dose Escalation and Dose Expansions Phases 
 
The study will consist of the following five stages: 
• 
Screening: After providing written informed consent for study participation, all patients 
will be screened for study eligibility. Eligible patients will proceed to leukapheresis. 
• 
Leukapheresis: Eligible patients will undergo leukapheresis to facilitate manufacture of 
AUTO3. If sufficient quantity of the cells (prescribed dose ±20%) are produced, the 
patient will proceed to the pre-conditioning phase. 

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• 
Pre-conditioning: If sufficient AUTO3 for the prescribed dose is successfully 
manufactured and the patients continue to meet eligibility requirements for the study, 
they will proceed to receive a prescribed lymphodepleting pre-conditioning treatment 
with CY and FLU before AUTO3 infusion.  
• 
Treatment: AUTO3 for the prescribed dose will be administered i.v. as a single infusion 
on Day 0 or split into two, with the second split dose given between Day 3-10 in patients 
with higher blast count in the BM. The treatment phase will extend from Day 0 (infusion 
day) until the end of the DLT observation period, 30 days (±3 days) post last AUTO3 
infusion. Phase I patients are expected to be admitted for a minimum of 30 days 
(±3 days), or longer if necessary for monitoring and management. The duration of 
admission of Phase II patients will be 30 days (±3 days) but may be reduced based on 
emerging data with a protocol amendment.  
• 
Follow-up: The follow-up phase will begin after the treatment stage and end 24 months 
(±14 days) after first infusion with AUTO3 or at disease progression or withdrawal of 
consent, which ever happens first (End of Study visit performed for early withdrawal). 
An overview of the five study stages is presented in Figure 4.  
Figure 4: 
Overview of the Stages of the Study 
From signing of consent until the 24 month visit or the End of Study visit in the case of early 
withdrawals, information relating to AEs, laboratory abnormalities, biomarker changes, and 
anti-leukaemic activity will be collected according to the Schedule of Assessments. 
All patients will be eligible for enrolment into a long-term follow-up protocol (AUTO-LT1) 
at the end of the study to be followed for safety evaluation and survival for 15 years from the 
first AUTO3 infusion or until death or withdrawal of consent, which ever happens first.  
Note: Patients who have received AUTO3 and have discontinued or completed the study will 
continue to be monitored periodically for AUTO3 treatment-related SAEs, AEs of special 
interest and new malignancies until they enrol onto the long-term follow-up study 
(AUTO-LT1). Additionally, blood samples for CAR T persistence and replication competent 
retroviruses (RCRs) may also be collected every 3 months. In such cases, the End of Study 
visit may be delayed until enrolment onto the long-term follow-up study. 
3.2 
PHASE I DOSE ESCALATION 
Phase I is designed to evaluate the optimum RP2D schedule of AUTO3 in paediatric and 
adult patients with B cell ALL. The paediatric/young adult (1-24 years) and adult (≥25 years) 
cohorts will run in parallel. The paediatric/young adult group will start at a dose of 
1.0 x 106/kg CD19/CD22 CAR-positive T cells. The adult patient (≥25 years) cohort will 
open at or below the dose after at least 3 patients in the paediatric/young adult group have 
been treated at a dose level and no DLTs or more than one case of Grade 3 CRS or 
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Dose escalation will follow a rolling 6 design (Skolnik et al. 2008) (Table 5). Each cohort 
may treat up to six patients. Evaluation of a dose level with at least three patients treated at 
the planned dose level completing the DLT evaluation period is required prior to declaring 
the dose and schedule safe. If patients are treated below the planned dose level due to 
AUTO3 manufacturing or other reasons, then those patients will not be considered evaluable 
for making dose escalation decisions (additional patients will be enrolled to meet the 
minimum number needed to make the decision). Similarly if a patient receives a retreatment 
dose at the higher dose before its declared safe (lower dose considered sub-therapeutic) then 
that patient will not be evaluable for dose escalation decision making (will be considered 
evaluable for dose decision making if they develop a DLT with retreatment). However, dose 
escalation decisions will consider all available data, including biomarker data and the safety 
profile of all patients treated. 
The trial is planned to comprise of up to 4 dose levels; eligible patients will be assigned to 
two subgroups based on disease burden concurrently. The inter-patient dosing interval for 
AUTO3 in Phase I will be at least 14 days, for patients enrolled in a cohort and at least 
7 days for patients enrolled to different cohorts until the dose schedule is declared safe, to 
allow for assessment of possible toxicity. Patients will be admitted to hospital (or ambulatory 
care setting) for a minimum of 30 days (±3 days), which can be extended as clinically 
indicated. The Safety Evaluation Committee (SEC) may increase the dosing interval based on 
emerging data. The DLT evaluation period will be 30 days (±3 days) after the last dose of 
AUTO3. 
The SEC will meet after the first patient in every cohort completes 14 days, to confirm 
continuation of enrolment to that cohort and thereafter meet again after the third or 
sixth patient in a cohort has completed the DLT assessment period.  
In paediatric and young adult patients (aged 1-24 years), the planned starting dose level of 
1.0 x 106/kg CD19/CD22 CAR-positive T cells will consist of two cohorts based on disease 
burden. Patients with <25% blasts (cohort 1A) in the BM will receive the total dose of 
1.0 x 106/kg CD19/CD22 CAR-positive T cells as a single dose, and those with ≥25% blasts 
(cohort 1B) in the BM will receive a split dose, 0.3 x 106/kg followed by 0.7 x 106/kg 
CD19/CD22 CAR-positive T cells (Table 6). The second split dose will be administered after 
3-10 days and will be delayed or withheld if a patient experiences a severe toxicity with the 
first split dose (Table 6). If the emerging data indicates that the starting dose level and the 
next dose level (3 x 106/kg) or a cohort in that dose has poor expansion, persistence or 
clinical response then SEC can recommend closure of that dose level or cohort after at least 
2 patients (including cohorts A & B) have completed the DLT assessment period and can 
recommend escalation to the next dose level if no CAR related Grade 3 CRS or Grade 3 
neurotoxicity has been noted. Dose level 2 is planned at 3.0 x 106/kg CD19/CD22 
CAR-positive T cells. As with dose level 1 the dosing will be tailored to the disease burden. 
Patients with <25% blasts (cohort 2A) will receive 3.0 x 106/kg CD19/CD22 CAR-positive 
T cells as a single dose and those with ≥25% blasts (cohort 2B) will receive 1.0 x 106/kg 
CD19/CD22 CAR-positive T cells followed by 2.0 x 106/kg CD19/CD22 CAR-positive 
T cells. Similarly, dose level 3 will evaluate a dose of 5 x 106/kg and dose level 4 will 
evaluate a dose of 10 x 106/kg CD19/CD22 CAR-positive T cells with the dosing schedule 
based on disease burden.  
The adult patient (≥25 years) cohort can open at 350 x 106 CD19/CD22 CAR-positive T cell 
dose (fixed dose equivalent to 5 x 106/kg CD19/CD22 CAR-positive T cells in a 70 kg adult) 
if 3 patients have been safely treated at 5 x 106/kg CD19/CD22 CAR-positive T cells dose in 

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the paediatric/young adult group. The starting dose will be lower (210 x 106 CD19/CD22 
CAR-positive T cells) if more than one case of Grade 3 CRS or neurotoxicity or a DLT has 
been observed in the paediatric group treated at 5 x 106/kg CD19/CD22 CAR-positive 
T cells. Patients will be dosed on a single or split dose schedule in the adult cohort 
(Schedules C & D) based on disease burden. Once initiated, dose escalation in the adult 
group will proceed independent of the paediatric/young adult group. 
If the single dose schedule is found to be safe (Table 5), then that dose may be declared as a 
RP2D for an age group. If two or more DLTs are observed in the first 3-6 patients enrolled to 
cohort A then further enrolment to that cohort will stop (Table 5). However, patients with 
similar disease burden (<25% blasts) may be evaluated using the split dosing regimen used in 
cohort B if emerging data confirms that approach is likely to be safer. Similarly, if cohort B is 
considered safe, then it will also be declared a RP2D. Additionally, after cohort B is declared 
safe, if emerging data suggests that it may be appropriate to treat patients with this disease 
burden (≥25% blasts) with a single dose, then they may be evaluated using the single dose 
regimen used in cohort A. Alternatively, if two or more DLTs are observed in the first 3-
6 patients enrolled to cohort B then further enrolment to that cohort will stop. The SEC will 
consider totality of data before declaring a dose safe and as a RP2D or recommend further 
escalation or de-escalation. Dose escalation decision or RP2D for single and split dose can 
happen independent of the other cohort and Phase II can be opened for patients with similar 
disease burden. If a cohort eg 3A is declared as RP2D after dosing 6 patients then 3B can be 
declared as RP2D after 3 patients have been dosed and no DLTs observed. Alternatively, if 
3 patients each are treated in cohort 3A and 3B then both cohorts can be declared as the 
Phase II dose. The decision for paediatric/young adults and older adult cohorts will be made 
independently. 
If emerging data indicate that evaluation of a higher dose level is warranted, then a dose at or 
up to a total dose of 10 x 106/kg CD19/CD22 CAR-positive T cells may be opened, applying 
a similar dosing strategy based on disease burden as for the lower doses (Table 6). Adult 
patients (≥25 years) will be treated at a fixed dose of up to 700 x 106 CD19/CD22 
CAR-positive T cells. Evaluation of a dose greater than 10 x 106/kg CD19/CD22 
CAR-positive T cells will not happen without a protocol amendment. 
Table 5: 
Rolling 6 Dose Escalation Decision Rules 
Number of Patients with DLT at 
a Given Dose Level/Schedule 
Escalation Decision Rules 
0 out of 3 
May declare dose safe and escalate (may continue to enrol additional 
patients for additional biomarker and safety data). 
0 out of 6 
Declare RP2D, may consider escalation to a higher dose level.  
1 out of 3 
Enrol 3 additional patients at the current dose level for a total of 
6 patients. 
1 out of 6 
Declare RP2D, may consider escalation to a higher dose level.  
2 or more patients in a dosing 
cohort (up to 6 patients)  
The MTD has been exceeded, stop further enrolment. May evaluate a 
split dose or lower dose than the current dose. 
DLT = dose limiting toxicity; MTD = maximum tolerated dose. 
Note: The Investigators may override these guidelines if there are safety issues for which moving to a higher dose is not 
considered appropriate. Additionally, dose level 1 & 2 can be declared safe if there is poor expansion, persistence and 
efficacy after 2 patients (including cohort A & B) have been treated and no DLTs observed. 

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The dose decisions will be made by the SEC (Section 13.1) and the study could be stopped by 
the SEC or Independent Data Monitoring Committee (IDMC) upon occurrence of any of the 
events described in Section 3.6. 
3.3 
PLANNED DOSE LEVELS 
The planned dose schedules for Phase I are presented in Table 6. These dose schedules were 
selected as they provide an optimum range for assessing safety, CAR T cell persistence and 
anti-tumour activity. This dose and dosing schedule is within the range assessed in other 
CAR T studies. Based on emerging data, intermediate dose levels may also be explored.  
Table 6: 
AUTO3 Treatment Cohorts & Schedules 
Dose 
Level 
Treatment 
Cohorts 
BM Blast % 
Dosing Schedule 
Paediatric/Young Adults (1-24y) 
(Schedules A&B) 
Dosing Schedule Adults (≥25y) 
(Schedules C&D) 
Dose 1 Day 0 
Dose 2 Day 3-10 
Dose 1 Day 0 
 Dose 2 Day 3-10 
Dose 
Level 
1  
Cohort 1A 
<25% blasts 
1.0 x 106/kg 
None 
n/a 
n/a 
Cohort 1B 
≥25% blasts 
0.3 x 106/kg 
0.7 x 106/kg 
n/a 
n/a 
Dose 
Level 
2 
Cohort 2A 
<25% blasts 
3.0 x 106/kg 
None 
n/a 
n/a 
Cohort 2B 
≥25% blasts 
1.0 x 106/kg 
2.0 x 106/kg 
n/a 
n/a 
Dose 
Level 
3 
Cohort 3A 
<25% blasts 
5.0 x 106/kg 
None 
 
 
Cohort 3B 
≥25% blasts 
2.0 x 106/kg 
3.0 x 106/kg 
 
 
Cohort 3C 
<25% blasts 
 
 
350 x 106 
None 
Cohort 3D 
≥25% blasts 
 
 
150 x 106 
200 x 106 
Dose 
Level 
4 
Cohort 4A 
<25% blasts 
10.0 x 106/kg 
None 
 
 
Cohort 4B 
≥25% blasts 
4.0 x 106/kg 
6.0 x 106/kg 
 
 
Cohort 4C 
<25% blasts 
 
 
700 x 106 
None 
Cohort 4D 
≥25% blasts 
 
 
300 x 106 
400 x 106 
Note: The adult starting dose will be lower (210 x 106 CD19/CD22 CAR-positive T cells) if a DLT has been observed in the 
paediatric group at 5 x 106/kg CD19/CD22 CAR-positive T cells. 
• 
Paediatric and young adult cohorts will enrol patients 1-24 years in Cohorts A & B and 
adult patients ≥25 years will be enrolled into adult Cohorts C & D. 
• 
A patient may be eligible for a dose level if the dose is within 20% of the prescribed dose 
(±20%). 
• 
Cohort will be decided based upon the results of the Day -7 BM blast count (can be local 
results) or the last blast count available during the screening period.  
• 
On occasion, AUTO3 production may fail to generate sufficient cells for the current dose 
level. In this case, the patient can be treated on study but at a lower dose, however if a 
production fails to generate <0.2 x 106/kg CD19/CD22 CAR-positive T cells (near the 
lowest known active dose of CD19 CAR-positive T cells, of 1.46 x 105 cells/kg, 
corresponding to approximately 10 x 106 total dose of CAR T-cells (Porter et al. 2011), 
then the patient will not be treated on study. Only patients treated at the planned dose 

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level will be evaluable for dose escalation decision making and primary efficacy 
analysis. 
• 
In each dose level, the two sub-cohorts will be opened concurrently. 
• 
In patients receiving a split dose the decision to administer the 2nd split dose will be made 
by the site PI or delegated individual in consultation with the Sponsor’s Medical 
Monitor. Patients will be monitored for early onset of high grade fever that is suspected 
to be CAR related and evaluated for toxicity during the 3 days after infusion of the initial 
dose. If no ≥Grade 3 CRS or ≥Grade 2 neurotoxicity has occurred, the 2nd dose may be 
administered 3-10 days after the first if CRS has resolved to ≤Grade 1 and neurotoxicity 
has completely resolved. Dosing of the 2nd split dose can be further delayed (beyond 
10 days) if clinically indicated. Patients who develop AUTO3 related ≥Grade 3 CRS, 
≥Grade 2 neurotoxicity or a DLT following the first split dose will not receive the 
second split dose.  
• 
Based on emerging data, patients with ≥25% blasts in the BM may be treated with a 
single dose if both single and split doses are determined to be safe.  
• 
Dose calculation should be made based on actual body weight, unless the patient is 
obese, in which case the dose calculation may be made based on ideal body weight for 
the age and height. Adult patients (≥25 years) will receive a fixed dose calculated based 
on a 70 kg adult weight.   
3.4 
PHASE II DOSE EXPANSION 
Once the RP2D (for a disease burden) is determined for paediatric and young adult patients, 
the Phase II dose expansion part of the study will open. Individual patients may get a single 
or split infusion of the dose based on the disease burden. This part will treat up to 24 patients.  
3.5 
DOSE LIMITING TOXICITY 
Toxicities will be graded for severity per the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0 and the CRS will be graded using Lee Criteria (Lee et al. 
2018). The DLT evaluation period will be 30 days (±3 days) after the last dose of AUTO3.  
Dose limiting toxicity will be defined as: 
• 
Any new non-haematological AE of Grade 3 or higher toxicity using the NCI CTCAE 
(version 5.0), which is probably or definitely related to AUTO3 therapy, which occurs 
within the DLT evaluation period, and which fails to resolve to Grade 2 or better within 
14 days, despite appropriate supportive measures. 
• 
A Grade 4 CRS or neurotoxicity, cerebral oedema, or Grade 3 neurotoxicity (including 
cerebral oedema) that lasts >72 hours. 
• 
Grade >3 disseminated intravascular coagulation (DIC).  
• 
Grade >2 infusion reaction. 
• 
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 SEC 
necessitates dose reduction or other modification to trial treatment to avoid a similar 
hazard in future patients.  

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− 
Effort should be made to perform an autopsy in the case of a fatal event where the 
aetiology is unclear. 
Reporting Requirements for DLT 
All DLTs must be reported to the Sponsor as SAEs within 24 hours of site staff becoming 
aware of them (see Section 12.3.2). All DLTs will be notified to the SEC and IDMC by the 
Sponsor.  
Maximum Tolerated Dose: The MTD is defined as the highest dose level of AUTO3 at 
which ≤one patient out of six patients experience a DLT during the DLT evaluation period. If 
two or more out of six patients at a dose level experience a DLT during the DLT evaluation 
period, the MTD has been exceeded. If the MTD is exceeded due to a specific toxicity that 
can be managed with supportive care, an additional three patients may be enrolled at the dose 
level that exceeded the MTD with establishment of supportive care measures after review and 
approval by the IDMC. A summary of available safety data and a description of the plans for 
supportive care measures with further enrolment at that dose level will be provided (as a 
notification) to Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) 
prior to dosing. 
Recommended Phase II Dose: The RP2D is either identical to the MTD or maximum 
administered dose or a lower dose level of AUTO3, selected based on a cumulative review of 
safety, persistence of the CAR T cells and clinical activity.  Recommended Phase II dose 
schedules may be defined based on disease burden. A minimum of 6 patients need to be 
treated in a cohort before it can be declared as the Phase II dose. For example, if 6 patients 
are treated in cohort 3A then it can be declared as the RP2D for patients with lower disease 
burden. Alternatively, if 3 patients each are treated in cohort 3A and 3B then both cohorts/the 
dose level can be declared as the Phase II dose. 
3.6 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL 
The study can be stopped by the SEC or IDMC upon occurrence of any of the following 
events: 
• 
Unexpected and related SAEs that exposed patients participating in the study to 
unacceptable risk of harm. (Class related toxicities such as CRS and neurotoxicities will 
not automatically result in stopping unless they are exposing patients to risk above what 
is expected for similar therapies). 
• 
Uncontrolled SAEs related to identified risks. 
• 
The occurrence of Grade 4 non-haematological toxicity in 3 patients. Unless in the 
opinion of the IDMC (after review), it is likely manageable with the institution of 
appropriate supportive care.  
• 
Death of a patient at any time after therapy that is definitely related to T cell therapy. 
• 
The occurrence of a second malignancy at any point after therapy that is definitely 
related to the T cell therapy. 
The study may be restarted after appropriate preventive or management guidelines have been 
instituted and a substantial protocol amendment has been approved by the regulatory 
authorities and ethics committees. 

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3.7 
STUDY DURATION 
The total study duration is estimated to be 5 years from first patient enrolled to the last 
patient, last visit (24-month visit). The end of the trial will be 24 months after the last patient 
has received a first AUTO3 infusion (or earlier if appropriate). Long-term follow up of 
patients for up to 15 years after AUTO3 treatment is described in Section 8.5.  
3.8 
NUMBER OF PATIENTS 
It is anticipated that approximately 100 patients will be enrolled (consented) into the study 
with up to 84 patients receiving the treatment as outlined below. The difference between the 
number of enrolled and treated patients accounts for manufacturing failures and inability of 
some patients to meet AUTO3 infusion criteria. 
• 
Phase I: A dose escalation involving up to a total of 36-60 treated paediatric and adult 
patients (up to 3-6 patients per dose cohort), which will consist of: 
o 
24-36 patients in the paediatric / young adult patient cohorts (age 1-24 years) 
o 
12-24 patients in the adult patient cohorts (≥25 years) 
− 
Additional number accounts for the possibility of patient with higher disease burden 
being evaluated using a single dose 
• 
Phase II: Dose expansion involving up to a total of 24 treated patients in 
paediatric/young adults (aged 1-24 years). 
Phase II of the study will follow Simon’s 2-stage optimal design as described in Section 14.1. 

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4 
SCIENTIFIC RATIONALE FOR STUDY 
4.1 
DESIGN RATIONALE 
This single-arm dose escalation and expansion Phase I/II study, is designed to assess safety, 
tolerability, and optimum RP2D schedule and MTD, if a MTD exists. Considering the 
experience the field has with targeting both CD19 and CD22 individually and the novelty of 
targeting CD19 and CD22 with a combined CAR, a starting dose of 1.0 x 106/kg CD19/CD22 
CAR-positive T cells encompassing splitting of dose based on disease burden is considered 
appropriate. Additionally, escalation to a higher dose of 3, 5 and then 10 x 106/kg 
CD19/CD22 CAR-positive T cells is incorporated as other CD19 41BB-ζ CARs in a similar 
patient population have indicated tolerability of these doses (2.0-5.0 × 106 CAR T cells/kg for 
≤50 kg and 1.0-2.5 x 108 cells for >50 kg) (Lee et al. 2014, Maude et al. 2014b) and our 
initial data indicate improved CAR T cell expansion/persistence at doses of 3 x 106/kg and 
above. Adult patients (≥25yrs) will be treated at a fixed dose (as per Schedule C and D) 
starting at 350 x 106 CD19/CD22 CAR-positive T cells if an equivalent dose has been 
administered to 3 pediatric/young adult patients and found to be safe; if not, treatment will 
start at a lower dose. The subsequent dose will be 700 x 106 CD19/CD22 CAR-positive T 
cells. This starting dose is in the range being evaluated with other CAR T cells in adult ALL, 
such as tisagenlecleucel (CTL019, Kymriah) of 100-500 x 106 CAR T cells which was dosed 
with a split dose schedule (Frey et al. 2016), escalation to higher doses will be based on 
emerging data from lower dose cohort. 
The rationale for our dose level and dosing schedule is outlined in detail in Sections 4.4 and 
4.5. In Phase I of the study, a starting dose level (1.0 x 106/kg CD19/CD22 CAR-positive 
T cells/kg), which is similar to the MTD of autologous CD19 CAR T cells in the National 
Institutes of Health (NIH) study in paediatric ALL, will be evaluated (Lee et al. 2015). Based 
on emerging data this dose could be declared RP2D or the dose further escalated as described 
above. 
During Phase I of the study, a minimum interpatient dosing interval of 2 weeks within a 
cohort and 1 week between cohorts is incorporated to reduce the risk of inducing severe 
adverse effects in more than one patient until a dose schedule is declared safe. Following 
evaluation of the safety of AUTO3 and determination of the RP2D, safety and efficacy will 
be further evaluated in a Phase II expansion cohort. There is no suggested interval between 
patients in the Phase II cohort as we anticipate to have generated safety data in at least 
15-18 patients by then, including a minimum of six patients treated at the Phase II 
dose/schedule.  
The number of patients in Phase I of the study is designed for dosing an adequate number of 
patients prior to evaluation of safety and biological activity such as serum cytokine levels and 
CAR T cell persistence and to facilitate better decision making. Phase II of the study is based 
on a Simon’s 2-stage optimal design; the rationale for dosing up to 24 patients is to detect 
early signs of efficacy in addition to generating additional safety data at the RP2D. 
4.2 
STUDY POPULATION RATIONALE 
AUTO3 is designed to specifically bind to CD19 and or CD22, which are only expressed on 
normal and malignant B lymphocytes. The study patient population for this study is 
paediatric and adult patients with B lineage ALL.  

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An age range of 1-24 years has been set for the paediatric and young adult patients because 
patients in this age range are treated with frontline and relapse protocols that differ from older 
patients with this disease. In addition, since this is an experimental therapy, the study patient 
population will be restricted to patients with HR relapsed or refractory B lineage ALL who 
are predicted to have a poor outcome even with intensified chemotherapy and SCT. As 
outlined in Section 1.1, the long-term survival of paediatric/young adult patients with HR 
relapse in large UK and European studies is 20-30%. Similarly, the outcomes of patients 
relapsing post allogenic SCT are also very poor. Long-term survival rates are of about 
10-20% in the population receiving a second allogenic SCT (but with considerably increased 
transplant-related morbidity and mortality), and negligible in those unable to proceed to a 
second transplant (Borgmann et al. 2003, Roy et al. 2005, Saarinen-Pihkala et al. 2006). 
These patients are appropriate candidates for clinical trials and data from ongoing trials using 
second-generation CD19 CAR T cells show unprecedented outcomes in patients with 
relapsed or refractory paediatric ALL (see Section 1.3). Since the recently approved CD19 
CAR therapy is not yet widely accessible, enrolling patients on clinical trials with a CAR 
therapy that is designed to prevent CD19 negative relapse is appropriate. 
The prognosis of adult ALL patients is worse than for paediatric/young adult patients and has 
not changed significantly during the last two to three decades, with long-term remission rates 
limited to 30–40%. Approximately 50% of all adult ALL patients will relapse, and 
UKALL12 data shows that 5-year OS in adults who relapse following standard multi-agent 
chemotherapy is 7%. Significant number of patients treated with CD19 or CD22 targeted 
therapy such as blinatumomab and inotuzumab ozogamicin relapse, these therapies are 
largely utilized as a bridge to allo-HSCT. A standalone targeted therapy is in need and CAR T 
cell therapy is likely to have significant therapeutic potential in these patients as a standalone 
therapy (Wierda et al. 2018). Considering the emerging safety and tolerability profile of 
AUTO3 (Section 1.6) it is appropriate to evaluate AUTO3 in these patients.  
Dual targeting of CD19 and CD22 is likely to improve outcomes further by preventing 
antigen negative escape and immune mediated rejection of CAR T cells.  
4.3 
CYCLOPHOSPHAMIDE AND FLUDARABINE PRE-CONDITIONING 
RATIONALE 
Pre-conditioning strategies that deplete host lymphocytes have been shown to enhance 
clinical responses to some adoptive T cell therapies (Muranski et al. 2006, Spear et al. 2013). 
Lymphodepletion prior to adoptive transfer of tumour specific T-lymphocytes is thought to 
enhance treatment efficacy by eliminating regulatory T cells and increasing access of the 
transfused CAR T cells to activating cytokines (Klebanoff et al. 2005, Wrzesinski and Restifo 
2005). Cyclophosphamide (CY) has an established history in lymphodepleting regimens used 
prior to adoptive cell immunotherapy (Sporn et al. 1993, Curti et al. 1998, Brentjens et al. 
2011, Chu et al. 2012).  It is used alone or often used in combination with other agents 
(Dudley et al. 2008, Laurent et al. 2010, Geller et al. 2011). Fludarabine (FLU), either as a 
single agent or in combination with other cytotoxic agents, has been used as a 
lymphodepleting preparative regimen to reduce transplant-related toxicities and allow SCT in 
elderly and medically infirm patients, as well as in adoptive T cell therapies, including CAR 
T cell therapy (Louis et al. 2011). Fludarabine is also commonly used in combination with 
CY in the treatment of patients with chronic lymphocytic leukaemia (Hallek 2013) where it is 
well tolerated. 

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Cyclophosphamide and FLU based pre-conditioning have become the preferred regimen for 
CAR T cell therapies and have been used in multiple studies (Kochenderfer et al. 2015, Lee 
et al. 2015, Ali et al. 2016). The combination is also considered to be superior to CY alone. In 
a CD19 CAR T cell study (JCAR014) in adult patients with ALL, those who received 
FLU-CY had a significantly greater expansion of CAR T cells at Day 28 and a lower rate of 
relapse (Turtle et al. 2016). Most relapses in the CY alone group were due to immune 
rejection of CAR T cells and it is likely that the addition of FLU to lymphodepletion may 
reduce the risk of this. Similarly, in the NIH study of CD19 CAR T cells in paediatric ALL, 
use of a FLU-CY regimen correlated with a higher response rate (29/44 patients, 66%) and 
LFS (53% at 18 months) than alternative regimens (2/8 patients, 25% responders P<0.05 and 
LFS of 0% at 18 months) (Lee et al. 2016b). We believe these data establish FLU-CY as the 
standard of care for lymphodepletion prior to CAR T cell therapy for ALL.  
The exact dose regimens used for lymphodepletion prior to CAR T cell therapy are variable.  
However, since the purpose of pre-conditioning chemotherapy is lymphodepletion and 
prolonged myelosuppression (particularly in post-transplant patients) is undesirable, higher 
doses of CY (2 to 4 g/m2 for 1 to 2 days) are probably unnecessary, especially when given 
with FLU. The regimen utilised in this study (FLU 30 mg/m2 for 4 days + CY 500 mg/m2 for 
2 days) is similar to that evaluated in studies with tisagenlecleucel (Kymriah) in multiple 
clinical studies including the multi-centre ELIANA study and appears both safe and active 
and is part of the Food and Drug Administration (FDA) and European Medicines Agency 
approved label (Lee et al. 2015, Ali et al. 2016, Fry 2016, Kochenderfer et al. 2016, Maude et 
al. 2016b, Neelapu et al. 2016, Turtle et al. 2016, FDA 2018a). 
Cyclophosphamide can cause haemorrhagic cystitis and cardiotoxicity but these are 
extremely rare at the proposed dose. The likely side effects of CY at this dosage are transient 
nausea and cytopenia. Patients will be given anti-emetics, prophylactic anti-microbials and 
transfusion support as per standard institutional policy. Fludarabine is generally well 
tolerated: the most common side effects are lymphopenia and infection. Neurotoxicity can 
occur but generally at higher doses, and at the dose proposed, neurotoxicity is rarely seen. 
However, severe neurotoxicity leading to death was reported recently in the JCAR015 
ROCKET trial (NCT02535364 2016) that used a FLU based conditioning regimen. On 
07 July 2016, the FDA suspended recruitment into the ROCKET trial following the deaths of 
three young adult patients with ALL due to cerebral oedema, although no detail of the 
neurological toxicity has yet been published. The three deaths occurred amongst 
approximately seven patients treated with FLU-CY conditioning prior to JCAR15 treatment, 
whereas this had not previously been seen with CY alone. The investigators subsequently 
re-opened the trial with CY alone as lymphodepletion. This study was placed on hold again 
on 23 November 2016 due to two further deaths because of cerebral oedema which happened 
in the absence of FLU based conditioning, suggesting that FLU was not primarily responsible 
for the observed neurotoxicity. Observations suggest that the severe neurotoxicity observed in 
that study may reflect the use of a relatively high dose of CD19 CAR T cells with a CD28 
costimulatory domain which appears to cause stronger early proliferation and cytokine 
secretion compared to CD19 CAR T cells with 41BB-ζ costimulatory domains.  
.In all the studies conducted at the University of Pennsylvania (UPENN) in the last 3 years, 
most of which utilised FLU-CY lymphodepletion and a CD19-41BB-ζ CAR (CTL019), only 
one neurotoxicity related death has been reported. In a larger multi-centric Phase II study, the 
same CAR was used (CTL019) in paediatric patients using the similar dose FLU-CY 
condition regimen to that proposed in this study, of the 75 patients (median age 11 years, 

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61% with prior HSCT) infused with a single dose of CTL019 at a median weight-adjusted 
dose of 3.1 × 106 transduced viable T cells per kilogram of body weight (range, 0.2 × 106 to 
5.4 × 106cells per kilogram),, 13% of patients experienced transient Grade 3 or 4 
neurotoxicity including confusion, delirium, encephalopathy, agitation and seizure but no 
cerebral oedema or deaths due to neurotoxicity was reported (Maude et al. 2018). 
Neurotoxicity is the most challenging clinical problem associated with CD19 CAR since it 
does not easily correlate with T cell dose, underlying disease or the neurological involvement 
of leukaemia/lymphoma or CRS. However, it is clear that this is not a direct effect of FLU. 
Data from multiple studies also suggest that a lower dose/intensity of pre-conditioning 
(Grupp et al. 2016, Kochenderfer et al. 2016, Neelapu et al. 2016), with CY (300 to 
500 mg/m2 for 2-3 days or 900 mg/m2 for 1 day) and FLU (30 mg/m2 for 3-4 days), 
compared to the ROCKET study (1 to 3 mg/m2 CY + 25 to 30 mg/m2 of FLU for 5 days 
which is repeated 2 to 4 weeks later) is safe and appropriate.  
In the current study, we propose to use FLU-CY (FLU [30 mg/m2 for 4 days] and CY 
[500 mg/m2 for 2 days]) based pre-conditioning regimen. A 3±1 day washout period prior to 
infusion of AUTO3 is also incorporated, taking into consideration the 20-hour half-life of 
FLU and the need to infuse early to maximize exposure to the transient IL-15 surge following 
lymphodepletion (Rossi et al. 2015). This would result in elimination of over 3 half-lives of 
FLU and will potentially decrease any risk of cumulative toxicity with AUTO3. Given the 
nature of our patient cohort being treated and the data cited above demonstrating that 
lymphodepletion with FLU-CY enhances the clinical efficacy of CAR T cells, we believe the 
proposed dose and regimen is justified. 
4.4 
STARTING DOSE RATIONALE 
The primary consideration for selection of a starting dose of 1.0 x 106/kg CD19/CD22 CAR-
positive T cells for the proposed trial in the paediatric/young adult population is the safety of 
the patient. Considerations for CAR T cell dosing are challenging. Chimeric antigen receptor 
T cells are a “living therapy” i.e. they can engraft within the study subject, they can expand 
and they have no half-life in the standard conception of the term (Ghorashian et al. 2015). 
Efficacy and toxicity appears related to the magnitude and tempo of engraftment (Maude et 
al. 2014b). A wide range of doses have been utilised in existing studies of CD19 CAR T cell 
therapy (5 x 105-1.7 x 107 CAR T cells/kg), with no clear correlation between cell dose 
administered and efficacy, reflecting the fact that infused CAR T cells can expand by several 
logs after transfer to a lymphodepleted host. Consequently, the correlation between CAR T 
cell dose and toxicity is much less clear than the correlation with standard small molecule or 
protein based therapeutics.  
In the only dose-finding study of CD19 CAR T cells, a Phase I dose escalation study CD19 of 
CAR T cells transduced with a second-generation FMC63-derived CAR containing a CD28 
co-stimulatory endodomain, a dose of 1 x 106/kg was defined as the MTD. Four patients were 
treated at a dose of 1 x 106/kg and none developed DLT. The subsequent four patients were 
then treated with 3 x 106/kg CAR T cells, but two of these four then developed DLT (Grade 4 
and 3 CRS). These findings are obscured by differences in CAR design and CAR T cell 
production processes. For example, in a study in children and young adults treated with a 
CD19 41BB-ζ CAR, a higher dose (2.0 to 5.0 × 106 cells/kg for ≤50 kg and 1.0 to 
2.5 x 108 cells for >50 kg) was considered tolerable (Maude et al. 2014b, Lee et al. 2015). 
However, a dose in the order of millions of CAR T cells/kg seems generally optimal.  

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The starting dose for adult ALL patients takes into consideration the current dose and safety 
data from the pediatric and young adult patients (Section 1.6). The adult dose escalation may 
start at a dose equivalent to the highest paediatric dose considered safe after at least 3 patients 
in that age group have been treated at a dose level and no DLTs or more than one case of 
Grade 3 CRS or neurotoxicity has been observed. Adult dosing will be based on a fixed dose 
which is equivalent to a dose in a 70 kg person, e.g. if 5 x 106/kg CD19/CD22 CAR-positive 
T cells dose is considered safe in paediatric patients then the adult starting dose (≥25 years) 
will be 350 x 106 CD19/CD22 CAR-positive T cells and the subsequent dose will be 
700 x 106 CD19/CD22 CAR-positive T cells. Patients will be dosed with a single or split 
dose based on disease burden as in the pediatric patients. Since the starting dose is based on 
the emerging data of AUTO3 in paediatric and young adult patients it is likely to be safe in 
the older adults that meet the study eligibility criteria. Additionally, this dose is in the range 
being evaluated with other CAR T cells therapies in adult ALL, such as tisagenlecleucel 
(CTL019, Kymriah) of 500 x 106 CAR T cells (Frey and Porter 2016).  
Dual targeting of CD19 and CD22 is not anticipated to result in more activity or toxicity over 
a CD19 or a CD22 CAR alone for several reasons: CD22 is significantly less densely 
expressed than CD19 on ALL blasts so the cumulative targetable antigen density will not be 
significantly increased (Lee et al. 2015, Shah et al. 2015). Further, little if any synergy is 
anticipated from signalling through both TNF-family receptor endodomains, as a signal 
through either OX40 or 41BB-ζ is likely to saturate the common signalling pathway. In the 
absence of a CD28 co-stimulatory domain less rapid proliferation is expected. Furthermore, 
no increases in cytotoxicity are observed between CD19 and CD19/CD22 CAR constructs 
with CD19+CD22+ target cells. Only in situations where the targets lose expression of CD19 
do we expect enhanced killing with the CD19/CD22 CAR. 
Other CD19 CAR studies, such as the CARPALL study in paediatric and young adult ALL 
(NCT02443831 2016), have used a fixed starting dose of 1 x 106 CAR T cells/kg and found it 
to be safe with no Grade 3 CRS in the 14 patients treated (P. Amrolia, personal 
communication). Recent experience with the NCI’s anti-CD22 41BB-ζ CAR also indicated a 
tolerable safety profile, no Grade 3 CRS or neurotoxicity were noted in the study that treated 
16 children and young adult  patients  at doses up to 3 x 106 CAR T cells/kg (Shah et al. 
2016). 
Considering the experience in the field with CD19 and CD22 targeted CARs, for this ALL 
study, the proposed starting dose of 1 x 106 CD19/CD22 CAR-positive T cells/kg, in 
paediatric and young adult patients, administered as a single or split dose based on disease 
burden (which is expected to add to the safety) is justified. The proposed starting dose will 
consist of two sub-cohorts, patients with <25% blasts in the BM will receive the total 
1.0 x 106/kg CD19/CD22 CAR-positive T cells dose as a single dose and those with ≥25% 
blasts in the BM will receive a split dose, 0.3 x 106/kg followed by 0.7 x 106/kg CD19/CD22 
CAR-positive T cells. The second split dose will be administered after 3-10 days and will be 
delayed or withheld if any patient experiences severe toxicity with the first split dose. In adult 
ALL, other CD19 CAR studies have demonstrated that the recommended dose of CD19 CAR 
T cells in adults is approximately twice that of paediatric patients. For example, the dose of 
axicabtagene ciloleucel (Yescarta) in paediatric patients is 0.5 x 106 CAR T cells/kg and in 
adults it is 1 x 106 CAR T cells/kg (Wierda et al. 2018); the dose of tisagenlecleucel 
(Kymriah) in paediatric patients is 2 to 5 × 106 cells/kg for ≤50 kg and 1 to 2.5 x 108 CAR T 
cells for >50 kg (Maude et al. 2014b, Lee et al. 2015), and in adults it is 500 x 106 CAR T 
cells (Frey and Porter 2016)). Therefore, the proposed starting dose in adult ALL based on 

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emerging data from AUTO3 in paediatric and young adult patients is likely to be safe and 
appropriate. 
4.5 
DOSING SCHEDULE RATIONALE 
Chimeric antigen receptor T cell therapies are generally administered once, undergo 
significant expansion in vivo upon contact with the target antigen expressed on tumour cells 
and, particularly where a 41BB-ζ costimulatory domain is incorporated into the CAR, persist 
long-term in a proportion of patients (Maude et al. 2014b). It is anticipated that AUTO3 will 
have similar expansion and persistence in vivo to the CD19 CAR T cells utilised in the 
UPENN studies, rendering the need for re-dosing unnecessary. On occasion, a re-treatment 
dose may be given if the patient meets the criteria for re-treatment (Section 8.4.7).  
There is now strong data from a number of different CD19 CAR T cell trials in ALL 
indicating that higher disease burden is predictive of more severe CRS (Davila et al. 2014, 
Lee et al. 2015). This has led some groups to mitigate this toxicity by either administering a 
lower dose of CAR T cells to patients with higher disease burden (Lee et al. 2015, Turtle et 
al. 2016), or have tried splitting the total dose.  
Data presented at the American Society of Clinical Oncology 2016 meeting (Frey and Porter 
2016), provide support for a split dosing schedule in patients with higher leukaemic burden. 
In that study in adult patients with ALL there was a high incidence (three out of six patients) 
of fatal, refractory CRS when patients were treated with a single dose of 5 x 108/kg CD19 
CAR T cells. However, when the dose was split over 3 days (10%, 30% and 60%), no deaths 
occurred and nine out of 12 patients had manageable Grade 3 to 4 CRS with an objective 
response rate of 83% (9 of 12 patients reached CR; 1 of 12 patients reached PR). Split dosing 
gave an opportunity to hold or delay the subsequent dose when signs of early CRS were 
observed. Fractionation may reduce the extent and rate of expansion, and thereby the severity 
of CRS.  
To optimise safety and overcome the problem of T cell exhaustion in patients with high 
leukaemic burden, we propose to combine these two approaches. Patients treated at the 
planned starting dose of 1.0 x 106/kg CD19/CD22 CAR-positive T cells, will be stratified per 
leukaemia burden. Patients with <25% BM blasts (M1, M2 disease) at the start of 
lymphodepletion will receive the full dose of 1.0 x 106/kg CD19/CD22 CAR-positive T cells 
as a single dose. In those with ≥25% BM blasts (M3 disease), AUTO3 will be administered 
as a split dose 0.3 x 106/kg at Day 0 followed 3-10 days with a second dose of 0.7 x 106/kg 
CD19/CD22 CAR-positive T cells. This approach allows for safer administration of doses 
that are more likely to be effective, the idea being that the initial lower dose “debulks” the 
tumour load allowing for safer administration of a subsequent dose. Similarly if the dose is 
escalated to the higher dose levels of 3, 5 or 10 x 106/kg CD19/CD22 CAR-positive T cells, 
the dose will be similarly split (Table 6).  
Additionally, cytokine surge, especially the IL-15 surge, observed during post-conditioning 
chemotherapy with FLU-CY happens in the first few days and returns rapidly to baseline 
around 10 days later (Rossi et al. 2015). The experience in the first few patients in this study 
also indicates that significant IL-15 surge lasts only for a few days and returns to baseline in 
10-14 days similar to what has been reported in literature (Rossi et al. 2015). It is important 
to dose the CAR T cells early within this window as IL-15 is necessary for CAR T cell 
expansion, engraftment and resulting efficacy (Xu et al. 2014). Moreover, availability of 
antigen (tumour cells) at the time of administration of the second split dose is also necessary 
for expansion and engraftment. The flexibility in timing the second split dose i.e. 3-10 days, 

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will allow the use of available biomarker data and clinical judgement in administering the 
second dose after the peak signs and symptoms related to CRS have resolved or hold for 
severe toxicity.  
A recent analysis of 133 patients with relapsed or refractory B cell malignancies (B-ALL, 
n=47; NHL, n=62; CLL, n=24) indicated that early onset of high grade fever  ≥38.9ºC within 
the first 36 hours after CAR-T cell infusion was noted in all patients who subsequently 
developed Grade ≥4 CRS (Hay et al., 2017). Fever also occurred earlier after CART cell 
infusion in patients who subsequently developed Grade ≥3 neurotoxicity compared with 
those who developed Grade 1–2 neurotoxicity (P = 0.0007). Fever ≥38.9°C occurring within 
36 hours of CAR T cell infusion had a 100% sensitivity for subsequent Grade ≥4 
neurotoxicity, the specificity was only 82%, in part due to other causes of fever in these 
patients with chemotherapy-induced neutropenia (Gust et al., 2017). In a paediatric ALL 
study, the median start of CRS was 4 days (range: 1-7 days) following CD19 CAR T cell 
infusion and lasted a mean of 4.8 days (range: 1-9 days) (Lee et al. 2015) and the median 
time to onset of Grade ≥1 neurologic AEs was  4 days after CAR T cell infusion (Gust et al., 
2017). The anticipated time to peak expansion of the infused CAR T cells is between 7 and 
14 days (Davila et al. 2014). The safety and the cellular kinetic data from ongoing clinical 
trials (Section 1.6) also support the early dosing of the 2nd split dose by Day 3 similar to the 
data from the UPENN study in adult ALL patients (Frey and Porter 2016).  
Based on these data, in patients receiving a split dose the decision to administer the 2nd split 
dose will be made by the site PI or delegated individual in consultation with the Sponsor’s 
Medical Monitor. Patients will be monitored for early onset of high grade fever that is 
suspected to be CAR related and evaluated for toxicity during the 3 days after infusion of the 
initial dose. If no ≥Grade 3 CRS or ≥Grade 2 neurotoxicity has occurred, the 2nd dose may be 
administered 3-10 days after the first dose if CRS has resolved to ≤Grade 1 and neurotoxicity 
has completely resolved. The dosing of 2nd split dose can be further delayed (beyond 10 days) 
if clinically indicated. Patients who develop AUTO3 related ≥Grade 3 CRS, ≥Grade 2 
neurotoxicity or a DLT following the first split dose will not receive the second split 
dose.  
After treatment with AUTO3, safety will be monitored closely (both in hospital and as an 
outpatient) and efficacy will be assessed periodically as described in the Schedule of 
Assessments. The timing of assessments is designed to capture early signs of toxicity and 
efficacy.  
4.6 
 
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5 
RISKS AND MITIGATION STRATEGY 
This exploratory study is designed to assess the safety and biological activity of different 
dose schedules of AUTO3 in a limited number of patients. Given the treatment novelty, this 
study will involve patients whose disease has progressed after treatment with the main 
approved classes of anti-leukaemia agents. Such patients are considered to have poor 
prognosis and are candidates for promising experimental therapies. 
Leukapheresis: This is necessary for enrolling onto this study as it is a prerequisite for 
preparing AUTO3. This is generally performed in specialist units, where such procedures are 
relatively standard. Cell production efficiency of at least 80% is anticipated and is dependent 
on the quality of the leukapheresate. AUTO3 infusion may or may not provide clinical 
benefit to these patients. Risks of leukapheresis are summarised in Table 7. 
Table 7: 
Leukapheresis – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Pain and bruising due to insertion of cannula/ 
central venous access. 
Experienced clinicians/nurses performing the 
procedure, analgesics to be used as needed for pain 
Bacterial bloodstream infections associated with 
the insertion of access and return venous access 
devices. 
The procedure will be carried out by trained and 
experienced personnel and risks will be minimised by 
strict adherence to aseptic measure. 
Symptoms of hypocalcaemia e.g. muscle cramps 
due to chelation by anticoagulants used to prevent 
clotting. 
Patients will be monitored for symptoms of 
hypocalcaemia, the rate of citrate infusion to the patient 
and duration of the procedure will be controlled by 
experienced personnel. Calcium supplements will be 
given as needed 
Pre-conditioning chemotherapy: Lymphodepletion with FLU and CY prior to adoptive 
transfer of CAR T cells enhances treatment efficacy by eliminating regulatory T cells and 
increasing access of the transfused CAR T cells to activating cytokines. Pre-conditioning is 
expected to increase the survival of AUTO3 and therefore the chance of anti-tumour efficacy. 
Pre-conditioning will only be undertaken after confirmation of the successful production of 
AUTO3. Risks of pre-conditioning with chemotherapy are summarised in Table 8. Please 
refer to the Summary of Product Characteristics for more details.  

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Table 8: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Myelosuppression and immunosuppression resulting in 
anaemia, neutropenia, thrombocytopenia, and 
lymphopenia, are the most common toxicities. In 
addition to being a manifestation of ALL, 
myelosuppression can be a toxicity of chemotherapy and 
also of CAR T cells treatment. Transient moderate to 
severe myelosuppression lasting up to 30 days is 
anticipated in this patient cohort. Bleeding, neutropenic 
fever, infections, and septic shock may occur and may 
sometimes be fatal. Herpes zoster and other viral 
reactivations may occur.  
The FLU and CY chemotherapy given is milder 
than most chemotherapy treatment regimens for 
patients with relapsed or refractory ALL and will 
be given only once (1 cycle, given over 3 days). 
Anti-microbial prophylaxis (including 
Pneumocystis prophylaxis and acyclovir) will be 
given to prevent infections and patients will be 
monitored for cytomegalovirus, adenovirus and 
Epstein-Barr virus viraemia weekly for the first 
month. If infections arise they will be treated as 
per institutional guidelines. Blood, platelet and 
fresh frozen plasma transfusions will be given as 
per standard institutional guidelines. All sites 
have extensive expertise in managing these 
complications in paediatric/adult patients with 
ALL and have on site intensive care unit support.  
Cyclophosphamide associated toxicities (as per 
approved label), including but not limited to 
nausea/vomiting, haemorrhagic cystitis, myocarditis and 
myopericarditis and tamponade, pneumonitis and 
pulmonary fibrosis, and veno-occlusive liver disease may 
occur. 
 Given the low dose and short duration of 
treatment, these toxicities are unlikely. Patients 
will be given anti-emetic prophylaxis and 
hydration during lymphodepletion as per 
institutional policy. If haemorrhagic cystitis 
occurs, i.v. fluids and mesna will be given. Other 
toxicities will be managed as per the standard 
institutional policy and by trained personnel.   
Fludarabine is generally well tolerated: the most 
common side effects are lymphopaenia and infection (see 
above). Neurotoxicity can occur but generally at higher 
doses. Other associated toxicities (as per the label) 
include, but are not limited to, autoimmune disorders, 
hepatic impairment, neurotoxicity, and renal impairment. 
Given the low dose and short duration of 
treatment, these toxicities are unlikely. Toxicities 
will be managed as per the standard institutional 
policy and by trained personnel. 
ALL = acute lymphoblastic leukaemia; CAR = chimeric antigen receptor; CY = cyclophosphamide; FLU = fludarabine; 
i.v. = intravenous. 

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AUTO3 infusion 
Risks associated with the infusion of AUTO3 are presented in Table 9 below and detailed 
management guidelines are presented in Section 9.6. 
Table 9: 
AUTO3 Infusion – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Infusion reactions may occur with the infusion of 
AUTO3. 
The product is autologous and the risk is likely to be low. 
Patients will be pre-medicated with chlorpheniramine 
and paracetamol. 
Cytokine-release syndrome is a key toxicity 
expected for any CAR T cell treatment. Cytokine 
release syndrome may present as fevers, myalgia, 
hypoxia, hypotension and potentially 
life-threatening cardiac dysfunction, acute 
respiratory distress syndrome, neurologic toxicity, 
renal and/or hepatic failure, and disseminated 
intravascular coagulation. The clinical features may 
overlap with macrophage activation syndrome. In 
studies with second generation CD19 CAR T cells, 
the majority of patients have developed CRS but the 
severity appears to correlate with leukaemic burden.  
The risk will be mitigated by adherence to CRS 
management guidelines as per (Lee et al. 2014), 
(Section 10.4) formulated based on prior CAR T cell-
gene therapy experience at various institutions. Splitting 
of the CAR T cell dose at the higher dose level may 
reduce risk of severe CRS in patients with higher disease 
burden.  
Neurotoxicity has been seen with CD19 CARs in 
patients with leukaemia and lymphoma. Clinical 
presentation can be variable and manifest as mild to 
severe encephalopathy, focal neurologic deficits 
particularly in speech, hallucinations, generalised 
seizures, severe irreversible neurologic deficits, 
cerebral oedema and occasionally death. The cause 
of neurotoxicity is not well-understood, although it 
is reported to be fully reversible in most cases. 
The patient will be closely monitored for neurological 
signs and symptoms, neuroimaging will be performed as 
appropriate. Patients will be managed with early 
supportive care (e.g. anti-convulsants) as appropriate. In 
patients who develop severe neurotoxicity or cerebral 
oedema, dexamethasone will be given (Section 10.6). 
Off-tumour toxicity could be due to either 
on-target (due to expression of the antigen on 
non-tumour cells) or off-target (recognition of a 
molecular target other than CD19 or CD22) 
interactions. Historically, there have been reports of 
on-target/off-tumour toxicity with CAR therapy as 
well as T cell receptor engineered T cells, the 
details are described in the IB.  
Preclinical toxicology indicates the risk to be low as 
CD19 and CD22 expression is largely limited to the B 
cell lineage. Ongoing CD19 and or CD22 CAR studies 
have not shown significant off-target toxicity. 
Considering the body of knowledge with regards to 
targeting CD19 and CD22, this risk is likely to be low. 
Cardiac toxicity: One cardiac-related fatality has 
been reported with CD19 CAR T cells, although the 
causality was unclear. 
The protocol excludes patients with underlying/prior 
cardiac history. Additionally, patients will be required to 
undergo echocardiogram (ECHO) or MUGA to 
demonstrate normal cardiac function prior to study 
enrolment and at the onset of CRS. 
Hypoxia: Severe hypoxia has been reported in 
patients treated with a CD22 CAR, JCAR018. The 
causality was unclear but in at least 1 case it was 
associated with CRS. Hypoxia is a recognised 
manifestation of severe CRS. It is unlikely to be a 
consequence of off-target toxicity specific for CD22 
as there is no expression of CD22 in lung except on 
the resident B-cells (as CD19). 
All patients will be evaluated for oxygen saturation at 
baseline, and through the duration of the study. Patients 
with a baseline oxygen saturation of <92% on room air 
and those requiring supplemental oxygen at the time of 
AUTO3 infusion will not be eligible to receive AUTO3. 
Patients with an oxygen requirement of >40% (or lower 
based on emerging data) in setting of CRS will receive 
treatment with tocilizumab. Patients with hypoxia will 
also be investigated for pulmonary infections and treated 
promptly.   

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Risks  
Mitigation Strategy  
Tumour lysis syndrome (TLS) may occur on 
treatment with AUTO3 due to rapid killing of 
malignant cells in the context of a high tumour 
burden, but this is rarely seen after CD19 CAR T 
cell therapy. 
In patients with high leukaemic burden (≥25% blasts in 
the BM) allopurinol and i.v. fluids will be given. If TLS 
occurs, all sites have extensive experience in managing 
this complication and supportive care will be initiated 
rapidly as per standard institutional protocols 
(Section 10.5). 
Hypogammaglobulinaemia may occur because of 
depletion of normal B cells by AUTO3. This may 
potentially increase the risk of infections. The 
degree of hypogammaglobulinaemia and its 
duration are variable depending on the persistence 
of CAR T cells. 
B cell recovery and Ig levels will be monitored regularly 
following AUTO3 infusion. Patients with recurrent and 
persistent severe hypogammaglobulinaemia will receive 
i.v. Ig replacement (Section 10.7). 
Insertional mutagenesis: Activation of proto-
oncogenes by retroviral-mediated insertional 
mutagenesis following gene therapy into 
haemopoietic stem cells has resulted in 
leukaemogenesis. However, this has not been seen 
after transduction of terminally differentiated T 
cells. There are no reported cases of insertional 
mutagenesis in >200 patients treated with 
genetically modified T cells (including CAR T 
cells) over an extended period of follow-up. 
Patients will be monitored for secondary malignancy and 
survival in a long-term follow-up protocol for a total of 
15 years. 
Risks associated with a RCR: There is a risk that a 
recombination event may occur during vector 
production that results in a RCR, which may be 
pathogenic in humans. 
All vector lots are tested for RCRs prior to release to 
sites. The risks of transmission of RCRs are extremely 
low and to date, no patient has developed a RCR 
following retroviral based CAR T cell therapy. Patients 
will be monitored for a RCR by polymerase chain 
reaction (PCR) during their scheduled follow-up visits. If 
a positive signal is confirmed, additional testing will be 
performed and medical and research experts will be 
consulted for the optimal treatment approach should any 
complication arise. 
Dimethyl sulfoxide (DMSO) which is part of 
cryopreservative buffer may cause an abnormal 
taste at the time of infusion and body odour lasting 
1-2 days afterwards. At high doses, DMSO may 
cause nausea, vomiting, abdominal pain, headache 
and haemolysis. Rarely, patients may experience 
mild or severe cardiac, pulmonary, renal, or 
neurological symptoms. 
Most patients are likely to be exposed to a small dose of 
DMSO. Even at the highest proposed dose of 10 x 106 
CAR-positive T cells/kg (or 700 x 106 CAR-positive T 
cells in a 70 kg adult), the maximum exposure to DMSO 
would be 52.5 g (assuming a 70 kg patient and a 
minimum transduction of 5% and formulation of product 
at 20 x 106 viable cells per mL) which is lower than the 
standard institutional maximum dose of 70 g (1 g/kg). At 
these dose levels the side effects are likely to be mild and 
short lasting. 
Graft versus host disease (GVHD): Some 
subjects, will be recruited to the study after 
allogenic HSCT and there is a theoretical risk of 
alloreactivity of AUTO3 and consequent GVHD. 
However the risk is low, several studies have 
reported little or no evidence of GVHD following 
CD19 CAR T cell therapy in patients treated post 
allogenic HSCT. 
Patients who have developed severe GVHD will be 
excluded from the study effectively screening out 
potential for alloreactivity. T cells will be collected from 
the recipient, these harvested donor T cells will have 
been subject to tolerization within the recipient including 
thymic education, reducing alloreactivity. In case of 
GVHD, study subjects will be treated as per institutional 
standard of care and at the investigator’s discretion. 
BM = bone marrow; CD = cluster of differentiation; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; 
DMSO = dimethyl sulfoxide; ECHO = echocardiogram; GVHD = graft versus host disease; IB = Investigator’s Brochure; 
Ig = immunoglobulin; i.v. = intravenous; MUGA = multigated acquisition; PCR = polymerase chain reaction; 
RCR = replication competent retrovirus; TLS = tumour lysis syndrome. 

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Unknown long-term risks of gene therapy: Following completion of this study, all patients 
will be enrolled and monitored for SAEs, AEs of interest and survival in a long-term 
follow-up study. 

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6 
PATIENT POPULATION 
Patients will be eligible for the trial if all the inclusion criteria are met and none of the 
exclusion criteria applies. There will be no exception to the eligibility requirements at the 
time of registration. Ensuring patient eligibility is the responsibility of the Principal 
Investigator or other delegated Investigator(s). 
6.1 
INCLUSION CRITERIA 
6.1.1 
Paediatric and Young Adult Patients 
Patients must meet all the following criteria for study entry: 
1. Male or female paediatric and young adult patients (aged 1-24 years) with HR relapsed 
or refractory B-lineage ALL and 
a. 
Any BM relapse or CNS relapse with detectable BM disease (>10-4) by flow 
cytometry/molecular MRD after allogeneic SCT and must be ≥6 months from SCT 
at the time of AUTO3 infusion, OR 
b. High Risk first relapse (as per International Study for Treatment of Childhood 
Relapsed ALL criteria Appendix 6), OR 
c. 
Standard risk relapse patients with HR cytogenetics (HR defined as mixed linkage 
leukaemia gene rearrangement (KMT2A), intrachromosomal amplification of 
chromosome 21 amplification, near-triploidy (60-78 chromosomes) or near-haploidy 
(<30 chromosomes) and low hypodiploidy (30-39 chromosomes), OR 
d. Second or greater relapse, OR 
e. 
Bone marrow MRD ≥10-3 prior to planned SCT, OR 
f. 
Any on-treatment relapse in patients aged 16-24 years. 
Phase II Only (criteria in addition to those described above) 
g. Primary refractory disease defined as MRD >5% blasts in the BM by flow cytometry 
or molecular assay following frontline induction therapy. For good risk cytogenetics, 
MRD >0.1% at Week 9 of consolidation chemotherapy is also required. (Note: For 
patients with good risk cytogenetics the leukapheresis may be done before starting 
consolidation therapy but manufacturing and AUTO3 infusion will only occur if 
MRD is >0.1% at Week 9 of consolidation), OR 
h. Patients with Philadelphia chromosome-positive ALL are eligible if they are 
intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy, or if tyrosine 
kinase inhibitor therapy is contraindicated, OR 
i. 
Isolated CNS relapse (post-SCT or pre-SCT if high risk, aged 16-24 years on 
therapy relapse or ≥2nd relapse) but with ≤CNS Grade 2 disease at time of 
enrolment. 
2. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, 
peripheral blood, or CSF by flow cytometry within 3 months of screening. 
3. Detectable disease in the BM at a level ≥10-4 by molecular or flow cytometry based 
methods (Phase I only) at enrolment (patients developing ≤10-4 BM disease due to 
bridging therapy may continue to receive AUTO3). 

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4. Absolute lymphocyte count ≥0.5 x 109/L at enrolment. 
5. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
- 
Serum creatinine based on age/gender ≤1.5 x upper limit of normal (ULN). 
- 
Serum alanine aminotransferase/aspartate aminotransferase ≤5 x ULN. 
- 
Total bilirubin ≤2 x ULN, except in subjects with Gilbert's syndrome. 
- 
Left ventricular shortening fraction ≥28% confirmed by ECHO, or left ventricular 
ejection fraction (LVEF) ≥45% confirmed by ECHO. 
- 
Baseline oxygen saturation >92% on room air. 
6. Karnofsky (age 10-24 years) or Lansky (age <10 years) score ≥50%. 
7. Willing and able to give written, informed consent to the current study (patient and/or 
parent or legal guardian). 
6.1.2 
Adult Patients 
1. 
Age 25 or older. 
2. 
Eastern cooperative oncology group (ECOG) performance status of 0 or 1. 
3. 
Relapsed or refractory B-precursor ALL defined as one of the following: 
a. 
Primary refractory disease 
b. First relapse if first remission ≤12 months 
c. 
Relapsed or refractory disease after 2 or more lines of systemic therapy 
d. Relapsed or refractory disease after allogeneic transplant provided individual is at 
least 6 months from stem cell transplant at the time of infusion. 
4. 
Patients with Philadelphia chromosome-positive ALL are eligible if they are intolerant to 
or have failed 2 lines of tyrosine kinase inhibitor therapy, or if tyrosine kinase inhibitor 
therapy is contraindicated.  
5. 
Documentation of CD19 and/or CD22 expression on leukaemic blasts in the BM, 
peripheral blood, or CSF by flow cytometry within 3 months of screening. 
6. 
For females of childbearing potential (defined as <24 months after last menstruation or 
not surgically sterile), a negative serum or urine pregnancy test must be documented at 
screening, prior to pre-conditioning and confirmed before receiving the first dose of 
study treatment.  
For females who are not postmenopausal (<24 months of amenorrhea) or who are not 
surgically sterile (absence of ovaries and/or uterus), two methods of contraception 
comprising of one highly effective method of contraception together with a barrier 
method must be used during the treatment period and for at least 12 months after the last 
dose of study treatment. They must agree not to donate eggs (ova, oocytes) for the 
purposes of assisted reproduction during the study and for 12 months after receiving the 
last dose of study drug (please refer to Appendix 5). 
7. 
For males, it must be agreed that two acceptable methods of contraception are used (one 
by the patient – usually a barrier method, and one highly effective method by the 
patient’s partner as defined in Appendix 5) during the treatment period and for at least 

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12 months after the last dose of study treatment and that sperm will not be donated 
during the treatment period and for at least 12 months after the last dose of study 
treatment.  
8. 
Absolute lymphocyte count ≥0.5 x 109/L at enrolment. 
9. 
Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a. 
Serum alanine aminotransferase/aspartate aminotransferase ≤2.5 x ULN. 
b. Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min. 
c. 
Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome. 
d. Left ventricular ejection fraction (LVEF) ≥45% confirmed by ECHO or MUGA. 
e. 
Baseline oxygen saturation >92% on room air. 
6.2 
EXCLUSION CRITERIA 
6.2.1 
Paediatric and Young Adult Patients 
Patients meeting any of the following exclusion criteria must not be enrolled into the study: 
1. Isolated extra-medullary disease relapse (in Phase II of the study, patients with isolated 
CNS relapse post-SCT or pre-SCT if high risk, aged 16-24 years on therapy relapse or 
≥2nd relapse with ≤CNS Grade 2 disease at time of enrolment are eligible). 
2. Active CNS involvement of ALL, defined by CNS Grade 3 per National Comprehensive 
Cancer Network guidelines. Patients developing CNS Grade 3 disease at any time after 
enrolment will also be excluded. 
3. Active infectious bacterial or viral disease (hepatitis B virus, hepatitis C virus, human 
immunodeficiency virus (HIV), human T-cell lymphotropic virus [HTLV], syphilis, 
West Nile (US only) or Zika viruses (US only)) requiring i.v. anti-microbials for 
treatment. 
4. Females who are pregnant or lactating. 
5. Females of child-bearing potential (defined as all females physiologically capable of 
becoming pregnant) and post-pubertal male participants who are unwilling to use highly 
effective methods of contraception during the treatment period and for a period of 1 year 
after the AUTO3 infusion. Note: Examples of highly effective contraception methods are 
described in Appendix 5. 
6. Inability to tolerate leukapheresis. 
7. Prior CD19 or CD22 targeted therapy with Grade 4 toxicity (except for haematological 
toxicity) or ≥Grade 3 CRS or ≥Grade 3 drug-related CNS toxicity. CD22 targeted 
therapy such as inotuzumab ozogamicin in patients that are CD19 negative (unless it is 
demonstrated that this therapy had no effect on CD22 target expression). In Phase II, 
patients with prior CAR therapy will be excluded. 
8. Pre-existing significant neurological disorder (other than CNS involvement of underlying 
haematological malignancy).  
9. Stem cell transplant patients only: Active significant (overall Grade ≥II, Seattle criteria) 
acute graft versus host disease (GVHD) or moderate/severe chronic GVHD (NIH 

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consensus criteria) requiring systemic steroids or other immunosuppressants within 
4 weeks of enrolment. 
10. The following medications are excluded: 
a. 
Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to AUTO3 
infusion and leukapheresis. However, physiological replacement doses of steroids 
are allowed: <12 mg/m2/day hydrocortisone or equivalent. 
b. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed 
>6 weeks prior to AUTO3 infusion. 
c. 
Graft versus host disease therapies: Any drug used for GVHD must be stopped 
>4 weeks prior to AUTO3 infusion.  
d. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to 
starting pre-conditioning chemotherapy.  
e. 
Intrathecal therapy: Methotrexate within 4 weeks and other intrathecal 
chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning 
chemotherapy. 
f. 
Live vaccine ≤4 weeks prior to enrolment. 
11. Known allergy to albumin, DMSO, CY or FLU. 
12. Any other condition which in the Investigator’s opinion would prevent the patient from 
undergoing protocol-based therapy. 
6.2.2 
Adult Patients 
1. Isolated extramedullary disease. 
2. Diagnosis of Burkitt's leukaemia/lymphoma according to World Health Organization 
(WHO) classification or chronic myelogenous leukaemia lymphoid blast crisis. 
3. Females who are pregnant or lactating. 
4. History or presence of clinically relevant CNS pathology such as epilepsy, paresis, 
aphasia, stroke within 3 months prior to enrolment, severe brain injuries, dementia, 
Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental 
illness, or psychosis.  
5. Presence of CNS-3 disease or CNS-2 disease with neurological changes. Patients 
developing CNS Grade 3 disease or symptomatic CNS-2 disease at any time after 
enrolment will also be excluded. 
6. Clinically significant, uncontrolled heart disease (New York Heart Association Class III 
or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
sick-sinus syndrome, or electrocardiographic evidence of acute ischaemia or Grade 3 
conduction system abnormalities unless the patient has a pacemaker) or a recent (within 
12 months) cardiac event. 
a. 
Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are 
not excluded). 
b. Evidence of pericardial effusion. 
7. Patients with a history (within 3 months) or evidence of pulmonary embolism requiring 
ongoing therapeutic anticoagulation at the time of pre-conditioning. 

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8. Patients with active gastrointestinal (GI) bleeding. 
9. Patients with any major surgical intervention in the last 3 months. 
10. Active infectious bacterial or viral disease or fungal (hepatitis B virus, hepatitis C virus, 
HIV, HTLV, syphilis, West Nile virus [US only] or Zika virus [US only]) requiring 
treatment with i.v. antimicrobials. 
11. History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic disease 
modifying agents within the last 24 months. Any autoimmune disease with CNS 
involvement. 
12. History of other malignant neoplasms unless disease free for at least 24 months 
(carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal 
therapy allowed). 
13. History of concomitant genetic syndrome such as Fanconi anaemia, Shwachman-
Diamond syndrome, Kostmann syndrome or any other known BM failure syndrome. 
14. Stem cell transplant patients only: Active significant (overall Grade ≥II, Seattle criteria) 
acute GVHD or moderate/severe chronic GVHD (NIH consensus criteria) requiring 
systemic steroids or other immunosuppressants within 4 weeks of enrolment. 
15. Prior CD19 or CD22 targeted therapy other than blinatumomab and inotuzumab 
ozogamicin. 
16. The following medications are excluded: 
a. 
Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 
72 hours prior to AUTO3 administration. However, physiological replacement, 
topical, and inhaled steroids are permitted. 
b. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks 
prior to leukapheresis or AUTO3 infusion. 
c. 
Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed 
>6 weeks prior to AUTO3 infusion. 
d. Graft versus host disease therapies: Any drug used for GVHD must be stopped 
>4 weeks prior to AUTO3 infusion.  
e. 
Chemotherapy including TKIs for Philadelphia chromosome-positive ALL: Should 
be stopped 1 week prior to leukapheresis or 2 days prior to starting pre-conditioning 
chemotherapy. 
f. 
Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment 
with clofarabine or cladribine within 3 months prior to leukapheresis. 
g. Live vaccine ≤4 weeks prior to enrolment. 
h. Intrathecal therapy: Methotrexate within 4 weeks and other intrathecal 
chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning 
chemotherapy. 
i. 
Systemic inhibitory/stimulatory immune checkpoint - At least 2 half-lives must have 
elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule 
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17. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, 
indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). 
Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath 
or Hickman catheter are permitted. 
18. Research participants receiving any other investigational agents, or concurrent 
biological, chemotherapy, or radiation therapy. 
19. Inability to tolerate leukapheresis. 
20. Patients, who in the opinion of the Investigator, may not be able to understand or comply 
with the safety monitoring requirements of the study or unlikely to complete all protocol-
required study visits or procedures, including follow-up visits. 
Note: Patients failing any of the eligibility criteria, after leukapheresis or AUTO3 product 
manufacture, such as those with progressive CNS disease and are discontinued may re-enter 
the study when they are considered to be eligible again. If AUTO3 product has been 
manufactured they can be treated at the current dose using the original product if it continues 
to meet release criteria.   
For Pre-conditioning or AUTO3 Infusion: Patients meeting any of the following exclusion 
criteria must not be given pre-conditioning or treated with AUTO3 or treatment should be 
delayed until they no longer meet these criteria:  
1. Severe intercurrent infection at the time of, or within 14 days of, scheduled AUTO3 
infusion.  
2. Requirement for supplementary oxygen at the time of scheduled pre-conditioning or 
AUTO3 infusion.  
3. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or 
moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled pre-
conditioning or AUTO3 infusion.  
Note: Such patients will be excluded until the patient is GVHD free and off steroids. 
4. Significant deterioration of renal or hepatic function (Serum creatinine ≥1.8 x ULN, 
Serum alanine aminotransferase or aspartate aminotransferase ≥6 x ULN, Total bilirubin 
≥3 x ULN, except in subjects with Gilbert's syndrome) prior to pre-conditioning.  
Note: Patient with ≥Grade 3 CRS, ≥Grade 2 neurotoxicity or a DLT following the first split 
dose should not receive the second split dose.  

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8 
STUDY PROCEDURES AND TREATMENT 
8.1 
CONSENT, SCREENING, AND REGISTRATION 
Consent: Patients, or their parent/legal guardian where appropriate, must sign an Informed 
Consent Form (ICF) prior to the conduct of any study-related procedures. The trial includes 
both paediatric and adult patients. Adults (≥16 or 18 years of age) will be informed of all 
aspects of the trial and will be asked for written consent. For patients aged <16 (or 18 as per 
local regulations) years, the person with parental responsibility or legal guardianship of the 
child must be informed of all aspects of the trial and written consent will be obtained from 
this person. Additionally, the clinician will explain the study to patients of appropriate age 
and assent will be obtained from the patient whenever it is possible to do so. The child must 
be informed about the trial to the extent compatible with their understanding.  
Information sheets are available for different age groups as well as for the parent/legal 
guardian. Sites are responsible for assessing a patient’s (and/or parent/legal guardian’s) 
capacity to give informed consent (or assent).  
Sites must ensure that all patients, and/or parents/legal guardians, have been given the current 
approved version of the Patient Information Sheets (PIS), are fully informed about the trial, 
and have confirmed their willingness to take part in the trial by signing the current approved 
consent (or assent) form. Sites must assess a patient’s (and/or parent/legal guardian’s) ability 
to understand verbal and written information in English or the local language, and whether an 
interpreter will be required to ensure fully informed consent. If a patient (and/or parent/legal 
guardian) requires an interpreter and none is available, the patient should not be considered 
for the trial.  
The Investigator, or, where delegated by the Investigator, other appropriately trained site 
staff, are required to provide a full explanation of the trial and all relevant treatment options 
to each patient (and/or parent/legal guardian) prior to trial entry. During these discussions, the 
current approved PIS for the trial should be discussed with the patient (and/or parent/legal 
guardian). Sufficient time must be allowed for the patient (and/or parent/legal guardian) to 
consider and discuss participation in the trial. Written informed consent/assent on the current 
approved version of the consent/assent form for the trial must be obtained (according to 
national requirements and guidance) before any trial-specific procedures are conducted. The 
discussion and consent/assent process must be documented in the patient notes. 
Patient ID number Assignment: After providing written informed consent, the patient will 
be issued with a unique patient identification number. The patient identification number will 
be used to identify the patient for the duration of the study. Patient identification numbers 
will not be reassigned or reused. 
Screening: Following informed consent, patients will be screened for eligibility for the study 
(Day -84 to Day -35). During the screening phase, eligibility criteria will be reviewed, a 
complete clinical evaluation and the investigations below will be performed. If an assessment 
was performed as part of the patient’s routine clinical evaluation and not specifically for this 
study, it does not need to be repeated after signed informed consent has been obtained if the 
assessments fulfil the study requirements and are performed within the specified timeframe 
prior to AUTO3 administration. Retesting of abnormal screening values that lead to exclusion 
is allowed during the screening phase (to reassess eligibility). The patient should continue to 
meet protocol specified renal, hepatic, and pulmonary function requirements prior to 
initiating pre-conditioning chemotherapy. Adverse events associated with screening 

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procedures will be collected. Baseline data will be collected during screening as described in 
the Schedule of Assessments and will include: 
• 
A full medical history and physical examination including weight, vital signs and oxygen 
saturations  
• 
Clinical assessment to exclude active significant (overall Grade ≥II, Seattle criteria) 
acute GVHD or moderate/severe chronic (NIH consensus criteria) GVHD (SCT patients 
only)  
• 
Karnofsky (age ≥10-24 years), Lansky (age <10 years), or ECOG (age ≥25 years) score  
• 
Assessment of patient notes to undergo leukapheresis  
• 
pregnancy test in female patients of child-bearing potential  
• 
Full blood count and coagulation 
• 
Biochemical assessment  
• 
Infectious disease screening (see below) 
• 
Peripheral blood chimerism in T cell and myeloid lineage (post-BM transplant patients 
only)  
• 
Electrocardiogram (ECG) and ECHO 
• 
Bone marrow sample for morphology, immunophenotyping, cytogenetics, molecular and 
flow-based MRD  
• 
Lumbar puncture  
• 
Blood for serum cytokines 
Infectious disease screening: Patients will be tested by the site (in accordance with the site 
Human Tissue Authority license for human application) for infectious diseases as outlined 
below prior to (within 30 days of) leukapheresis. Table 10 lists the tests that must be 
performed as a minimum requirement: 
Table 10: 
Infectious Disease Screening 
Pathogen  
Test  
HIV 1 and 2  
Anti-HIV-1 and 2  
Hepatitis B  
Hepatitis B surface antigen, 
anti-Hepatitis B core antibody 
Hepatitis C  
Anti-hepatitis C virus-antibody  
Syphilis  
Syphilis serology (chemiluminescent microparticle immunoassay)*  
HTLV 1 and 2  
Anti-HTLV-1 and 2  
West Nile and Zika (both US only) 
As per local testing 
HIV = human immunodeficiency virus; HTLV = human T-cell lymphotropic virus. 
* A validated testing algorithm must be applied to exclude the presence of active infection with Treponema pallidum. A non-
reactive test, specific or non-specific, can allow tissues and cells to be released. When a non-specific test is performed, a 
reactive result will not prevent procurement or release if a specific Treponema confirmatory test is non-reactive. A patient 
whose specimen tests reactive on a Treponema-specific test will require a thorough risk assessment to determine eligibility 
for clinical use. 
A screening log must be maintained by the site and filed in the Investigator Site File.  

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Patient Registration: Patient registration will be performed prior to commencement of any 
trial treatment/intervention. Following screening evaluations, confirmation of eligibility and 
consent of a patient or parent/legal guardian at a site, the registration form must be fully 
completed and then sent to Autolus. The eligibility information will be reviewed, and 
registration approved by the medical monitor.  
After registration of patients, the site will coordinate with Autolus on timing of leukapheresis 
to generate AUTO3. If the patient continues to meet the eligibility criteria for entry to the 
study (as outlined in Section 6), the site will liaise with the manufacturer to arrange transfer 
of the AUTO3 to the participating site. Further details are provided in the Cell Handling 
Instruction Manual. 
8.2 
LEUKAPHERESIS 
Following informed consent, confirmation of eligibility and registration to the study, patients 
will undergo an unstimulated leukapheresis for the generation of AUTO3.  
Prior to leukapheresis, the following medications are not permitted: 
• 
Steroids: therapeutic doses must be stopped at least 72 hours before leukapheresis. 
Physiological replacement doses are permitted: <12 mg/m2/day hydrocortisone or 
equivalent. 
• 
Chemotherapy: should be stopped 1 week prior to leukapheresis. 
Leukapheresis must be performed within 30 days of infectious disease testing and will be 
carried out following the standard institutional process. An additional infectious disease test 
will be done on the day of leukapheresis or within 7 days after. In general, leukapheresis 
should be performed approximately 35 days before the planned AUTO3 dosing date, based 
on emerging data this window can be changed. This may require insertion of a central venous 
access device and is a day case procedure. Typically, a double volume leukapheresis will be 
performed. Should there be any issues with the procedure, such as inadequate cell collection 
for primary dose or for re-treatment or due to contamination of the apheresate etc then the 
patient may undergo a repeat leukapheresis if clinically appropriate. 
The leukapheresate is the starting material for the manufacture of AUTO3. The total cell 
number that is required for successful manufacture varies according to the dose level. The 
target collection is 1 x 109 PBMCs. If the collection is insufficient, the Sponsor will advise as 
to the feasibility of successful manufacture. If collection is determined to be inadequate, then 
collected cells may be used for research purposes as per the consent. The leukapheresate will 
be transported to the Sponsor for generation of AUTO3 at a temperature of 2 to 8°C within 
48 hours, ideally within 24 hours. US centres will transport the leukapheresate to a freezing 
facility for onward frozen shipment to the manufacturing facility. Further details regarding 
this process can be found in the Cell Handling Instruction Manual. 
Each leukapheresate will be identified by a unique patient identification number plus any 
additional patient identifiers as allowed per local regulations (typically initials and date of 
birth). 
Note: For patients who have relapsed following SCT, AUTO3 will be generated from the 
patient (not the stem cell donor). 
Note: Patients failing any of the eligibility criteria after apheresis or AUTO3 product 
manufacture such as those with progressive CNS disease should hold further study related 

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activity until they are considered to be eligible again even if it extends the overall screening 
window beyond 84 days. If stored apheresate from a prior leukapheresis (on the current 
study) is available or if AUTO3 product has been manufactured they can be treated using the 
original product (or manufactured using the available apheresate) if it continues to meet 
release criteria. These patients do not need to undergo leukapheresis again, but may do so if 
necessary and clinically appropriate.  Patients should undergo evaluation and monitoring as 
prescribed from Day -7 onwards or earlier as appropriate. Additional investigations and 
assessments should be performed as clinically indicated (eg ECHO or ECG). 
8.3 
PRE-CONDITIONING CHEMOTHERAPY 
Patients that still meet eligibility requirements for the study and in whom AUTO3 meets the 
release criteria will be admitted at the study site from the day before starting pre-conditioning 
chemotherapy until a minimum of 30 days (±3 days) post first infusion of AUTO3 (longer if 
necessary for monitoring and management). The pre-conditioning phase will begin with 
administration of pre-conditioning chemotherapy and will end with the beginning of 
treatment with AUTO3 infusion. 
Prior to administration of pre-conditioning chemotherapy, patients will undergo clinical and 
laboratory assessments and the site investigator, or his designee will determine if the patient 
is fit to receive pre-conditioning chemotherapy. Assessment will include: 
• 
Clinical history and physical examination (including neurological examination, see 
below) including weight, vitals and oxygen saturations  
• 
Clinical assessment to exclude active significant (overall Grade ≥II, Seattle criteria) 
acute GVHD or moderate/severe chronic (NIH consensus criteria) GVHD (SCT patients 
only)  
• 
Karnofsky (paediatric/young adult cohort age ≥10-24 years) or Lansky (age <10 years)  
or ECOG (adult cohort age ≥25 years) 
• 
Repeat pregnancy test in female patients of child-bearing potential  
• 
Full blood count  
• 
Biochemical assessment  
• 
Lymphocyte subsets and Igs 
• 
Baseline assessment of serum cytokine levels 
• 
Bone marrow sample for morphology, immunophenotyping, cytogenetics, molecular 
and/or flow-based MRD  
• 
Lumbar puncture if clinically indicated 
• 
Blood for RCR testing and insertional mutagenesis  
See Schedule of Assessments for details. 
Neurological examination: In any patient experiencing new CNS signs or symptoms at any 
time after enrolment, a detailed neurological assessment should be performed by a 
neurologist including appropriate imaging and diagnostics.  

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Following these assessments, patients will proceed to receive a lymphodepleting 
pre-conditioning treatment with CY for 2 days and FLU for 4 days (starting Day -6), timed to 
end 3 (±1) days before AUTO3 infusion.  
8.3.1 
Pre-conditioning Chemotherapy Dose and Regimen 
Cyclophosphamide and fludarabine dosing is described below. Fludarabine will be 
administered first. 
• 
Fludarabine 30 mg/m2 followed by cyclophosphamide 500 mg/m2 day 1 (Day -6) 
• 
Fludarabine 30 mg/m2 followed by cyclophosphamide 500 mg/m2 day 2 (Day -5) 
• 
Fludarabine 30 mg/m2 (Day -4) 
• 
Fludarabine 30 mg/m2 (Day -3) 
The pre-conditioning chemotherapy should be completed a minimum of 3 days (±1 day) prior 
to AUTO3 infusion. 
Fludarabine (FLU) will be given by i.v. infusion over 30 minutes in sodium chloride 0.9%. 
For patients with renal impairment (glomerular filtration rate 30-60 mL/min/1.73 m2, or those 
who weigh <10 kg, the dose of FLU should be reduced according to standard institutional 
practice. When patients receive both cyclophosphamide (CY) and FLU, FLU will be given 
first. Patients that have received a cumulative fludarabine dose of >300 mg/m2 and those who 
have received prior cranial irradiation (not total body irradiation) may receive only 90 mg/m2 
pre-conditioning.  
Cyclophosphamide will be given by i.v. infusion over 30 minutes. Adequate pre- and 
post-hydration for up to 4 to 6 hours (or as per institutional practice) should be given post 
infusion to induce diuresis. Use of Mesna may be considered per institutional practice.  
The dose of both drugs may be adjusted for weight of the patient as clinically appropriate. 
The anticipated minimum weight is approximately 10 kg, but may be slightly lower in some 
patients. 
Anti-emetic prophylaxis will be given as per standard institutional policy. Prophylaxis for 
TLS with allopurinol and i.v. fluids may be given in patients with high leukaemic burden 
(≥25% blasts)  
For additional information regarding both the drugs, please refer to the Summary of Product 
Characteristics. 
8.3.2 
Supply of Cyclophosphamide and Fludarabine 
Cyclophosphamide and FLU are Non-Investigational Medicinal Products as they are not 
being tested or used as a comparator in this trial.  Cyclophosphamide and FLU will be used to 
induce lymphodepletion in the current study as a pre-conditioning treatment, prior to AUTO3 
treatment. Both drugs are authorised and commercially available in the UK, US and EU. 
Investigators will be responsible for their own supply of CY and FLU. Sufficient quantities of 
CY and FLU will be dispensed to cover the prescribed dose and will be prepared as per site 
Standard Operating Procedures and accordingly to manufacturer recommendations. 
Cyclophosphamide and FLU are cytotoxics and must be handled with care in accordance 
with local policy. Good aseptic practice must be employed when preparing CY and FLU 
solutions for infusion.  

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8.3.3 
Accountability of Cyclophosphamide and Fludarabine 
Pharmacy records should be kept of the CY and FLU dispensed to trial patients. The expiry 
date, batch number used, and manufacturer (if known) should be recorded as well as details 
of vials dispensed.  
8.4 
AUTO3 TREATMENT AND PATIENT MONITORING 
The treatment phase will involve infusion of AUTO3 on Day 0 and will extend until the 
completion of the DLT period or until start of a new ALL therapy, whichever happens first. 
8.4.1 
Assessment Prior to AUTO3 Infusion 
Prior to administration of AUTO3, patients will undergo clinical and laboratory assessments 
and the site Investigator or his designee will determine if the patient is eligible to receive 
AUTO3 as per Section 6. These assessments should be performed prior to the first infusion of 
AUTO3 and will include: 
• 
Clinical history and physical examination including vitals and oxygen saturations  
• 
Clinical assessment to exclude active significant (overall Grade ≥II, Seattle criteria) 
acute GVHD or moderate/severe chronic (NIH consensus criteria) GVHD (SCT patients 
only) 
• 
Full blood count 
• 
Pregnancy test in female patients of child-bearing potential 
• 
Biochemical assessment  
• 
Coagulation 
• 
Ferritin 
• 
Baseline assessment of serum cytokine levels 
• 
Bone marrow sample for morphology, immunophenotyping, cytogenetics, molecular and 
flow-based MRD if clinically indicated  
• 
Lumbar puncture if clinically indicated 
See Schedule of Assessments for details.  
Note: Patients will not be eligible for infusion of AUTO3 if they have, or had, severe 
intercurrent infection within 14 days of infusion, have active significant (≥Grade II) acute 
GVHD or moderate/severe chronic GVHD requiring systemic steroids, supplemental oxygen 
or active pulmonary infiltrates (Section 6.2). In this situation, AUTO3 infusion will be 
delayed and infusion may be performed as per dose delay guidelines (Section 8.4.4). 
In addition, where patients are to receive a split dose, if after the first dose they experienced: 
• 
Grade 4 or refractory Grade 3 CRS, Grade 4 neurotoxicity or a DLT: the second dose 
should not be given. 
8.4.2 
AUTO3 Administration 
AUTO3 will be administered as a single rapid i.v. infusion within 30 minutes (as quickly as 
possible) from AUTO3 being thawed on Day 0 in an in-patient setting. Full details will be 

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provided in the Cell Handling Instruction Manual. Only the Investigator or Investigator’s 
designee will dispense the study product.  
Premedication with chlorpheniramine and paracetamol may be given prior to infusion of 
AUTO3 as per standard institutional practice (see Section 10.2), but steroids should not be 
given as part of premedication. 
The Investigator or Investigator’s designee or a study research nurse experienced in the 
administration of cellular blood products as per the trial-specific procedure will verify the 
patient details (unique patient identification number, initials, and date of birth) on the 
AUTO3 label matches the recipient, check the dose of cells, volume and number of cryobags 
to be infused and prescribe AUTO3 on a blood product chart. Details of the exact dose, 
volume, time of completion of thawing and time of completion of infusion will be 
documented in the applicable study records. 
AUTO3 will be infused as described in the Cell Handling Instruction Manual. In brief, 
AUTO3 will be thawed in a 37°C water bath under sterile conditions the bag will be gently 
massaged until the cells have just thawed. There should be no frozen clumps left in the bag.  
For patients ≤50 kg, the entire contents of the bag may be drawn up into a syringe, a normal 
saline rinse of the bag should be performed to ensure all cells have been drawn. AUTO3 will 
then be given as an i.v. infusion through a central venous line over up to 5-10 minutes by the 
Investigator, Investigator’s designee, or a study research nurse experienced in the 
administration of cellular blood products as per the Cell Handling Instruction Manual and the 
line flushed with normal saline. Aseptic techniques will be applied during the syringe filling 
process and administration. 
For patients >50 kg, following thawing of the bag in a 37°C water bath under sterile 
conditions, the entire contents of the bag will be given through an appropriate gauge blood set 
as an i.v. infusion through a central venous line over 5-15 minutes by the Investigator, 
Investigator’s designee, or a study research nurse experienced in the administration of 
cellular blood products as per the Cell Handling Instruction Manual and the line flushed with 
normal saline. NO FILTER should be used in the line used for the infusion of the T cell 
product. Alternatively, the administration may be performed using a syringe as described 
above for patients weighing ≤50 kg. If the AUTO3 cell product appears to have a damaged or 
leaking bag, or otherwise appears to be compromised, it should not be infused. 
The time between completion of thawing and completion of infusion should not exceed 
30 minutes.  
8.4.3 
Monitoring During and After AUTO3 Administration 
All patients will be monitored closely with temperature, pulse, blood pressure, respiratory 
rate and oxygen saturations observed immediately prior to, and every 30 minutes 
(±10 minutes) for 4 hours after, AUTO3 infusion. In the event of allergic adverse reactions, 
anti-histamines may be administered, as well as oxygen and salbutamol in the event of 
respiratory distress. 
Patients will be observed as an in-patient (in hospital or ambulatory care as clinically 
appropriate [ambulatory care setting is a facility close to hospital where a patient is seen by 
physician/nursing staff at least once a day]) for a minimum of 30 days (±3 days) post-
AUTO3 infusion or longer if necessary for monitoring and management. Patients may be re-
admitted based on emerging safety findings. During hospitalisation/ambulatory care, patients 
will be monitored clinically as per clinical practice and will undergo appropriate blood tests 

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(see Schedule of Assessments) for signs of toxicity, in particular for CRS, TLS and 
neurological disturbance and managed as detailed in Section 9.6. Transfusions of blood 
products, antibiotics, analgesics, and intensive care will also be provided as clinically 
indicated. Urate levels will be monitored and treatment started if indicated.   
Patients may be discharged from hospital/ambulatory care when clinically appropriate after a 
minimum of 30 days (±3 days) after AUTO3 infusion if deemed appropriate by the treating 
physician. The in-patient stay may be extended if this is felt to be necessary by the treating 
physician. The duration of admission of Phase II patients will be 30 days (±3 days) but may 
be reduced based on emerging data with a protocol amendment. The required study 
procedures and assessments to be conducted during the Treatment Stage are outlined in the 
Schedule of Assessments. Clinical evaluations and laboratory studies may be repeated more 
frequently, if clinically indicated. 
Data regarding intensity of care will be collected on a periodic basis e.g. duration of in-
patient stay or ambulatory care admission, ICU/ITU stay, duration of vasopressor support, 
mechanical ventilation, dialysis etc. 
8.4.4 
Dose Delay 
If the pre-conditioning regimen is interrupted for intercurrent illness or other reasons, the 
patient may complete or recommence the pre-conditioning regimen after recovery, according 
to the Investigator’s judgment after consultation with the Sponsor. Patients will be closely 
monitored during and after the pre-conditioning regimen.  
If the patient has completed the pre-conditioning regimen but is unable to receive AUTO3 on 
Day 0 for any reason, clinical judgement will be used to decide whether it is appropriate to 
delay the administration of AUTO3 or to wait for the patient’s safety blood results to recover 
sufficiently before repeating the pre-conditioning regimen and administering AUTO3. 
If the patient is deemed unsuitable to receive the AUTO3, they will be discontinued from the 
clinical trial (see Section 15.3) and replaced. Each such case will be discussed with the 
Sponsor. 
8.4.5 
Interruption of Infusion 
In the event of severe infusion reaction, the FLU/CY/AUTO3 infusion should be stopped and 
the patient treated as clinically indicated. When the patient has recovered, the infusion may 
be restarted.  
Interruption of AUTO3 should not be greater than 30 minutes after thawing of AUTO3. 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. In case of 
uncertainty, individual cases should be discussed with the Sponsor and documented.  
8.4.6 
Duration of Treatment 
In most patients, it is expected that AUTO3 will be given once, or twice as a split dose. 
However, if a patient has sufficient AUTO3 remaining from the original manufacture and 
meets the re-treatment criteria, a second treatment may be given (see Re-treatment of 
Patients; Section 8.4.7). 
8.4.7 
Re-treatment of Patients 
It is expected that most patients will receive a single or split dose infusion of AUTO3, given 
3-10 days apart as part of their treatment. However, some patients may be considered 

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appropriate to receive a re-treatment (as a single or split infusion) of their own stored 
AUTO3. Prior to re-treatment, the patient needs to meet the following criteria: 
 
 
 
 
OR 
 
 
  
OR 
 
 
 
  
AND all of the following: 
 
 
  
 
 
 
 
 
 
  
 
 
  
Patients undergoing a second AUTO3 infusion should receive the same pre-conditioning. The 
dose of AUTO3 can be at (or up to) the highest dose that has been declared safe after a 
minimum of 3 patients have completed the DLT period and evidence of efficacy 
(Appendix 1) has been shown. These patients will not be considered evaluable for dose 
escalation decision making but in the event of a DLT in these patients, it will be considered in 
dose escalation decision making. A minimum of 7 days will be maintained between any 
patients treated at this dose level. Depending on the number of cells available, an 
intermediate dose may also be administered if considered appropriate. The decision to re-treat 
a patient will be made by the treating Investigator and Sponsor in consultation with the SEC. 
The retreatment will occur only after CRS or neurotoxicity has resolved. Patients re-treated 
will be monitored in a similar way to patients being treated for the first time, in that they 
would start evaluation and management as defined in the protocol, starting from the 
pre-conditioning stage. 
Patients treated in the US will not have an option of retreatment until it is agreed upon after 
discussions with the FDA. 
8.5 
FOLLOW-UP PHASE 
Upon completion of the treatment phase (30 days [±3 days] post last AUTO3 infusion), 
patients will enter the follow-up phase where they will continue to be followed monthly for 
the first 4 months (relative to the first dose) and then every other month until the end of the 

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year and then every 3 months until 24 months for the assessment of anti-tumour response. 
Responding patients will undergo clinical assessment, laboratory tests and biomarker 
evaluations as described in the Schedule of Assessments. Grade 3 or higher AEs that are 
considered related to the study medication will be recorded/reported as detailed in 
Section 12.3.  
Patients that have disease progression or those withdrawn from the study earlier than 
24 months will complete the End of Study visit and transition into a long-term follow-up 
study (AUTO-LT1 – see Section 8.6). The End of study visit can be delayed until start of a 
new treatment, and additional biomarkers related to disease relapse or CAR persistence may 
be collected.   
Note: Patients who have received AUTO3 and have discontinued or completed the study may 
continue to be periodically monitored for AUTO3 treatment-related SAEs, AEs of special 
interest, and new malignancy until they enrol onto the long-term follow-up study 
(AUTO-LT1), and the End of Study visit will be delayed until time of such enrolment. 
Additionally, blood samples for CAR T cell persistence and RCRs may also be collected 
every 3 months. 
8.6 
LONG-TERM FOLLOW-UP 
Provided that patients, or parents/legal guardian(s), are willing, and sign a new informed 
consent/assent form, they will be enrolled onto a long-term follow-up protocol (AUTO-LT1) 
after completion of AUTO3-PA1. They will be monitored for SAEs considered related to the 
study treatment, AEs of special interest and any new malignancy for a period of up to 
15 years following treatment with AUTO3. 

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9 
STUDY ASSESSMENTS 
9.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS 
The following will be collected at screening to determine eligibility and baseline status of the 
patient. 
9.1.1 
Demographic Data and Baseline Variables 
Demographic data will include self-reported race/ethnicity, age, gender, and height and will 
be recorded at the screening visit prior to leukapheresis. 
9.1.2 
Medical/Leukaemia History 
Medical history includes clinically significant diseases, surgeries, leukaemia history 
(including highest white blood cell [WBC] count cytogenetics/CNS involvement at 
presentation, timing, and sites of relapse, immunophenotype including CD19 and CD22 
expression at relapse, all prior therapy for leukaemia including transplant, and prior GVHD 
and current disease status), all medications used by the patient and known allergies. 
Histological/cytological confirmation of disease diagnosis will be obtained (pathology 
report). 
9.1.3 
Pregnancy Test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing will be performed for 
females of childbearing potential at the screening visit and will be repeated when the patient 
is admitted prior to starting lymphodepletion as described in the Schedule of Assessments. 
9.2 
SAFETY EVALUATIONS 
All patients who receive AUTO3 will be considered evaluable for toxicity assessment. Any 
clinically relevant changes occurring during the study must be recorded in the AE section of 
the Electronic Case Report Form (eCRF). Safety assessments will be based on medical 
review of AE reports and the results of vital sign measurements, ECGs, physical 
examinations, and clinical laboratory tests performance status assessment at specified time 
points as described in the Schedule of Assessments. Any clinically significant abnormalities 
persisting at the end of the study/early withdrawal will be followed by the Investigator until 
resolution, or until a clinically stable endpoint is reached. The study will be monitored by the 
SEC and IDMC; details regarding the SEC and IDMC are provided in Section 13. The study 
will include the following evaluations of safety and tolerability according to the time points 
provided in the Schedule of Assessments. 
9.2.1 
Adverse Events and Toxicity 
Adverse events will be noted by clinic staff or reported by the patient (or, when appropriate, 
by a caregiver, surrogate, or the patient's legally acceptable representative) for the duration of 
the study. Adverse event recording and reporting is described in detail in Section 12.3.  
Toxicity will be graded using the NCI CTCAE version 5.0 criteria. To assess the effect of 
AUTO3 on normal B cell immunity, circulating B cell counts and Ig levels will be assessed 
as outlined in the Schedule of Assessments and the incidence and duration of 
hypogammaglobulinaemia determined. 

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9.2.2 
Clinical Laboratory Tests  
Blood samples for haematology, coagulation and biochemistry will be collected at each visit 
as specified in the Schedule of Assessments. Where appropriate, tests must be performed 
prior to receiving pre-conditioning treatment or AUTO3 infusion. More frequent clinical 
laboratory tests may be performed if indicated by the overall clinical condition of the patient 
or by abnormalities that warrant more frequent monitoring. Assessments for Flu/Cy 
chemotherapy drug levels may be undertaken if clinically indicated. Screening laboratory 
results must be available to the Investigator for evaluation before AUTO3 infusion and 
subsequent laboratory results should be available at the time of the patient’s evaluation by the 
treating physician. The Investigator must review the laboratory reports, document this review, 
and ensure that any clinically relevant changes occurring during the study are recorded in the 
AE section of the eCRF. The laboratory reports must be filed with the source documents. A 
summary of the tests that will be performed by the local laboratory is presented in Table 11. 
Table 11: 
Clinical Laboratory Tests 
Assessment 
Description 
Haematology 
Haemoglobin, platelet count, and WBC count with differential (neutrophils, 
lymphocytes). 
Coagulation 
Prothrombin time, international normalised ratio, activated partial thromboplastin 
time, and fibrinogen. 
Biochemistry 
Sodium, phosphate, potassium, magnesium, chloride, bicarbonate or total CO2, 
alanine aminotransferase, serum uric acid/urate, blood urea nitrogen/urea, creatinine, 
serum creatine phosphokinase, total bilirubin, calcium, C-reactive protein, and 
albumin. All tests must be performed prior to AUTO3 infusion on Day 0.  
Limited Panel 
Ferritin weekly until Day 21 or until resolution of CRS.  
Pregnancy test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing for females of 
childbearing potential. 
Serology (at screening 
only) 
• 
HIV antibody. 
• 
Hepatitis B core antibody: if positive, further testing (deoxyribonucleic acid 
[DNA] by PCR) to rule out active disease or chronic carrier. Must be confirmed 
negative prior to screening. 
• 
Hepatitis C virus antibody: if positive for hepatitis C virus, further testing (by 
ribonucleic acid PCR) should be performed to rule out active infection. 
• 
Anti-HTLV-1. 
• 
Anti-HTLV-2. 
• 
Syphilis Serology. 
• 
West Nile and Zika viruses (both US only) 
CRS = cytokine release syndrome; DNA = deoxyribonucleic acid; HIV = human immunodeficiency virus; HTLV = human 
T-cell lymphocyte virus; PCR = polymerase chain reaction; WBC = white blood cell. 
9.2.3 
12-lead Electrocardiogram 
A 12-Lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, RR, QRS, QT, and corrected QT intervals. Refer to the Schedule 
of Assessments for details regarding the frequency of ECG assessments. At each time point, a 
single 12-lead ECG will be performed by qualified site personnel. The clinical Investigator or 
designee will review the printout, including ECG morphology. The ECG should be repeated 
in triplicate if motion artefacts or clinically relevant abnormalities are noted. Additional 
cardiovascular assessments should be performed as clinically appropriate to ensure patient 

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safety. If blood sampling or vital sign measurement is scheduled for the same time point as 
ECG recording, the procedures should be performed in the following order: ECG(s), vital 
signs, blood draw. 
9.2.4 
Echocardiogram and Multigated Acquisition 
Echocardiogram is the preferred method to assess if left ventricular shortening fraction is 
≥28% or LVEF is ≥45% at screening; MUGA is an acceptable alternative for adult patients. 
Additional ECHO or MUGA assessments should be performed at the onset of CRS and when 
clinically indicated. 
9.2.5 
Vital Signs 
Vital signs will include temperature, pulse/heart rate, respiratory rate, blood pressure (systolic 
and diastolic), oxygen saturation and weight. Blood pressure and pulse/heart rate 
measurements should be recorded with the patient in a seated or lying position. Multiple time 
points (minimum of 3) will be collected prior to treatment to establish a good baseline blood 
pressure for the patient. Blood pressure and pulse/heart rate measurements will be assessed 
with an automated device or manual techniques. 
9.2.6 
Physical Examination 
A complete physical examination including detailed neurological assessment will be 
conducted at screening and on Day -7 as per the institutional standard practice. Thereafter, a 
symptom-directed physical examination will be conducted at subsequent visits. The schedule 
for physical examinations is provided in the Schedule of Assessments. In any patient 
experiencing new CNS signs or symptoms at any time after enrolment, a detailed 
neurological assessment should be performed by a neurologist including appropriate imaging 
and diagnostics. 
9.2.7 
Karnofsky or Lansky or ECOG Performance Status 
The Karnofsky and Lansky scales provided in Appendix 2 and Appendix 3 will be used to 
grade changes in the patient’s daily activities for patients aged <10 years and 10-24 years, 
respectively. For patients aged ≥25 years, the ECOG scale provided in Appendix 4 will be 
used to grade changes in the patient’s daily living activities. The frequency of assessments is 
provided in the Schedule of Assessments. 
9.3 
PHARMACODYNAMICS AND BIOMARKER EVALUATION 
Blood-based pharmacodynamic biomarkers will be evaluated in all patients as described in 
the Schedule of Assessments. Peripheral and BM biomarkers may be assessed pre- and 
post-treatment with AUTO3. Assessment at additional or fewer time points may be 
performed based on emerging data. Details regarding sample collection and processing are 
provided in the laboratory manual.  
9.3.1 
Evaluation of AUTO3 Persistence in Peripheral Blood 
Blood samples (9-18 mL) will be used to measure the expansion/persistence of CD19/CD22 
T cells at time points indicated in the Schedule of Assessments. Flow cytometry will be used 
to measure the frequency of CD19/CD22 CAR-positive T cells per microliter of whole blood 
and/or a qPCR assay/digital PCR assay will be used to quantify the number of copies of the 
CD19/CD22 CAR transgene per microgram of genomic DNA and/or per cell in peripheral 
blood. Please refer to the AUTO3-PA1 laboratory manual for the handling and storage of 
samples.  

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9.3.2 
Evaluation of RCR in Peripheral Blood 
As per health authorities’ guidelines, tests will be performed to evaluate and monitor the 
presence of RCR by qPCR; 5 mL blood will be collected for this analysis. Confirmatory 
assays may be performed if the initial results are positive. Please refer to the AUTO3-PA1 
laboratory manual for the handling and storages of samples. 
9.3.3 
Insertional Mutagenesis 
Insertional mutagenesis leading to oncogenesis is a recognised safety concern of vector-based 
gene therapy. Samples will be stored and archived before and after treatment (per the 
Schedule of Assessments) with the intent to be analysed for insertional mutagenesis, should a 
patient develop a new malignancy. The result will allow establishing a potential relationship 
between AUTO3 treatment and the development of any new malignancy. 
9.3.4 
 
Serum cytokine profile: (minimum dataset of TNF-α, IFN-γ, and IL-6) will be measured 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
9.3.5 
 
 
 
 

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9.4 
EFFICACY EVALUATION 
Response evaluations for the primary endpoint/final analysis will be based on the response 
criteria for ALL according to the National Comprehensive Cancer Network guidelines 
version 2.2014, listed in Appendix 1. Efficacy will be assessed by determining morphological 
CR/CRi as well as molecular remission based on MRD in the BM aspirate using IgH qPCR 
and/or next generation sequencing and flow cytometry as outlined in the Schedule of 
Assessments in all patients. The proportion of patients achieving molecular remission at 
1 month post AUTO3 infusion will be determined. The duration of response and EFS and 
RFS at 6, 12 and 24 months will be assessed. Relapse rate and proportion of patients in 
molecular remission without further therapy at 6 months, 1 and 2 years will be determined. 
It is important that instances and evidence of disease progression be reported to the Sponsor 
as soon as possible. The Medical Monitor will review the data to confirm that the criteria for 
disease progression have been met. If the Medical Monitor concurs, the Investigator will be 
notified and the patient will be withdrawn from the study 
9.4.1 
Bone Marrow Aspiration and Biopsy 
Bone marrow will be used for haematological assessment for morphological remission and 
for evaluation of MRD by IgH qPCR and/or next generation sequencing and flow cytometry. 
Trephine will be performed if the patient is pancytopenic according to Investigator clinical 
judgment. Morphological and cytogenetic analysis of the BM will be done by the local 
laboratory, but MRD analysis will be performed at Bristol Genetics Laboratory or other 
designated laboratories. Bone marrow aspirates will be performed (usually under general 
anaesthetic) as outlined in the Schedule of Assessments. Details regarding sample collection 
and processing are provided in the laboratory manual. The first screening (morphology and 
cytogenetics) assessment can be performed at the referring institution and reports should be 
available. In general, BM samples will be analysed as below and may be stored for later 
analysis.  
Morphology: Bone marrow smears (slides), will be analysed to determine the degree of 
leukaemic infiltration (% blasts) and the recovery of normal haemopoiesis. 
Leukaemia Immunophenotype: The B-precursor phenotype should be confirmed at 
screening by flow cytometry and should include CD19 and CD22 markers as well as 
development of a leukaemia-associated immunophenotype (LAIP) for subsequent 
assessment. In patients who relapse post AUTO3, the expression of CD19 and CD22 on the 
leukaemic blasts will also be assessed. 
Minimal Residual Disease (by qPCR & Flow cytometry): A sample of BM aspirate should 
be sent for IgH qPCR and/or next generation sequencing at the Molecular Haematology 
laboratory at Bristol Genetics Laboratory or other designated laboratories. Flow cytometric 
MRD assessment will also be done. 

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Cytogenetics: Known leukaemia associated cytogenetic and molecular aberrations will be 
documented in the eCRF at baseline and at disease progression. Where an abnormality is 
detected, this may be optionally assessed on follow-up BM samples post AUTO3 infusion. 
9.4.2 
Treatment Response 
The treatment is defined to be efficacious, when the patient is stated to be in morphological 
remission (CR or in CRi) and has MRD-negative response. Responses will be assessed within 
30 days (±3 days) post first AUTO3 infusion. The morphological treatment response criteria 
are defined in Appendix 1. The MRD will be defined as: 
Minimal Residual Disease Negative Response: 
Minimal residual disease negative response is achieved if MRD is <10-4 (0.01%) by PCR 
amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing 
(next generation sequencing may also be carried out). 
Minimal Residual Disease CR: 
Minimal residual disease CR is achieved if no PCR amplification of individual 
rearrangements of Ig genes can be detected using an appropriately sensitive assay (generally 
<5 x 10-5 copies). Minimal residual disease CR is achieved if blast count is <0.01% by flow 
cytometry or qPCR. 
Progressive Disease: 
Progressive disease is defined as an increase of ≥25% in the absolute number of circulating or 
BM blasts or development of extramedullary disease. 
Disease Relapse: 
Morphological relapse is defined as patients who achieved a CR or CRi and who have 
reappearance of blasts in the blood (≥1%), or reappearance of blasts in BM (≥5%), or 
reappearance of any extramedullary disease after CR or CRi (Appendix 1). 
Molecular/flow MRD relapse is defined as patients who achieved a MRD negative CR by 
PCR or flow and who now have disease detectable by qPCR and flow cytometry (>0.01%). 
Patients with qPCR only relapse may be followed until they have flow cytometry and 
morphological relapse if clinically appropriate. This will help evaluate the reasons for the 
relapse such as loss of CD19 and or CD22 or PD-L1 expression. The proportion of patients in 
morphological and molecular CR without further treatment at 6 months and 1 and 2 years 
post AUTO3 infusion will be determined. 
9.4.3 
Documentation of CNS/Extramedullary Disease 
All patients will be assessed for CNS disease by lumbar puncture prior to lymphodepletion, 
on Day 0 and Day 30 and 2 years (±14 days) after AUTO3 infusion or if clinically indicated. 
In patients with extramedullary disease without detectable BM disease at the time of AUTO3 
infusion (chiefly patients with isolated CNS relapse in Phase II of the study), other restaging 
investigations e.g. additional lumbar punctures and imaging will be performed as clinically 
indicated. 
Complete remission is achieved when no lymphoblasts are detected in CSF by cytospin or 
flow cytometry (Appendix 1). 

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9.5 
PATIENT REPORTED OUTCOMES  
Health-related quality of life (HRQOL) measures may be collected at periodic intervals 
(paper or electronic) prior to AUTO3 infusion and then at 1, 3, 6, 8, 12 and 24 months, and as 
necessary. The instruments may include the Pediatric Quality of Life Inventory (PedsQL) 
which is a brief, standardised, generic assessment instrument that systematically assesses 
patients’ and parents’ perceptions of HRQOL in pediatric patients. Additional instruments 
such as the EQ-5D, which is a standardised instrument developed by the EuroQol Group as a 
measure of health-related quality of life, will also be used, as age appropriate.  
9.6 
BLOOD VOLUME COLLECTIONS 
In general, blood will be taken from a Hickman line or other central venous access device for 
the first year after AUTO3 infusion so that venepuncture will not be needed. If blood is taken 
peripherally at later time points, patients will be offered local anaesthetic cream/spray. The 
maximum volume of blood collected for study related assessments on any 1 day will not 
exceed 80 mL, or 2 mL/kg in patients less than 30 kg. In patients under 40 kg, the blood 
collection may be spread over 2-3 days. Additional samples may be collected as required to 
ensure the safety of the patient.  Refer to the laboratory manual for the handling and storage 
of samples. 

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10 
GUIDELINES 
FOR 
PREVENTION, 
MONITORING, 
AND 
MANAGEMENT OF ADVERSE EVENTS 
The guidelines detailed in Table 12 are suggested ways of managing key toxicities, however 
deviations from suggested recommendations are allowed per the Investigator’s judgement 
and local institutional practice. 
10.1 
GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY 
The recommendations should be modified appropriately to suit patients’ age and weight. 
Table 12:  
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy 
Toxicity 
Preventive and Supportive Care Interventions 
Prophylaxis 
Patients should receive pneumocystis prophylaxis with trimethoprim-sulfamethoxazole 
or suitable alternative agents, and either acyclovir or valacyclovir for herpes virus 
prophylaxis from the start of conditioning chemotherapy until 6 months post AUTO3 
infusion.  
All patients should be monitored for CMV by PCR weekly during admission or as 
necessary.   
Additional anti-microbial (e.g. ciprofloxacin) and anti-fungal prophylaxis to be given as 
per institutional practice.  
All patients with fevers while neutropenic must have blood cultures drawn and receive 
broad-spectrum antibiotics as per institutional practice. 
Constitutional 
Administer paracetamol for symptomatic management of fevers in patients; 
Avoid corticosteroids and if thrombocytopaenic non-steroidal anti-inflammatory drugs. 
Respiratory 
Monitor for oxygen saturation at every visit, a significant decrease in oxygen saturation 
at room air should be investigated and managed with supportive care including 
supplemental oxygen, anti-microbials and ventilator support as appropriate. Patients with 
an oxygen requirement of >40%  (or lower based on emerging data) in setting of CRS 
should receive treatment with Tocilizumab 
Cardiovascular 
Stop or taper antihypertensive medications prior to cell infusion; 
Monitor vital signs at least every 4-8 hours on an inpatient unit during hospital stay; 
Monitor vital signs every 2 hours in patients with fevers and tachycardia; 
Initiate replacement i.v. fluids for patients with poor oral intake or high insensible losses 
to maintain net even fluid balance; 
Administer i.v. fluid boluses for patients with systolic blood pressure less than 80% of 
their pre-infusion baseline and poor peripheral perfusion. A 20 mL/kg normal saline 
bolus (500 mL if age ≥16) should be given initially and the patient reassessed after 
30 minutes. Consider a further bolus of 20 mL/kg (500 mL if age ≥16) if blood pressure 
remains low and ongoing poor perfusion. 
In patients receiving >2 i.v. fluid bolus (or as age appropriate) for hypotension, consider 
transfer to the intensive care unit, an ECG and an ECHO/MUGA should be performed to 
evaluate for cardiac toxicity. 
Noradrenaline is the preferred first-line vasopressor for patients with hypotension 
initiated on inotropic support. 

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Toxicity 
Preventive and Supportive Care Interventions 
Hematologic 
Initiate allopurinol and i.v. fluid prophylaxis for TLS prophylaxis at start of 
lymphodepletion in patients with high leukaemic burden (≥25% BM blasts); (see 
Section 10.5) 
Monitor complete blood count with differential at least daily. 
Maintain haemoglobin of ≥80 g/L; 
Maintain platelets ≥20,000/μL; 
If absolute neutrophil count<500/μL at 30 days (±3 days) post AUTO3 infusion (or 
earlier if clinically indicated), initiate granulocyte colony stimulating factor support. 
Continue until absolute neutrophil count increases to ≥1000 μL; 
Transfuse fresh frozen plasma with a goal of normalisation of partial thromboplastin 
time (PTT) in patients with a PTT >1.5-fold above the ULN; and 
Transfuse cryoprecipitate to maintain fibrinogen of ≥1g/L. If patient is bleeding, a higher 
level of fibrinogen should be maintained. 
Neurologic 
The nursing staff conducts focused neurologic examinations every 4-6 hours in patients 
experiencing neurologic toxicity; 
Perform brain magnetic resonance imaging (MRI) in any patient experiencing neurologic 
toxicity; 
Perform lumbar puncture to evaluate for infectious pathogens, cytokine levels, and CAR 
T cell levels in patients experiencing neurologic toxicity whenever feasible; 
Consider a neurology consultation for any patient experiencing neurologic toxicity; and 
Standard antiepileptic medications for patients with active seizures. Prophylactic 
antiepileptic medications are not required. 
BM = bone marrow; CAR = chimeric antigen receptor; ECG = electrocardiogram; ECHO = echocardiogram; 
i.v. = intravenous; MRI = magnetic resonance imaging; PTT = partial thromboplastin time; TLS = tumour lysis syndrome; 
ULN = upper limit of normal. 
Taken from (Brudno and Kochenderfer 2016). 
10.2 
PRE- AND POST-INFUSION SUPPORTIVE THERAPY 
AUTO3 is an autologous product, with fully human CAR constructs and is less likely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, the following 
medications should be given 30 minutes before the study drug infusion: paracetamol orally 
and an antihistamine (chlorpheniramine or equivalent) i.v. These medications may be 
discontinued based on emerging data. In addition, pre-infusion medications listed in Table 13 
may also be administered if necessary.  
Post-infusion medication listed in Table 13 may be considered following AUTO3 infusion if 
necessary. Post-infusion medication(s) may be continued for up to 48 hours after the infusion. 
Use of additional supportive care measures may be instituted as clinically necessary at the 
discretion of the Investigator. 

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Table 13: 
Pre- and Post-infusion Medications (Dose Adjusted as Age Appropriate) 
Medication 
Dose 
Administration 
Pre-infusion 
Post-infusion 
Antihistamine 
Chlorpheniramine  
(age <5 years, 2.5 mg; age 
6-11, 5 mg; age ≥12, 10 mg, 
6 hourly) 
I.v. – administer at 
least 30 minutes prior 
to study drug 
X 
Optional 
Antipyretic 
Paracetamol  
(age ≥12 years, 1000 mg; 
age ≤11 years, 15 mg/kg, 
6 hourly)  
Oral - administer at 
least 30 minutes prior 
to study drug 
X 
Optional as 
clinically 
indicated 
Antiemetic 
Ondansetron  
(age ≤17 years, 150 µg/kg 
maximum 8 mg; age ≥18 years, 
8 mg or equivalent 
I.v. - start infusion 
30 minutes prior to 
study drug 
Optional 
N/A 
Ondansetron  
(weight <11 kg, 2 mg; weight 
11-40 kg, 4 mg; weight >40 kg, 
8 mg, twice daily) or equivalent 
Oral - as clinically 
indicated 
N/A 
Optional 
i.v. = intravenous; N/A = not appropriate 
Note: Steroids should in general be avoided but may be used in case of severe reactions not controlled by other measures.  
10.3 
TREATMENT OF INFUSION RELATED REACTIONS 
Patients who experience infusion-related reactions (to pre-conditioning or AUTO3) that 
manifest as wheezing, flushing, hypoxemia, fever, chills, rigors, bronchospasm, headache, 
rash, pruritus, arthralgia, hypo- or hypertension or other symptoms, should have the 
symptoms managed according to the recommendations provided in Table 14 or as per 
institutional practice. All NCI CTCAE Grade 3 or 4 infusion-related reactions should be 
reported within 24 hours to the Sponsor. If the event meets the criteria of an SAE, follow 
SAE reporting criteria in Section 12.3.2. 

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Table 14: 
Guidelines for the Management of Infusion-related Reactions (Dose 
Adjusted as Age Appropriate) 
NCI CTCAE Grade 
Treatment/Intervention 
Premedication at Subsequent 
Dosing (if patient receiving split 
dosing) 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
No intervention indicated 
Monitor patient as medically indicated until 
recovery from symptoms. 
May consider chlorpheniramine  
(age <5 years, 2.5 mg;  
age 6-11, 5 mg;  
age ≥12, 10 mg 6 hourly) or 
equivalent and or paracetamol (age 
≥12 years, 1000 mg; age ≤11 years, 
15 mg/kg 6 hourly) orally. 
Grade 2  
Moderate reaction; 
requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment 
Interrupt infusion 
Start i.v. fluids; give chlorpheniramine (age 
<5 years, 2.5 mg; age 6-11, 5 mg; age ≥12, 
10 mg 6 hourly) (or equivalent) i.v. and/or 
paracetamol; consider bronchodilator therapy; 
may also consider corticosteroids if necessary; 
monitor patient closely until recovery from 
symptoms. 
Restart infusion if AUTO3 dose has not been 
fully administered. 
Symptoms recur: Stop and discontinue further 
infusion. 
The amount of AUTO3 infused must be 
recorded on the eCRF. 
Chlorpheniramine  
(age <5 years, 2.5 mg; age 6-11, 
5 mg; age ≥12, 10 mg 6 hourly) or 
equivalent and/or paracetamol (age 
≥12 years, 1000 mg; age ≤11 years, 
15 mg/kg 6 hourly) orally. 
Grade 3 or 4 
Severe reaction; 
 
Grade 3: prolonged 
(i.e. not rapidly 
responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalisation 
indicated for other 
clinical sequelae (e.g. 
renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
life-threatening; pressor 
or ventilator support 
indicated 
Stop infusion 
Start i.v. saline infusion; recommend 
bronchodilators and chlorpheniramine 
(age <5 years, 2.5 mg; age 6-11, 5 mg; age 
≥12, 10 mg 6 hourly) i.v. +/- adrenaline 
1 µg/kg for patients <50 kg and 50 µg for 
patients over 50 kg, injected slowly for i.v. 
administration or administer intramuscularly. If 
unresponsive, give with methylprednisolone 
1 mg/kg (max 80 mg) i.v. (or equivalent), as 
needed, and other drugs as appropriate. 
Patients should be monitored until the 
Investigator is comfortable that the symptoms 
will not recur. Investigators should follow their 
institutional guidelines for the treatment of 
anaphylaxis. In the case of late-occurring 
hypersensitivity symptoms (e.g. appearance of 
a localised or generalised pruritus within 
1 week after treatment), symptomatic treatment 
may be given (e.g. oral antihistamine or 
corticosteroids), as appropriate.  
 
 
 
Grade 3: Discuss with Sponsor’s 
Medical Monitor about merits of 
completing AUTO3 infusion if full 
dose has not been administered.  
 
 
 
 
 
 
 
 
 
Grade 4: Permanently discontinue 
any remaining AUTO3. 
General 
Appropriate personnel and appropriate resuscitation equipment should be available in 
or near the infusion room and a physician should be readily available during the 
infusion of study drug.  
CTCAE = Common Terminology Criteria for Adverse Events; eCRF = Electronic Case Report Form; i.v. = intravenous; 
NCI = National Cancer Institute. 

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10.4 
GRADING 
AND 
MANAGEMENT 
OF 
CYTOKINE 
RELEASE 
SYNDROME 
Cytokine release syndrome is a known toxicity with CAR T cell therapies and can be severe 
in 20 to 30% of patients, particularly those with high leukaemic burden. Clinical symptoms 
indicative of CRS may include, but are not limited to, culture negative fever (with or without 
rigors), myalgia, nausea/vomiting, tachycardia, hypoxia, hypotension, headache, confusion, 
tremor, and delirium. Potentially life-threatening complications of CRS may include cardiac 
dysfunction, acute respiratory distress syndrome, renal and/or hepatic failure, and 
disseminated intravascular coagulation (DIC). DIC, macrophage activation syndrome (MAS) 
and hemophagocytic lymphohistiocytosis may occur in some for whom CAR-mediated 
inflammatory responses continue to evolve. The clinical syndrome of MAS is characterised 
by high grade non-remitting fever, cytopenias affecting at least two of three lineages, and 
hepatosplenomegaly. It is associated with biochemical abnormalities, such as high circulating 
levels of serum ferritin, soluble interleukin-2 receptor (sCD25), and triglycerides, together 
with a decrease of circulating NK activity. Other findings include variable levels of 
transaminases up to signs of acute liver failure and coagulopathy with findings consistent 
with DIC.  
Patients will be admitted as an inpatient for a minimum of 30 days (±3 days) (longer if 
necessary for monitoring or management) after first AUTO3 infusion and will be closely 
monitored for early signs and symptoms indicative of CRS with clinical review and blood 
tests including C-reactive protein/clotting as well as 3 times weekly monitoring of serum 
cytokines for the first 14 days or longer if clinically indicated. Clinical personnel will be 
trained in the management of CRS. Resources necessary for resuscitation and supportive care 
including intensive care should be readily available. In the event of severe CRS, as major 
paediatric/adolescent haematology centres, all sites have extensive experience in resuscitation 
and an intensive care unit on site. Recommendations for the clinical management of CRS are 
provided in Table 15. 
For the purposes of capture in the eCRF, as CRS can present with multiple signs and 
symptoms, it is important to assess the character and nature of these occurrences.  Therefore, 
avoid entering events of ‘Cytokine Release Syndrome’ in the eCRF.  Please add the 
associated adverse events and indicate their association with CRS, as indicated in the CRF. 

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Table 15A: 
Severity Grading of Cytokine Release Syndrome (ASBMT CRS 
Consensus Grading) 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever† 
Temperature ≥38°C Temperature ≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
With either: 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring one 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
And/or‡ 
Hypoxia 
None 
Requiring low-flow 
nasal cannula^ or 
blow-by 
Requiring high-flow 
nasal cannula^, 
facemask, non-
rebreather mask, or 
Venturi mask 
Requiring positive 
pressure (eg: CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
CPAP: Continuous positive airway pressure; BiPAP: Bilevel positive airway pressure 
† Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
‡ CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring one vasopressor and hypoxia requiring low-flow 
nasal cannula is classified as having Grade 3 CRS. 
^ Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
Taken from (Lee et al. 2018). 

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Table 15B: 
Management of Cytokine Release Syndrome (Dose Adjusted as Age 
Appropriate) 
CRS Grade 
Treatment 
Grade 1 
Symptoms are not life-threatening and 
require symptomatic treatment only, e.g. 
fever, nausea, fatigue, headache, 
myalgia, and malaise or organ toxicity. 
Supportive care per institutional standards including analgesics and 
antipyretics, assess and treat for neutropenic infections.  
Consider tocilizumab or siltuximab for persistent (lasting >3 days) 
and refractory fever. 
Grade 2 
Symptoms require and respond to 
moderate intervention 
 
Supportive care including fluid substitution is recommended. 
Use tocilizumab (or siltuximab) early if persistent fever of ≥39°C 
despite antipyretics for 10 hours, persistent/ recurrent hypotension 
after initial fluid bolus, and initiation of oxygen supplementation.  
Low-flow-oxygen (nasal cannula or blowby). 
Use dexamethasone if hypotension persists after 1 to 2 doses of 
anti-IL-6 therapy. 
Grade 3 
Symptoms require and respond to 
aggressive intervention 
 
Intensive care should be considered. 
Immunotherapy with tocilizumab (or siltuximab). Repeat dose of 
tocilizumab at 6-12 hours if no clinical improvement. Add 
siltuximab as necessary if not previously administered. 
Add steroids if unresponsive within 24 hours. Also, consider 
anti-TNF antibodies as clinically appropriate. 
Low-dose vasopressor therapy. 
Oxygen (flow ≥40% fraction of inspired oxygen) (high flow oxygen 
through nasal cannula oxygen or facemask, continuous positive 
airway pressure or bilevel positive airway pressure). 
Uncontrolled MAS or haemophagocytosis may also be treated with 
anakinra, an IL-1 receptor antagonist, as a steroid-sparing agent at a 
dose of 100 mg by subcutaneous injection, to be repeated daily as 
clinically indicated (Shah et al. 2017).   
Grade 4  
Life-threatening symptoms 
Intensive care. 
Ventilatory support requiring positive pressure 
(CPAP/BIPAP/mechanical ventilation) 
Multiple vasopressors or high-dose vasopressors. 
Immunotherapy with tocilizumab, ± siltuximab, and high dose 
steroids. Consider alternative agents such as anti-TNF, and other 
agents as appropriate (Kenderian et al. , Gargett et al. 2015, Ruella 
et al. 2016). 
Uncontrolled MAS or haemophagocytosis may also be treated with 
anakinra, an IL-1 receptor antagonist, as a steroid-sparing agent at a 
dose of 100 mg by subcutaneous injection, to be repeated daily as 
clinically indicated (Shah et al. 2017). 
Grade 5  
Death 
 
CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer 
Institute; TNF = tumour necrosis factor. 
Taken from (Lee et al. 2018). 
Details of supportive medication and steroid doses are presented in Table 16 and Table 17.  

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Table 16:  
Definitions and Doses of Vasopressors (Dose Adjusted as Age 
Appropriate) 
Definition of High-Dose Vasopressors 
Vasopressor 
Dose for ≥3 hours 
Noradrenaline monotherapy 
≥0.2 mcg/kg/minute 
Dopamine monotherapy 
≥10 mcg/kg/minute 
Adrenaline monotherapy 
≥0.1 mcg/kg/minute 
If on vasopressin 
High dose of vasopressin + noradrenaline equivalent of 
≥0.1 mcg/kg/minute (using Vasopressin and Septic Shock 
Trial formula) 
If on combination vasopressors (not vasopressin) 
Noradrenaline equivalent of ≥20 mcg/minute  
An overview of the CRS management is presented in Figure 5. 
Figure 5: 
CRS Management Overview 
 

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The pharmacologic management of CRS is presented in Table 17. 
Table 17:  
Pharmacologic Management of CRS/MAS (Dose Adjusted as Age 
Appropriate)  
Drug 
Indication 
Dose 
Tocilizumab 
 
 
 
 
 
Siltuximab 
Siltuximab is an 
alternative to 
tocilizumab        and 
may be used according 
to local institutional 
guidance. Siltuximab 
has been approved to 
treat Castleman’s 
disease (Grupp et al. 
2013, Calabrese and 
Rose-John 2014, Maude 
et al. 2014a, Teachey et 
al. 2018), but not 
currently for CRS.  
 
Siltuximab may be 
added if there is no 
response to 
tocilizumab+/- 
corticosteroids. 
LVEF <40% by ECHO; 
Creatinine >2.5-fold higher than the most recent 
level prior to CAR T cell infusion; 
Norepinephrine requirement at a dose 
>2 µg/minute for 48 hours since the first 
administration of norepinephrine, even if 
administration is not continuous; 
Systolic blood pressure of 90 mm Hg that cannot 
be maintained with norepinephrine; 
Oxygen requirement of fraction of inspired 
oxygen >50% or more for more than 2 hours 
continuously; 
Dyspnoea that is severe enough to potentially 
require mechanical ventilation; 
Activated PTT >2 × the ULN; 
Clinically-significant bleeding; and 
Creatine kinase >5 × the ULN for longer than 
2 days. 
Early use criteria: May consider using for 
persistent fever of ≥39°C despite antipyretics for 
10 hours, persistent/ recurrent hypotension after 
initial fluid bolus, and initiation of oxygen 
supplementation 
Tocilizumab 
Weight >30 kg, 8 mg/kg; 
weight <30 kg, 12 mg/kg given 
i.v. over 1 hour.  
NB: organ dysfunction 
secondary to CRS and 
cytopaenias due to 
disease/chemotherapy will not 
constitute a contraindication to 
tocilizumab. 
Repeat dose if no response 
within 8 hours and consider 
steroids as below if 
unresponsive at 24 hours.  
Refer to local prescribing 
information and institutional 
guidance. 
 
 
Siltuximab 
11mg/kg i.v. over 1 hour as an 
intravenous infusion as a single 
dose (Grupp et al. 2013, Shah 
et al. 2017). 
Methylprednisolone 
CRS toxicity refractory to tocilizumab. 
2 mg/kg i.v. every 12 hours 
weaned over 5 days. 
Anakinra 
Uncontrolled CRS or haemophagocytosis or 
Macrophage activation syndrome (MAS) and or 
Disseminated intravascular coagulation (DIC) 
refractory to standard measures (Brudno and 
Kochenderfer 2016, Shah et al. 2017, Liu and 
Zhao 2018). 
100 mg (or as age appropriate) 
by subcutaneous injection, to 
be repeated daily as clinically 
indicated. 
CAR = chimeric antigen receptor; CRS = cytokine release syndrome; ECHO = echocardiogram; i.v. = intravenous; 
LVEF = left ventricular ejection fraction; PTT = partial thromboplastin time; ULN = upper limit of normal. 
Reference: (Brudno and Kochenderfer 2016); Tocilizumab (Actemra) label (FDA 2018b). 
10.5 
MANAGEMENT OF TUMOUR LYSIS SYNDROME 
Treatment with CAR T cells, such as AUTO3, can lead to rapid killing of malignant B cells, 
which can occasionally result in TLS associated with a release of intracellular ions and 
metabolic by-products into the systemic circulation in patients with a high leukaemic burden. 
Clinically, TLS can be characterised by rapid development of hyperuricemia, hyperkalaemia, 
hyperphosphatemia, hypocalcaemia, and potentially acute renal failure.  

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Patients with a high leukaemic burden (≥25% BM blasts) will be given allopurinol and i.v. 
fluids from the start of lymphodepletion to prevent TLS. Patients will be monitored vigilantly 
for early signs and symptoms of TLS with daily clinical review and blood biochemistry. 
Should TLS occur, supportive care will be given as per standard institutional protocols. 
Management of TLS will include i.v. fluids, aggressive correction of abnormal laboratory test 
results such as hyperkalaemia, hyperuricemia, and hypocalcaemia, together with rasburicase 
to increase urate excretion if needed.  
10.6 
GRADING AND MANAGEMENT OF NEUROTOXICITY (ICANS) 
Neurotoxicity has been seen in patients with leukaemia and lymphoma after treatment with 
CD19 CAR T cells and is now referred to as ‘Immune Effector Cell-associated Neurotoxicity 
Syndrome’ (ICANS). The cause of neurotoxicity is not well-understood, although it is 
generally reported to be fully reversible. Transient neurological complications have also been 
reported with CD19 bispecific T cell engagers, suggesting that the target may have some 
relevance. In neither case do these toxicities correlate with CRS/macrophage activation 
syndrome. However, close attention should be paid to neurological signs and symptoms.  
Although symptoms can vary, the early manifestations of ICANS are often tremor, 
dysgraphia, mild difficulty with expressive speech especially naming objects, impaired 
attention, apraxia, and mild lethargy.  Other symptoms can include confusion, depressed level 
of consciousness/ encephalopathy, hallucinations, dysphasia, ataxia, apraxia, cranial nerve 
palsies, and seizures.  Headache is a non-specific symptom, frequently occurring during fever 
or after chemotherapy, thus, headache alone is not a useful marker of ICANS. Expressive 
aphasia, on the other hand, appears to be a very specific symptom of ICANS. 
There appears to be no correlation between ICANS and CRS/macrophage activation 
syndrome and both can occur together or separately. 
Patients will be admitted as an inpatient for a minimum of 30 days (±3 days) (longer if 
necessary for monitoring or management) after first AUTO3 infusion and closely monitored 
for neurological signs and symptoms of neurotoxicity. If neurotoxicity is observed, a 
neurology opinion should be sought, MRI imaging performed and patients will receive 
supportive care (e.g. anti-convulsants), as appropriate. In general, neurotoxicity is transient 
and resolves spontaneously with no long-term sequelae so that supportive care alone is 
sufficient in most patients. Steroids may be given for Grade 3 or 4 neurotoxicity or in the case 
of cerebral oedema or generalised seizures but otherwise treatment with steroids should be 
avoided as this may be deleterious to the persistence of AUTO3.  
Neurotoxicity may also be caused by FLU but generally at higher doses (Helton et al. 2013) 
than those being administered in this protocol. Symptoms including objective weakness, 
agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness, 
and coma have been reported in CLL patients treated with multiple cycles of FLU. As 
described in Section 4.3, death of three young adult ALL patients due to cerebral oedema was 
partly attributed to FLU; however, two additional deaths due to cerebral oedema in the 
absence of FLU indicates that was not the cause. Moreover, it now appears that cerebral 
oedema is likely a consequence of very rapid CAR T cell proliferation, driven by the CD28 
co-stimulatory domain, this event has not been reported with CARs containing a 41BB-ζ co-
stimulatory domain which results in a slower proliferation. Patients should be closely 
monitored and managed as appropriate. Please see Table 18 for suggested assessment and 
grading of neurotoxicity as per the ASBMT guidelines for Immune effector Cell-Associated 
Neurotoxicity Syndrome (ICANS) (Lee et al. 2018). Patients may be managed as per the 

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suggested guidelines below but may also be managed as per institutional management 
guidelines. 
Table 18:  
Assessment & Grading of Neurological AEs (ASBMT ICANS Consensus 
Grading for Adults (Lee et al. 2018) 
Neurotoxicity Domain Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE Score for 
children 
>12 years^ 
(see scale below) 
7-9 
3-6 
0-2 
0 (patient is unarousable 
and unable to perform 
ICE) 
CAPD score for 
children ≤12 years 
(see scale below) 
<9 
<9 
≥9 
Unable to perform CAPD 
Depressed level of 
consciousness* 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to tactile 
stimulus 
Patient is unarousable or 
requires vigorous or 
repetitive tactile stimuli to 
arouse; stupor or coma 
Seizure (any age) 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly; or 
Non-convulsive  
seizures on EEG that 
resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between. 
Motor weakness (any 
age)§ 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or paraparesis 
Raised ICP / Cerebral 
Edema (any age) 
 
 
Focal/local edema on 
neuroimaging# 
Decerebrate or decorticate 
posturing; or Cranial nerve 
VI palsy; or Papilledema; 
or Cushing's triad; or 
Signs of diffuse cerebral 
edema on neuroimaging 
ICANS grade is determined by the most severe event (ICE or CAPD score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause. 
^A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global 
aphasia. But a patient with an ICE score of 0 may be classified as having Grade 4 ICANS if the patient is unarousable. 
*Depressed level of consciousness should be attributable to no other cause (e.g. no sedating medication) 
§ Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0  
but they do not influence ICANS grading. 
# Intracranial hemorrhage with or without associated edema is not considered a  neurotoxicity  feature  and  is  
excluded from ICANS grading. It may be graded according to CTCAE v5.0. 
ICE: Immune effector Cell-associated Encephalopathy; CAPD: Cornell Assessment of Pediatric Delirium; ICP: 
Intracranial pressure; EEG: electroencephalogram 
Taken from (Lee et al. 2018)  
Encephalopathy Assessment for Children ≥12 (Encephalopathy Assessment Tools for 
Grading of Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS)) 
Immune effector Cell-associated Encephalopathy (ICE) 
Orientation: orientation to year, month, city, hospital: 4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points 

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Following commands: ability to follow simple commands (eg, “Show me 2 ﬁngers” or 
“Close your eyes and stick out your tongue”): 1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 
point 
Attention: ability to count backwards from 100 by 10: 1 point 
Scoring 
10, no impairment; 
7-9, grade 1 ICANS; 
3-6, grade 2 ICANS; 
0-2, grade 3 ICANS; 
0 due to patient unarousable and unable to perform ICE assessment, grade 4 ICANS 
Encephalopathy Assessment for Children <12 years using Cornell Assessment of 
Pediatric Delirium (CAPD) (Traube et al. 2014).  
Answer the following based on 
interactions with the child over the 
course of the shift 
Never 4 
Rarely 3 
Sometimes 2 Often 1 
Always 0 
1. 
Does the child make eye contact 
with the caregiver? 
2. 
Are the child’s actions purposeful? 
3. 
Is the child aware of his/her 
surroundings? 
4. 
Does the child communicate needs 
and wants? 
5. 
Is the child restless? 
6. 
Is the child inconsolable? 
7. 
Is the child underactive – very little 
movement while awake? 
8. 
Does it take the child a long time to 
respond to interactions? 
For patients age 1-2 years, the following serve as guidelines to the corresponding questions: 
1. 
Holds gaze. Prefers primary parent. Looks at speaker. 
2. 
Reaches and manipulates objects, tries to change position, if mobile may try to get up 
3. 
Prefers primary parent, upset when separated from preferred caregivers. Comforted by familiar objects 
(i.e., blanket or stuffed animal) 
4. 
Uses single words or signs 
5. 
No sustained calm state 
6. 
Not soothed by usual comforting actions, for example, singing, holding, talking, and reading 
7. 
Little if any play, efforts to sit up, pull up, and if mobile crawl or walk around 
8. 
Not following simple directions. If verbal, not engaging in simple dialogue with words or jargon 

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Table 18A: 
Management and Follow-up of Neurological AEs and CRES  
Management and Follow-up of Neurological AEs.  
Grade 1 
Monitor closely. Treat symptomatically.  
Vigilant supportive care; aspiration precautions; IV hydration  
Withhold oral intake of food, medicines, and fluids, and assess swallowing  
Convert all oral medications and/or nutrition to IV if swallowing is impaired  
Avoid medications that cause central nervous system depression  
Low doses of lorazepam (0.25 to 0.5 mg IV every 8 hours or as age appropriate) or 
haloperidol (0.5 mg IV every 6 hours as age appropriate) can be used, with careful 
monitoring, for agitated patients  
Neurology consultation  
Fundoscopic exam to assess for papilloedema  
MRI of the brain with and without contrast; diagnostic lumbar puncture with 
measurement of opening pressure; MRI spine if the patient has focal peripheral 
neurological deficits; CT scan of the brain can be performed if MRI of the brain is not 
feasible  
Daily 30 min EEG until toxicity symptoms resolve; if no seizures are detected on EEG.  
Consider levetiracetam 750 mg (as age appropriate) every 12 hours (oral or IV) for a 
month. 
If EEG shows non-convulsive status epilepticus, treat as per algorithm in Table 18B. 
Consider anti-IL-6 therapy with tocilizumab or siltuximab, if neurotoxicity is associated 
with concurrent CRS (see Section 10.4).  
Worsening: treat as ≥Grade 2 
Grade 2 
Monitor closely. Supportive care and neurological work-up as indicated for Grade 1.  
Tocilizumab or siltuximab if associated with concurrent CRS. 
Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV (as age 
appropriate) every 12 hours if refractory to anti-IL-6 therapy, or for neurotoxicity without 
concurrent CRS.  
Consider transferring patient to ICU if neurotoxicity is associated with Grade ≥2 CRS.  
Worsening: treat as Grade 3 to 4 
Grade 3  
Supportive care and neurological work-up as indicated for Grade 1 if not done already.  
ICU transfer is recommended  
Anti-IL-6 therapy if associated with concurrent CRS, as described for Grade 2 
neurotoxicity and if not administered previously.  
Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV (as age 
appropriate) every 12 hours if refractory to anti-IL-6 therapy, or for neurotoxicity without 
concurrent CRS; continue corticosteroids until improvement to Grade 1 neurotoxicity and 
then taper. 
Anakinra, at a dose of 100 mg by subcutaneous injection, to be repeated daily as 
clinically indicated (Brudno and Kochenderfer 2016, Norelli et al. 2016, Liu and Zhao 
2018). 
Stage 1 or 2 papilloedema with CSF opening pressure <20 mmHg should be treated as 
per algorithm presented in Table 18C.  
Consider repeat neuroimaging (CT or MRI) every 2 to 3 days if patient has persistent 
Grade ≥3 neurotoxicity. 
Grade 4  
Supportive care and neurological work-up as outlined for Grade 1 neurotoxicity. 
ICU monitoring; consider mechanical ventilation for airway protection.  
Anti-IL-6 therapy and repeat neuroimaging as described for Grade 3 neurotoxicity.  

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Management and Follow-up of Neurological AEs.  
High-dose corticosteroids continued until improvement to Grade 1 neurotoxicity and then 
taper; for example, methylprednisolone IV 1 g/day for 3 days, followed by rapid taper at 
250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 60 mg every 12 
hours for 2 days.  
Anakinra, at a dose of 100 mg by subcutaneous injection, to be repeated daily as 
clinically indicated (Brudno and Kochenderfer 2016, Norelli et al. 2016, Liu and Zhao 
2018). 
For convulsive status epilepticus, treat as per algorithm in Table 18B. 
Stage ≥3 papilloedema, with a CSF opening pressure ≥20 mmHg or cerebral oedema, 
should be treated as per algorithm in Table 18C. 
Worsening: May consider use of lymphodepleting drugs such as cyclophosphamide 
(Garfall et al. 2015) or other drugs (Klinger et al. 2016) if unresponsive to standard 
immunosuppressive therapies. 
General 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  
Prophylactic antibiotics or other antimicrobials as clinically appropriate. 
Rigorous control of blood pressure and electrolytes (particularly calcium and 
magnesium). 
AE=adverse event; CRS=cytokine release syndrome; CSF=cerebrospinal fluid; CT=computerised tomography; 
EEG=electroencephalogram; ICU=intensive-care unit; IV=intravenous; MRI=magnetic resonance imaging. 
Table 18B: 
Recommendations for the Management of Status Epilepticus After CAR 
T Cell Therapy 
Event 
Management 
Non-convulsive 
status 
epilepticus 
Assess airway, breathing, and circulation; check blood glucose.  
Lorazepam 0.5 mg IV, with additional 0.5 mg IV every 5 min, as needed, up to a total of 
2 mg (as age appropriate) to control electrographical seizures.  
Levetiracetam 500 mg IV bolus (as age appropriate), as well as maintenance doses.  
If seizures persist, transfer to ICU and treat with phenobarbital loading dose of 60 mg IV(as 
age appropriate).  
Maintenance doses after resolution of non-convulsive status epilepticus are as follows: 
lorazepam 0.5 mg IV every 8 hours for three doses; levetiracetam 1000 mg IV every 
12 hours; phenobarbital 30 mg IV every 12 hours (as age appropriate).  
Convulsive 
status 
epilepticus 
Assess airway, breathing, and circulation; check blood glucose.  
Transfer to ICU.  
Lorazepam 2 mg IV, with additional 2 mg IV to a total of 4 mg to control seizures (as age 
appropriate).  
Levetiracetam 500 mg IV bolus, as well as maintenance doses (as age appropriate).  
If seizures persist, add phenobarbital treatment at a loading dose of 15 mg/kg IV (as age 
appropriate).  
Maintenance doses after resolution of convulsive status epilepticus are: lorazepam 0.5 mg IV 
every 8 hours for three doses; levetiracetam 1000 mg IV every 12 hours; phenobarbital 1–3 
mg/kg IV every 12 hours (as age appropriate).  
Continuous electroencephalogram monitoring should be performed, if seizures are refractory 
to treatment.  
ICU=intensive-care unit; IV=intravenous. 

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Table 18C: 
Recommendation for Management of Raised Intracranial Pressure (ICP) 
After CAR T Cell Therapy 
Condition  
Management 
Stage 1 or 2 papilloedema with 
CSF opening pressure of 
<20 mmHg without cerebral 
oedema 
Acetazolamide 1000 mg IV, followed by 250 to 1000 mg IV every 12 hours 
(adjust dose based on renal function and acid–base balance, monitored 1 to 
2 times daily) (dose as age appropriate).  
Stage 3, 4, or 5 papilloedema, 
with any sign of cerebral 
oedema on imaging studies, or 
a CSF opening pressure of 
≥20 mmHg 
Use high-dose corticosteroids with methylprednisolone IV 1 g/day (as age 
appropriate), as recommended for Grade 4 CAR-T-cell-related 
encephalopathy syndrome (Table 18A).  
Elevate head end of the patient’s bed to an angle of 30 degrees.  
Hyperventilation to achieve target partial pressure of arterial carbon dioxide 
(PaCO2) of 28 to 30 mmHg, but maintained for no longer than 24 hours. 
Hyperosmolar therapy with either mannitol (20 g/dl solution) or hypertonic 
saline (3% or 23.4%, as detailed below) Mannitol: initial dose 0.5 to 1 g/kg; 
maintenance at 0.25 to 1 g/kg every 6 hours while monitoring metabolic 
profile and serum osmolality every 6 hours, and withhold mannitol if serum 
osmolality is ≥320 mOsm/kg, or the osmolality gap is ≥40.  
Hypertonic saline: initial 250 mL of 3% hypertonic saline; maintenance at 50 
to 75 mL/h while monitoring electrolytes every 4 hours, and withhold 
infusion if serum Na levels reach ≥155 mEq/l. 
For patients with imminent herniation: initial 30 mL of 23.4% hypertonic 
saline; repeat after 15 minutes, if needed.  
If patient has ommaya reservoir, drain CSF to target opening pressure of 
<20 mmHg.  
Consider neurosurgery consultation and IV anaesthetics for burst-suppression 
pattern on electroencephalography.  
Metabolic profiling every 6 hours and daily CT scan of head, with 
adjustments in usage of the aforementioned medications to prevent rebound 
cerebral oedema, renal failure, electrolyte abnormalities, hypovolemia, and 
hypotension.  
CSF=cerebrospinal fluid; CT=computerised tomography; IV=intravenous. 
10.7 
HYPOGAMMAGLOBULINAEMIA 
Hypogammaglobulinaemia may occur as a consequence of depletion of normal B cells by 
AUTO3. However, the degree and duration of this is likely to depend on the persistence of 
CAR T cells in the body and could last for months to years. At worst, the clinical 
consequences of therapeutic B cell elimination will resemble X-linked agammaglobulinaemia 
and patients with this disorder have a normal life expectancy when treated with regular i.v. Ig 
replacement. Immunoglobulin levels will be monitored regularly as in the Schedule of 
Assessments and patients with severe hypogammaglobulinaemia (serum IgG level is <4 g/L) 
persisting longer than 6 months will be treated with i.v. Ig administration until recovery of 
B cells and normal IgM levels, or lifelong if this does not occur. Management of 
hypogammaglobulinaemia associated with AUTO3 will be per the suggested guidance or as 
per the local institutional standards.  

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10.8 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS DUE 
TO ON-TARGET BUT OFF-TUMOUR TOXICITY 
Though it is unlikely that AUTO3 will cause immune-related AEs (irAEs) due to on-target 
but off-tumour toxicity, the patients will be closely monitored for signs and symptoms 
indicative of irAEs, which may allow for an early recognition of these events. Special 
attention will be paid to vital organs and irAEs of any grade involving vital organs (e.g. lung, 
brain, and eyes), more aggressive monitoring and rapid institution of appropriate supportive 
care including systemic steroids should be administered. In case of severe irAE, not 
successfully managed by general supportive care, treatment with steroids and other agents 
may be considered. 

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11 
CONCOMITANT MEDICATIONS AND THERAPIES 
Any medication the patient is receiving on Day -7 must be recorded. Thereafter only those 
that are related to an AE or are study related prophylaxis must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
Concomitant medication may be given as medically indicated. Details (including doses, 
frequency, route and start and stop dates) of the concomitant medication/treatment given 
must be recorded in the patient’s medical records and details entered into the eCRF. Standard 
drugs required by the patient may be administered alongside the trial protocol.  
All safety management guidelines are only recommendations and deviations from this 
scheme are allowed according to the Investigator’s judgement and local institutional practice. 
11.1 
ALLOWED CONCOMITANT MEDICATIONS/THERAPIES 
Palliative radiotherapy: Palliative radiotherapy may be given concomitantly as clinically 
appropriate.  
Other permitted therapies: The following medications and supportive therapies are 
examples of support therapies that may be used during the study: 
• 
Anti-microbial prophylaxis may be given 
• 
Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells. 
Pre-and Post-AUTO3 Infusion Supportive Therapies: 
Please refer to Section 10.2. 
11.2 
PROHIBITED AND CAUTIONARY THERAPIES 
Herbal, Homeopathic agents: 
No herbal, homeopathic agents should be used between Day -10 and Day 30 (±3 days) 
following last AUTO3 infusion, unless recommended by the Principal Investigator.  
Corticosteroids and Immunosuppressant (except for managing treatment related 
toxicity): 
The use of immunosuppressants such as high dose corticosteroids should be avoided where 
possible, as these are likely to influence the efficacy and possibly safety of AUTO3. 
Therapeutic doses (doses of >5 mg prednisolone or equivalent) of steroids must be stopped at 
least 72 hours prior to leukapheresis and AUTO3 infusion. However, physiological 
replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent. 
Corticosteroids should also be avoided post-AUTO3 infusion if possible, although it is 
recognised that their use may be required in the context of development of CRS or infusion 
reactions. 
Physicians may use any medication as clinically appropriate and necessary to manage 
emerging AEs. The use of other immunosuppressants should be discussed with the Sponsor’s 
Medical Monitor. 

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Investigators can use any medication based on their clinical judgement and local institutional 
practice to optimise patient safety. 
11.3 
BRIDGING THERAPY 
Patients may receive bridging therapy while the product is being manufactured. The dates of 
bridging therapy, the chemotherapy agents and the doses given must be recorded in the 
eCRF. Additionally, the intent of bridging therapy such as prevention of disease progression 
or induction of remission in rapidly progressing disease should be documented in the eCRF. 
Chemotherapy must be stopped 1 week before leukapheresis and 2 days prior to starting 
pre-conditioning chemotherapy. 
Any donor lymphocyte infusion must be completed at least 6 weeks prior to AUTO3 
infusion. 
Any drug used for GVHD must be stopped at least 4 weeks prior to AUTO3 infusion. 
11.4 
OVER-DOSAGE 
There is currently no experience of overdose of AUTO3 as no clinical studies have been 
performed to date. There is no specific treatment for an overdose of AUTO3. In event of 
overdose, any adverse reactions could be treated symptomatically. In the event of 
unmanageable toxicity, steroids may be used to deplete AUTO3. 
AUTO3 cells will be provided in patient specific dose aliquots and will be administered by 
trained staff in a hospital setting; therefore, the chance of overdose is unlikely. 
11.5 
DIETARY AND LIFESTYLE RESTRICTIONS  
No dietary restrictions are recommended. A normal balanced diet is recommended; the 
patient may also continue his/her normal diet as appropriate. 
Donating blood products and organs: 
Patients should not donate blood, organs, tissue or cells to others if they receive AUTO3. 

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12 
SAFETY AND PHARMACOVIGILANCE 
12.1 
DEFINITIONS 
12.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product which does not necessarily have a causal relationship with the treatment.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.  
12.1.2 
Definition of an Adverse Reaction 
An adverse reaction is any untoward and unintended responses to a medicinal product related 
to any dose administered.  A causal relationship between a medicinal product and an AE is at 
least a reasonable possibility, e.g. the relationship cannot be ruled out.  
An unexpected adverse reaction is an adverse reaction in which the nature or severity of 
which is not consistent with the Reference Safety Information section outlined in the IB for 
AUTO3. 
12.1.3 
Definition of a Serious Adverse Event 
An SAE is defined as an AE that meets any of the following criteria: 
• 
Results in death (death due to disease progression will not be considered as an SAE). 
• 
Life-threatening (the term ‘life-threatening’ refers to an event in which the patient was 
at risk of death at the time of the event. It does not include any AE that, had it occurred 
in a more severe form, might have caused death). 
• 
Requires in-patient hospitalisation or prolonged existing hospitalisation. 
• 
Results in persistent or significant disability/incapacity. 
• 
Congenital anomaly/birth defect. 
• 
Medically significant (e.g. important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed above). 
If the event was initially non-serious, the onset of the SAE should be considered the time 
when the AE met the above seriousness criteria.  Resolution of the SAE should also be 
considered when the event no longer is serious and is either a non-serious event or has 
resolved.  
Protocol-specific SAEs are as follows: 
• 
Grade 4 CRS and neurotoxicity/ICANS. 
• 
Any new primary cancers. 
• 
Significant cardiac dysfunction such as Grade 3 or higher decrease in LVEF. 
• 
Grade 4 non-haematological laboratory abnormalities (not disease related) when 
considered clinically significant. 

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Serious adverse events must be reported by the Investigator to the Sponsor within 24 hours of 
being made aware of their existence (see Section 12.3.2 for reporting instructions). 
Events NOT considered as SAEs: 
• 
A procedure requiring hospitalisation for protocol/disease-related investigations 
(e.g. surgery, scans, endoscopy, sampling for laboratory tests, and BM sampling). 
However, hospitalisation or prolonged hospitalisation for a complication of such 
procedures remains a reportable SAE. 
• 
Extension of routine in-patient hospital stay beyond the recommended 30 days (±3 days) 
for general management purposes or if it is standard process for the management of 
underlying disease.  
• 
Routine treatment or monitoring of the indication not associated with any deterioration in 
condition. 
• 
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalisation or prolonged hospitalisation for a complication of 
such transfusion remains a reportable SAE.  
o Prolonged Grade 4 cytopenia lasting more than 60 days or those considered medically 
significant or requiring significant management in addition to transfusions and 
growth factor support (e.g. stem cell top up or transplant) should be reported as SAEs. 
• 
Hospitalisation or prolongation of hospitalisation for technical, practical, or social 
reasons, in absence of an AE. 
• 
Hospitalisations not intended to treat an acute illness or AE (e.g. social reasons such as 
pending placement in a long-term care facility). 
• 
A procedure that is planned (i.e. planned prior to starting of treatment on study) must be 
documented in the source document and the eCRF. Hospitalisation or prolonged 
hospitalisation for a complication remains a reportable SAE. 
• 
An elective treatment of a pre-existing condition unrelated to the studied indication.  
• 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
• 
An event which is part of the natural course of the disease under study (i.e. disease 
progression or hospitalisation due to disease progression, or pain control, stabilisation of 
fractures) does not need to be reported as an SAE. Death due to the disease under study 
is to be recorded on the Death Case Report Form. However, if the underlying disease 
(i.e. progression) is greater than that which would normally be expected for the patient, 
or if the Investigator considers that there was a causal relationship between treatment 
with study medication(s) or protocol design/procedures and the disease progression, then 
this must be reported as an SAE.  
12.1.4 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is any suspected adverse reaction 
related to the study treatment that is both unexpected and serious (see Section 12.3.3). 

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12.1.5 
Adverse Events of Special Interest 
The following are AEs of special interest:  
• 
Grade 2-5 CRS. 
• 
Grade 2-5 neurotoxicity (including depressed level of consciousness, dysphagia, ataxia, 
seizures and cerebral oedema). 
Adverse events of special interest ≥Grade 3 will be reported on an AESI/SAE form to the 
Sponsor within 24 hours of becoming aware of the event. Events can be both an AESI and a 
SAE. 
12.2 
ASSESSMENT OF ADVERSE EVENTS 
Adverse events will be elicited at each study visit as indicated in the Schedule of 
Assessments and as clinically necessary. Patients will be instructed to report any AEs 
occurring between study visits to the study site. Adverse events will be assessed by the 
Investigator, or appropriately qualified designee, for severity, relationship to study treatment, 
action taken, outcome and whether the event meets criteria as an SAE according to the 
guidelines presented in Section 12.1.3. 
12.2.1 
Severity of Adverse Events 
The severity of AEs will be graded according to the NCI CTCAE (version 5.0). 
Adverse events that are not defined in the NCI CTCAE should be evaluated for severity 
according to the following scale: 
Table 19: 
Severity Grading of AEs Not Listed on the NCI CTCAE Grading System 
Grade 
Severity 
1 
Mild  
Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
2 
Moderate 
Mild to moderate limitation in activity, some assistance may be needed; no or 
minimal medical intervention/therapy required. 
3 
Severe 
Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalisation is possible. 
4 
Life-threatening 
Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required, hospitalisation or hospice care probable. 
5 
Fatal 
Death as a result of this AE. 
AE = adverse event. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 12.1.3.  
12.2.2 
Relationship of Adverse Events to Treatment 
The Investigator must determine the relationship between the administration of the study drug 
and the occurrence of an AE/SAE as defined below: 
Relationship assessments classified as “Not Related” to study treatment:  
Not Related: 
The AE is not related to the investigational product. The patient either 
did not receive the investigational product or the event is related to an 

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aetiology other than the investigational product (the alternative 
aetiology must be documented in the study patient’s medical record). 
Unlikely Related:  
The AE is doubtfully related to the investigational product.  
The event is not clearly related to an identified aetiology other than the 
investigational product; but there is no plausible mechanism for the 
event to be related to the investigational product and/or there is no clear 
association between the event and the administration of the 
investigational product. 
Relationship assessments classified as “Related” to study treatment: 
Possibly Related: 
The AE may reasonably be related to the investigational product.  
Probably Related: 
The AE is likely to be related to the investigational product.  
There is an association between the event and the administration of the 
investigational product, there is a plausible mechanism for the event to 
be related to the investigational product, the event is less likely to be 
explained by known characteristics of the patient’s clinical status, and 
an alternative aetiology is not apparent. 
Definitely Related: 
The AE is clearly related to the investigational product. 
If an event is assessed as related to a drug other than the investigational product which has 
not been provided by the Sponsor, the name of the manufacturer must be provided when 
reporting the event. 
12.3 
REPORTING PROCEDURES 
12.3.1 
All Adverse Events  
All AEs will be recorded in the eCRF using medical terminology that accurately reflects the 
event. A diagnosis should be recorded when signs and symptoms are due to a common 
aetiology. The relationship of the AE to study therapy must be recorded in the eCRF by the 
Investigator or designee. All measures required to manage an AE must be recorded in the 
patient’s medical notes and reported accordingly in the eCRF.  
Anaemia, neutropenia, lymphopenia, thrombocytopenia requiring transfusion are expected 
(due to disease and pre-conditioning) and are not subject to reporting unless they persist 
beyond Day 30, are considered clinically significant and/or require advanced intervention 
above blood product and GCSF support, or meet the criteria as an SAE.  
Similarly, Grade 1-2 laboratory abnormalities are extremely frequent in this patient 
population and are not subjected to reporting unless felt to be clinically significant and/or 
require advanced intervention above blood product and GCSF support.  
Laboratory related AEs should be entered along with laboratory values in the laboratory 
section of CRF.  Whenever possible, AEs associated with laboratory values, should have 
these values included in the CRF. Reporting of events such as febrile neutropenia should 
associated with temperature reading entry in vitals and ANC in laboratory section. Non 
laboratory related AEs should be entered in the AE section. 

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AEs/SAEs related to leukaemia or due to holding chemotherapy administered after enrolment 
but before pre-conditioning should not be reported as AEs/SAEs for this study. Significant 
events should be added to the patient’s medical history. 
The reporting period for all AEs is described in Table 20. 
Table 20: 
Reporting Period for All AEs 
From: ICF signature  
Until: Day -7 
From: Day -7  
Until: Day 60 post last 
AUTO3 infusion* 
From: Day 60 post last AUTO3 
infusion  
Until: End of study * 
• 
AEs/SAEs related to study 
procedures (leukapheresis, 
bone marrow assessments, 
lumbar punctures etc). 
• 
Note:  AEs/SAEs associated 
with holding/bridging 
therapy prior to admission 
for conditioning 
chemotherapy, are not 
associated with study 
procedures and therefore do 
not need to be reported as 
AEs.   
• 
All AEs  
• 
All SAEs 
• 
Treatment related (to AUTO-3) 
Grade 3-5 AEs  
• 
Treatment related (to AUTO-3) 
SAEs  
• 
AEs of special interest 
(Section 12.1.5) 
• 
AEs related to study procedure 
(e.g. BM aspirate, lumbar 
puncture) 
AE = adverse event; SAE = serious adverse event. 
* or until withdrawal whichever occurs first. 
** as patients may be getting intervening non-study related treatments. Adverse events occurring out of this window may be 
reported if the Investigator considers them to be related to this study. 
The Investigator should follow each AE until 1 of the following occurs: 
• 
Adverse event has resolved to baseline or Grade 1 
• 
Adverse event is assessed as stable by the Investigator 
• 
Patient is lost to follow-up or 
• 
Patient withdraws consent 
If a drug related AE and/or any SAE is ongoing at the time of study completion (2 years after 
dosing or disease progression, whichever happens first) the event will be followed until 
resolved or stabilised for up to a maximum of 6 months, or earlier if one of the following 
apply: 
• 
Death 
• 
Withdrawal of consent 
• 
Start of new treatment or  
• 
Patient lost to follow-up 
12.3.2 
Serious Adverse Event Reporting 
All SAEs occurring during the study must be reported to the Sponsor within 24 hours of 
becoming aware of the event. Additional or follow-up SAE reports should be submitted with 
relevant information promptly. Should the regulatory authority require the Sponsor to submit 
additional data on the event, the Investigator will be requested to provide additional data to 
the Sponsor promptly.  

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Information to be Provided for an SAE: 
Although much information will have been provided in the eCRF, this information may not 
always be readily available at the time of evaluating each Serious Adverse Event, or when 
reporting to the regulatory authorities, so it is essential that as much relevant information is 
included on the AESI/SAE form.  At a minimum, the following is required. 
• 
An identifiable patient (patient number)  
• 
Reporter details 
• 
The AUTO product (if not clear on the AESI/SAE form) if administered 
• 
The Protocol (if not clear on the AESI/SAE form) 
• 
The Adverse Event, with a description of the event and a causality assessment 
Please also ensure that this information is accurate, at the time of reporting.  Missing 
information, or information that is inconsistent with the eCRF will automatically generate 
queries. The initial SAE report will be provided to the Sponsor (or designee) using the 
AEI/SAE form. The Sponsor or designee will require the following information related to the 
event: 
The SAE form completion and reporting must not be delayed, even if all of the information is 
not available at the time of the initial contact.  
The SAE report should be submitted to the following by fax or email:  
• 
SAE Fax number: +44 (0) 1252 842277 
• 
Email: Autolus@tmcpharma.com 
The 24-Hour Safety Hotline: 
TMC Pharma Services Ltd 
Hartley Wintney 
Hampshire 
RG27 8AS, UK 
Tel: +44 (0)1252 842255 
Fax numbers and email address are listed on the SAE form and in the SAE form completion 
guidelines. 
SAE Follow-up Reporting: 
After the initial SAE report, the Investigator is required to provide additional follow-up 
information on the SAE by submitting an updated SAE report form to the Sponsor (or 
designee). New significant information includes, but is not limited to, the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 

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Serious adverse events must be followed through to resolution by the Investigator. Resolution 
is defined as a return to baseline status, Grade 1, or stabilisation of the condition with the 
expectation that it will remain chronic. For all SAEs, the Investigator may be requested to 
obtain additional information in an expedited manner. This additional information will allow 
for a complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes such as concomitant medication and illnesses 
must be provided. 
The Medical Monitor may specify a longer period of time, if required, to assure the safety of 
the patient. 
At the end of the study, or following discontinuation, the events listed below will be reported 
under the long-term follow-up protocol: 
• 
Adverse events of special interest 
• 
Serious adverse events related to the study drug 
• 
New malignancies 
12.3.3 
Suspected Unexpected Serious Adverse Reaction Reporting 
If the event is evaluated as a SUSAR, i.e. unexpected events that are related (reasonable 
possibility) to AUTO3, the Sponsor will submit the SUSAR to the regulatory authorities and 
the Research Ethics Committee within 7 calendar days for initial reports of 
fatal/life-threatening events (with a follow-up report within a further 8 calendar days) and 
15 calendar days for all other events, or in accordance with local regulatory requirements. 
Where there are conflicting evaluations of causal relationship, the more conservative will be 
used for reporting purposes. 
All reporting to regulatory authorities will be by Autolus, or through an Autolus designated 
vendor. 
The Sponsor (or designee) will notify Investigators of all SUSARs, in accordance with local 
regulations. The Investigator must immediately review with the Investigator’s site team and 
retain the documentation in the Investigator Site File. 
12.3.4 
Adverse Events of Special Interests Reporting 
Adverse events of special interest that are ≥Grade 3 will follow the same reporting procedure 
and timelines as described in Section 12.3.2 for SAEs. The report form should be completed 
and faxed or emailed to the sponsor or designee (fax numbers and email address are listed on 
the bottom of the form and in the SAE form completion guidelines) within 24 hours of 
becoming aware of the event. 
12.3.5 
Pregnancy Reporting and Management 
Pregnancies 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 12 months after the last dose 
of study treatment. Any pregnancies during this period must be reported to the Sponsor (or 
designee) within 24 hours of knowledge of the event using the pregnancy report form (fax 
numbers and email address are listed on the bottom of the form). 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 

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Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs and must be reported to the Sponsor 
immediately using the SAE form (i.e. no more than 24 hours after learning of the event). 
The Investigator must counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the foetus. Monitoring of the patient should continue until conclusion of 
the pregnancy. 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed to immediately inform the Investigator if their partner 
becomes pregnant during the study or within 12 months after the last dose of study treatment. 
Any pregnancies during this period must be reported to the Sponsor (or designee) within 
24 hours of knowledge of the event using the pregnancy report form (fax numbers and email 
address are listed on the bottom of the form). 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study treatment. The pregnant partner 
will be asked to sign an authorisation for use and disclosure of pregnancy health information. 
The Investigator may provide information on the risks of the pregnancy and the possible 
effects on the foetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
Outcome 
Additional information on the course and outcome of the pregnancy should be provided to the 
Sponsor (or designee) as soon as becoming available (i.e. no more than 24 hours after 
obtaining the information) using the paper pregnancy report form. The following pregnancy 
outcomes will be considered to be SAEs and should be reported according to the procedure in 
Section 12.3.2. 
• 
Spontaneous abortion (as the Sponsor considers spontaneous abortions to be medically 
significant events). 
• 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient.   
• 
All neonatal deaths occurring within 30 days of birth should be reported as SAEs, 
without regard to causality.  
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required.  
12.3.6 
Overdose Reporting and Dosing Errors 
Safety information on the study drug may require expedited reporting and/or safety 
evaluation. This will include: 
• 
Overdose of a study drug  
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to a study drug 
• 
Medication error involving a study drug  
A study drug overdose is the accidental or intentional use of AUTO3 in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not an 

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AE unless it results in untoward medical effects. Any AUTO3 overdose or incorrect 
administration of AUTO3 should be noted on the corresponding eCRF page. All AEs 
associated with an overdose or incorrect administration of AUTO3 should be recorded on the 
AE eCRF page. If the associated AE fulfils the criteria for an SAE, the event should be 
reported immediately (i.e. no more than 24 hours after learning of the event; see 
Section 12.3.2). 

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13 
OVERSIGHT COMMITTEES 
13.1 
SAFETY EVALUATION COMMITTEE  
Patient safety will be monitored throughout all parts of the study by a SEC established by the 
Sponsor. This internal committee will monitor treatment-emergent data on an ongoing basis 
throughout study conduct for the purpose of ensuring the continued safety of patients enrolled 
in this study. 
The SEC will be chaired by the Sponsor’s Medical Monitor and membership will include 
Study Investigators, statistician, safety/pharmacovigilance and biomarker representative, 
along with additional Sponsor staff as appropriate. The team will meet at regular frequencies 
throughout study conduct;  
During Phase I (dose escalation), the SEC will meet:  
1. After the first patient in each cohort completes 2 weeks  
2. After the third patient in each cohort completes the DLT evaluation period of 30 days 
(±3 days) (after the last dose of AUTO3 in the case of split dosing). In case of DLT, will 
meet again after the sixth patient has been treated to make the dose escalation and 
schedule decision 
3. Additional ad hoc meetings if safety stopping criteria is met  
4. When clinically necessary based on emerging data. 
During Phase II (dose expansion), the SEC will meet:  
1. On a periodic basis not exceeding 3 to 6 months to assess cumulative safety data  
2. After 10 patients have completed 30 days following AUTO3 infusion 
3. After 20 patients have completed 30 days following AUTO3 infusion 
The Sponsor will maintain documentation of meeting outcomes. Decisions with the potential 
to impact patients’ safety (e.g. unfavourable change in risk/benefit assessment) will be 
promptly communicated to Investigators, ethics committees and regulatory authorities as 
appropriate. Throughout the trial, information regarding all SAEs and potential DLTs will be 
sent to the SEC members. Dose limiting toxicities will be monitored centrally and the 
decision to assign the optimal dose will be taken by the SEC. 
Dose escalation decisions in Phase I of the study will be made by the SEC. The schedule of 
dose escalation meetings will depend on the time to completion of a cohort frequency of DLT 
and when a RP2D is determined. The SEC may stop further enrolment into one or more of 
the cohorts if treatment-emergent toxicity is determined to result in an unfavourable change 
in patient benefit/risk. Decisions and/or recommendations made by the SEC will be 
communicated to the Principal Investigators at all active study centres and to the Sponsor.  
Mandatory SEC processes will be included in a SEC Charter. 
13.2 
INDEPENDENT DATA MONITORING COMMITTEE 
An IDMC, consisting of 2 independent physicians and 1 statistician, will be established by 
the Sponsor and they will review serious safety events. The IDMC will meet up on 
occurrence at the following; the decision of the IDMC will supersede that of SEC: 
• 
When any safety stopping, criteria (Section 3.6) is met 

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• 
Prior to opening Phase II 
• 
Every 6 months during Phase II to review cumulative safety data 
Throughout the trial, information regarding all SAEs and DLTs will be sent to the IDMC 
members. IDMC can ask for and will be provided with any additional information relevant to 
the SAEs and DLTs. The IDMC will receive all dose evaluation/escalation meeting minutes 
(as soon as possible following the meeting) and will have the opportunity to review and can 
over-rule the SEC decision if clinically warranted and necessary.  
When a RP2D decision is made by the SEC, the decision will need to be reviewed and 
endorsed by the IDMC prior to commencing Phase II. 
Upon occurrence of any events as defined above, detailed event summaries and cumulative 
safety data will be sent to the IDMC. A decision to continue or to hold or modify the study 
will be made by the IDMC.  If and when a study is stopped, it will be re-started after a 
protocol amendment has been approved by the regulatory authorities and ethics committees. 
Decisions and/or recommendations made by the IDMC will be communicated to the Principal 
Investigators at all active study centres and to the Sponsor.  
Mandatory IDMC processes will be included in the IDMC Charter. 

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14 
STATISTICS 
Further details of the statistical analysis of all the endpoints will be included in a separate 
Statistical Analysis Plan. Any analysis that deviates from the Statistical Analysis Plan will be 
documented and justified in the Clinical Study Report. 
14.1 
SAMPLE SIZE ESTIMATION 
Up to 100 patients in total are expected to be enrolled into both the dose escalation and 
expansion parts of the study, and up to 84 patients in total are anticipated to be treated with 
AUTO3 therapy. The difference between the number of enrolled and treated patients 
accounts for manufacturing failures and inability of some patients to meet AUTO3 infusion 
criteria.  
• 
Phase I (Escalation): Up to 36-60 patients treated in total (up to 3-6 per dose cohort, 
following a Rolling 6 design (Skolnik et al. 2008), which will consist of: 
o 
24-36 patients in the paediatric / young adult patient cohorts (age 1-24 years) 
o 
12-24 patients in the adult patient cohorts (≥25 years) 
− 
Additional number accounts for the possibility of patient with higher disease burden 
being evaluated using a single dose 
• 
Phase II (Expansion): Dose expansion: up to 24 evaluable paediatric/young adult 
patients (aged 1-24 years) in total, using a Simon’s 2-stage optimal design. 
Simon's 2-stage design (Simon 1989) will be used for Phase II. The null hypothesis that the 
true response rate is 25% will be tested against a 1-sided alternative. In the first stage, nine 
patients will be accrued. If there are two or fewer responses in these nine patients, the study 
will be stopped. Otherwise, 15 additional patients will be accrued for a total of 24. The null 
hypothesis will be rejected if 10 or more responses are observed in 24 patients. This design 
yields a 1-sided type I error rate of 5% and 80% power when the true response rate is 50%. 
14.2 
DESCRIPTION OF ANALYSIS DATASETS 
14.2.1 
Full Analysis Set 
The full analysis set will consist of all patients enrolled into the study. 
14.2.2 
Safety Analysis Set for the Study and for Study Treatment 
All patients who have started pre-conditioning therapy of FLU and CY will be included in the 
safety analysis set for the study. A patient who has pre-conditioning therapy but not AUTO3 
therapy will not be excluded from the safety analysis set for the study. 
All patients who receive at least one dose (complete or partial dose) of AUTO3 therapy will 
be included in the safety analysis set for the study treatment. 
14.2.3 
Efficacy Analysis Set 
All patients who receive at least one dose (complete or partial dose) of AUTO3 therapy will 
be included in the efficacy analysis set. 

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14.3 
STATISTICAL ANALYSES AND METHODS 
Continuous data will be summarised using the mean, median, standard deviation, minimum 
and maximum, while frequency counts and percentages will be presented for discrete 
variables. Time to event endpoints will be summarised using the Kaplan-Meier (KM) 
method. Summary statistics will be presented for baseline characteristics. 
The paediatric/young adult patient cohorts (age 1-24 years) will be analysed separately from 
the adult patient cohorts (≥25 years) in Phase I.  
14.4 
PRIMARY ENDPOINTS 
The primary endpoints of the study are as follows: 
Phase I: Safety and RP2D 
• 
Incidence of Grade 3-5 toxicity occurring within the DLT period (30 days [±3 days] after 
last dose) following AUTO3 infusion.  
• 
Frequency of DLT. 
Phase II: Anti-Leukaemic Effect and Safety 
• 
Proportion of patients achieving morphological remission (CR/CRi) and MRD-negative 
response in BM within 30 days (±3 days) post AUTO3 administration. 
• 
For patients with isolated CNS disease, anti-tumour effect will be assessed by the 
proportion of patients achieving clearance of their CSF from CNS disease with ongoing 
BM CR 30 (±3) days post AUTO3 infusion (or first post-infusion CNS assessment).  
14.4.1 
Phase I: Safety 
Safety associated with AUTO3 administration (only those who received AUTO3). 
Summary statistics and analyses will be provided by dose level and overall. The safety 
analysis set for the study and study treatment will be used for the analysis of safety data. 
Safety evaluations will be based on the incidence, severity and type of AEs, and changes in 
the patient’s vital signs and clinical laboratory results.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities AE 
coding system for purposes of summarisation. All AEs occurring on study will be listed in 
by-patient 
data 
listings. 
Treatment-emergent 
events 
will 
be 
tabulated, 
where 
treatment-emergent is defined as any AE that occurs during or after administration of 
AUTO3 up to 60 days after the last infusion, any ≥Grade 3 event that is considered drug-
related regardless of the start date of the event. Events that are considered related to treatment 
(possibly, probably, or definitely related) will also be tabulated. Adverse events by the NCI 
CTCAE toxicity grade will also be summarised. Deaths and SAEs will be tabulated in data 
listings including additional relevant information on the patient. 
Laboratory toxicity grades will be calculated for the appropriate laboratory parameters per 
NCI CTCAE version 5.0. 
Adverse events of special interest will be analysed in greater depth, including the time to 
onset and time to resolution where appropriate. 

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14.4.2 
Phase I: Recommended Phase II Dose and Maximum Tolerated Dose 
At the end of the Phase I dose escalation part of the study, the RP2D and dose schedule will 
be identified based on the safety data and evaluation of the activity data collected during 
Phase I. 
14.4.3 
Phase II: Anti-Leukaemic Effect 
The primary endpoints for Phase II (efficacy) will be assessed as follows: 
• 
Proportion of patients achieving morphological remission (CR or CRi) and 
MRD-negative complete response in the first post-infusion BM assessment within 
30 days (±3 days) post first AUTO3 administration. 
• 
For patients with isolated CNS disease anti-tumour effect will be assessed by whether 
patients clear their CSF disease with ongoing BM remission within 30 days (±3 days) 
post first AUTO3 administration 
The response rate calculations will be based on the entire Phase II patient populations. 
14.5 
SECONDARY ENDPOINTS 
The secondary endpoints of the study are as follows: 
Safety of AUTO3 
• 
Frequency and severity of AEs and SAEs.  
• 
Incidence and duration of severe hypogammaglobulinaemia (serum IgG level is <4 g/L). 
Feasibility of AUTO3 Manufacture in this Patient Population (All Patients) 
• 
Feasibility of product generation will be examined by assessing the number of AUTO3 
successfully manufactured as a fraction of the number of patients undergoing 
leukapheresis (and all patients registered).  
Clinical Efficacy of AUTO3 
• 
Proportion of patients (all and prior CD19 CAR T treatment naïve) achieving 
morphological remission (CR/CRi) and MRD-negative response within 30 days (±3 
days) post first AUTO3 administration based on flow or PCR. Evaluate clinical 
outcomes including RFS, EFS, PFS, and OS. 
Relapse free survival (RFS): Relapse free survival is measured by the time from 
achievement of CR or CRi (whichever occurs first) to relapse or death due to any cause 
during CR or CRi. In case a patient does not have relapse or death due to any cause prior to 
data cut-off, RFS will be censored at the date of the last adequate disease assessment. 
In the main analysis of RFS, patients who proceed to SCT after AUTO3 infusion will be 
censored at the time of SCT. In addition, a sensitivity analysis of RFS will be performed 
without taking time of SCT into account. 
RFS will be assessed only in patients with the best overall response of CR or CRi. The 
distribution function of RFS will be estimated using the KM method. The median RFS along 
with 95% confidence intervals will be presented if appropriate. The 6, 12, and 24 months EFS 
will also be assessed. 
• 
Event free survival (EFS): Event free survival is the time from date of first AUTO3 
infusion to the earliest of the following: 

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• 
Death from any cause  
• 
Morphological relapse 
• 
Treatment failure: Defined as no response in the study and discontinuation from the 
study due to any of the following reasons: 
o 
Adverse event  
o 
Lack of efficacy or progressive disease 
o 
New anticancer therapy 
In case of treatment failure, the event date will be set to study Day 0. In case a patient does 
not have relapse, death due to any cause or treatment failure (e.g. discontinuation because of 
withdrawal of consent, lost to follow-up, protocol violation or administrative problems or 
transplant prior to relapse) prior to data cut off, EFS is censored at the date of last adequate 
disease assessment. Patients who undergo SCT or other therapy prior to morphological 
relapse will also be censored at the date of last adequate disease assessment. 
EFS will be assessed in the efficacy analysis set. The distribution function of EFS will be 
estimated using the KM method. The median EFS along with 95% confidence intervals will 
be presented if appropriate. The 6, 12, and 24 months EFS will also be assessed. 
• Progression-free survival will be calculated from the date of AUTO3 treatment to the date 
of disease relapse or disease progression. Patients who have not progressed, relapsed or 
died from disease will be censored at the last adequate disease assessment. 
• Overall survival will be calculated from the date of AUTO3 treatment to the date of 
death. Patients who have not died will be censored at the date of last contact (clinic visit 
or telephone contact).  
• Proportion of patients in molecular remission without further therapy at 6 months, 1 and 
2 years (±14 days) following treatment with AUTO3. 
• Incidence of CD19 and or CD22-negative relapse. 
Biomarker, Pharmacokinetic and Pharmacodynamic Effects of AUTO3 
The following analyses on the pharmacokinetics and pharmacodynamic effects of AUTO3 
will be performed for patients who received AUTO3: 
• 
Expansion and persistence of CD19/CD22 CAR-positive T cells as determined by qPCR 
and/or flow cytometry will be summarised using the appropriate statistical methods.  
− 
Expansion is defined as the maximum level of CD19/CD22 CAR expression in both 
qPCR (copies/μg genomic DNA) and/or flow cytometry (cells/µL) assays during 
follow-up.  
− 
Engraftment is defined as detection of any level of CD19/CD22 CAR expression in 
circulating T cells (i.e. PBMC) by qPCR (viral insertions per genome) and/or flow 
cytometry following infusion (cells/µL) above baseline controls.  
− 
Persistence is defined as the duration of detectability, from infusion to the first 
negative result (less than detection limit). 
• 
The kinetics of CD19/CD22 CAR-positive T will be documented over time for each 
patient and the area under the curve calculated, then summarised for all patients. 

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• 
Duration of B cell aplasia as determined by flow cytometry in the peripheral blood. 
14.6 
 
• 
 
• 
  
 
 
  
 
 
 
14.7 
IMMUNOGENICITY DATA 
Analyses of immunogenicity data will be documented in the Statistical Analysis Plan. 
14.8 
PHARMACOKINETICS 
See above biomarker evaluation for cellular kinetics (Section 14.5). 
14.9 
OTHER ANALYSES 
Not applicable. 
14.10 
INTERIM ANALYSIS 
An interim analysis on safety and preliminary efficacy will be performed for the Phase I 
paediatric and adult cohorts separately when all Phase I patients have been followed for a 
minimum of 3 months. The start of the Phase II part of the study is not dependent on this 
interim analysis. 
In Phase II of the study, an interim analysis will be performed when 9 paediatric/young adult 
(1-24 years old) patients have been evaluated for response. The response from the patients 
will be monitored on an ongoing basis:  
• If 3 or more responses are observed before the 9th patient is evaluated for response, the 
study will continue without stopping recruitment.  
• Otherwise recruitment will halt temporarily until all 9 patients have been assessed for 
response. Recruitment will re-start when 3 or more responses are observed in these 
9 patients; otherwise the study will terminate. 

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15 
STUDY COMPLETION/DISCONTINUATION AND WITHDRAWAL 
OF PATIENTS 
15.1 
COMPLETION 
A patient will be considered to have completed the study if he or she has completed 
assessments up to and including the End of Study visit or has experienced a clinical endpoint 
that precludes further continuation in the study (e.g. death, unacceptable toxicity, disease 
progression). 
15.2 
DISCONTINUATION IN STUDY  
A patient should be discontinued if: 
• 
Disease progression as assessed by the Investigator. 
− 
Patients with frank morphologic relapse per Response Criteria for Acute 
Lymphoblastic Leukaemia (Appendix 1) will come off study. 
− 
Patients with molecular evidence of disease, defined as BM MRD >10-4 within the 
first 2 years after infusion by qPCR and/or flow cytometry, will have the BM MRD 
re-assessed 2-4 weeks later. If MRD >10-4 is confirmed, the patient may come off 
study to start a subsequent therapy. However, where possible, data regarding disease 
progression by morphological relapse should be collected to facilitate evaluations of 
aetiology of relapse.  
• 
Clinical progression as assessed by the Investigator. 
• 
The patient received concurrent (non-protocol) anticancer treatment. 
• 
Intercurrent illness that prevents administration of pre-conditioning chemotherapy and or 
AUTO3 administration. 
• 
Intercurrent illness that prevents further follow-up. 
• 
Patient refuses further follow-up. 
• 
Non-compliance with study procedures. 
If a patient achieves a transient disease response but then shows evidence of recurrent disease 
associated with loss of detectable circulating CD19/CD22 CAR-positive T cells, further doses 
of AUTO3 may be given if available but the patient will be censored from the primary 
efficacy assessment at that time point but not discontinued from the study.  
If a patient is discontinued after apheresis or AUTO3 product manufacture they may re-enter 
the study at the current dose level if and when they are considered to be eligible again. 
If a patient discontinues the study, this will not result in automatic halt of data collection for 
the study. Following discontinuation, the patient should complete the End of Study visit as 
described in the Schedule of Assessments. The primary reason for treatment discontinuation 
will be documented in the eCRF. Once a patient discontinues, they will be eligible for entry 
into a long-term follow-up study if they have received AUTO3. If a patient has ongoing 
toxicity related to the study their exit from the study may be delayed until the event resolves 
or stabilizes. 

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15.3 
PATIENT WITHDRAWAL FROM THE STUDY 
A patient, or their parents/legal guardian, may withdraw consent and/or may be discontinued 
by the Investigator for any reason at any time.  
A patient may withdraw or be withdrawn from the study for any of the following reasons: 
• 
Lost to follow-up 
• 
Withdrawal of consent1 
• 
The Sponsor discontinues the study. 
If a patient is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the patient, or their parents/legal guardian, and determine the reason for 
discontinuation/withdrawal. The measures taken to follow-up must be documented. 
When a patient withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Patients who withdraw may be 
replaced at the discretion of the Sponsor. 
A patient who withdraws from the study will be eligible for entry into the long-term follow-
up study. Additionally, research/biomarker samples collected will be retained and used in 
accordance with the original separate informed consent for research samples. 
Future Data Collection and Withdrawal of Consent: Informed consent is a continuous and 
dynamic process. Patients, or their parents/legal guardian, are free to withdraw their consent 
at any point in the clinical study and without detriment to their future medical care. However, 
patients, or their parents/legal guardian, who wish to withdraw consent from further 
intervention/study visits may be willing to be followed in the clinical trial so as to enable the 
collection of key safety information. In this case, the Investigator will discuss this possibility 
with the patient, or their parents/legal guardian, to continue in the study and be contacted by a 
suitable means of communication agreeable to the patient, or their parents/legal guardian, to 
enable collection of information (survival status and evaluation of safety). In this event, the 
details should be recorded in the patient’s hospital records and only key information entered 
into the eCRF thereafter. The above information will be presented in the main PIS and ICF to 
ensure the patient or their parent/legal guardian understands the available options. 
15.3.1 
Procedures for Handling Withdrawals 
A patient, or their parents/legal guardian, may, of their own volition, withdraw their consent 
at any time during the course of the study without any resulting detriment. All data collected 
up to the point of withdrawal will be maintained in the study database and included in 
subsequent analyses, as appropriate. Where a patient is withdrawn from the trial at their own 
request, or the request of their parents/legal guardian, or based on a decision of the 
Investigator, the follow-up should be maintained for safety review, subject to the continuing 
consent of the patient, or their parents/legal guardian. The Investigator will discuss the 
arrangements for withdrawing from any further study interventions and continuing to be 
followed for safety purposes.   
If a patient is lost to follow-up at a site, every effort should be made to contact the patient’s 
family doctor/general practitioner to obtain information on the patient’s status. 
 
1 Following withdrawal, no further protocol procedures can be performed. However, patients may be followed in 
the long-term follow-up protocol based on consent. 

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In the case AUTO3 does not meet the specifications of the release criteria, the case will be 
discussed with the Principal Investigator. It may be necessary to generate AUTO3 again if 
time permits (and biological screening repeated if necessary), otherwise the patient will be 
withdrawn from the study. 
15.4 
REPLACEMENT POLICY 
If a patient is unable to be dosed on the planned day, they may undergo delayed dosing and 
be re-pre-conditioned (if appropriate) as long as they continue to meet the study enrolment 
criteria. Bone marrow sampling and imaging studies may not be repeated if the patient has 
not received any other anti-leukaemia therapy in the interim (excluding steroids and 
pre-conditioning chemotherapy). Patients undergoing delayed dosing may be evaluable for 
dose escalation decision making if the SEC so concludes.  
Patients that have disease progression prior to completion of the DLT evaluation period or 
withdrawn from the study for reasons other than toxicity may be replaced, unless the SEC 
concludes that the patient is evaluable for dose escalation decision making. 

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16 
END OF TRIAL/TERMINATION 
For clinical trials located in the EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c) and for those 
countries outside the EU, local regulations will be followed.  
The study will be considered complete when the last patient completes their final follow-up 
visit. A final Clinical Study Report will be provided to the relevant authorities within 
6 months after the end of the study.  
The Sponsor reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented per 
local requirements (e.g. IEC/IRB, regulatory authorities). In addition, the Investigator or the 
Sponsor has the right to discontinue a single site at any time during the study for medical or 
administrative reasons such as: 
• 
Significant non-compliance with contractual enrolment timelines and targets 
• 
Serious or continued Good Clinical Practice (GCP) non-compliance 
• 
Inaccurate, incomplete, or delayed data collection 
• 
Failure to adhere to the study protocol 
• 
Failure to provide requested follow-up information for data queries. 

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17 
ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 
ETHICS COMMITTEE REVIEW AND APRROVAL 
The final Clinical Study Protocol, including the final version of the written PIS, ICF and any 
other relevant patient facing material, must be approved, or given a favourable opinion in 
writing by an IEC/IRB as appropriate.  
If it is necessary to amend the protocol or the PIS/ICF during the study, an IEC/IRB approval 
of the amended protocol and/or PIS/ICF must be obtained prior to implementation of the 
amended procedures and before new patients are consented to participate in the study using 
the amended version of the PIS/ICF.  
17.2 
REGULATORY AUTHORITY REVIEW AND APPROVAL 
The study will not commence before approval from the regulatory authority has been granted 
according to local requirements. The Sponsor (or designee) will be responsible for the 
preparation, submission, and confirmation of receipt of any regulatory authority approvals 
required prior to release of study treatment for shipment to the study site. 
During the study, the Sponsor (or designee) is also responsible for submitting subsequent 
amendments and notifications to the regulatory authority according to local requirements.  
17.3 
INVESTIGATOR RESPONSIBILITIES 
17.3.1 
Overall Responsibilities 
The Investigator is responsible for conducting the study in full accordance with the Clinical 
Study Protocol, the latest revision of the Declaration of Helsinki, the GCP Consolidated 
Guideline, and all applicable national and local laws and regulations for clinical research. 
Information regarding any investigational sites participating in this study that cannot comply 
with these standards will be documented and appropriate actions taken. For studies conducted 
in the EU/European Economic Area countries, the Investigator will ensure compliance with 
the EU Clinical Trial Directive (2001/20/EC). For studies conducted in the United States or 
under a United States Investigational New Drug, the Investigator will additionally ensure 
adherence to the basic principles of “Good Clinical Practice” as outlined in the current 
version of 21 Code of Federal Regulations, subchapter D, part 312, “Responsibilities of 
Sponsor and Investigators”, part 50, “Protection of Human Subjects”, and part 56, 
“Institutional Review Boards”. 
17.3.2 
Site Review 
Prior to the study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and 
all the instructions and procedures found in this protocol, and to give access to all relevant 
data and records to Clinical Research Associates, auditors and regulatory authorities as 
required. Investigators ascertain they will apply due diligence to avoid protocol deviations. 
The Investigator will make appropriate reports on the progress of this study to the Sponsor or 
its designee in accordance with applicable government regulations and their agreement with 
the Sponsor/Contract Research Organisation. 

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17.3.3 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent/assent from 
patients, or their parents/legal guardian, prior to conducting any study-related procedures. All 
consent documentation must be in accordance with applicable regulations and International 
Council on Harmonisation (ICH) GCP. Each patient, or their parents/legal guardian, is 
requested to sign and date the informed consent/assent form after she/he has received and 
read the PIS and received an explanation of what the study involves, including but not limited 
to the objectives, potential benefits and risk, inconveniences and the patient’s rights and 
responsibilities.  
Patients, or their parents/legal guardian, will be given adequate time to evaluate the 
information given to them before signing and dating the informed consent/assent form. It will 
also be explained to the patients, or their parents/legal guardian, that patients are free to 
refuse entry into the study at any time and without prejudice to future treatment. The 
informed consent/assent form must also be signed and dated by the person obtaining consent. 
The original signed informed consent/assent form for each patient, or their parents/legal 
guardian, will be retained on file by the Investigator, a copy will be given to the patient, or 
their parents/legal guardian and a copy will be kept in the patient’s hospital notes. 
Informed consent/assent forms must be retained for all screened patients and must be 
available for verification by the Study Monitor at any time.  
In the event of changes to the informed consent/assent form during the study, the Investigator 
must always use the most current IEC/IRB approved form for documenting written informed 
consent. 
17.3.4 
Delegation of Investigator Duties 
The Investigator should ensure that all persons involved in the clinical study are adequately 
qualified, informed about the protocol, any amendment to the protocol, the study treatments, 
and their study related duties and functions before any involvement takes place. Delegation of 
any study related duties and documentation of training performed will be recorded in the 
signature and delegation log. 
17.3.5 
Communication with Independent Ethics Committee/Institutional Review 
Board 
A list of IEC/IRB members should be obtained by the Investigator or qualified designee and 
provided to the Sponsor/representative. 
The Sponsor, or its designee, is responsible to assist the Investigator with applicable 
documentation for communication with IECs/IRBs. Before initiating a trial, the 
Investigator/institution should have written and dated approval of the study protocol, the 
patient ICF, any written information to the patients, patient recruitment procedures (e.g. 
advertisement if applicable), IB, Investigational Medicinal Product labelling (if applicable) 
and the coordinating investigator’s curriculum vitae to the relevant IEC/IRB for evaluation 
before the study start. The IEC/IRB’s unconditional approval statement will be transmitted by 
the Investigator to the Sponsor or a designee prior to shipment of AUTO3 to the site. This 
approval must refer to the study by exact protocol title and number, and should identify the 
documents reviewed and the date of review. 
During the trial, the Investigator (or designee) is responsible for forwarding the applicable 
documents for approval and/or review including protocol deviations, protocol amendments, 

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ICF changes or revisions of other documents originally submitted for review including 
serious and/or unexpected adverse experiences occurring during the study, new information 
that may affect adversely the safety of the patients or the conduct of the study, an annual 
update and/or request for re-approval, and when the study has been completed. The 
Investigator or designee will follow national and local requirements.  
The Investigator must supply the Sponsor with a copy of the list of members of the IEC/IRB 
and the letter(s) of approval(s) defining the version of each document approved. 
17.3.6 
Confidentiality of Trial Documents and Patient Records 
The Investigator must ensure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorised parties. The Sponsor will maintain confidentiality 
standards by assigning a unique coded identification number to each patient included in the 
study. Patient names will never be included in data sets that are transmitted to the Sponsor or 
their representatives, or to third parties as permitted by the ICF.  
On eCRFs or other documents submitted to the Sponsor, patients will not be identified by 
their names, but by an identification code. The Investigator will keep a patient enrolment log 
relating codes to the names of patients. The Investigator will maintain documents not for 
submission to the Sponsor, e.g. patients’ written consent forms, in strict confidence. Records 
will not be destroyed without giving the Sponsor prior written notice and the opportunity to 
further store such records, at the Sponsor’s cost and expense. 
After obtaining a patient’s consent, the Investigator will permit the study monitor, 
independent auditor, or regulatory agency personnel to review the portion of the patient’s 
medical record directly related to the study. This shall include all study relevant 
documentation (e.g. patient medical history to verify eligibility, laboratory tests result, 
admission/discharge summaries for hospital admissions occurring while the patient is on 
study and autopsy reports for deaths occurring during the study). 
Patient medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the ICF signed by the patient, unless permitted or required by 
law. 
17.4 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL 
FUTURE RESEARCH 
Samples collected in this study may be stored by Autolus Ltd or an authorised designee for 
up to 15 years (or according to local regulations) for additional research. Samples will only 
be used to further understand AUTO3, to understand advanced cancers, to understand 
differential drug responders, and to develop tests/assays related to AUTO3 and advanced 
cancer. The research may begin at any time during the study or the post-study storage period.  
Stored samples will be coded throughout the sample storage and analysis process and will not 
be labelled with personal identifiers.  

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18 
ADMINSTRATIVE REQUIREMENTS 
18.1 
DATA QUALITY CONTROL AND ASSURANCE 
18.1.1 
Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in the approved protocol. All revisions to the 
protocol must be discussed with and be prepared by the Sponsor. The Investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favourable opinion from the IEC/IRB of an amendment, except where necessary to 
eliminate an immediate hazard(s) to the study patients. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IEC/IRB approval such deviation or change will be submitted for approval 
as soon as possible to:  
• 
Independent Ethics Committee/IRB for review and approval/favourable opinion 
• 
The Sponsor 
• 
Regulatory authority(ies) if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IEC(s)/IRB(s) must 
be sent to the Sponsor. 
If an amendment substantially alters the study design or increases the potential risk to the 
patient (1) the ICF must be revised and submitted to the IEC(s)/IRB(s) for review and 
approval/favourable opinion; (2) the revised form must be used to obtain consent from 
patients currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new patients prior to enrolment. 
If the revision is an administrative letter, investigators must inform their IEC(s)/IRB(s). 
18.1.2 
Protocol Violations and Deviations 
All patients who are enrolled into the study, irrespective of whether or not they receive any 
treatment, will be followed according to the protocol regardless of the number of treatments 
received, unless consent for follow-up is withdrawn. Minor protocol deviations that do not 
result in harm to the study patients or significantly affect the scientific value of the reported 
results of the study will be recorded. In case of a major protocol deviation occurring (i.e. a 
deviation that could have a significant effect on the patient’s safety, rights, or welfare and/or 
on the integrity of the study data), the Investigator must notify the Sponsor and the 
appropriate IEC/IRB as soon as possible or as per local requirements. Major protocol 
deviations that meet the criteria for a serious breach of GCP (e.g. a protocol violation, or 
non-reporting of critical safety information potentially jeopardising patients’ safety) should 
be reported within 24 hours to the Sponsor. The Sponsor is required to report a serious GCP 
breach within 7 days to the applicable Health Authorities. Protocol deviations will be 
recorded on the source documents with an explanation for the deviation. No deviation from 
the inclusion/exclusion criteria will be permitted.  
18.1.3 
Monitoring 
Before the trial can be initiated at a site, the prerequisites for conducting the trial must be 
clarified and approved by the Sponsor.  

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Representatives of the Sponsor (or designee) must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity according to FDA, EU directives 
and ICH GCP. On-site they will review study records and directly compare them with source 
documents, discuss the conduct of the study with the Investigator and verify that the facilities 
remain acceptable.  
Electronic Case Report Form completion and accuracy will be checked by performing source 
data verification that is a direct comparison of the entries made against the appropriate source 
documentation. Any resulting discrepancies will be reviewed with the Investigator(s) and/or 
his/her site staff and resolved. Monitoring procedures require that patients’ informed 
consents, adherence to the inclusion/exclusion criteria and SAE documentation be verified. 
Additional monitoring activities maybe outlined in the study specific monitoring plan. The 
Sponsor may request adequately redacted source documents and hospital records for review 
by medical monitor (e.g. pathology reports, lab or investigations reports, consultation notes, 
cancer treatment history), this may help to better understand patient’s general condition, 
emerging safety issues, effectiveness of their management and the efficacy. 
The Sponsor must be informed immediately of any change in the personnel involved in the 
conduct of the trial. 
18.1.4 
Audits and Site Inspections 
Authorised personnel from domestic and foreign regulatory authorities and the Sponsor’s 
Quality Assurance specialist (or designee) may carry out inspections and audits respectively. 
The purpose of an audit/inspection is to ensure that ethical, regulatory and quality 
requirements are fulfilled in the Sponsor studies. 
The Investigator will permit international, national and local health authorities, the Sponsor 
monitors, representatives, and collaborators, and the IECs/IRBs to inspect facilities and 
records relevant to this study. The Investigator should promptly notify the Sponsor or their 
authorised representative of any inspections scheduled by any regulatory authorities and 
promptly forward to the Sponsor or their authorised representative copies of any audit reports 
received. 
18.2 
DATA HANDLING AND RECORD KEEPING 
18.2.1 
Data Management 
Data will be entered in a timely manner, for each patient into the (Sponsor approved) clinical 
database via electronic data capture (EDC). The EDC application uses system controls to 
ensure that unauthorised users cannot access or modify data. All users must have successfully 
undergone EDC application training prior to entering data into the EDC system. Electronic 
Case Report Forms should be reviewed and electronically signed and dated by the 
Investigator or a designee. The eCRF system will be compliant with the FDA Code of 
Federal Regulations 21 Part 11 and EU Clinical Trial Directive (EC) No. 2001/20/EC. 
It is the responsibility of the Investigator to ensure that the data included in the eCRF is 
accurate, complete and electronically signed where appropriate.  
The data will be electronically verified through use of on-line checks during data entry and 
through programmed edit checks specified by the clinical team. Discrepancies in the data will 
be brought to the attention of the investigational site personnel. Data entered into the eCRF 
will be validated as defined in the data validation specifications. All updates to queried data 
will be made by authorised study site personnel only and all modifications to the database 

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will be recorded in an audit trail. Once all the queries have been resolved, eCRFs will be 
locked by password protection. Any changes to locked eCRFs will be approved by the 
Investigator. Once the full set of eCRFs have been completed and locked, the Sponsor will 
authorise database lock and all electronic data will be sent to the designated statistician for 
analysis. Subsequent changes to the database will then only be made by written agreement of 
the Sponsor. 
Adverse events and medical/cancer history terms will be coded from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities. Prior and 
concomitant medications and therapies will be coded according to the World Health 
Organisation Drug Dictionary. Coding review will be performed by the Sponsor (or designee) 
prior to database lock. 
At the end of the study, the clinical data will be transferred to the Sponsor and the 
investigative site will receive patient data for their site in a readable format that must be kept 
with the study records. 
18.2.2 
Study Documentation and Retention of Records 
The Investigator must maintain records of all study documents and supporting information 
relating to the conduct of the study. This documentation should include but is not limited to, 
protocols, eCRF data, SAE reports, patient source data, correspondence with health 
authorities and IEC/IRBs, ICFs, Investigator(s) and study team members’ curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae (Essential documentation listed in ICH 
GCP [CPMP/ICH/135/95]). Patient files and other source data must be kept for the maximum 
period of time required by applicable regulations and guidelines or institution procedures or 
for the period specified by the Sponsor, whichever is longer. The Sponsor must be consulted 
if the Investigator(s) wishes to assign the study files to someone else, remove them to another 
location or is unable to retain them for the specified period. 
The patient medical records must contain the product name/code, the trial reference code, 
trial subject code and administration dates and dose in order to ensure that a link can be made 
back to the identity of the product and the further traceability records of the Investigator and 
Sponsor. 
18.3 
CLINICAL TRIAL AGREEMENT, FINANCE AND INSURANCE 
This study will be conducted under a Clinical Trial Agreement between Autolus (“Sponsor”) 
and the institution(s) representing the investigational study site(s) (“Investigator”). Financial 
support to the investigational site(s) will be detailed in the Clinical Trial Agreement. The 
Clinical Trial Agreement must be signed before the commencement of the study and will 
clearly delineate the responsibilities and obligations of the Investigator and the Sponsor, and 
will form the contractual basis under which the clinical study will be conducted.  
A Certificate of Clinical Trials Insurance will be provided to the study centres by the 
Sponsor, where required. Details of the Sponsor’ s arrangement for clinical study insurance to 
provide for compensation to patients for any claim for bodily injury or death arising from 
participation in the clinical study are provided in the Patient Information Sheet.  

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19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Both the EU Data Protection Regulations and the FDA Amendments Act mandates the 
registration with ClinicalTrials.gov of certain clinical trials of drugs (including biological 
products) and medical devices subject to the European Medicines Agency and FDA 
regulations for any disease or condition. The International Committee of Medical Journal 
Editors requires study registration as a condition for publication of research results generated 
by a clinical study (http://www.icmje.org). 
All information supplied by the Sponsor in connection with this study and not previously 
published to the public, is considered confidential information (“Confidential Information”). 
This confidential information includes, but is not limited to, the Investigators’ Brochure, 
Clinical Study Protocol, eCRFs and other scientific data. Any data collected during the study 
are also considered confidential information. This confidential information shall remain the 
sole and exclusive property of the Sponsor, shall not be disclosed to others without prior 
written consent of the Sponsor, and shall not be used except in the performance of this study.  
The information developed during the conduct of this study is also considered confidential 
information, and will be used by the Sponsor in connection with the development of AUTO3. 
The confidential information may be disclosed as deemed necessary by the Sponsor. To allow 
the use of the confidential information derived from this study, the Investigator is obliged to 
provide the Sponsor with complete test results and all data developed in this study. 
The Sponsor has full ownership of the original eCRFs completed as part of the study. 
By signing the Clinical Study Protocol, the Investigator agrees that the results of the study 
may be used for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals. The authorities will be notified of 
the Investigator’s name, address, qualifications, and extent of involvement.  
It is agreed that, consistent with scientific standards, publication of the results of the study 
shall be made only as part of a publication of the results obtained by all sites performing the 
protocol.  
Should the Investigator wish to publish the results of this study, the Investigator agrees to 
provide the Sponsor with a manuscript for review 60 days prior to submission for publication. 
The Sponsor retains the right to delete from the manuscript, information that is confidential 
or proprietary and to object the suggested publication and/or its timing (at the Sponsor’s 
discretion). 
In addition, if requested by the Sponsor, the Investigator shall withhold publication for an 
additional 6 months to allow for filing a patent application or taking other such measures as 
the Sponsor deems appropriate to establish and preserve its proprietary rights.  
In the event that the Sponsor chooses to publish the data from this study, a copy will be 
provided to the Investigator at least 30 days prior to the expected date of submission to the 
intended publisher. 

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20 
REFERENCES 
Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. (2016) T cells expressing an 
anti-B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple 
myeloma. Blood 128(13):1688-1700. 
American Cancer Society CFF (2018). Atlanta: American Cancer Society; 2018. Retrieved 
14 January 2019, from https://www.cancer.org/research/cancer-facts-statistics/all-cancer-
facts-figures/cancer-facts-figures-2018.html. 
Bajwa R, Schechter T, Soni S, Gassas A, Doyle J, Sisler I, et al. (2013) Outcome of children 
who experience disease relapse following allogeneic hematopoietic SCT for hematologic 
malignancies. Bone Marrow Transplant 48(5):661-5. 
Balduzzi A, Di Maio L, Silvestri D, Songia S, Bonanomi S, Rovelli A, et al. (2014) Minimal 
residual disease before and after transplantation for childhood acute lymphoblastic 
leukaemia: is there any room for intervention? Br J Haematol 164(3):396-408. 
Benjamin R, Grham C, Yallop D, Jozwik A, Ciocarlie O, Jain N, et al. Preliminary Data on 
Safety, Cellular Kinetics and Anti-Leukemic Activity of UCART19, an Allogeneic Anti-
CD19 CAR T-Cell Product, in a Pool of Adult and Pediatric Patients with High-Risk CD19+ 
Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia. ASH 2018. Abstract #896 
Borgmann A, von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, et al. (2003) 
Unrelated donor stem cell transplantation compared with chemotherapy for children with 
acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 
101(10):3835-9. 
Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. (2011) Safety and 
persistence of adoptively transferred autologous CD19-targeted T cells in patients with 
relapsed or chemotherapy refractory B-cell leukemias. Blood 118(18):4817-4828. 
Brudno JN, Kochenderfer JN. (2016) Toxicities of chimeric antigen receptor T cells: 
recognition and management. Blood 127(26):3321-30. 
Calabrese LH, Rose-John S. (2014) IL-6 biology: implications for clinical targeting in 
rheumatic disease. Nat Rev Rheumatol 10(12):720-7. 
Chessells JM, Veys P, Kempski H, Henley P, Leiper A, Webb D, et al. (2003) Long-term 
follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 123(3):396-
405. 
Chu CS, Boyer J, Schullery DS, Gimotty PA, Gamerman V, Bender J, et al. (2012) Phase I/II 
randomized trial of dendritic cell vaccination with or without cyclophosphamide for 
consolidation therapy of advanced ovarian cancer in first or second remission. Cancer 
Immunol Immunother 61(5):629-641. 
Conter V, Arico M, Basso G, Biondi A, Barisone E, Messina C, et al. (2010) Long-term 
results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 
87, 88, 91 and 95 for childhood acute lymphoblastic leukemia. Leukemia 24(2):255-64. 

AUTOLUS LTD 
 
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CONFIDENTIAL 
 
PAGE 140 OF 155 
Coustan-Smith E, Gajjar A, Hijiya N, Razzouk BI, Ribeiro RC, Rivera GK, et al. (2004) 
Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia 
after first relapse. Leukemia 18(3):499-504. 
Curti BD, Ochoa AC, Powers GC, Kopp WC, Alvord WG, Janik JE, et al. (1998) Phase I trial 
of anti-CD3-stimulated CD4+ T cells, infusional interleukin-2, and cyclophosphamide in 
patients with advanced cancer. J Clin Oncol 16(8):2752-2760. 
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. (2014) Efficacy and 
toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. 
Sci Transl Med 6(224):224ra25. 
Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. (2008) Adoptive 
cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative 
chemoradiation preparative regimens. J Clin Oncol 26(32):5233-5239. 
Eapen M, Raetz E, Zhang MJ, Muehlenbein C, Devidas M, Abshire T, et al. (2006) 
Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-
precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the 
Children's Oncology Group and the Center for International Blood and Marrow Transplant 
Research. Blood 107(12):4961-7. 
Eckert C, Hagedorn N, Sramkova L, Mann G, Panzer-Grumayer R, Peters C, et al. (2015) 
Monitoring minimal residual disease in children with high-risk relapses of acute 
lymphoblastic leukemia: prognostic relevance of early and late assessment. Leukemia 
29(8):1648-55. 
FDA 
(2018a). 
Kymriah 
package 
insert. 
from 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/App
rovedProducts/UCM573941.pdf (accessed from www.fda.gov 26th January 2018). 
FDA 
(2018b). 
Actemra 
(Tocilizumab) 
package 
insert. 
from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125276s092lbl.pdf 
(accessed 
from www.fda.gov 26th January 2018). 
Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. (2007) 
Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC 
UKALL12/ECOG 2993 study. Blood 109(3):944. 
Frey NV, Porter DL. (2016) CAR T-cells merge into the fast lane of cancer care. Am J 
Hematol 91(1):146-50. 
Frey NV, Shaw PA, Hexner EO, Gill S, Marcucci K, Luger SM, et al. (2016) Optimizing 
chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory 
(r/r) acute lymphoblastic leukemia (ALL). J Clin Oncol 34(15_suppl):7002-7002. 
Fry EE. CD22 CAR Update and Novel Mechanisms of Leukemic Resistance. Clin Cancer 
Res.  

AUTOLUS LTD 
 
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PAGE 141 OF 155 
Gardner R, Annesley C, Finney O, Summers C, Lamble A, Rivers J, et al. Early Clinical 
Experience of CD19 x CD22 Dual Specific CAR T Cells for Enhanced Anti Leukemic 
Targeting of Acute Lymphoblastic Leukemia. ASH 2018. Abstract #278 
Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. (2017) Intent-to-
treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children 
and young adults. Blood 129(25):3322-3331. 
Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, et al. (2015) 
Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med 
373(11):1040-7. 
Gargett T, Fraser CK, Dotti G, Yvon ES, Brown MP. (2015) BRAF and MEK inhibition 
variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro. J 
Immunother 38(1):12-23. 
Gaynon PS, Harris RE, Altman AJ, Bostrom BC, Breneman JC, Hawks R, et al. (2006) Bone 
marrow transplantation versus prolonged intensive chemotherapy for children with acute 
lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the 
completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 
24(19):3150-6. 
Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA, et al. (2011) A phase II 
study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and 
breast cancer. Cytotherapy 13(1):98-107. 
Geyer MB, Brentjens RJ. (2016) Review: Current clinical applications of chimeric antigen 
receptor (CAR) modified T cells. Cytotherapy. 
Ghorashian S, Kramer AM, Albon SJ, Wright G, Castro F, Popova B, et al. (2017) A Novel 
Low affinity CD19CAR results in durable disease remissions and prolonged CAR T cell 
persistence without severe CRS or neurotoxicity in patients with paediatric ALL. Am Soc 
Hematol Oral Abstract: 806. 
Ghorashian S, Pule M, Amrolia P. (2015) CD19 chimeric antigen receptor T cell therapy for 
haematological malignancies. Br J Haematol 169(4):463-78. 
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. (2013) Chimeric 
antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509-
18. 
Grupp SA, Laetsch TW, Buechner J, Bittencourt H, Maude SL, Verneris MR, et al. (2016) 
Analysis of a Global Registration Trial of the Efficacy and Safety of CTL019 in Pediatric and 
Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL). Blood 
128(22):221. 
Grupp SA, Maude SL, Shaw P, Aplenc R, Barrett DM, Callahan C, et al. T Cells Engineered 
with a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Have Long Term 
Persistence and Induce Durable Remissions in Children with Relapsed, Refractory ALL | 
Blood Journal. ASH. 380 

AUTOLUS LTD 
 
AUTO3-PA1 
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Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 142 OF 155 
Hallek M. (2013) Chronic lymphocytic leukemia: 2013 update on diagnosis, risk 
stratification and treatment. Am J Hematol 88(9):803-816. 
Helton KJ, Patay Z, Triplett BM. (2013) Fludarabine-induced severe necrotizing 
leukoencephalopathy in pediatric hematopoietic cell transplantation. Bone Marrow 
Transplant 48(5):729-731. 
Henze G, Fengler R, Hartmann R, Kornhuber B, Janka-Schaub G, Niethammer D, et al. 
(1991) Six-year experience with a comprehensive approach to the treatment of recurrent 
childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM 
group. Blood 78(5):1166-72. 
Huang L, Wang N, Cao Y, Li C, Xia Y, Xiao M, et al. CAR22/19 Cocktail Therapy for 
Patients with Refractory/Relapsed B-Cell Malignancies. ASH 2018. Abstract #1408 
Irving JA, Enshaei A, Parker CA, Sutton R, Kuiper RP, Erhorn A, et al. (2016) Integration of 
genetic and clinical risk factors improves prognostication in relapsed childhood B-cell 
precursor acute lymphoblastic leukemia. Blood 128(7):911-22. 
Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. (2017) 
Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl 
J Med 376(9):836-847. 
Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. (2016) 
Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N 
Engl J Med 375(8):740-53. 
Kenderian SS, Porter DL, Gill S. Chimeric Antigen Receptor T Cells and Hematopoietic Cell 
Transplantation: How Not to Put the CART before the Horse. Biology of Blood and Marrow 
Transplantation. 
Khaled S, Blanchard S, Wang X, Wagner J, Naranjo A, Simpson J, et al. Adult Patients with 
ALL Treated with CD62L+ T Naïve/Memory-Enriched T Cells Expressing a CD19-CAR 
Mediate Potent Antitumor Activity with a Low Toxicity Profile. ASH 2018. Abstract #4016 
Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. (2005) Sinks, suppressors 
and antigen presenters: how lymphodepletion enhances T cell-mediated tumor 
immunotherapy. Trends Immunol 26(2):111-117. 
Klinger M, Benjamin J, Kischel R, Stienen S, Zugmaier G. (2016) Harnessing T cells to fight 
cancer with BiTE® antibody constructs – past developments and future directions. 
Immunological Reviews 270(1):193-208. 
Kochenderfer J, Somerville R, Lu T, Shi V, Yang JC, Sherry R, et al. (2016) Anti-CD19 
chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions 
of advanced lymphoma. J Clin Oncol 34(suppl; abstr LBA3010). 

AUTOLUS LTD 
 
AUTO3-PA1 
Version 8.0, 10 May 2019 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 143 OF 155 
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson 
M, et al. (2015) 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 33(6):540-9. 
Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. (2010) Adoptive transfer of 
syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 
can eradicate lymphoma and normal B cells. Blood 116(19):3875-3886. 
Laurent J, Speiser DE, Appay V, Touvrey C, Vicari M, Papaioannou A, et al. (2010) Impact 
of 3 different short-term chemotherapy regimens on lymphocyte-depletion and reconstitution 
in melanoma patients. J Immunother 33(7):723-734. 
Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, et al. (2000) The UK 
experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the 
medical research council UKALLR1 study. Br J Haematol 108(3):531-43. 
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. (2014) Current 
concepts in the diagnosis and management of cytokine release syndrome. Blood 124(2):188-
195. 
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. 
(2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic 
leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 
385(9967):517-28. 
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. (2018) 
ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity 
Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 
Lee DW, Stetler-Stevenson M, Yuan CM, Shah NN, Delbrook C, Yates B, et al. Long-Term 
Outcomes Following CD19 CAR T Cell Therapy for B-ALL Are Superior in Patients 
Receiving 
a 
Fludarabine/Cyclophosphamide 
Preparative 
Regimen 
and 
Post-CAR 
Hematopoietic Stem Cell Transplantation. ASH.  
Lee L, Bounds D, Paterson J, Herledan G, Sully K, Seestaller-Wehr LM, et al. (2016b) 
Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated 
cytotoxicity in multiple myeloma. Br J Haematol n/a-n/a. 
Liu D, Zhao J. (2018) Cytokine release syndrome: grading, modeling, and new therapy. J 
Hematol Oncol 11(1):121. 
Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. (2011) Antitumor activity 
and long-term fate of chimeric antigen receptor-positive T cells in patients with 
neuroblastoma. Blood 118(23):6050-6056. 
Ma F, Ho J, Du H, Xuan F, Wu X, Liu Y. Evidence of Long-Lasting Anti-CD19 Activity of 
Engrafted CD19 Chimeric Antigen Receptor Modified T Cells in a Phase I Study Targeting 
Pediatrics with Acute Lymphoblastic Leukemia. . ASH 2018. Abstract #2701 

AUTOLUS LTD 
 
AUTO3-PA1 
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Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 144 OF 155 
Maude SL, Barrett D, Teachey DT, Grupp SA. (2014a) Managing cytokine release syndrome 
associated with novel T cell-engaging therapies. Cancer J 20(2):119-122. 
Maude SL, Barrett DM, Rheingold SR, Aplenc R, Teachey DT, Callahan C, et al. (2016a) 
Efficacy of Humanized CD19-Targeted Chimeric Antigen Receptor (CAR)-Modified T Cells 
in Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia. 
Blood 128(22):217-217. 
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. (2014b) Chimeric 
antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507-
17. 
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. (2018) 
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N 
Engl J Med 378(5):439-448. 
Maude SL, Pulsipher MA, Boyer MW, Grupp SA, Davies SM, Phillips CL, et al. (2016b) 
Efficacy and Safety of CTL019 in the First US Phase II Multicenter Trial in Pediatric 
Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis. Blood 
128(22):2801. 
Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. (2009) 
Chimeric receptors containing CD137 signal transduction domains mediate enhanced 
survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17(8):1453-1464. 
Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. (2010) Long-
term results of five consecutive trials in childhood acute lymphoblastic leukemia performed 
by the ALL-BFM study group from 1981 to 2000. Leukemia 24(2):265-84. 
Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, et al. (2006) 
Increased intensity lymphodepletion and adoptive immunotherapy--how far can we go? Nat 
Clin Pract Oncol 3(12):668-681. 
NCT02028455 (2016). A Pediatric and Young Adult Trial of Genetically Modified T Cells 
Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia - Full Text View - 
ClinicalTrials.gov. 
Retrieved 
11 
April 
2017, 
from 
https://clinicaltrials.gov/ct2/show/NCT02028455. 
NCT02443831 (2016). CARPALL: Immunotherapy With CD19 CAR T-cells for CD19+ 
Haematological 
Malignancies. 
Retrieved 
14 
February 
2017, 
from 
https://clinicaltrials.gov/ct2/show/NCT02443831?term=NCT02443831&rank=1. 
NCT02535364 (2016). Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell 
Acute Lymphoblastic Leukemia (B-ALL) - Full Text View - ClinicalTrials.gov. Retrieved 11 
April 2017, from https://clinicaltrials.gov/ct2/show/NCT02535364. 

AUTOLUS LTD 
 
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Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 145 OF 155 
Neelapu SS, Locke FL, Bartlett NL, Siddiqi T, Chavez JC, Hosing C, et al. (2016) Ongoing 
complete remissions (CR) in the phase 1 of ZUMA-1: a phase 1-2 multicenter study 
evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in subjects with 
refractory aggressive B-cell Non-Hodgkin Lymphoma (NHL). J Clin Oncol 34(suppl; abstr 
7559). 
Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, et al. (2008) Factors 
influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology 
Group study. Leukemia 22(12):2142-50. 
Norelli M, Casucci M, Bonini C, Bondanza A. (2016) Clinical pharmacology of CAR-T 
cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects. 
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1865(1):90-100. 
O'Connor D, Moorman AV, Wade R, Hancock J, Tan RMR, Bartram J, et al. (2017) Use of 
Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute 
Lymphoblastic Leukemia. J Clin Oncol JCO2016696278. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. (1982) 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-55. 
Pan J, Deng B, Liu S, Wang J, Wu T, Gao Z, et al. (2018) Efficacy and Safety of Cd22 
Directed Car-T Cell Therapy in 15 Pediatric Refractory or Relapsed B Acute Lymphoblastic 
Leukemia Patients. EHA Abstract #S832. 
Park JH, Geyer MB, Brentjens RJ. (2016) CD19-targeted CAR T-cell therapeutics for 
hematologic malignancies: interpreting clinical outcomes to date. Blood 127(26):3312-20. 
Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. (2010) Effect of 
mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia 
(ALL R3): an open-label randomised trial. The Lancet 376(9757):2009-2017. 
Poon VI, Roth M, Piperdi S, Geller D, Gill J, Rudzinski ER, et al. (2015) Ganglioside GD2 
expression is maintained upon recurrence in patients with osteosarcoma. Clin Sarcoma Res 5( 
Porter DL, Levine BL, Kalos M, Bagg A, June CH. (2011) Chimeric antigen receptor-
modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725-733. 
Pui CH, Pei D, Campana D, Cheng C, Sandlund JT, Bowman WP, et al. (2014) A revised 
definition for cure of childhood acute lymphoblastic leukemia. Leukemia 28(12):2336-43. 
Pui CH, Robison LL, Look AT. (2008) Acute lymphoblastic leukaemia. Lancet 
371(9617):1030-43. 
Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, et al. (2008a) 
Reinduction platform for children with first marrow relapse of acute lymphoblastic 
Leukemia: A Children's Oncology Group Study[corrected]. J Clin Oncol 26(24):3971-8. 

AUTOLUS LTD 
 
AUTO3-PA1 
Version 8.0, 10 May 2019 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 146 OF 155 
Raetz EA, Cairo MS, Borowitz MJ, Blaney SM, Krailo MD, Leil TA, et al. (2008b) 
Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic 
leukemia in marrow relapse: a Children's Oncology Group Pilot Study. J Clin Oncol 
26(22):3756-62. 
Rossi JM, Neelapu SS, Go WY, Shen Y-w, Sherman M, Locke FL, et al. (2015) Phase 1 
Biomarker Analysis of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study 
Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with 
Refractory Aggressive Non-Hodgkin Lymphoma (NHL). Blood 126(23):2730-2730. 
Roy A, Cargill A, Love S, Moorman AV, Stoneham S, Lim A, et al. (2005) Outcome after 
first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom 
R2 trial. Br J Haematol 130(1):67-75. 
Ruella M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, et al. (2016) 
Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric 
antigen receptor T cells for B-cell neoplasms. Leukemia. 
Saarinen-Pihkala UM, Heilmann C, Winiarski J, Glomstein A, Abrahamsson J, Arvidson J, et 
al. (2006) Pathways through relapses and deaths of children with acute lymphoblastic 
leukemia: role of allogeneic stem-cell transplantation in Nordic data. J Clin Oncol 
24(36):5750-62. 
Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. (2011) CD28 
costimulation improves expansion and persistence of chimeric antigen receptor-modified T 
cells in lymphoma patients. J Clin Invest 121(5):1822-6. 
Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. (2012) Outcomes 
after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 
366(15):1371-81. 
Schulz L, Davis K, Baggott C, Chaudry C, Marcy A, Mavrukakis S, et al. Phase 1 Study of 
CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young 
Adults with B Cell Acute Lymphoblastic Leukemia (ALL). ASH 2018. Abstract #898 
Sellar RS, Rowntree C, Vora AJ, Furness CL, Goulden N, Mitchell C, et al. (2015) Relapse 
in Teenage and Young Adult (TYA) Patients Treated on a Pediatric Minimal Residual 
Disease (MRD) Stratified Protocol Is Associated with a Poor Outcome: Results from 
UKALL2003. Blood 126(23):2493. 
Shah N, Shalabi H, Yates B, Kane E, Dulau-Florea A, Cullinane A, et al. 1277 Beyond 
Cytokine Storm: Optimizing Treatment Strategies to Target the Complex Interplay between 
CAR Mediated Inflammatory Response, Disseminated Intravascular Coagulation and 
Macrophage Activation Syndrome In: American Society of Hematology 59th Annual 
Meeting and Exposition. Atlanta GA: 2017. 
Shah NN, Stetler-Stevenson M, Yuan CM, Shalabi H, Yates B, Delbrook C, et al. (2016) 
Minimal Residual Disease Negative Complete Remissions Following Anti-CD22 Chimeric 
Antigen Receptor (CAR) in Children and Young Adults with Relapsed/Refractory Acute 
Lymphoblastic Leukemia (ALL). Blood 128(22):650-650. 

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Clinical Study Protocol 
 
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PAGE 147 OF 155 
Shah NN, Stevenson MS, Yuan CM, Richards K, Delbrook C, Kreitman RJ, et al. (2015) 
Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer 
62(6):964-9. 
Simon R. (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
10(1):1-10. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. (2008) Shortening the timeline 
of pediatric phase I trials: the rolling six design. J Clin Oncol 26(2):190-5. 
Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. (2015) Convergence 
of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 
Immunotherapy. Cancer Discov 5(12):1282-95. 
Spear P, Barber A, Sentman CL. (2013) Collaboration of chimeric antigen receptor (CAR)-
expressing T cells and host T cells for optimal elimination of established ovarian tumors. 
OncoImmunology 2(4):e23564. 
Sporn JR, Ergin MT, Robbins GR, Cable RG, Silver H, Mukherji B. (1993) Adoptive 
immunotherapy with peripheral blood lymphocytes cocultured in vitro with autologous tumor 
cells and interleukin-2. Cancer Immunol Immunother 37(3):175-180. 
Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. (2010) Long-term 
outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-
relapse stratification and intensified short-course multidrug chemotherapy: results of trial 
ALL-REZ BFM 90. J Clin Oncol 28(14):2339-47. 
Teachey DT, Bishop MR, Maloney DG, Grupp SA. (2018) Toxicity management after 
chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol 
15(4):218. 
Terwilliger T, Abdul-Hay M. (2017) Acute lymphoblastic leukemia: a comprehensive review 
and 2017 update. Blood Cancer J 7(6):e577. 
Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. (2015) Safety 
and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute 
lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 16(1):57-
66. 
Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. (2014) Phase 
II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and 
molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic 
leukemia. J Clin Oncol 32(36):4134-40. 
Traube C, Silver G, Kearney J, Patel A, Atkinson TM, Yoon MJ, et al. (2014) Cornell 
Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in 
the PICU*. Crit Care Med 42(3):656-63. 

AUTOLUS LTD 
 
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Clinical Study Protocol 
 
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PAGE 148 OF 155 
Tu S, Huang R, Deng L, Zhou X, He Y, Zhou W, et al. Therapy of 4s Chimeric Antigen 
Receptor T Cells Achieves Long-Term Disease-Free Survival with No Severe CRS or Cres in 
Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia. ASH 2018. Abstract 
#2696 
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. (2016) CD19 
CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 
126(6):2123-38. 
Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. (2013) Treatment 
reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined 
by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 
14(3):199-209. 
Wierda WG, Bishop MR, Oluwole OO, Logan AC, Baer MR, Donnellan WB, et al. (2018) 
Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T 
Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. 
Blood 132(Suppl 1):897-897. 
Wrzesinski C, Restifo NP. (2005) Less is more: lymphodepletion followed by hematopoietic 
stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin 
Immunol 17(2):195-201. 
Xu Y, Zhang M, Ramos CA, Durett A, Liu E, Dakhova O, et al. (2014) Closely related T-
memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved 
by IL-7 and IL-15. Blood 123(24):3750-3759. 
Yang J, Li J, Zhang X, LV F, Guo X, Wang Q, et al. A Feasibility and Safety Study of CD19 
and CD22 Chimeric Antigen Receptors-Modified T Cell Cocktail for Therapy of B Cell 
Acute Lymphoblastic Leukemia. ASH 2018. Abstract #277 
Zhang X, Lu X, Yang J, Fanyong L, Xiong M, Zhang J, et al. (2018) Efficacy and Safety of 
CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Cell Acute Lymphocytic 
Leukemia (B-cell ALL) in a Large Cohort Including Patients with Extramedullary Disease 
(EMD), High Leukemia Burden, BCR-ABL (+) Mutation, TP53 Mutation, and Post 
Transplant Relapse. Blood 132(1):280. 
 

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21 
APPENDICES 
Appendix 1:  Response Criteria for Acute Lymphoblastic Leukaemia (National 
Comprehensive Cancer Network Guidelines) 
Patients with acute lymphoblastic leukaemic (ALL) will be evaluated using Response Criteria 
for Acute Lymphoblastic Leukaemia (National Comprehensive Cancer Network Guidelines, 
version 2.2014) for documenting disease response as shown below. 
Response Criteria for Blood and Bone Marrow 
Complete response  
(CR)  
• 
No circulating blasts or extramedullary disease  
• 
No lymphadenopathy, splenomegaly, skin/gum infiltration, 
testicular mass, or central nervous system (CNS) 
involvement  
• 
Trilineage haematopoiesis and <5% blasts  
• 
Absolute neutrophil count >1000/μL  
• 
Platelet count >100,000/μL 
• 
No recurrence for 4 weeks  
CR with incomplete recovery of 
counts (CRi) 
• 
Recovery of platelets to <100,000/μL  
• 
Recovery of absolute neutrophil count to <1000/μL  
Overall response rate 
Sum of CR and CR with incomplete recovery of counts. 
Refractory ALL  
Failure to achieve CR at the end of induction therapy. 
Progressive ALL  
Increase ≥25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease. 
Relapsed ALL  
Reappearance of blasts in the blood or bone marrow (>5%) or 
any extramedullary site after CR. 
Response Criteria for CNS Disease  
CNS remission  
Achievement of no lymphoblast in cerebrospinal fluid (CSF) 
(cytospin or flow) regardless of white blood cell (WBC) count in 
patients with WBC count <5/mcL or ≥5/mcL and presence of 
lymphoblasts in CSF at diagnosis. 
CNS relapse  
New development of WBC count ≥5/mcL and presence of 
lymphoblasts in CSF or clinical signs of CNS leukaemia such as 
facial nerve palsy, brain/eye involvement, or hypothalamic 
syndrome. 
Response Criteria for Mediastinal Disease  
CR 
Complete resolution of mediastinal enlargement by CT. 
CR unconfirmed 
Residual mediastinal enlargement that has regressed by >75% in 
sum of the products of the greatest perpendicular diameters. 
Partial response 
>50% decrease in the sum of the products of the greatest 
perpendicular diameters. 
Progressive disease 
>25% increase in the sum of the products of the greatest 
perpendicular diameters. 
No response 
Failure to qualify for partial response or progressive disease.  
Relapse  
Recurrence of mediastinal enlargement after achieving CR or CR 
unconfirmed. 
ALL = acute lymphoblastic leukaemia; CNS = central nervous system; CR = complete response; CSF = cerebrospinal fluid; 
WBC = white blood cell. 

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Appendix 2:  Karnofsky Score 
For assessment of eligibility in patients ≥10 years 
100% 
Normal, no complaints, no signs of disease 
90% 
Capable of normal activity, few symptoms, or signs of disease 
80% 
Normal activity with some difficulty, some symptoms, or signs 
70% 
Caring for self, not capable of normal activity or work 
60% 
Requiring some help, can take care of most personal requirements 
50% 
Requires help often, requires frequent medical care 
40% 
Disabled, requires special care and help 
30% 
Severely disabled, hospital admission indicated but no risk of death 
20% 
Very ill, urgently requiring admission, requires supportive measures or treatment 
10% 
Moribund, rapidly progressive fatal disease processes 
0% 
Death 
 

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Appendix 3: Lansky Score 
For assessment of eligibility in patients <10 years 
100% 
Fully active, normal 
90% 
Minor restrictions in strenuous physical activity  
80% 
Restricted in strenuous play, tires more easily, otherwise active 
70% 
Greater restriction of play and less time spent in play activity  
60% 
Up and around, but active play minimal; keeps busy by being involved in quieter activities  
50% 
Lying around much of the day, but gets dressed; no active playing participates in all quiet play 
and activities  
40% 
Mainly in bed; participates in quiet activities  
30% 
Bedbound; needing assistance even for quiet play  
20% 
Sleeping often; play entirely limited to very passive activities  
10% 
Doesn't play; does not get out of bed  
0% 
Unresponsive  
 
 
 

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Appendix 4: Eastern Cooperative Oncology Group Performance Status Score 
Grade  
Eastern Cooperative Oncology Group Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken et al. 1982). 
 
  
 

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Appendix 5:  Highly Effective Methods of Birth Control 
For females of childbearing potential (defined as <2 years after last menstruation or not 
surgically sterile), a negative serum or urine pregnancy test must be documented at screening, 
prior to pre-conditioning and confirmed before receiving the first dose of study treatment.  
For females who are not post-menopausal (24 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus), highly effective methods of contraception must be used 
during the treatment period and for at least 12 months after the last dose of study treatment. 
They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction 
during the study and for 12 months after receiving the last dose of study drug. 
For males, it must be agreed that a barrier method of contraception should be used and that 
sperm will not be donated during the treatment period and for at least 12 months after the last 
dose of study treatment.  
Birth Control Methods Considered Highly Effective: 
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods. Such methods include: 
1. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are NOT acceptable methods of contraception. 
2. Female sterilisation (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment. 
3. Male sterilisation (at least 6 months prior to screening). For female patients on the 
study the vasectomised male partner should be the sole partner for that patient. 
4. BOTH of the following forms of contraception must be utilised: 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
5. Use of intrauterine devices are excluded due to increased risks of infection and 
bleeding in this population. 
6. In case of use of oral contraception, females must be stable on the same pill for a 
minimum of 3 months before taking study treatment. 

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Birth Control Methods Which May NOT Be Considered as Highly Effective  
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include:  
- 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action.  
- 
Male or female condom with or without spermicide. 2 
- 
Cap, diaphragm, or sponge with spermicide. 2 
Birth Control Methods Which are Considered UNACCEPTABLE in Clinical Trials  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. A female condom and male condom should not be used together. 
Paediatric Patients Acceptable Methods Include 
Females who are not of reproductive potential (defined as either <11 years of age, Tanner 
Stage 1, post-menopausal for at least 24 consecutive months or have undergone 
hysterectomy, salpingotomy, and/or bilateral oophorectomy) are eligible without requiring 
the use of contraception. Acceptable documentation includes written or oral documentation 
communicated by the clinician or clinician's staff of 1 of the following: 
a. Demographics show age <11. 
b. Physical examination indicates Tanner Stage 1. 
c. Physician report/letter. 
d. Operative report or other source documentation in the patient record. 
e. Discharge summary. 
f. Follicle stimulating hormone measurement elevated into the menopausal range. 
 
2 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also considered 
acceptable, but NOT highly effective, birth control methods. 

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Appendix 6:  International Study for Treatment of Childhood Relapsed Acute 
Lymphoblastic Leukaemia Definition of Risk Groups in Relapsed 
Paediatric Acute Lymphoblastic Leukaemia 
The time-point of relapse is defined in relation to the date of primary diagnosis and the date 
of the end of frontline therapy. Completion of primary therapy is defined as the end of 
anti-leukaemic therapy according to the frontline protocol. In most cases, it is the end of 
maintenance therapy, but may also be the last treatment after interruption of the intensive 
treatment or of an inadequately short primary therapy. Since the duration of maintenance 
therapy varies between different protocols and individual patients (in most patients and 
protocols duration of treatment is 24 months), completion of primary therapy is a flexible 
time-point in contrast to time-point definitions referring to the date of primary diagnosis. 
In the rare case of inadequately short frontline therapy (e.g. according to B cell Non-Hodgkin 
lymphoma/acute lymphoblastic leukaemia [ALL] protocols) the interval after completion of 
primary therapy is the decisive one for time-point classification. The site of relapse is 
classified based on conventional light microscopy using the French-American-British criteria. 
In morphologically undetermined situations such as bone marrow (BM) involvement of 
around 5% in extramedullary relapse, minimal residual disease quantification may be 
regarded as secondary criterion to determine the extent of BM involvement.   
Definition of Time-Point of Relapse 
Time-point 
After primary diagnosis 
After completion of primary therapy 
Very early 
<18 months 
and 
<6 months 
Early 
≥18 months 
and 
<6 months 
Late 
 
 
≥6 months 
Definition of Site of Relapse 
Bone marrow 
M1 (<5% blasts) 
M2 
(≥5% 
and 
<25% blasts) 
M3 (≥25% blasts) 
Extramedullary 
relapse 
No 
No ALL relapse 
Requires follow-up 
control 
Isolated BM relapse 
Yes 
Isolated extramedullary 
relapse 
Combined BM/extramedullary relapse 
ALL = acute lymphoblastic leukaemia; BM = bone marrow. 
Definition of International Study for Treatment of Childhood Relapsed ALL Standard 
Risk (SR)/High Risk (HR) 2010 Risk Groups 
 
Immunophenotype: B cell precursor 
Site 
Time-point  
Extramedullary isolated 
BM combined 
BM isolated 
Very early 
HR 
HR 
HR 
Early 
SR 
SR 
HR 
Late 
SR 
SR 
SR 
BM = bone marrow; HR = high risk; SR = standard risk.