A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO2, a CAR T Cell Treatment Targeting BCMA and TACI, in Patients With Relapsed or Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Autolus Limited

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Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 1 OF 120 
 
CLINICAL STUDY PROTOCOL 
A SINGLE-ARM, OPEN-LABEL, MULTI-CENTRE, PHASE I/II STUDY 
EVALUATING THE SAFETY AND CLINICAL ACTIVITY OF AUTO2, A CAR 
T CELL TREATMENT TARGETING BCMA AND TACI, IN PATIENTS WITH 
RELAPSED OR REFRACTORY MULTIPLE MYELOMA 
Study Number: 
AUTO2-MM1 
Study Product: 
AUTO2 for IV infusion 
Development Phase: 
I/II 
Sponsor: 
Autolus Ltd 
 
 
 
 
 
Protocol Version: 
Version 7.0  
EudraCT Number: 
2016-003893-42 
 
 
Protocol Date: 
27 June 2018 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International 
Conference 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 Ltd). This information must not be made public without written 
permission from Autolus Ltd. 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 Ltd 
 
 
 
 
 
Tel: 
 
 
Contact List 
The List of Service Providers for the study will be maintained separately by Autolus Ltd and 
kept in the Trial Master File/Sponsor Oversight File. 
 
Primary Medical Monitor: 
 
 
  
Telephone: 
 
Mobile: 
 
Email: 
 
 
Secondary Medical Monitor:  
 
  
Telephone: 
 
Mobile: 
 
Email: 
 
 
 
Sponsor’s Clinical Project Manager: 
 
  
Telephone: 
 
Email: 
 
 
Notification of SAEs:  
 
SAE Fax number: 
 
 
 
 
 
 
Email: 
 
24 Hour Safety Hotline: 
 
 
Address: 
 
Telephone: 
 
 
 

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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 AUTO2, a CAR T Cell Treatment Targeting BCMA and 
TACI, in Patients with Relapsed or Refractory Multiple Myeloma 
Protocol Number: 
AUTO2-MM1 
Version Number:  
Version 7.0  
Version Date:  
27 June 2018 
I have read the protocol AUTO2-MM1 titled “A Single-Arm, Open-Label, Multi-Centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO2, a CAR T Cell 
Treatment Targeting BCMA and TACI, in Patients with Relapsed or Refractory Multiple 
Myeloma”. 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 Conference on 
Harmonisation) and applicable regulatory requirements. 
Changes to the protocol will only be implemented after written approval is received from 
Autolus Ltd 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 of Investigator> 
<Affiliation of Investigator> 
 
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 AUTO2, a CAR T Cell Treatment 
Targeting BCMA and TACI, in Patients with Relapsed or Refractory 
Multiple Myeloma. 
Study Number 
AUTO2-MM1 
Sponsor 
Autolus Ltd 
Development Phase 
I/II 
Study Product 
AUTO2, an advanced therapy investigational medicinal product, 
comprising of autologous enriched T Cells retrovirally transduced to 
express a proliferation inducing ligand (APRIL) Chimeric Antigen 
Receptor (CAR) and the RQR8 safety switch. 
Study Population 
Patients with confirmed diagnosis of multiple myeloma (MM) as per the 
International Myeloma Working Group (IMWG) who have relapsed or 
become refractory after exposure to alkylator therapy or monoclonal 
antibody, immunomodulatory drug and proteasome inhibitor.  
Study Duration 
The study will take approximately 4.5 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 AUTO2 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 APRIL 
CAR T cells administered intravenously (IV) in adults with MM. A 
proliferation inducing ligand is a ligand for B cell maturation antigen 
(BCMA), and for the transmembrane activator and calcium modulator 
and cyclophilin ligand interactor (TACI), present on plasmablasts and 
plasma cells. A proliferation inducing ligand CAR is a third generation 
CAR construct with endodomains of CD28, OX40 and CD3 zeta. The 
receptor-binding domain of APRIL targets both BCMA and TACI. 
AUTO2 is autologous enriched T cell product retrovirally transduced to 
express a proliferation inducing ligand (APRIL) CAR and the RQR8 
safety switch. This first-in-human study will assess the safety of 
AUTO2, determine the appropriate dose for Phase II and evaluate the 
preliminary efficacy of the AUTO2 in relapsed or refractory MM 
patients. 

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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 safety and tolerability 
of AUTO2 administration. 
Incidence of Grade 3 to 5 toxicity 
occurring within the dose-limiting 
toxicity (DLT) period (28 days post 
AUTO2 infusion). 
To identify the recommended Phase 
II dose and maximum tolerated dose 
(MTD), if an MTD exists, of 
AUTO2. 
Frequency of DLT and the 
persistence of AUTO2. 
Phase II 
To evaluate the anti-tumour effect of 
AUTO2. 
Best Overall Response post-AUTO2 
infusion.  
Study Design 
This is a Phase I/II, open-label, multi-centre study to characterise the 
safety and clinical activity of APRIL CAR T cells when administered to 
patients with relapsed or refractory MM. The study will consist of 
2 parts, a Phase I/dose escalation followed by a Phase II/expansion. Both 
parts of the study will involve patients going through the following 
5 sequential 
stages: 
screening, 
leukapheresis, 
pre-conditioning, 
treatment and follow-up.  
Phase I (Dose Escalation): To identify the optimal dose (based on 
safety, tolerability and antitumour activity) of AUTO2 using an 
accelerated titration design (Simon et al. 1997). Up to 5 cohorts and a 
maximum of 42 patients with MM will be dosed. Doses from 15 × 106 to  
up to 
 RQR8/APRIL CAR positive T cells will be evaluated. 
Phase II (Dose Expansion): To further characterise the safety and 
assess the efficacy of AUTO2 at the recommended dose identified in 
Phase I, 30 patients will be treated in the dose expansion phase.  
Biomarkers relating to the CAR T cells and tumours will be evaluated in 
all patients. All patients enrolled in Phase I and II will attend clinic visits 
for up to 24 months (or less in the event of early discontinuation) post 
AUTO2 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 
AUTO2 treatment and early withdrawal from this study, all patients will 
be followed until death or for up to 15 years from treatment 
administration under a separate long-term follow-up study protocol. 

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Number of Patients 
Up to 80 patients in total are expected to be enrolled into both the 
escalation and expansion phases of the study, and up to 72 patients in 
total are anticipated to receive the AUTO2 therapy. 
 
Phase I (Escalation): An accelerated titration design (in which a 
single patient will be dosed at the lowest dose level, before 
reverting to a standard 3+3 dose escalation design upon observation 
of Grade 2 or higher toxicity that is probably or definitely related to 
AUTO 2 during the DLT period or at dose level 2 whichever is 
earlier); up to 42 patients in total will be dosed (up to 6 per dose 
cohort and up to 12 at RP2D).  
 
Phase II (Expansion): Dose expansion: 30 patients in total.  
Phase II of the study will follow Simon’s 2-stage optimal design.  
Key Criteria for 
Eligibility 
Only patients whose leukapheresis sample has been successful in 
generating AUTO2 in adequate quantity will be treated. Some key 
criteria for patient eligibility are summarised as follows:  
 
Confirmed diagnosis of MM as per IMWG. 
 
Male or female patients aged 18 or over and willing and able to 
give written informed consent to the current study. 
 
Relapse or refractory disease and have had at least 3 different prior 
lines of therapy including proteasome inhibitor (e.g. bortezomib or 
carfilzomib) 
and 
immunomodulatory 
therapy 
(IMiD; 
e.g. 
thalidomide, lenalidomide or pomalidomide) and alkylator or 
monoclonal antibody, or have "double refractory" disease to a 
proteasome inhibitor and IMiD, defined as progression on or within 
60 days of receiving these agents. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0 to 1. 
 
Patients should have adequate bone marrow function without the 
requirement for ongoing blood product or granulocyte-colony 
stimulating factor support.  
 
Women who are pregnant or lactating will be excluded. 
 
Prior treatment with investigational or approved gene therapy or 
cell therapy products or allogenic stem cell transplant will be 
excluded. 
 
Patients with clinically significant, uncontrolled heart disease, 
history or evidence of deep vein thrombosis or pulmonary 
embolism requiring ongoing therapeutic anticoagulation at the time 
of pre-conditioning and chronic renal impairment requiring 
dialysis, or creatinine clearance <30 mL/min will be excluded. 
 
Patients with significant liver disease: alanine aminotransferase or 
aspartate aminotransferase ≥3 × upper limit of normal (ULN), or 
total bilirubin ≥25 µmol/L (1.5 mg/dL), except in patients with 
Gilbert’s syndrome, or evidence of end-stage liver disease (e.g. 
ascites, hepatic encephalopathy) will be excluded. 
 
Patients with active infectious bacterial or viral disease (hepatitis B 
virus, hepatitis C virus, human immunodeficiency virus, human 
T-lymphotropic virus or syphilis) requiring treatment will be 
excluded. 
 
Patients that received any anti-myeloma therapy within the last 
7 days prior to pre-conditioning or leukapheresis will be excluded. 

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Study Product Dose, 
Dosing Regimen and 
Administration  
Eligible patients will receive AUTO2 IV following pre-conditioning 
treatment. The AUTO2 product contains both transduced (RQR8/APRIL 
CAR positive) and non-transduced cells. The dose is expressed as the 
number of RQR8/APRIL CAR positive T cells. Five dose cohorts are 
planned in Phase I: 
 
Cohort 1, Dose Level 1: 15 × 106 RQR8/APRIL CAR positive T 
cells  
 
Cohort 2, Dose Level 2: 75 × 106 RQR8/APRIL CAR positive T 
cells  
 
Cohort 3, Dose Level 3: 225 × 106 RQR8/APRIL CAR positive T 
cells  
 
Cohort 4, Dose Level 4: 600 × 106 RQR8/APRIL CAR positive T 
cells 
 
Cohort 5, Dose Level 5: 900 to 
 RQR8/APRIL CAR 
positive T cells  
 
The Safety Evaluation Committee will convene after the first and third 
patient as well as at the end of each cohort to decide on the next dose 
level, after the last cohort in the escalation phase to decide on the dose 
level for Phase II, and at the interim analysis stage. When a 
recommended Phase II dose decision is made by the Safety Evaluation 
Committee, the decision will need to be reviewed and endorsed by the 
Independent Data Monitoring Committee prior to opening Phase II. On 
occasion, a patient may receive re-treatment upon satisfying re-treatment 
criteria. 
Pre-conditioning 
Treatment 
All patients will receive a pre-conditioning regimen using fludarabine 
30 mg/m2 
IV 
over 
30 
minutes 
immediately 
followed 
by 
cyclophosphamide 300 mg/m2 IV over 30 minutes. Both these drugs will 
be given on Days -6, -5, and -4 before AUTO2 infusion.  
Safety Evaluation 
Safety will be assessed by physical examinations, ECOG status, 
laboratory tests, vital signs, electrocardiograms, AE and SAE 
monitoring, and concomitant medication usage. The severity of AEs will 
be assessed using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (Version 4.03), with the exception of 
cytokine release syndrome (CRS), which will be graded according to the 
CRS grading. 
Efficacy Evaluation 
Efficacy will be evaluated as per IMWG criteria. 
Biomarker Evaluation 
Biomarker evaluation will include the following: 
 
Expansion and persistence of RQR8/APRIL CAR positive T cells 
as determined by quantitative polymerase chain reaction and/or 
flow cytometry. 
 
 
 
Special Study 
Procedures 
All patients will undergo leukapheresis for AUTO2 generation. 

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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.  
The Phase II part of the study will enrol up to 30 evaluable patients. 
With this number of patients, assuming an overall response rate of 30%, 
the lower bound of the 2-sided 95% confidence interval for overall 
response rate will exclude 14%. 
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 
In the Phase II part of the study, an interim analysis will be performed 
after 10 patients are enrolled and evaluable. The study will be stopped at 
this first stage if no more than 1 response (as per the IMWG) has been 
observed. 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................ 5 
 10 
TABLE OF CONTENTS ...................................................................................................... 14 
LIST OF TABLES ................................................................................................................. 18 
LIST OF FIGURES ............................................................................................................... 18 
LIST OF ABBREVIATIONS ............................................................................................... 19 
1 
 21 
1.1 
 21 
1.2 
 
 
 
 22 
1.3 
 
 22 
1.4 
 24 
1.5 
 24 
 
 25 
 
 26 
1.6 
SUMMARY OF CLINICAL STUDIES ............................................................... 27 
1.7 
OVERALL RATIONALE FOR THE STUDY .................................................... 28 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 29 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS ................................................... 29 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS ............................................. 29 
2.3 
 30 
3 
STUDY OVERVIEW .................................................................................................... 31 
3.1 
STUDY DESIGN AND METHODOLOGY ........................................................ 31 
3.1.1 Study Overview ......................................................................................... 31 
3.1.2 Study Duration ........................................................................................... 32 
3.1.3 Phase I Dose Escalation ............................................................................. 32 
3.1.4 Dose Limiting Toxicity.............................................................................. 35 
3.1.5 Planned Dose Levels.................................................................................. 36 
3.1.6 Phase II Dose Expansion ........................................................................... 37 
3.2 
RATIONALES FOR STUDY DESIGN, DOSE AND POPULATION............... 37 
3.2.1 Study Design Rationale ............................................................................. 37 
3.2.2 Study Population Rationale ....................................................................... 38 
3.2.3 Cyclophosphamide and Fludarabine Pre-conditioning Rationale ............. 38 
3.2.4 Starting Dose Rationale ............................................................................. 40 
3.2.5 Dosing and Assessment Rationale ............................................................. 41 
3.2.6 
 42 
3.3 
RISKS AND MITIGATION STRATEGY ........................................................... 42 

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4 
PATIENT POPULATION ............................................................................................ 46 
4.1 
NUMBER OF PATIENTS.................................................................................... 46 
4.2 
INCLUSION CRITERIA ...................................................................................... 46 
4.3 
EXCLUSION CRITERIA..................................................................................... 47 
4.3.1 Discontinuation of Study ........................................................................... 49 
4.3.2 Patient Withdrawal from the Study ........................................................... 50 
4.3.3 Procedures for Handling Withdrawals....................................................... 50 
4.3.4 Replacement Policy ................................................................................... 51 
5 
52 
5.1 
 52 
5.2 
 52 
5.3 
 53 
5.4 
 53 
5.5 
 53 
6 
CONTRAINDICATIONS, CONCOMITTANT MEDICATIONS AND 
PROHIBITED THERAPIES ....................................................................................... 55 
6.1 
ALLOWED CONCOMITTANT MEDICATIONS/THERAPIES ....................... 55 
6.2 
PROHIBITED AND CAUTIONARY THERAPIES ........................................... 56 
6.3 
OVER-DOSAGE .................................................................................................. 56 
6.4 
DIETARY AND LIFESTYLE RESTRICTIONS ................................................ 56 
7 
STUDY PROCEDURES ............................................................................................... 58 
7.1 
LEUKAPHERESIS ............................................................................................... 58 
7.2 
PRE-CONDITIONING CHEMOTHERAPY FOR AUTO2 THERAPY ............ 58 
7.2.1 Supply of Cyclophosphamide and Fludarabine ......................................... 59 
7.2.2 Accountability of Cyclophosphamide and Fludarabine ............................ 59 
7.3 
AUTO2 TREATMENT AND PATIENT MONITORING .................................. 59 
7.3.1 Treatment Allocation and Blinding ........................................................... 59 
7.3.2 AUTO2 Administration ............................................................................. 59 
7.3.3 Monitoring During and After Drug Administration .................................. 60 
7.3.4 Dose Delay................................................................................................. 60 
7.3.5 Interruption of AUTO2 Infusion ............................................................... 60 
7.3.6 Re-treatment of Patients ............................................................................ 61 
8 
GUIDELINES FOR PREVENTION, MONITORING AND MANAGEMENT 
OF ADVERSE EVENTS .............................................................................................. 62 
8.1 
GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY .............................................................. 62 
8.2 
PRE- AND POST-INFUSION SUPPORTIVE THERAPY ................................. 63 
8.3 
TREATMENT OF INFUSION RELATED REACTIONS .................................. 64 
8.4 
GRADING AND MANAGEMENT OF CYTOKINE RELEASE 
SYNDROME ........................................................................................................ 66 
8.5 
MANAGEMENT OF TUMOUR LYSIS SYNDROME ...................................... 68 
8.6 
GRADING AND MANAGEMENT OF NEUROTOXICITY ............................. 69 

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8.7 
MANAGEMENT OF THROMBOCYTOPENIA ................................................ 73 
8.8 
MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS DUE TO 
ON-TARGET BUT OFF-TUMOUR TOXICITY ................................................ 73 
8.9 
 73 
9 
STUDY VISITS AND ASSESSMENTS ...................................................................... 75 
9.1 
STUDY OVERVIEW ........................................................................................... 75 
9.1.1 Screening Phase ......................................................................................... 75 
9.1.2 Leukapheresis Phase .................................................................................. 75 
9.1.3 Pre-conditioning Phase .............................................................................. 75 
9.1.4 Treatment Phase......................................................................................... 76 
9.1.5 Follow-up Phase ........................................................................................ 76 
9.1.6 Long-term Follow-up................................................................................. 76 
9.2 
DETAILS OF STUDY ASSESSMENTS ............................................................. 76 
9.2.1 Demographic and Baseline Assessments .................................................. 76 
9.2.2 Safety Evaluations ..................................................................................... 77 
9.2.3 Pharmacodynamics and Biomarker Evaluation ......................................... 79 
9.2.4 Efficacy Evaluation ................................................................................... 80 
9.2.5 Blood Volume Collections ........................................................................ 83 
10 
SAFETY MANAGEMENT .......................................................................................... 84 
10.1 ADVERSE EVENTS DEFINITIONS .................................................................. 84 
10.1.1 Adverse Event ............................................................................................ 84 
10.1.2 Adverse Reactions ..................................................................................... 84 
10.1.3 Serious Adverse Events ............................................................................. 85 
10.1.4 Suspected Unexpected Serious Adverse Reactions ................................... 86 
10.1.5 Adverse Events of Special Interest ............................................................ 86 
10.2 ADVERSE EVENTS ASSESSMENT ................................................................. 86 
10.2.1 Severity of Adverse Events ....................................................................... 87 
10.2.2 Assessment of Relationship ....................................................................... 87 
10.3 ADVERSE EVENTS REPORTING PROCEDURES ......................................... 88 
10.3.1 All Adverse Events .................................................................................... 88 
10.3.2 Serious Adverse Events ............................................................................. 89 
10.3.3 Adverse Events of Special Interest ............................................................ 91 
10.3.4 Management of Pregnancy ........................................................................ 91 
10.3.5 Other Significant Events Reporting ........................................................... 92 
10.3.6 Reporting Exemptions ............................................................................... 92 
10.4 SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL ...................... 93 
10.5 SAFETY EVALUATION COMMITTEE ............................................................ 93 
10.6 INDEPENDENT DATA MONITORING COMMITTEE ................................... 94 
11 
STATISTICS ................................................................................................................. 95 
11.1 SAMPLE SIZE ESTIMATION ............................................................................ 95 
11.2 DESCRIPTION OF ANALYSIS DATASETS .................................................... 95 

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11.2.1 Full Analysis Set ........................................................................................ 95 
11.2.2 Safety Analysis Set for the Study and for Study Treatment ...................... 95 
11.2.3 Efficacy Analysis Set ................................................................................. 95 
11.3 STATISTICAL ANALYSES AND METHODS ................................................. 95 
11.3.1 Primary Endpoints ..................................................................................... 96 
11.3.2 Secondary Endpoints ................................................................................. 97 
11.3.3 
 98 
11.3.4 
 98 
11.3.5 Pharmacokinetics ....................................................................................... 98 
11.3.6 Other Analyses........................................................................................... 98 
11.3.7 Interim Analysis......................................................................................... 98 
12 
DATA QUALITY CONTROL AND ASSURANCE .................................................. 99 
12.1 COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS ..... 99 
12.2 PROTOCOL VIOLATIONS AND DEVIATIONS ............................................. 99 
12.3 MONITORING ..................................................................................................... 99 
12.4 AUDITS AND SITE INSPECTIONS ................................................................ 100 
13 
DATA HANDLING AND RECORD KEEPING ..................................................... 101 
13.1 DATA MANAGEMENT .................................................................................... 101 
13.2 STUDY DOCUMENTATION AND RETENTION OF RECORDS ................. 101 
14 
CLINICAL TRIAL AGREEMENT, FINANCE AND INSURANCE ................... 102 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 103 
15.1 ETHICS COMMITTEE REVIEW AND APRROVAL ..................................... 103 
15.2 REGULATORY AUTHORITY REVIEW AND APPROVAL ......................... 103 
15.3 INVESTIGATOR RESPONSIBILITIES ........................................................... 103 
15.3.1 Overall Responsibilities ........................................................................... 103 
15.3.2 Site Review .............................................................................................. 103 
15.3.3 Informed Consent .................................................................................... 103 
15.3.4 Delegation of Investigator Duties ............................................................ 104 
15.3.5 Communication with Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) ................................................................................ 104 
15.3.6 Confidentiality of Trial Documents and Patient Records ........................ 105 
15.4 LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE 
RESEARCH ........................................................................................................ 105 
16 
STUDY COMPLETION ............................................................................................. 106 
17 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS.......... 107 
18 
REFERENCES ............................................................................................................ 108 
19 
APPENDICES ............................................................................................................. 115 
 
 
 

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LIST OF TABLES 
Table 1: 
Primary Objectives and Endpoints for Phase I ................................................. 29 
Table 2: 
Primary Objectives and Endpoints for Phase II ............................................... 29 
Table 3: 
Secondary Objectives and Endpoints ............................................................... 29 
Table 4: 
3+3 Dose Escalation Decision Rules ............................................................... 35 
Table 5: 
Treatment Cohorts ............................................................................................ 36 
Table 6: 
Leukapheresis – Risks and Mitigation Strategy ............................................... 42 
Table 7: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy ................... 43 
Table 8: 
AUTO2 Infusion – Risks and Mitigation Strategy ........................................... 43 
Table 9: 
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy ............................................................................................................. 62 
Table 10: 
Pre- and Post-infusion Medications ................................................................. 64 
Table 11: 
Guidelines for the Management of Infusion-related Reactions ....................... 65 
Table 12: 
Severity Grading and Management of CRS ..................................................... 66 
Table 13: 
Definitions and Doses of Vasopressors ............................................................ 67 
Table 14: 
Pharmacologic Management of CRS ............................................................... 68 
Table 15: 
Grading of Neurological AEs and CAR-T-Cell-Related Encephalopathy 
Syndrome (CRES) ............................................................................................ 70 
Table 15A: 
Management and Follow-up of Neurological AEs .......................................... 70 
Table 15B: 
Recommendations for the Management of Status Epilepticus after CAR T 
Cell Therapy ..................................................................................................... 72 
Table 15C: 
Recommendation for Management of Raised Intracranial Pressure (ICP) 
after CAR T Cell Therapy ................................................................................ 72 
Table 16: 
Clinical Laboratory Tests ................................................................................. 78 
Table 17: 
Severity Grading of AEs Not Listed on the NCI CTCAE Grading System .... 87 
Table 18: 
Reporting Period for All AEs ........................................................................... 88 
LIST OF FIGURES 
Figure 1: 
Structure of the Constructs Expressed on AUTO2 .......................................... 24 
Figure 2: 
Efficacy of RQR8-APRIL CAR T Cells in a Xenograft Tumour Model ......... 26 
Figure 3: 
Dose Escalation and Dose Expansions Phases ................................................. 31 
Figure 4: 
Overview of the Stages of the Study ................................................................ 32 
Figure 5: 
CRS Management Overview ............................................................................ 67 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event  
ALL 
Acute lymphoblastic leukaemia 
ALT 
Alanine aminotransferase 
APRIL 
A proliferation inducing ligand 
AST 
Aspartate aminotransferase 
ATIMP 
Advanced therapy investigational medicinal product 
BCMA 
B cell maturation antigen 
CAR 
Chimeric antigen receptor 
CD3, -19, -20, -28, -134 
Cluster of differentiation 3, 19, 20, 28, 134 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRF 
Case Report Form 
CRS 
Cytokine release syndrome 
CT 
Computerised tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cy/Flu 
Cyclophosphamide and fludarabine 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EU 
European Union 
EudraCT 
European Clinical Trials Database  
FDA 
Food and Drug Administration 
FLC 
Free light chain 
GCP 
Good clinical practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMiD 
Immunomodulatory therapy 
IMWG 
International Myeloma Working Group 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 

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Abbreviation 
Definition 
IV 
Intravenous(ly) 
M-protein 
Monoclonal protein 
MAD 
Maximum administered dose 
MM 
Multiple myeloma 
MR 
Minor response 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
MUGA 
Multiple gated acquisition 
NCI 
National Cancer Institute 
NSG 
NOD Scid Gamma 
ORR 
Overall response rate 
OS 
Overall survival 
OX40 
Also known as tumour necrosis factor receptor superfamily 4 
[TNFRSF4] and cluster of differentiation 134 [CD134]) 
PBMCs 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PET-CT 
Positron emission tomography-computerised tomography 
PFS 
Progression-free survival 
PR 
Partial response 
PTT 
Partial thromboplastin time 
qPCR 
Quantitative polymerase chain reaction 
RCR 
Replication competent retrovirus 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase II dose 
RQR8 
Safety switch gene containing 2 copies of the rituximab 
mimotope flanking the QBEnd10 epitope on a CD8 stalk 
SAE 
Serious adverse event 
sCR 
Stringent complete response 
SEC 
Safety Evaluation Committee 
SPEP 
Serum protein electrophoresis 
TACI 
Transmembrane activator and calcium modulator and 
cyclophilin ligand interactor 
TLS 
Tumour lysis syndrome 
TNF 
Tumour necrosis factor 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
VGPR 
Very good partial response 
 
 

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1.7 
OVERALL RATIONALE FOR THE STUDY 
The past decade has seen major progress in the understanding of the molecular oncogenesis 
of plasma cell neoplasms, which has significantly influenced the clinical management of 
these tumours. Despite these major advances, most cases of MM have remained incurable 
with the currently established therapy modalities. A considerable number of MM patients will 
ultimately experience a final tumour relapse without an additional, effective treatment option. 
Novel treatment concepts are therefore needed that address and overcome the limitations of 
current therapeutic modalities. 
Novel immunotherapies such as CAR T cell therapies hold promise for significant 
improvement in the overall outcome of MM. Anti-CD19 CAR T cells in clinical development 
for the treatment of B-lineage malignancies have demonstrated efficacy in clinical trials. 
Several ongoing clinical studies are utilising CARs targeting BCMA. Early results with this 
approach have shown encouraging results in the treatment of MM. Unlike BCMA, CAR 
AUTO2 expressing APRIL can target 2 antigens expressed on myeloma cells, BCMA and 
TACI; enabling targeting of tumour cells expressing low antigen. Dual BCMA/TACI 
targeting may also prevent escape by target antigen down-regulation as observed with CD19 
targeting. AUTO2 has also been engineered to be more active with the incorporation of both 
proliferation CD28 and survival OX40 co-stimulatory signals. Additionally, incorporation of 
RQR8 safety switch into the CAR adds to the overall safety of AUTO2. This first-in-human, 
Phase I/II study will assess the safety and preliminary activity of AUTO2 in patients with 
relapsed or refractory MM. 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS 
Primary objectives and endpoints for Phase I are presented in Table 1. 
Table 1: 
Primary Objectives and Endpoints for Phase I 
Objectives 
Endpoints 
To assess the safety and tolerability of AUTO2 
administration.  
Incidence of Grade 3 to 5 toxicity occurring within the 
DLT period (28 days post AUTO2 infusion). 
To identify the recommended Phase II dose (RP2D) 
and maximum tolerated dose (MTD), if an MTD 
exists, of AUTO2. 
Frequency of DLT and the persistence of AUTO2. 
AE=adverse event; DLT=dose limiting toxicity; MTD=maximum tolerated dose; RP2D=recommended Phase II dose; 
SAE=serious adverse event. 
Primary objectives and endpoints for Phase II are presented in Table 2. 
Table 2: 
Primary Objectives and Endpoints for Phase II 
Objectives 
Endpoints 
To evaluate the anti-tumour effect of AUTO2 
Best overall response post-AUTO2 infusion.  
To assess the safety and tolerability of AUTO2 
administration. 
Frequency and severity of AEs and SAEs. 
AE=adverse event; SAE=serious adverse event. 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives and endpoints are presented in Table 3. 
Table 3: 
Secondary Objectives and Endpoints 
Objectives 
Endpoints 
To evaluate the feasibility of generating the ATIMP, 
AUTO2. 
Proportion of patients for whom an AUTO2 product 
can be generated (feasibility). 
To evaluate the clinical efficacy of AUTO2 
 Determine the clinical benefit (stringent complete 
response + complete response + very good partial 
response + partial response + minor response 
[sCR+CR+VGPR+PR+MR]) rate following 
treatment with AUTO2. 
 To evaluate clinical outcomes including duration of 
response, time to disease progression, PFS and OS. 
Biomarker and pharmacodynamic effects of AUTO2  
Quantitative PCR (qPCR) and/or flow cytometry at a 
range of time points in the peripheral blood. 
CR=complete response; MR=minor response; PR=partial response; qPCR=qualitative polymerase chain reaction; 
sCR=stringent complete response; VGPR=very good partial response. 

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2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
STUDY OVERVIEW  
3.1 
STUDY DESIGN AND METHODOLOGY 
3.1.1 
Study Overview 
This multi-centre, single-arm study will consist of 2 phases, a Phase I/dose escalation phase 
and a Phase II/expansion phase:  
 
Phase I: Dose escalation to identify the optimal dose of AUTO2 (doses from 15 × 106 to 
up to 
 RQR8-APRIL positive CAR T cells to be assessed). 
 
Phase II: Dose expansion to further assess safety and anti-tumour activity at the 
recommended dose identified in Phase I. 
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 5 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 
the ATIMP, AUTO2. If sufficient quantity of the cells (prescribed dose ±20%) are 
produced, the patient will proceed to the Pre-Conditioning Phase. 
 
Pre-conditioning: If sufficient AUTO2 for the prescribed dose is successfully 
manufactured and the patients continue to meet eligibility requirements for the study, 
they will proceed to receive a lymphodepleting pre-conditioning treatment with 
cyclophosphamide and fludarabine for 3 days, timed to end 4 days before AUTO2 
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 
Treatment: AUTO2 for the prescribed dose will be administered IV as a single infusion 
on Day 0. The treatment phase will extend from Day 0 (infusion day) until the end of the 
DLT observation period (28 days post last AUTO2 infusion). 
 
Follow-up: The follow-up phase will begin after the treatment stage and end 2 years 
(±14 days) after infusion with AUTO2 or at disease progression or withdrawal of 
consent, which ever happens first (End of Study visit). 
An overview of the 5 study stages is presented in Figure 4.  
Figure 4: 
Overview of the Stages of the Study 
 
From signing of consent until the End of Study visit, patients will be closely monitored for 
AEs, laboratory abnormalities, CR and biomarker changes according to the schedule of 
assessments. 
All patients will be enrolled into a long-term follow-up protocol (AUTO-LT1) at the End of 
Study visit and will be followed for safety evaluation and survival for 15 years from the first 
AUTO2 infusion or until death or withdrawal of consent, which ever happens first. 
Note: Patients who have received AUTO2 and have discontinued or completed the study may 
continue to be monitored for AUTO2 treatment-related SAEs and AEs until they enrol onto 
the long-term follow-up study (AUTO-LT1) and the End of Study visit will be delayed. 
3.1.2 
Study Duration 
The total study duration is estimated to be 4.5 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 AUTO2 infusion (or earlier if appropriate). 
3.1.3 
Phase I Dose Escalation 
The dose escalation phase is designed to determine the RP2D of AUTO2 (based on total 
RQR8/APRIL positive CAR T cells) in patients with relapsed or refractory MM. Dose 
escalation will initially follow an accelerated dose titration design, in which a single patient 
will be dosed at the lowest dose level, followed by a 3+3 design (Figure 3). The trial will 
consist of up to 5 dose levels; eligible patients will be assigned to treatment groups 
sequentially. The inter-patient dosing interval for AUTO2 will be at least 14 days, to allow 
for assessment of possible toxicity, the dosing interval between the 1st and 2nd AUTO2 naive 
patient in every cohort will be a minimum of 28 days. The Safety Evaluation Committee 
(SEC) may change the dosing interval based on emerging data. This window may be reduced 
to 1 week after a cohort has enrolled at least 3 patients and has been declared safe by the 
SEC. The DLT evaluation period will be 28 days after the AUTO2 dose. Patients will be 
admitted to hospital for at least 10 days (or longer) for monitoring after receiving AUTO2 or 
until all AUTO2 related non-haematological toxicities have returned to ≤Grade 1 or baseline, 
or longer as clinically necessary. 

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3.1.3.1 
Accelerated Titration 
Dose escalation will follow an accelerated titration design and will start according to the 
following principles (Simon et al. 1997):  
 
A single patient will be treated with AUTO2 at the starting dose of 15 × 106 
RQR8/APRIL positive CAR T cells.  
 
Accelerated titration will be stopped after the first occurrence of Grade 2 or higher 
toxicity that is considered probably or definitely related to AUTO2 during the DLT 
evaluation period. If the aforementioned events occur at the first dose level of 
15 × 106 RQR8/APRIL positive CAR T cells, the study will transition to a 3+3 phase, 
where a minimum of 3 and maximum of 6 patients will be treated with the same dose. 
 
Based on emerging data (for example, 1st patient is considered to have low disease 
burden, <20% of bone marrow cells are plasma cells), the SEC may consider enrolling a 
second patient prior to dose escalation, even if the criteria for transition to 3+3 (as 
outlined above) have not been met.  
 
If the decision to dose escalate is made, then the second cohort will be opened at the dose 
level of 75 × 106 RQR8/APRIL positive CAR T cells.  
 
The study will transition to 3+3 phase at the second dose cohort, where a minimum of 3 
and maximum of 6 patients will be treated with the same dose. 
3.1.3.2 
3+3 Dose Escalation 
Once the criteria for stopping the accelerated dose titration phase have been met, or a dose 
level of 75 × 106 RQR8/APRIL positive CAR T cells has been reached (i.e. second dose level 
escalations), whichever comes first, dose escalation will transition to the 3+3 scheme 
(Table 4). Each dose level may enrol up to 6 patients. Evaluation of a dose level with at least 
3 patients treated at the planned dose level completing the DLT evaluation period is required 
prior to escalation to the next dose level, except in cohort 1. 
Based on emerging data, the SEC may decide whether it is safe to escalate the dose when 
fewer than three patients (but no fewer than two) have been treated in the 75 x 106 
RQR8/APRIL positive CAR T cells (e.g. escalation from a dose level that may be considered 
sub therapeutic based on the emerging CAR T expansion, persistence and efficacy data); this 
may be done with a protocol amendment.  
Patients treated at doses below the planned dose level will not be considered evaluable for 
making dose escalation decisions (additional patients will be enrolled to meet the minimum 
number needed to make the dose escalation decision). Similarly, if a patient is treated at the 
higher dose before it is 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 escalation decision making if they develop a DLT with retreatment). However, dose 
escalation decisions will take into account all available data, including biomarker data and the 
safety profile of all patients treated in prior dose levels.  
The SEC will meet after the first patient in every cohort completes the DLT assessment 
period, to confirm continuation of enrolment to that cohort and thereafter meet again after the 
third patient in a cohort has completed the DLT assessment period. Only once a cohort is 
declared safe by the SEC can the next higher dose level be opened. Back filling of a cohort 
(maximum n=6 evaluable patients/cohort) declared safe may be undertaken in parallel to the 
ongoing enrolment of a higher dose level, to obtain additional safety and efficacy data in 

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patients who are unable to wait for the required inter-patient dosing interval due to risk of 
clinical deterioration. A minimum dosing interval of 7 days will be maintained between 
patients enrolled to a cohort for back filling purposes as well as for those being re-treated as 
per Section 7.3.6.  
Dose escalation will continue until the planned maximum administered dose (MAD) of up to 
 RQR8/APRIL positive CAR T cells is reached or lower if patients experience 
adverse effects (Table 4) that are presumed to be related to AUTO2 and are considered 
unacceptable due to severity and/or irreversibility. Intermediate doses may be explored based 
on emerging data, however it will not exceed the current maximum suggested dose of 
 RQR8/APRIL positive CAR T cells without a protocol amendment.  
Recent safety data from two anti-BCMA CAR T studies (Berdeja et al. 2017, Fan et al. 2017) 
has shown mostly mild CRS and no Grade 3 or 4 neurotoxicity at various escalating doses. 
Notably the CRB-401 study (Berdeja et al. 2017) evaluated 4 dose cohorts: 50, 150, 450 and 
800 × 106 CAR-T cells given as a single dose. No DLTs were observed in these cohorts and 
treatment was well tolerated up to 800 × 106 CAR T cells. Seventy one percent of patients 
had CRS most of which was mild (Grade 1 or 2), 2 patients had Grade 3 CRS that resolved 
within 24 hours. This study has initiated expansion phase evaluating the active doses from 
150 to 450 × 106 CAR-T cells. Updated data from this expansion cohort (Raje et al. 2018) 
showed that the safety profile remained well tolerated with manageable CRS and 
neurotoxicity for patients treated at a dose of 450 x 106 cells. 
Updated data from an anti-BCMA CAR study from NCI (Brudno et al. 2018) reported 
16 patients dosed at 9 x 106 cells/kg. These 16 patients were heavily pretreated and most of 
them were refractory to their last line of treatment. The ORR was 81%, and all 11 patients 
evaluated for MRD were MRD negative by flow. Patients dosed at lower doses had ORR of 
only 20%. Patients in this higher cohort did have severe CRS; however, it was not correlated 
with peak of CAR T cell expansion but did correlate with higher disease burden. Data from 
another study of an anti-BCMA CAR T therapy using a second generation CAR T with 41BB 
endodomain and gamma retroviral transduction (Liu et al. 2018) showed that in 9 evaluable 
patients treated at a dose of 9 x 106 cells/kg, the ORR was 78%, including patients with deep 
responses and the median PFS was 15 months. CAR T cell expansion and persistence were 
consistently observed. With this encouraging preliminary efficacy data, no severe CRS or 
neurotoxicity was reported. 
Based on this emerging data, it is likely that significantly higher doses may be necessary for 
better engraftment and more robust expansion. Therapeutic dose range is likely to be at least 
600 x 106 RQR8/APRIL positive CAR T cells or higher. Given the safety profile and reported 
data from other anti-BCMA CAR T studies, specifically the BB2121 study and data reported 
by Liu et al using a 41BB endodomain, it is appropriate to continue dose escalation to 600 
and up to 
 dose cohorts in the absence of an earlier MTD. Additionally, 
considering the current safety profile and CAR T cell expansion data from 2 patients treated 
at 225 x 106 CAR T cells, it is relevant to continue to escalate the dose by approximately 
3 times as done in the lower cohorts. The next planned dose cohort should be 600 x 106 
which is within range of what has been evaluated and administered safely as a single dose in 
other studies. 
In summary, based on safety data and manufacturing feasibility, dose escalation up to 
 cells may be undertaken. In addition, based on emerging safety data, if evaluation 
of a split dose regimen is considered appropriate a protocol amendment will be submitted to 
implement it. 

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Table 4: 
3+3 Dose Escalation Decision Rules 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Escalate to the next 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 
Escalate to the next dose level with a dose increase of ≤100% of the next 
planned dose level.  
2 or more patients in a dosing 
cohort (up to 6 patients)  
The MTD has been exceeded. Either:  
 
May evaluate an intermediate dose lower than the current dose. 
 
Expand a prior cohort up to 6 patients.  
DLT=dose limiting toxicity; MTD=maximum tolerated dose.  
Note: The Investigators may override these guidelines if there are particular safety issues, for which moving to a higher dose 
is not considered appropriate. 
The dose escalation decisions will be made by the SEC (Section 10.5) and the study could be 
stopped by the Independent Data Monitoring Committee (IDMC) or SEC upon occurrence of 
any of the events described in Section 10.4. 
3.1.4 
Dose Limiting Toxicity 
Toxicities will be graded for severity according to the National Cancer Institute Common 
(NCI) Terminology Criteria for Adverse Events (CTCAE), Version 4.03 and the CRS will be 
graded as per (Lee et al. 2014). The DLT evaluation period will end 28 days after the AUTO2 
dose. The DLT criteria take into consideration the single dose nature of AUTO2 treatment 
(unlike repeat dose treatments of usual anti-cancer agents) and the potential for differential 
expansion of CARs post infusion in different patients. As well as features inherent to CAR 
therapy, transient fever due to low grade CRS, and in the setting of pre-conditioning, induced 
cytopenias/neutropenia are seen in most patients. These are not necessarily classical 
neutropenic fevers related to infection. The CRB 401 study with anti-BCMA CAR shows 
86% patients had Grade 3/4 neutropenia that was related to preconditioning and lasted for 
several weeks after infusion. None of these patients had a DLT. Similarly, both anti-CD19 
CAR-T therapies axicabtagene ciloleucel and tisagenlecleucel have prolonged cytopenias 
after infusion related to lymphodeleting therapy (FDA 2017, FDA Undated), 40% of patients 
treated with tisagenlecleucel had Grade3/4 neutropenia lasting more than 28 days after 
treatment. Another anti-CD19 CAR, JCAR017 (NCT03310619) study showed the majority of 
patients had Grade 4 neutropenia. 
Dose limiting toxicity will be defined as: 
 
Any new non-haematological AE of Grade 3 or higher toxicity using the NCI CTCAE 
(Version 4.03), which is probably or definitely related to AUTO2 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. 
 
Any other reason for activation of the safety switch after receiving AUTO2. 
 
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 

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hazard in future patients. Effort should be made to perform an autopsy in case of fatal 
event where the aetiology is unclear. 
 
Any event that in the opinion of treating investigators and/or Medical Monitor puts the 
patient at undue risk may also be considered a DLT. 
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 10.1.5). All DLTs will be notified to the SEC by the Sponsor.  
Although not necessarily considered a DLT, a decision to activate the safety switch by 
administration of rituximab at any time should be reported as an SAE to the Sponsor. The 
SEC will also be informed by the Sponsor (see Section 10.1.3). 
Maximum Tolerated Dose: The MTD is defined as the highest dose level of AUTO2 at 
which ≤1 patient out of 6 patients experience a DLT during the DLT evaluation period. If 
2 or more out of 6 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 3 patients may be enrolled at the dose 
level that exceeded the MTD with establishment of supportive care measures. 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 to Independent Ethics Committees/Institutional 
Review Boards (IECs/IRBs) prior to dosing. 
Maximum Administered Dose: The planned MAD for this study is up to 
 
RQR8/APRIL positive CAR T cells in case the MTD is not defined. The MAD may be lower 
based on emerging data. 
Recommended Phase II Dose: The RP2D is either identical to the MTD or MAD or a lower 
dose level AUTO2 is selected on the basis of a cumulative review of safety, persistence of the 
CAR T cells and clinical activity. The RP2D dose level may be expanded up to 12 patients to 
further characterise safety and cellular kinetics. Additionally, based on emerging data, more 
than one RP2D may be determined. For example, if 600 × 106 APRIL/RQR8 positive CAR T 
cells is declared as RP2D then Phase II can be opened and in parallel further dose escalation 
may be continued to determine a second RP2D dose and schedule. 
3.1.5 
Planned Dose Levels 
The 5 planned dose cohorts are presented in Table 5. 
Table 5: 
Treatment Cohorts 
Treatment Cohorts 
RQR8/APRIL CAR Positive T Cell Dose 1 - Day 0 
Cohort 1 
15 × 106 
Cohort 2 
75 × 106 
Cohort 3 
225 × 106 
Cohort 4  
600 × 106 
Cohort 5  
900 to 
 
APRIL=a proliferation inducing ligand; CAR=chimeric antigen receptor; RQR8=safety switch gene. 
Patients weighing less than 50 kg will have a 25% reduction in total dose, patients weighing 
more than 100 kg may receive a 25% increase in total dose. 

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These dose levels were selected as they provide an optimum range for assessing safety, CAR 
T cell persistence and anti-tumour activity. This range is within the dose levels assessed in 
other CAR T studies. Based on emerging data, intermediate dose levels may also be explored. 
On occasion, RQR8/APRIL CAR positive T cell production may fail to generate sufficient 
cells for the current dose level. In this case, the patient can be treated on study but at the dose 
level achieved during manufacture. If a production fails to generate sufficient RQR8/APRIL 
CAR positive T cells for Cohort 1, the patient cannot be treated on study.  
At higher doses i.e. 
, if recommended DMSO is exceeded, the AUTO2 dose may 
be given up to 5 days apart for ease of infusion and amount of preservative DMSO 
administered. 
Note: The dose determination is based solely upon the transduced cells (i.e. RQR8/APRIL 
CAR positive T cells). The non-transduced cells in the drug product will not be counted 
towards determining the dose. A patient may be eligible for dosing if the dose is within 
20% of the prescribed dose (±20%). 
3.1.6 
Phase II Dose Expansion 
Once the RP2D is determined, the Phase II dose expansion part of the study will open. This 
part will enrol up to 30 patients. There is no required inter-patient dosing interval. 
3.2 
RATIONALES FOR STUDY DESIGN, DOSE AND POPULATION 
3.2.1 
Study Design Rationale 
This single-arm dose-escalation Phase I/II study, is designed to assess safety, tolerability and 
optimum RP2D and MTD, if a MTD exists. Due to the novelty of targeting TACI, the design 
encompasses an accelerated phase allowing for low starting dose whilst exposing a minimum 
number of patients to a potential sub-therapeutic dose, should there be no significant 
off-target toxicity. A minimum dosing interval has been incorporated to reduce the risk of 
inducing severe adverse effects in more than 1 patient. There will be a 28-day observation 
period between the 1st and 2nd patient in every cohort and at least 14 days between subsequent 
patients until the dose is declared safe. The rationale for the dosing interval is based on the 
anticipated peak expansion of the infused cells that is likely to happen within the 1st 14 days. 
Following the accelerated phase, the subsequent escalation is based on the standard 3+3 
format and is considered reasonable for these cohorts. This design would allow 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. However, based on emerging data, if a 
dose cohort is considered safe but has poor expansion, persistence or clinical response, then 
the SEC can recommend escalation to the next dose level to minimise patients being dosed at 
a sub-therapeutic dose. The dose may be escalated after SEC endorsement and a protocol 
amendment.  Additionally, should emerging safety data indicate that splitting the total dose is 
likely to be safer and effective then this will be implemented after a protocol amendment The 
current experience from CRB 401 (Berdeja et al. 2017) and other BCMA CAR studies 
suggest that single dose is likely to be safe and effective. The proposed design incorporates 
assessing a range of doses from 15 × 106 to up to 
CAR T cells. This would allow 
for de-risking any potential for off target binding of TACI at the lower doses and still allow 
safely escalating the dose to a range that has been found to be safe and active in BCMA CAR 
T cell studies (Ali et al. 2016, Berdeja et al. 2017, Fan et al. 2017). 

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The Phase II/expansion part of the study is based on a Simon’s 2-stage optimal design; the 
rationale for dosing up to 30 patients is to detect early signs of efficacy in addition to 
generating additional safety data at the RP2D. 
3.2.2 
Study Population Rationale 
AUTO2 is designed to specifically bind to BCMA or TACI, which are only expressed on 
plasma cells. The study therefore will restrict the patient population to the plasma cell 
malignancy MM. In addition, since this is an experimental therapy, the study patient 
population will be restricted to only those with confirmed diagnosis of MM as per the 
IMWG, that have relapse or intolerance after exposure to alkylator therapy, 
immunomodulatory drugs and proteasome inhibitor. Patients included in this study would 
have received at least 3 prior lines of myeloma therapy or double refractory to IMiD and 
proteasome inhibitor. Moreover, only patients whose leukapheresis sample has been 
successful in generating AUTO2 in adequate quantity will be treated (or undergo pre-
conditioning), as this is a pre-requisite for AUTO2 therapy. 
3.2.3 
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 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, 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 stem cell transplantation 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 
cyclophosphamide (and rituximab) in the treatment of patients with chronic lymphocytic 
leukaemia (CLL) (Hallek 2013). Here-in its given every 4 weeks for multiple cycles 
compared to a single cycle therapy used for pre-conditioning.  
Cyclophosphamide and fludarabine based pre-conditioning have become the preferred 
regimen for CAR T 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 
cyclophosphamide alone. In an anti-CD19 CAR T cell study (JCAR014) patients with acute 
lymphoblastic leukaemia (ALL) who received cyclophosphamide and fludarabine (Cy/Flu) 
based lymphodepletion were compared with 1-third who received cyclophosphamide without 
fludarabine. At 18 months, a disease-free survival rate of approximately 60% was seen in the 
Cy/Flu ALL group compared with <10% of the cyclophosphamide-only arm (p = 0.0005) 
(Turtle et al. 2016). Additionally, in Non-Hodgkin lymphoma, the objective response rate for 
patients treated with Cy/Flu and CAR-modified T cells at the MTD (n = 19; 2 × 106/kg) was 
84% (47% CR). Chimeric antigen receptor T cell expansion and persistence, and OS and PFS 
were better in Cy/Flu patients compared to those who received cyclophosphamide alone 
(objective response rate 50%, CR 8%, n = 12).  
Cyclophosphamide administered alone is given at a high dose (2 to 4 gm/m2). However, since 
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higher doses of cyclophosphamide (2 to 3 gm/m2 × 1 to 2 days) is probably unnecessary, 
especially when given with fludarabine (Turtle et al. 2016). A lower dose of 
cyclophosphamide (300 mg/m2 × 3 days or 900 mg/m2 × 1) is likely to be adequate as this 
regimen has been evaluated in multiple clinical studies and considered relatively safe (Lee et 
al. 2015) and active (Ali et al. 2016, Neelapu et al. 2016). 
Fludarabine like all purine analogues is neurotoxic, and neurotoxicity was commonly 
observed in the 1980s while the therapeutic window was being established. At "standard" 
doses of 25 to 30 mg/m2, neurotoxicity is rarely seen. However, severe neurotoxicity leading 
to death was reported recently in the JCAR015 ROCKET trial (NCT02535364 2016) that 
used a fludarabine based conditioning regimen. 
On 07 July 2016, the Food and Drug Administration (FDA) had suspended recruitment into 
the ROCKET trial following the deaths of 3 young adult ALL patients due to cerebral 
oedema. The 3 deaths occurred amongst approximately 7 patients treated with Cy/Flu 
conditioning prior to JCAR15 treatment. Previous patients in the trial had been conditioned 
with cyclophosphamide alone (approximately 14 patients; 20 patients recruited to the trial in 
total) with no deaths or unexpected toxicity. The Sponsor’s report mentions "cerebral 
oedema", although no detail of the neurological syndrome is yet available. Most studies have 
described the neurotoxicity associated with CD19 targeting as a leukoencephalopathic 
picture. In the absence of post mortem data, there is little sound information about the 
pathophysiology of this process. The FDA lifted the recruitment hold a week later 
(13 July 2016) following agreement to return to conditioning with cyclophosphamide alone in 
this trial. No other trials (including similar trials using Cy/Flu conditioning) were affected. A 
subsequent announcement on the 14 July 2016 indicated that there are now 4 confirmed 
deaths from cerebral oedema in the ROCKET trial (NCT02535364 2016) attributable to 
therapy. Of note, it has been reported that the ZUMA-1 trial (NCT02348216 2016) had 
successfully completed recruitment of 72 patients to its trial of CD19-targeted therapy (using 
KTE-CD19), in which Cy/Flu conditioning was used but at lower doses than in the ROCKET 
trial, with no neurotoxicity-related deaths. There have been 50 patients on the NCI studies 
with no deaths due to neurotoxicity. In all of the studies conducted at the University of 
Pennsylvania using Cy/Flu and a CD19-41BB-zeta CAR in the last 3 years, only 
1 neurotoxicity death has been reported. 
There is overwhelming evidence that the toxicity is attributable to the enhanced conditioning 
of fludarabine potentiating the CD19 CAR T cells, which affect an immunological 
neurotoxicity dependent on the anti-CD19 single chain fragment variable component of the 
CAR, rather than being a direct effect of fludarabine.  
 
Neurotoxicity is a feature of all CD19 CAR studies and of bi-specific T cell engagers 
(Goebeler et al. 2016) which target CD19 (e.g. blinatumomab). Approximately 30 to 
40% of patients with CD19 CAR T cell engraftment report some form of neurotoxicity. 
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. 
 
This toxicity does not seem to occur with other CAR therapies where T cells engraft for 
instance against CD22 and BCMA (Fry et al. 2015, Ali et al. 2016) although there have 
been fewer patients treated. One theory is that CD19 or CD19-like protein is expressed 
on glial cells. 
 
The ZUMA-1 study used similar T cell doses. The receptor is also anti-CD19/28-Z, but 
containing a different single chain fragment variable and reports neurotoxicity including 

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a few severe cases but no deaths. This study employed a lower dose/intensity of 
pre-conditioning (Kochenderfer et al. 2016, Neelapu et al. 2016) with cyclophosphamide 
(300 to 500 mg/m2 × 3 days or 900mg/m2 × 1) and fludarabine (30 mg/m2 × 3 days) 
compared to the ROCKET study’s 1 to 3 gm/m2 cyclophosphamide + 25 to 30 mg/m2 of 
fludarabine × 5 days which is repeated 2 to 4 weeks later. Additionally, a short washout 
period of only 1 day after pre-conditioning may also have contributed to this toxicity. 
 
The most likely explanation of the ROCKET trial deaths is that the addition of 
fludarabine potentiated the CD19 CAR activity and resulted in CD19 CAR mediated 
neurotoxicity. It is possible that the higher dose of fludarabine (additionally giving 
2 cycles of it) used in the ROCKET trial combined with the specific CD19 CAR 
(JCAR015) are a combination particularly prone to causing neurotoxicity. 
Cyclophosphamide administered alone is given at a high dose (2 to 4 gm/m2) and could result 
in severe myelosuppression. However, since the purpose of pre-conditioning chemotherapy is 
lymphodepletion and not myelosuppression, higher doses of cyclophosphamide are probably 
unnecessary, especially when given with fludarabine (Turtle et al. 2016). A lower dose of 
cyclophosphamide (300 mg/m2 × 3 days or 900 mg/m2 × 1) is likely to be adequate as this 
regimen has been evaluated in multiple clinical studies and considered relatively safe (Lee et 
al. 2015) and active (Ali et al. 2016, Fry 2016, Kochenderfer et al. 2016, Neelapu et al. 
2016).  
In the current study, we propose to start at a very low initial dose of 15 × 106 RQR8/APRIL 
CAR Positive T Cells (approximately 2 × 105 cells/kg) combined with the 
cyclophosphamide/fludarabine based pre-conditioning regimen and titrate the dose up based 
on emerging safety data. In addition, we plan to administer a low dose of both 
cyclophosphamide (300 mg/m2 × 3 days) and fludarabine (30 mg/m2 × 3 days), followed by a 
4-day washout period prior to infusion of AUTO2 which has taken into consideration the 
half-life of fludarabine of 20 hours. This would result in elimination of over 4 half-lives of 
fludarabine and will potentially decrease any cumulative toxicity with AUTO2. A longer 
washout period is unlikely to add any further benefit and is likely to be suboptimal as the 
cytokine surge, especially the IL-15 surge, observed post-conditioning chemotherapy with 
Cy/Flu happens in the first few days and returns to baseline around 10 days later (Rossi et al. 
2015). It is probably ideal to dose the CAR T cells early within this window as IL-15 is 
necessary for CAR T cell expansion and resulting efficacy (Xu et al. 2014). In an anti-CAR 
19 study in refractory diffuse large B cell lymphoma, patients obtaining CR or PR had higher 
peak levels of IL-15 and IL-10 than patients with stable disease or progressive disease 
(Kochenderfer et al. 2016). Considering the nature of the patients being treated and the fact 
that pre-conditioning with Cy/Flu has been shown to increase clinical activity, we believe the 
proposed dose and regimen is justified. 
3.2.4 
Starting Dose Rationale 
The primary consideration for selection of a starting dose for the proposed trial is the safety 
of the patient. Chimeric antigen receptor T cell dosing is a challenging area and the standard 
methods for dose determination based on pre-clinical data are not transposable for cell 
therapies. Chimeric antigen receptor T cells expand in vivo, with expansion differing from 
one patient to another. Consequently, efficacy and toxicity cannot easily be correlated with 
the starting dose administered. Therefore, the choice of the starting dose has been based 
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For CAR T therapies, there is no clear correlation with dose given and either efficacy or 
toxicity, although there is a suggestion from 1 CD19 CAR study in children and young adults 
that 106 CAR T cells/kg is the MTD (Lee et al. 2016) this could vary based on the disease 
burden and degree of expansion of the infused CAR T cells. In another study in adult patients 
with ALL, a dose of 2 × 107/kg was considered unacceptable and 2 × 106/kg was considered 
to manageable, a further recommendation was to administer this dose to patients with 20% or 
less BM blasts to further reduce severe CRS (Turtle et al. 2016) Based upon published 
literature and recent presentations/discussions in the field of CD19 CAR T cell therapies, the 
minimum effective therapeutic dose is considered to be around 106 CAR T cells/kg. The 
MTD is also likely to vary based on the CAR T cell construct and the target antigen 
expression, lower antigen expression is likely to require higher dose of cells to see biological 
activity. 
B cell maturation antigen and TACI expression on MM cells is significantly less compared to 
CD19 expression on B-cells. Recently, the interim results of a NCI clinical study using a 
BCMA CAR (a single chain fragment variable recognising BCMA) in MM patients have 
been published (Ali et al. 2016). Eleven patients were treated at 1 of 4 dose levels, 0.3 × 106, 
1 × 106, 3 × 106, and 9 × 106 CAR T cells/kg. Toxicity among the 9 patients treated with the 
lowest 3 dose levels was mild and included cytopenias (attributable to chemotherapy), fever, 
and signs of CRS (including tachycardia and hypotension). More severe CRS was noted at 
the highest dose level which was considered to be at or near MTD. The recommendation was 
to administer this dose (9 × 106 CAR T cells/kg) only to patients with less than 50% bone 
marrow plasma cells. 
The proposed starting dose of 15 × 106 RQR8/APRIL CAR positive T cells (fixed dose) 
corresponding to a dose of 2 × 105 RQR8/APRIL CAR positive T cells/kg based on an 
average person weight of 75 kg, is considered a safe starting dose as it is at the lower end of 
starting doses in CD19 CAR T clinical trials (refer to the IB) and lower than the 106 CAR T 
cells/kg suggested to be an effective clinical dose. It is slightly lower than the starting dose in 
the BCMA CAR T cell clinical trial and 45-fold lower than doses at which severe CRS was 
observed. Although it is possible that this dose level is sub-therapeutic based on the BCMA 
CAR trial, efficacy has been observed at similar doses in some patients in CD19 trials. 
Furthermore, Autolus believes that AUTO2 may be more potent than the NCI BCMA CAR 
(Ali et al. 2016), as it is designed to trimerise on binding BCMA/TACI. Trimerisation may 
contribute to activity at low antigen density but does not increase maximal activity. 
Additionally, early clinical data from testing of a 3rd generation CD19 CAR does not show 
increased CRS despite doses of 2 × 108 CAR T cells/m2 (equivalent approximately to a flat 
dose of 1 × 108 (Enblad et al. 2015). It seems less likely hence that 3rd generation CARs will 
intrinsically have significantly greater propensity for toxicity. Since there is less precedence 
for the use of CAR T cells in MM than there is in other haematological malignancies, we 
have chosen a conservative starting dose which is based on a body of clinical experience of 
CAR T cell therapy. Moreover, with the proposed study design, only 1 or 2 patients may be 
exposed to this dose level. 
3.2.5 
Dosing and Assessment Rationale 
Patients will be treated with AUTO2 once at doses that are likely to be safe and efficacious. 
Most CAR T therapies are generally administered once and thereafter undergo expansion in 
vivo upon contact with the target antigen expressed on tumour cells, resulting in significant 
anticancer activity in most patients. It is anticipated that AUTO2 will have similar expansion 
in vivo, rendering the need for re-dosing un-necessary. On occasion, a re-treatment dose may 

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be given if the patient meets the criteria for re-treatment (Section 7.3.6). Subsequent to 
treatment with AUTO2, 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. 
3.2.6 
 
 
 
 
 
 
 
 
  
3.3 
RISKS AND MITIGATION STRATEGY 
This exploratory study is designed to assess the safety and biological activity of different 
doses of AUTO2 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-myeloma 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 AUTO2. Cell production efficiency of at least 80% is anticipated and is dependent 
on the quality of the leukapheresate. AUTO2 infusion may or may not provide clinical 
benefit to these patients. Risks of leukapheresis are summarised in Table 6. 
Table 6: 
Leukapheresis – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Pain and bruising due to blood draw. 
Experienced people 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. 
Anticoagulant Citrate Dextrose Solution, 
Solution A toxicity is a recognised complication 
as blood that comes into contact with the artificial 
surfaces of the extracorporeal tubing set must be 
anticoagulated 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. 
Pre-conditioning 
Chemotherapy: 
Lymphodepletion 
with 
cyclophosphamide 
and 
fludarabine prior to adoptive transfer of tumour specific T cells is thought to enhance 
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 
AUTO2 and therefore the chance of anti-tumour efficacy. Pre-conditioning will only be 
undertaken after confirmation of the successful production of AUTO2. Risks of 
pre-conditioning with chemotherapy are summarised in Table 7. 

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Table 7: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Myelosuppression resulting in anaemia, 
thrombocytopenia and lymphopenia, are the most 
common toxicities. Moderate to severe 
myelosuppression is possible. Nadir for granulocyte is 
1 to 2 weeks and platelets 2 to 4 weeks after 
chemotherapy, with recovery usually within 4 to 6 
weeks. Neutropenic fever, infections, sepsis and septic 
shock may occur and may sometimes be fatal. 
The fludarabine and cyclophosphamide 
chemotherapy given is milder compared to 
general chemotherapy received by patients and 
will be given only once (1 cycle, given over 
3 days). 
Cyclophosphamide associated toxicities, including but 
not limited to haemorrhagic cystitis, pyelitis, myocarditis 
and myopericarditis, pneumonitis and pulmonary 
fibrosis, veno-occlusive liver disease (per approved 
label) may also occur. 
Considering the low dose and short duration of 
treatment, these toxicities are less likely. 
Toxicities will be managed as per standard 
institutional policy and by trained personnel. 
Fludarabine is generally well tolerated: the most 
common side effects are lymphopenia and infection. 
Serious, and sometimes fatal infections, including 
opportunistic infections and reactivations of latent viral 
infections such as Herpes zoster, Epstein-Barr virus and 
progressive multifocal leukoencephalopathy, have been 
reported in patients treated with higher doses and for 
much longer durations. 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. 
Considering the low dose and short duration of 
treatment, these toxicities are less likely to occur. 
Toxicities will be managed as per standard 
institutional policy and by trained personnel. 
AUTO2 Infusion 
Risks associated with the infusion of AUTO2 are presented in Table 8. 
Table 8: 
AUTO2 Infusion – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Infusion reactions may occur with the infusion of 
AUTO2. 
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. Potentially 
life-threatening complications of CRS may include 
cardiac dysfunction, acute respiratory distress 
syndrome, neurologic toxicity, renal and/or 
hepatic failure, and disseminated intravascular 
coagulation. A number of Investigators have noted 
an association between CRS/macrophage 
activation syndrome and clinical response when 
administering CD19 CAR-redirected T cell 
therapies. The absolute level of risk is difficult to 
determine. 
The risk will be mitigated by adherence to CRS 
management guidelines as per Lee et al (2014), 
(Section 8.4) formulated based on prior CAR T cell-
gene therapy experience at various institutions. Splitting 
of CAR T dose at the highest dose level is likely to 
reduce risk of severe CRS. Additionally, presence of 
RQR8, which allows selective depletion of APRIL CAR 
T cells will help manage unresponsive CRS. 
Neurotoxicity has been seen with the CD19 CARs 
in patients with leukaemia and lymphoma. Clinical 
presentation can be variable and manifest as mild 
to severe encephalopathy, focal neurologic 
deficits, generalised seizures, severe irreversible 
neurologic deficits and death in a patient with 
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 as appropriate. 

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Risks  
Mitigation Strategy  
ALL. The cause of neurotoxicity is not 
well-understood, although it is reported to be fully 
reversible in most cases. 
Thrombocytopenia is often seen in CAR-treated 
patients. Thrombocytopenia was observed in 
2 patients in a BCMA-CAR study that responded 
to treatment; in 1 case thrombocytopenia was 
severe, requiring platelet transfusions for 9 weeks 
after infusion of the CAR T cells. 
Thrombocytopenia is believed to be 
efficacy-related, due to release of cytokines in the 
bone marrow. 
Thrombocytopenia will be managed as per standard 
institutional guidelines which may include platelet 
transfusion as necessary. 
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 BCMA or TACI) 
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 
BCMA and TACI expression is largely limited to 
plasma. Ongoing BCMA CAR studies have not shown 
any off-target toxicity. Bone marrow monocytes from 
some MM patients are also known to express TACI, but 
it remains to be investigated if the expression is 
adequate to trigger a CAR T cell response. Presence of 
RQR8, which allows selective depletion of APRIL CAR 
T cells, will help manage any severe off-target toxicity. 
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 multiple gated 
acquisition (MUGA) cardiac scans to demonstrate 
normal cardiac functioning prior to study enrolment.  
Tumour lysis syndrome may occur on treatment 
with AUTO2 due to rapid killing of malignant 
plasma cells and B cells. 
Tumour lysis syndrome is a common toxicity seen with 
the treatment of haematological malignancies; 
supportive care will be initiated rapidly. 
Hypogammaglobulinemia may occur as a 
consequence of depletion of the plasma cells by 
AUTO2 increasing the risk of infections. 
Hypogammaglobulinemia is seen with other commonly 
used agents such as rituximab. Oncologists are generally 
well versed with managing patients with chemotherapy 
associated hypogammaglobulinemia. 
Sepsis: Sepsis leading to death has been noted in 
3 patients treated with very high doses (5 × 108 
CAR T cells) of CD19 CAR in a study done at the 
Hospital of University of Pennsylvania 
Gradual titration of dose, splitting of dose at the highest 
dose level, prophylactic antibiotics and antiviral 
medications, close monitoring of patients and early 
intervention is likely to reduce the risk. 
Insertional mutagenesis: Disruption of the 
cellular transcriptome by retroviral-mediated 
insertional mutagenesis can, in rare cases, give rise 
to haematopoietic stem cells with elevated 
expression of growth-related genes, which can 
subsequently result in T cell leukaemia and/or 
lymphoma. 
T cells that have been transduced with a retrovirus have, 
to date, been proven safe. Unlike haematopoietic stem 
cells, T cells are highly resistant to retroviral vector-
induced transformation. The 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 a RCR prior to release to 
sites. The risks of a RCR are unknown. To date, no 
patient has developed an RCR with a retroviral based 
CAR T cell therapy. Patients will be monitored for a 
RCR by 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. 

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Risks  
Mitigation Strategy  
Dimethyl sulfoxide which is part of 
cryopreservative buffer may cause at high doses 
nausea, vomiting, abdominal cramps, and 
headache. Some patient may also experience a 
strong taste of garlic in their mouth or have a 
similar body odour lasting for a few days. Rarely, 
they may experience mild or severe cardiac, 
pulmonary, renal or neurological symptoms. 
Most patients are likely to be exposed to a small dose of 
DMSO, and in any case, the product will be formulated 
such that the general institutional maximum limit of 
70 g is not exceeded. Additionally, at these dose levels 
the side effects are likely to be mild and short lasting. In 
the rare event that the product dose is formulated such 
that DMSO maximum institutional limit (e.g. highest 
dose of 
 RQR8/APRIL CAR positive T cells) 
is exceeded, then the dose may be given up to 5 days 
apart. 
APRIL=a proliferation inducing ligand; BCMA=B cell maturation antigen; CAR=chimeric antigen receptor; CD=cluster of 
differentiation; CRS=cytokine release syndrome; DMSO=dimethyl sulfoxide; ECHO=echocardiogram; IB=Investigator’s 
Brochure; MM=multiple myeloma; MUGA=multiple gated acquisition; PCR=polymerase chain reaction; RCR=replication 
competent retrovirus; RQR8= safety switch gene; TACI=transmembrane activator and calcium modulator and cyclophilin 
ligand interactor. 
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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4 
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). 
4.1 
NUMBER OF PATIENTS 
It is anticipated that approximately 80 patients will be enrolled (consented) into the study 
with up to 72 patients receiving the treatment as outlined below: 
 
Phase I: A dose escalation involving up to a total of 42 patients (up to 6 patients per dose 
cohort and up to 12 at RP2D). 
 
Phase II: Dose expansion involving up to a total of 30 patients.  
Phase II of the study will follow Simon’s 2-stage optimal design as described in Section 11.1. 
4.2 
INCLUSION CRITERIA 
Patients must meet all the following criteria for study entry: 
1. Male or female patients, aged ≥18. 
2. Willing and able to give written, informed consent for the current study protocol 
AUTO2-MM1. 
3. Confirmed diagnosis of MM as per IMWG. 
4. Measurable disease as defined by any 1 of the following: 
 
Serum M-protein ≥500 mg/dL; 
 
Urine M-protein ≥200 mg/24 hours; 
 
Involved serum free light chain level ≥10 mg/dL, provided serum free light chain 
ratio is abnormal. 
5. Relapsed or refractory disease after either 1 of the following:  
a. Had at least 3 different prior lines1 of therapy including proteasome inhibitor 
(e.g. bortezomib or carfilzomib), and IMiD; e.g. thalidomide, lenalidomide or 
pomalidomide) and alkylator or monoclonal antibody. 
or 
b.  Have "double refractory" disease to a proteasome inhibitor and IMiD, defined as 
progression on or within 60 days of receiving these agents. 
6. 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.  
                                                 
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a. 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 3). 
b. 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 3) 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.  
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. 
8. Patients must weigh >30 kg.  
9. Serum calcium (corrected for serum albumin) or ionised calcium+ ≤upper limit of normal 
(ULN). Note: Prior treatment of hypercalcaemia is permitted and patients may enrol if 
hypercalcaemia returns to normal with standard treatment. 
10. Peripheral blood total lymphocyte count >0.5 × 109/L at enrolment and prior to 
leukapheresis. 
11. Patient has adequate bone marrow function without requiring ongoing blood product or 
granulocyte-colony stimulating factor support, and meets the following criteria: 
 
Neutrophils ≥1.0 × 109/L; 
 
Haemoglobin ≥80 g/L; 
 
Platelets ≥75 × 109/L. 
4.3 
EXCLUSION CRITERIA 
Patients meeting any of the following exclusion criteria must not be enrolled into the study: 
1. Women who are pregnant or lactating. 
2. Previous diagnosis of systemic light chain amyloidosis. 
3. Prior treatment with investigational or approved gene therapy or cell therapy products. 
4. Patient has previously received an allogenic stem cell transplant. 
5. 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 
6 months) cardiac event. 
6. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not 
excluded). 
7. Corrected QT interval (QTc)>470 ms on the screening electrocardiogram (ECG). 
8. Patients with evidence of uncontrolled hypertension. 

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9. Patients with a history of hypertension crisis or hypertensive encephalopathy. 
10. Left Ventricular Ejection fraction <50 (by ECHO or MUGA) unless the institutional 
lower limit of normal is lower. 
11. Patients with a history or evidence of deep vein thrombosis or pulmonary embolism 
requiring ongoing therapeutic anticoagulation at the time of pre-conditioning. 
12. Patients with active gastrointestinal bleeding. 
13. Patients with any major surgical intervention in the last 3 months, cement augmentation 
for vertebral collapse is permitted. 
14. Significant liver disease: alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≥3 × ULN, or total bilirubin ≥25 µmol/L (1.5 mg/dL), except in patients with 
Gilbert’s syndrome or evidence of end-stage liver disease (e.g. ascites, hepatic 
encephalopathy). 
15. Chronic renal impairment requiring dialysis, or calculated creatinine clearance 
<30 mL/min. 
16. Active infectious bacterial or viral disease (hepatitis B virus, hepatitis C virus, human 
immunodeficiency virus, human T-lymphotropic virus or syphilis) requiring treatment. 
17. Known active central nervous system involvement of MM. History or presence of 
clinically relevant central nervous system 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.  
18. Patients receiving corticosteroids at a dose of >5 mg prednisolone per day (or equivalent) 
that cannot be discontinued. 
19. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to AUTO2 
infusion. 
20. Active autoimmune disease requiring immunosuppression. 
21. Past or current history of other neoplasms, except for: 
 
Curatively treated non-melanoma skin cancer; 
 
Adequately treated in situ carcinoma of the cervix. 
Other cancer curatively treated and with no evidence of disease for at least 2 years or 
malignancy that in the opinion of the Investigator, with concurrence with the Sponsor 
Chief Medical Officer or medical designee, is considered cured with minimal risk of 
recurrence. 
22. Received any anti-myeloma therapy within the last 7 days prior to pre-conditioning or 
leukapheresis. G-CSF should stop 10 days prior to leukapheresis. 
23. Received any radiotherapy within the last 7 days prior to pre-conditioning or 
leukapheresis. Localised radiation to a single site, e.g. for bone pain is permitted at any 
time. 
24. Life expectancy <3 months. 
25. Known allergy to albumin, dimethyl sulfoxide (DMSO), cyclophosphamide or 
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26. Any other condition which in the Investigator’s opinion would make the patient 
unsuitable for the clinical trial. 
Prior to initiating the pre-conditioning and for AUTO2 Infusion: Patients meeting any of 
the following criteria must not initiate pre-conditioning or infusion with AUTO2 or must 
have treatment delayed until they no longer meet these criteria:  
1. Severe intercurrent infection at the time of treatment. 
2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of 
scheduled AUTO2 infusion. 
3. Clinical deterioration of organ functions (hepatic or renal function) exceeding the criteria 
set at study entry EARLY DISCONTINUATION 
4.3.1 
Discontinuation of Study 
A patient should be discontinued if: 
 
Disease progression as assessed by the Investigator. 
 
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 
AUTO2 administration. 
 
Intercurrent illness that prevents further follow-up. 
 
Patient refuses further follow-up. 
 
Noncompliance with study procedures. 
If a patient discontinues the study, this will not result in automatic withdrawal of the patient 
from the study. Following discontinuation, the patient should complete the End of Study visit 
as described in Section 9.1.5. The primary reason for treatment discontinuation will be 
documented in the electronic Case Report Form (eCRF). Patients who discontinue due to 
intercurrent illness that prevents administration of pre-conditioning chemotherapy and / or 
AUTO2 administration, may enrol back into the study after discussion with the Sponsor.    
Once a patient discontinues, they will be entered into a long-term follow-up study (or 
continue to be monitored in this study until they enrol onto the long-term study), unless the 
patient refuses to participate in the study. Patients who discontinue prior to AUTO2 infusion 
are not eligible for the long-term follow-up study. 
Of note, patients becoming pregnant will not be discontinued but will stay on study for 
follow-up. However, these patients will not undergo any invasive procedure or scans during 
the follow-up phase nor will they be eligible for retreatment.  

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4.3.2 
Patient Withdrawal from the Study 
A patient will be withdrawn from the study for any of the following reasons: 
 
Lost to follow-up. 
 
Withdrawal of consent*. 
 
The Sponsor discontinues the study. 
* Following withdrawal, no further protocol procedures can be performed. However, patients may be followed 
in the long-term protocol based on consent. 
If a patient is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the patient and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented. Data, such as information on survival or 
potential endpoints, may be collected from healthcare providers, public or medical records, or 
other sources as allowed by local guidelines and regulations. These data will be collected 
until the end of the study, even if the patient no longer attends study visits, unless the patient 
specifically withdraws consent and refuses to allow the collection of further data. 
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 invited to participate in 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. 
Withdrawal from the use of samples in future research 
The patient may withdraw consent for use of samples for future research. In such a case, 
samples will be destroyed after they are no longer needed for the clinical study. Details of the 
sample retention for research are presented in the main patient information sheet and 
informed consent form. 
4.3.3 
Procedures for Handling Withdrawals 
A patient 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 based on a 
decision of the Investigator, the follow-up should be maintained for safety review, subject to 
the continuing consent of the patient. 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. 
In the case AUTO2 does not meet the specifications of the release criteria, the case will be 
discussed with the Principal Investigator. It may be necessary to generate AUTO2 again if 
time permits (and biological screening repeated if necessary), otherwise the patient will be 
withdrawn from the study. 

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4.3.4 
Replacement Policy 
If a patient is unable to be dosed on the planned day, they may undergo delayed dosing and 
be re-preconditioned (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-myeloma 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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6 
CONTRAINDICATIONS, CONCOMITTANT MEDICATIONS AND 
PROHIBITED THERAPIES 
Any medication the patient is receiving at the time of enrolment and receives for an AE 
during the study until 60 days post AUTO2 infusion must be recorded along with: 
 
Reason for use. 
 
Dates of administration, including start and end dates. 
 
Dosage information including dose and frequency. 
Only concomitant medication related to AEs attributed to AUTO2 treatment will be recorded 
from Day 60 post AUTO2 infusion onwards. 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 patients will receive full supportive care, including pre-medication with antihistamine 
(dose in accordance with product licence) 30 minutes before T cell infusion, and IV fluids. 
Transfusions of blood products, antibiotics, analgesics, anti-epileptics and intensive care will 
also be provided as clinically indicated. Details of these should be recorded in the eCRF. 
CRS will be managed according to guidelines provided in the protocol (Section 8.4) and as 
per local policy. All safety management guidelines are only recommendations and deviations 
from this scheme are allowed according to the Investigator’s judgement and local institutional 
practice. 
6.1 
ALLOWED CONCOMITTANT MEDICATIONS/THERAPIES 
Bisphosphonate therapy: 
Bisphosphonates can be given to patients with evidence of lytic destruction of bone or with 
osteopenia, according to the American Society of Clinical Oncology Clinical Practice 
Guidelines, unless specifically contraindicated (Kyle et al. 2007). If bisphosphonate therapy 
was not started before the study, then it can be started 4 weeks after AUTO2 infusion and 
administered as per the standard practice. 
Palliative radiotherapy: 
Radiotherapy may be given concomitantly for the palliative control of pain. Irradiated lesions 
will not be evaluable for response. 
Other permitted therapies: 
The following medications and supportive therapies are examples of support therapies that 
may be used during the study: 
 
Antimicrobials or other supportive therapy as required to prevent infections. 
 
Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells. 
Pre and post AUTO2 infusion supportive therapies: 
Please refer to Section 8.1. 

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6.2 
PROHIBITED AND CAUTIONARY THERAPIES 
Herbal, homeopathic agents or high dose vitamins and mineral supplements: 
No herbal, homeopathic agents or high dose vitamin and mineral supplements will be allowed 
between Day -10 and Day 28 following AUTO2 infusion, unless recommended by the 
Principal Investigator.  
Corticosteroids and immunosuppressant (except for managing treatment related 
toxicity): 
Patients should not be receiving corticosteroids at doses of >5 mg prednisolone or equivalent 
at the time of AUTO2 infusion. 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 AUTO2. Corticosteroids should also be avoided post-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. 
Anti-cancer therapies: 
In general, patients should not receive other anti-cancer therapy (including radiotherapy 
except for pain management as mentioned above) or any other investigational drugs after 
AUTO2 infusion. Administration of other systemic anti-cancer therapy at any time after 
AUTO2 infusion will be considered an indicator of treatment failure (progressive disease). 
However, palliative radiotherapy for symptom control can be administered without 
necessarily indicating progressive disease. Patients who have been administered AUTO2 and 
subsequently require alternative anti-cancer therapy will complete the End of Study visit and 
roll on to a follow-up protocol.  
Intervening/bridging anti-cancer therapy administered during the screening period is 
permitted as long as compliant with the defined washout period. This therapy will be 
recorded in a new medical history eCRF covering the whole screening period. Please refer to 
see Section 10.3.1 and eCRF completion guidelines. 
Investigators can use any medication based on their clinical judgement and local institutional 
practice to optimise patient’s safety. 
6.3 
OVER-DOSAGE 
There is currently no experience of overdose of AUTO2 as no clinical studies have been 
performed to date. There is no specific treatment for an overdose of AUTO2. In event of 
overdose, any adverse reactions could be treated symptomatically. In the event of 
unmanageable toxicity, rituximab may be used to deplete AUTO2. 
AUTO2 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. 
6.4 
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. 

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Donating blood products and organs: 
Patients should not donate blood, organs, tissue and cells to others for transplant purposes 
after receiving AUTO2. 

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7 
STUDY PROCEDURES 
7.1 
LEUKAPHERESIS 
Enrolled patients who meet the eligibility criteria will be scheduled for leukapheresis to have 
their white blood cells collected. The leukapheresis may be repeated if inadequate number of 
cells has been collected, the leukapheresate is contaminated, or additional leukapheresate is 
necessary for re-treatment. The leukapheresate will be shipped to the Sponsor to prepare the 
cell product (Cell Handling Manual). Leukapheresis may be performed as per the preferred 
institutional process.  
The leukapheresate is considered to be the starting material for the manufacture of the 
ATIMP, AUTO2. The total cell number that is required for successful manufacture varies 
according to the dose level. The target collection may vary from 1 × 108 to 1 × 109 (for the 
highest dose proposed) leukocytes. If the collection is below this number, 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 AUTO2 at a temperature 
of 2 to 8°C within 24 hours, ideally within 3 hours (Cell Handling Manual). Further details 
regarding this process can be found in the Cell Handling Manual. 
Each leukapheresate will be identified by a unique patient ID number plus any additional 
patient identifiers as allowed as per local regulations.  
7.2 
PRE-CONDITIONING CHEMOTHERAPY FOR AUTO2 THERAPY 
Cyclophosphamide and fludarabine will be used for the pre-conditioning regimen prior to 
administration of AUTO2. The patients should receive fludarabine and cyclophosphamide 
daily for 3 days. The dosing is described below and fludarabine will be given first. 
 
Fludarabine 30 mg/m2 followed by cyclophosphamide 300 mg/m2 Day 1 (Day -6) 
 
Fludarabine 30 mg/m2 followed by cyclophosphamide 300 mg/m2 Day 2 (Day -5) 
 
Fludarabine 30 mg/m2 followed by cyclophosphamide 300 mg/m2 Day 3 (Day -4) 
The pre-conditioning chemotherapy should be completed 4 days (+/- 1 day) prior to AUTO2 
infusion. 
Fludarabine will be given by IV infusion over approximately 30 minutes in sodium chloride 
0.9%. For patients with renal impairment (glomerular filtration rate [GFR] 30 to 
60 mL/min/1.73m2 [corrected]), the dose of fludarabine should be reduced according to 
routine clinical practice (generally by 25%). When patients receive both cyclophosphamide 
and fludarabine, the fludarabine will be given first. 
Cyclophosphamide will be given by IV infusion over approximately 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 for the prescribed dose is generally considered 
unnecessary but may be considered based on institutional practice. Cyclophosphamide dose 
may be reduced if the leukocyte count is <2500 cells/ microliter with 6 hours post hydration.  
In the event of severe infusion reaction, the cyclophosphamide or fludarabine infusion should 
be stopped and the patient treated as clinically indicated. When the patient has recovered, the 
infusion may be restarted. If the patient develops an allergic reaction or has a history of 

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allergy to the drugs in the pre-conditioning regimen, then alternative drugs as per the 
institutional practice may be considered after discussion with the Sponsor. 
For additional information regarding both the drugs please follow the Summary of Product 
Characteristics. 
7.2.1 
Supply of Cyclophosphamide and Fludarabine 
Cyclophosphamide and fludarabine are considered to be non-investigational medicinal 
products as they are not being tested or used as a comparator used in this trial. 
Cyclophosphamide and fludarabine will be used to induce a physiological response in the 
current study as a pre-conditioning treatment, prior to ATIMP treatment. Both drugs are 
authorised and commercially available in the Member States. The Investigators will be 
responsible for their own supply of cyclophosphamide and fludarabine. Sufficient quantities 
of cyclophosphamide and fludarabine 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 fludarabine are cytotoxics and must be handled 
with care in accordance with local policy. Good aseptic practice must be employed when 
preparing cyclophosphamide and fludarabine solutions for infusion.  
7.2.2 
Accountability of Cyclophosphamide and Fludarabine 
Pharmacy records should be kept of the cyclophosphamide and fludarabine dispensed to trial 
patients.  
7.3 
AUTO2 TREATMENT AND PATIENT MONITORING 
7.3.1 
Treatment Allocation and Blinding 
7.3.1.1 
Patient 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. 
7.3.1.2 
Randomisation and Blinding Procedures 
Randomisation will not be used in this study. Patients will be allocated to receive study 
treatment in the order in which they qualify for the study. As this is an open-label study, 
blinding procedures are not applicable.  
7.3.2 
AUTO2 Administration 
AUTO2 (fulfilling the release criteria) will be administered as a single rapid IV infusion 
under 30 minutes from AUTO2 being thawed on Day 0 in an in-patient setting. Full details 
will be provided in the Cell Handling Manual. Only the Investigator or Investigator’s 
designee will dispense the study product. The Investigator or Investigator’s designee will 
verify the dose calculation and dose preparation in each treatment period. Details of the exact 
dose, time of preparation, and time of study medication administration will be documented in 
the applicable study records. 
In brief, AUTO2 will be thawed in a 37°C water bath under sterile conditions and the entire 
contents of the bag will be given as an IV infusion through a central or peripheral venous line 

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by a study research nurse experienced in the administration of cellular blood products as per 
the trial-specific procedure. The infusion line and the bag should be flushed as described in 
the Handling Manual to ensure all cells have been administered. 
7.3.3 
Monitoring During and After Drug Administration 
All patients will receive full supportive care, including pre-medication (see Section 8.2) 
30 minutes before T cell infusion, and IV fluids (approximately 125 mL/m2/hour) from 
1 hour prior to the T cell infusion until 2 to 4 hours post infusion. The patient will be 
monitored closely every 15 min (± 5 min) for the first hour and then every 30 minutes 
(± 10 min) for the next 3 hours as clinically indicated and thereafter monitored as per hospital 
policy but no less than 3 times a day. Transfusions of blood products, antibiotics, analgesics, 
and intensive care will also be provided as clinically indicated. Prophylaxis for tumour lysis 
syndrome (TLS) may be initiated if the risk is considered high or for all new patients if TLS 
occurs at a certain dose level. In the event of allergic adverse reactions, anti-histamines and 
hydrocortisone may be administered, as well as oxygen and salbutamol in the event of 
respiratory distress. Patients will be admitted to hospital for at least 10 days (or longer) for 
monitoring after receiving AUTO2 or until all AUTO2 related non-haematological toxicities 
have returned to ≤ Grade 1 or baseline, or longer as clinically necessary. 
After completing the study (Month 24, post AUTO2 administration or after disease 
progression), the patients will be followed on a separate long-term follow-up protocol 
(AUTO-LT1). 
7.3.4 
Dose Delay 
In the event that the pre-conditioning regimen is interrupted for intercurrent illness or other 
reasons, the patient may complete or recommence the preparative 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 AUTO2 on Day 0 for any reason, 
clinical judgement will be used to decide whether it is appropriate to delay the administration 
of AUTO2 or to wait for the patient’s safety blood results to recover sufficiently before 
repeating the pre-conditioning regimen and administering AUTO2. 
If the patient is deemed unsuitable to receive the AUTO2, they will be discontinued from the 
clinical trial (see Section 4.3.1 discontinuation of study) and replaced. Each case will be 
discussed with the Sponsor. 
7.3.5 
Interruption of AUTO2 Infusion 
In the event of severe infusion reaction, the AUTO2 infusion should be stopped and the 
patient treated as clinically indicated. When the patient has recovered, the infusion may be 
restarted as long as the cells remaining in the bag are given within the 30 minutes of thawing. 
In the event of the dose consisting of multiple bags, interruption of AUTO2 should not be 
greater than 2 hours between the first and the last bag administered. 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 and administered 
within 30 minutes of thawing. In case of uncertainty, individual cases should be discussed 
with the Sponsor. Duration of Treatment  

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In most patients, it is expected that AUTO2 will be given once. However, if a patient has 
sufficient AUTO2 remaining from the original manufacture and meets the re-treatment 
criteria, a second treatment may be given (see re-treatment of patient Section 7.3.6).  
7.3.6 
Re-treatment of Patients 
It is expected that most patients will receive a single as part of their treatment. However, 
some patients may have sufficient transduced T cells leftover, or leukapheresate which can be 
used to manufacture transduced cells, or they may be eligible for repeat leukapheresis, for a 
re-treatment at a later date. Such patients may receive a re-treatment of their own stored 
AUTO2. Prior to re-treatment, the patient needs to meet the following criteria: 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
Patients undergoing a second AUTO2 infusion may receive the same or modified 
pre-conditioning as clinically appropriate. If bridging therapy is required, it should be with an 
IMiD-based regimen, when clinically feasible. The dose of AUTO2 can be  up to the highest 
dose level cohort that is actively recruiting patients. Patients who are being re-treated will not 
be considered when making dose escalation decisions in that dose cohort, unless a DLT 
occurs as per DLT criteria in Section 3.1.4. 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. 
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. A patient with progressive disease that receives re-treatment 
will be censored from primary efficacy analysis at point of progression but will continue to 
remain on the study. 

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8 
GUIDELINES 
FOR 
PREVENTION, 
MONITORING 
AND 
MANAGEMENT OF ADVERSE EVENTS 
The guidelines detailed in Table 9 are suggested ways of managing key toxicities, however 
patients may be managed as per local institutional guidelines and or using clinical judgement. 
8.1 
GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY 
Table 9: 
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy 
Toxicity 
Preventive and Supportive Care Interventions 
Constitutional 
Administer acetaminophen for symptomatic management of fevers in patients 
with normal hepatic function; 
 
Provide cooling blankets for fevers >40°C; 
 
Avoid corticosteroids and non-steroidal anti-inflammatory drugs; and 
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 to 6 hours during hospital or ambulatory care 
stay 
 
Monitor vital signs every 2 hours in patients with fevers and tachycardia; 
 
Initiate replacement IV fluids for patients with poor oral intake or high insensible 
losses to maintain net even fluid balance; 
 
Administer IV fluid boluses for patients with systolic blood pressure less than 
their pre-infusion baseline; 
 
Patients with a systolic blood pressure <80% of their pre-infusion baseline and 
<100 mm Hg receive a 1 litre normal saline bolus; 
 
Patients with a systolic blood pressure <85 mm Hg receive a 1 litre normal saline 
bolus regardless of baseline blood pressure; 
 
Patients receiving >1 IV fluid bolus for hypotension or patients in the intensive 
care unit for toxicity management have a serum troponin drawn, and an ECG and 
an ECHO performed to evaluate for cardiac toxicity; and 
 
Norepinephrine is the preferred first-line vasopressor for patients with 
hypotension initiated on vasopressor support. 
Infectious disease 
Initiate prophylactic antimicrobials, such as trimethoprim-sulfamethoxazole, for 
Pneumocystis prophylaxis prior to conditioning chemotherapy; 
 
Initiate prophylactic antimicrobials, such as acyclovir or valacyclovir, for herpes 
virus prophylaxis prior to conditioning chemotherapy; and 
 
All patients with fevers and neutropenia have blood cultures drawn and 
assessment for broad-spectrum antibiotics as per institutional practice.  

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Toxicity 
Preventive and Supportive Care Interventions 
Hypogammaglobulinemia 
Consider IV Ig administration if the serum IgG level is <400mg/dl and or 
clinically appropriate. 
Hematologic 
Initiate allopurinol for TLS prophylaxis in patients without a contraindication 
prior to conditioning chemotherapy; if indicated. 
 
Transfuse packed red cells for goal haemoglobin of ≥80 g/dL; 
 
Transfuse platelets for a goal platelet count of ≥20,000/μL; 
 
Monitor complete blood count with differential at least daily. When absolute 
neutrophil count decreases to <500/μL, initiate granulocyte colony stimulating 
factor support. Continue until absolute neutrophil count increases to ≥1500 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 ≥100 mg/dL. If patient is 
bleeding, a higher level of fibrinogen should be maintained. 
Neurologic 
The nursing staff conducts focused neurologic examinations at least every 4 to 
6 hours in patients experiencing neurologic toxicity; 
 
Perform brain 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.  
CAR=chimeric antigen receptor; ECG=electrocardiogram; ECHO=echocardiogram; Ig=immunoglobulin; IV=intravenous; 
MRI=magnetic resonance imaging; PTT=partial thromboplastin time; ULN=upper limit of normal. 
Reference: (Brudno and Kochenderfer 2016). 
8.2 
PRE- AND POST-INFUSION SUPPORTIVE THERAPY 
AUTO2 is an autologous product, with fully human CAR construct 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 
(acetaminophen; 650 to 1000 mg orally) and an antihistamine (diphenhydramine 25 to 50 mg, 
or equivalent). These medications may be discontinued based on emerging data. In addition, 
pre-infusion medications listed in Table 10 may also be administered if necessary.  
Post-infusion medication listed in Table 10 may be considered following AUTO2 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 10: 
Pre- and Post-infusion Medications 
Medication 
Dose 
Administration  
Pre-infusion 
Post-infusion 
Antihistamine 
Diphenhydramine/ 
Chlorpheniramine 
(10 to 20 mg) or equivalent 
Oral – administer at least 
1 hour prior to study drug 
 
IV or as appropriate – 
administer at least 
30 minutes prior to study 
drug 
X 
 
 
Diphenhydramine/ 
Chlorpheniramine (8 to 
16 mg) or equivalent 
Oral - as clinically 
indicated 
 
Optional 
Antipyretic 
Paracetamol 
(acetaminophen) (650 to 
1000 mg) or equivalent 
Oral - administer at least 
30 minutes prior to study 
drug 
X 
 
 
Paracetamol 
(acetaminophen) (650 to 
1000 mg) or equivalent 
Oral - as clinically 
indicated 
 
Optional 
H2-antagonist 
Ranitidine or equivalent 
(50 mg) 
IV- start infusion 
30 minutes prior to study 
drug 
Optional 
 
Antiemetic 
Ondansetron (16 mg) or 
equivalent 
IV - start infusion 
30 minutes prior to study 
drug 
Optional 
 
 
Ondansetron (8 mg) or 
equivalent (long or short 
acting agents) 
Oral - as clinically 
indicated 
 
Optional 
IV=intravenous. 
Note: Steroids may be used in case of severe reactions not controlled by other measures. 
8.3 
TREATMENT OF INFUSION RELATED REACTIONS 
Patients who experience infusion-related reactions (to pre-conditioning or AUTO2) 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 11 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 10.1.3. 

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Table 11: 
Guidelines for the Management of Infusion-related Reactions 
NCI CTCAE Grade 
Treatment/Intervention 
Premedication 
at 
Subsequent 
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 
10 to 20 mg or equivalent and or 
paracetamol (acetaminophen) 650 
to 1000 mg if not instituted (see 
Table 10). 
Grade 2  
Moderate reaction; 
requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment 
Interrupt infusion 
Start IV fluids; give diphenhydramine 50 mg 
(or equivalent) IV and/or paracetamol 500 to 
1000 mg (acetaminophen); consider 
bronchodilator therapy; may also consider 
corticosteroids if necessary; monitor patient 
closely until recovery from symptoms. 
Restart infusion if AUTO2 dose has not been 
fully administered  
Symptoms recur: Stop and discontinue further 
infusion. 
The amount of AUTO2 infused must be 
recorded on the eCRF. 
Diphenhydramine/ 
Chlorpheniramine 10 to 20 mg or 
equivalent and/or paracetamol 
(acetaminophen) 500 to 1000 mg if 
not instituted (see Table 10). 
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 IV saline infusion; recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1:10000 
solution injected slowly for IV administration, 
and/or diphenhydramine/chlorpheniramine 
50 mg IV with methylprednisolone 100 mg IV 
(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 
medical monitor about merits of 
completing AUTO2 infusion if full 
dose has not been administered.  
Grade 4: Permanently discontinue 
any remaining AUTO2. 
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; IV=intravenous; 
NCI=National Cancer Institute. 

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8.4 
GRADING 
AND 
MANAGEMENT 
OF 
CYTOKINE 
RELEASE 
SYNDROME 
Cytokine release syndrome is a known toxicity with CAR T therapies. Clinical symptoms 
indicative of CRS may include but are not limited to fever (with or without rigors), arthralgia, 
nausea, vomiting, tachycardia, hypotension, headache, confusion, tremor, and delirium. 
Potentially life-threatening complications of CRS may include cardiac dysfunction, acute 
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and 
disseminated intravascular coagulation. Patients should be closely monitored for early signs 
and symptoms indicative of CRS. Patients with temperature ≥38.9°C within the first 36 hours 
after AUTO2 infusion are at higher risk of severe CRS and should be monitored closely. 
Trained clinical personnel should be prepared to intervene in the event of CRS. Resources 
necessary for resuscitation and supportive care including intensive care should be readily 
available. Recommendations for the clinical management of CRS are provided in Table 12. 
Table 12: 
Severity Grading and Management of CRS 
CRS Grade 
Treatment 
Grade 1 
Symptoms are not life threatening and require 
symptomatic treatment only, e.g. fever, nausea, 
fatigue, headache, myalgia, malaise. 
Supportive care according to 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 
Oxygen requirement <40% or 
Hypotension responsive to fluids or low dose of 
1 vasopressor or NCI CTCAE Grade 2 organ 
toxicity or Grade 3 transaminitis. 
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-dose vasopressor therapy. 
Low-flow-oxygen (<40% fraction of inspired oxygen). 
Use dexamethasone if hypotension persists after 1 to 
2 doses of anti-IL-6 therapy, dexamethasone can be used at 
10 mg IV every 6 hours.  
Hospitalisation for observation (for longer than 24 hours) 
as clinically appropriate. 
Grade 3 
Symptoms require and respond to aggressive 
intervention 
Oxygen requirement ≥40% or 
Hypotension not responsive to fluid therapy 
within 24 hours and requiring high dose or 
multiple vasopressors or NCI CTCAE Grade 3 
organ toxicity or Grade 4 transaminitis. 
Intensive care should be considered. 
Immunosuppressive therapy with tocilizumab (or 
siltuximab), repeat dose of tocilizumab at 6 to 12 hours if 
no clinical improvement.  
Consider adding siltuximab if not previously administered. 
Add steroids if unresponsive within 24 hours, 
dexamethasone 10 mg IV every 6 hours; if refractory, 
increase to 20 mg IV every 6 hours.  
Consider anti-tumour necrosis factor (TNF) antibodies as 
clinically appropriate. 
Multiple vasopressors or high-dose vasopressors. 
Oxygen (flow ≥40% fraction of inspired oxygen) (nasal 
cannula oxygen, high flow oxygen, continuous positive 
airway pressure or bilevel positive airway pressure). 
May consider use of rituximab to activate safety-switch if 
unresponsive to standard immunosuppressive therapies. 

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CRS Grade 
Treatment 
Grade 4  
Life-threatening symptoms, requirement for 
ventilator support or NCI CTCAE Grade 4 
organ toxicity (excluding transaminitis). 
Intensive care. 
Immunosuppressive therapy with tocilizumab +/-, 
siltuximab and high dose steroids (methylprednisolone 
1 g/day IV). 
If unresponsive, consider alternative agents such as anti-
TNF, and other agents as appropriate (Gargett et al. 2015, 
Kenderian et al. 2017, Ruella et al. 2017). 
Use of rituximab to activate safety-switch. 
Grade 5  
Death 
 
CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; TNF=tumour necrosis factor. 
Reference: (Lee et al. 2014). 
Details of the steroid doses and supportive medication doses are presented in Table 13. 
Table 13: 
Definitions and Doses of Vasopressors 
Definition of High-Dose Vasopressors 
Vasopressor 
Dose for ≥3 hours 
Noradrenaline monotherapy 
≥0.2 µg/kg/min 
Dopamine monotherapy 
≥10 µg/kg/min 
Phenylephrine monotherapy 
≥200 µg/min 
Adrenaline monotherapy 
≥0.1 µg/kg/min 
If on vasopressin 
High dose if vasopressin + noradrenaline equivalent of 
≥0.1 µg/kg/min (using Vasopressin and Septic Shock 
Trial formula) 
If on combination vasopressors (not vasopressin) 
Noradrenaline equivalent of ≥20 µg/min (using 
Vasopressin and Septic Shock Trial formula) 
An overview of the CRS management is presented in Figure 5. 
Figure 5: 
CRS Management Overview 
 
The pharmacologic management of CRS is presented in Table 14. 

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Table 14: 
Pharmacologic Management of CRS 
Drug 
Indication 
Dose 
Tocilizumab 
 
And/Or  
 
Siltuximab 
Consider using (early use criteria) if 
Persistent fever of ≥39°C despite antipyretics for 10 hours; 
Persistent/ recurrent hypotension after initial fluid bolus, 
and 
Initiation of oxygen supplementation (Gardner et al. 
2016). 
Highly recommended - if 
Left ventricular ejection fraction <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 pg/min 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. 
Tocilizumab: 8 mg/kg 
infused over 1 hour, 
dose not to exceed 
800 mg.  
Repeat dose if no 
response within 6 to 
12 hours and consider 
steroids as below. 
 
Siltuximab: 11 mg/kg 
infused over 1 hour. 
Methylprednisolone 
Cytokine Release Syndrome toxicity refractory to 
tocilizumab. 
1 to 2 mg/kg IV every 
12 hours 
For Grade 4 CRS use 
1 gm/day. 
CAR=chimeric antigen receptor; ECHO=echocardiogram; IV=intravenous; PTT=partial thromboplastin time; ULN=upper 
limit of normal. 
Reference: (Brudno and Kochenderfer 2016). 
8.5 
MANAGEMENT OF TUMOUR LYSIS SYNDROME 
Treatment with CAR T cells, such as AUTO2, can lead to rapid killing of malignant B cells, 
which can be associated with a release of intracellular ions and metabolic by-products into 
the systemic circulation and can thus, result in signs and symptoms indicative of TLS. 
Clinically, TLS can be characterised by rapid development of hyperuricemia, hyperkalaemia, 
hyperphosphatemia, hypocalcaemia, and potentially acute renal failure.  
Early recognition and monitoring of signs and symptoms of patients at risk for TLS, 
including identification of abnormal clinical and laboratory values, can lead to successful 
prevention of the serious clinical complications of the condition. Supportive care should be 
initiated according to the institutional standards and at the Investigator’s discretion. 
Management of TLS, including dehydration and management of abnormal laboratory test 
results such as hyperkalaemia, hyperuricemia, and hypocalcaemia, is highly recommended. It 
is also recommended that high-risk patients, i.e. those with a high tumour burden, be treated 
prophylactically in accordance with local standards (e.g. rehydration; diuretics; allopurinol 
and medication to increase urate excretion). 

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8.6 
GRADING AND MANAGEMENT OF NEUROTOXICITY 
Neurotoxicity has been seen with the CD19 CARs in patients with leukaemia and lymphoma, 
with a time course similar to CRS. The cause of neurotoxicity is not well-understood, 
although it is 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. Ongoing studies with BCMA CAR in myeloma patients have not reported any 
severe neurotoxicity or only reported occasional cases of neurotoxicity. However, close 
attention should be paid to neurological signs and symptoms.  
Neurological AEs can manifest as central abnormalities (e.g. aseptic meningitis or 
encephalitis) or peripheral sensory/motor neuropathies (e.g. Guillain-Barre Syndrome). The 
onset can be early after treatment, within hours to days. In general severe neurotoxicity is 
observed at or after the peak CRS. Patients with baseline thrombocytopenia may be at higher 
risk of severe neurotoxicity. Early recognition and treatment of neurologic AEs is critical to 
their management. Patients should be closely monitored for neurologic signs and symptoms 
such as headaches, confusion, alterations in wakefulness, hallucinations, dysphasia, ataxia, 
apraxia, facial nerve palsy, tremor, dysmetria, and seizures. These events are likely to be 
reversible; they should be managed with supportive care as appropriate.  
Neurotoxicity may also be caused by fludarabine but generally at higher doses (Helton et al. 
2013) than those being administered in the AUTO2-MM1 protocol. Symptoms including 
objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic 
neuropathy, blindness and coma have been reported in chronic lymphocytic leukaemia (CLL) 
patients treated with multiple cycles of fludarabine. As described in Section 3.2.3 death of 
3 young adults ALL patients due to cerebral oedema was partly attributed to fludarabine; 
however, two additional deaths due to cerebral oedema in the absence of fludarabine 
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 costimulatory 
domain which results in a slower proliferation. Patients should be closely monitored and 
managed as appropriate. Please see Table  for suggested grading and guidelines for 
management of neurotoxicity (Neelapu et al. 2017); however, the patient may be managed as 
per institutional management guidelines. 

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Table 15: 
Grading of Neurological AEs and CAR-T-Cell-Related Encephalopathy 
Syndrome (CRES) 
Symptoms or Sign  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
General neurotoxicity by 
NCI CTCAE 
Mild  
Moderate  
Severe 
Life threatening  
CAR-T-cell-related 
encephalopathy syndrome  
Neurological assessment 
score (by CARTOX-10*)  
7–9  (mild 
impairment)  
3–6 
(moderate 
impairment)  
0–2 (severe 
impairment)  
Patient in critical 
condition, and/or obtunded 
and cannot perform 
assessment of tasks  
Raised intracranial 
pressure  
NA  
NA  
Stage 1–2 
papilloedema‡, or CSF 
opening pressure <20 
mmHg  
Stage 3–5 papilloedema‡, 
or CSF opening pressure 
≥20 mmHg, or cerebral 
oedema  
Seizures or motor 
weakness  
NA  
NA  
Partial seizure, or 
non-convulsive 
seizures on EEG with 
response to 
benzodiazepine  
Generalized seizures, or 
convulsive or non-
convulsive status 
epilepticus, or new motor 
weakness  
CAR=chimeric antigen receptor; CARTOX-10=CAR-T-cell-therapy-associated toxicity 10-point neurological assessment 
CSF=cerebrospinal fluid; EEG=electroencephalogram; NA=not applicable.  
*In the CARTOX-10, one point is assigned for each of the following tasks that is performed 
correctly (normal cognitive function is defined by an overall score of 10):  
Orientation to year, month, city, hospital, and President/Prime Minister of country of 
residence (total of 5 points);  
Name three objects — for example, point to clock, pen, button (maximum of 3 points);  
Write a standard sentence, for example, ‘our national bird is the bald eagle’ (1 point);  
Count backwards from 100 in tens (1 point).  
Papilloedema grading is performed according to the modified Frisén scale (Frisen 1982). 
Table 15A: 
Management and Follow-up of Neurological AEs 
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 haloperidol (0.5 mg 
IV every 6 hours) 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 

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Management and Follow-up of Neurological AEs.  
EEG.  
Consider levetiracetam 750 mg every 12 hours (oral or IV) for a month. 
If EEG shows non-convulsive status epilepticus, treat as per algorithm in 
Table 15B. 
Consider anti-IL-6 therapy with tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg 
IV, if neurotoxicity is associated with concurrent CRS.  
Worsening: treat as ≥Grade 2 
Grade 2 
Monitor closely. Supportive care and neurological work-up as indicated for 
Grade 1.  
Tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV if associated with concurrent 
CRS. 
Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV 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 neurologic 
toxicities, with the 
exception of headaches, 
that last continuously 
for 24 hours or longer 
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 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.  
Stage 1 or 2 papilloedema with CSF opening pressure <20 mmHg should be 
treated as per algorithm presented in Table 15C.  
Consider repeat neuroimaging (CT or MRI) every 2 to 3 days if patient has 
persistent Grade ≥3 neurotoxicity. 
Consider using rituximab to activate safety-switch if unresponsive to standard 
immunosuppressive therapies. 
Grade 4 neurologic 
toxicity of any duration  
 
Any generalized 
seizures 
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.  
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.  
Consider using rituximab to activate safety-switch if unresponsive to 
immunosuppressive therapies. 
For convulsive status epilepticus, treat as per algorithm in Table 15B. 
Stage ≥3 papilloedema, with a CSF opening pressure ≥20 mmHg or cerebral 
oedema, should be treated as per algorithm in Table 15C. 
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. 

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Management and Follow-up of Neurological AEs.  
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 15B: 
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 to control electrographical seizures.  
Levetiracetam 500 mg IV bolus, as well as maintenance doses.  
If seizures persist, transfer to ICU and treat with phenobarbital loading dose of 60 mg 
IV.  
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.  
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.  
Levetiracetam 500 mg IV bolus, as well as maintenance doses.  
If seizures persist, add phenobarbital treatment at a loading dose of 15 mg/kg IV.  
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.  
Continuous electroencephalogram monitoring should be performed, if seizures are 
refractory to treatment.  
ICU=intensive-care unit; IV=intravenous. 
Table 15C: 
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).  
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 
recommended for Grade 4 CAR-T-cell-related encephalopathy syndrome 
(Table A).  
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 

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Condition  
Management 
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. 
8.7 
MANAGEMENT OF THROMBOCYTOPENIA  
Thrombocytopenia is often seen in CAR-treated patients, and in the case of the NCI BCMA 
CAR study was seen in 2 patients that responded to treatment; in 1 case, thrombocytopenia 
was severe, requiring platelet transfusions for 9 weeks after infusion of the CAR T cells. 
Thrombocytopenia is believed to be efficacy-related, due to release of cytokines in the bone 
marrow, and presumably is seen in myeloma because the tumour mass is largely located in 
the bone marrow. Efficacy-related symptoms, including CRS, neurotoxicity and 
thrombocytopenia all have a fast onset and are highly likely to be observed in the first week 
following CAR T cell infusion. Blood counts should be monitored closely and 
thrombocytopenia managed as per standard institutional guideline which may include platelet 
transfusion as necessary. 
8.8 
MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS DUE 
TO ON-TARGET BUT OFF-TUMOUR TOXICITY 
Though it is unlikely that AUTO2 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 organ and irAEs of any grade involving vital organs (e.g. lung, 
brain, and eyes), more aggressive monitoring and rapid institution of appropriate supportive 
care should be conducted. In case of severe irAE, not successfully managed by general 
supportive care, rituximab rescue therapy may be considered. 
8.9 
 
 
 
 
 
 
 
  

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9 
STUDY VISITS AND ASSESSMENTS 
9.1 
STUDY OVERVIEW 
9.1.1 
Screening Phase 
All patients must sign an informed consent form prior to the conduct of any study-related 
procedures. The Screening phase begins when the first screening assessment is conducted. 
During the Screening phase, eligibility criteria will be reviewed, demographic data obtained, 
and a complete clinical evaluation will be performed. Screening procedures will be 
performed up to 12 weeks before AUTO2 is administered (Schedule of Assessments). 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 provided that the assessments fulfil the study requirements and are performed 
within the specified timeframe prior to the ATIMP administration. Retesting of abnormal 
screening values that lead to exclusion is allowed during the screening phase (to reassess 
eligibility). The patients’ last results obtained prior to administering the pre-conditioning 
chemotherapy will be used to determine eligibility. The measurements collected at the time 
closest to, but prior to, the administration of AUTO2 will be defined as the baseline values 
for safety assessment and treatment decisions. Adverse events associated with screening 
procedures will be collected. Baseline data will be collected during screening as described in 
the Schedule of Assessments. 
Intervening/bridging anti-cancer therapy administered during the screening period is 
permitted. Where clinically feasible, an anti-CD38 antibody and IMiD combination regimen 
is to be preferred otherwise bridging therapy will be at the discretion of the investigator as it 
is compliant with the eligibility criteria and the defined washout periods. 
9.1.2 
Leukapheresis Phase 
The Leukapheresis Phase will begin with venepuncture for the collection of PBMCs. Patients 
will undergo an unstimulated leukapheresis for the generation of the AUTO2, following 
provision of informed consent and confirmation of registration into the study. Details of the 
leukapheresis procedure are provided in Section 7.1. During this period, the assessments 
described in the Schedule of Assessments will be performed. 
If a patient is unable to receive treatment as per original schedule after successful 
leukapheresis and manufacture of AUTO2 but subsequently re-screens and is eligible for 
treatment, repeat leukapheresis and manufacturing of AUTO2 may not be necessary and 
should be discussed with the Sponsor. 
9.1.3 
Pre-conditioning Phase 
Patients that still meet eligibility requirements for the study will proceed to receive a 
lymphodepleting pre-conditioning treatment with cyclophosphamide and fludarabine for 
3 days (starting Day -6), timed to end 4 days (±1 day) before AUTO2 infusion. The 
pre-conditioning phase will end with the beginning of treatment with AUTO2 infusion. 
During this phase, AEs associated with pre-conditioning chemotherapy as well as use of 
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9.1.4 
Treatment Phase 
The Treatment Phase will involve infusion of AUTO2 on Day 0 and will extend until the 
completion of DLT period (28 days afterAUTO2 infusion). The patient will be admitted to 
hospital prior to, or on the day of, infusion for up to 10 days for monitoring and management 
of CRS (longer if clinically necessary). Following infusion, the patient will be closely 
monitored as described in Section 7.3.3. The patient may be discharged from hospital when 
clinically appropriate or following successful management of CRS, even if it is prior to 
10 days if deemed appropriate by the treating Investigator. 
Following discharge from the hospital, the patient will be closely monitored for AEs and 
laboratory abnormalities, at least on a weekly basis. 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. Provided that all criteria are satisfied (see Section 7.3.6), patients may 
receive re-treatment of AUTO2. The patients will transition to the follow-up stage after 
completion of the DLT evaluation period. Safety and efficacy assessments described in the 
Schedule of Assessments will be performed and AEs and concomitant medications will be 
documented. The AUTO2 administration does not require the presence of a representative of 
the Sponsor. 
9.1.5 
Follow-up Phase 
Upon completion of the Treatment Phase, patients will enter the Follow-up Phase where they 
will continue to be followed for assessment of AEs and anti-tumour response until the End of 
Study. End of study will occur at the 2-year anniversary (±14 days) of the start of treatment, 
or at the time of disease progression, or withdrawal of consent. In the event that the patient is 
having a treatment related AE or SAE at the planned End of Study, then they can be further 
followed for up to a maximum period of 6 months or until it stabilises, or death, or 
withdrawal of consent or start of new treatment, whichever happens first. Laboratory 
assessments and visits for monitoring will be undertaken as clinically appropriate. Grade 3 or 
higher AEs that are considered related to the study medication will be recorded/reported as 
detailed in Section 10.3. 
9.1.6 
Long-term Follow-up 
Provided that patients signed an informed consent form, they will be enrolled on to a 
long-term follow-up protocol after completion of the study. They will be monitored for SAEs 
considered related to the study for a period of up to 15 years from the first AUTO2 infusion. 
The long-term follow-up protocol will be available prior to dosing the first patient.  
Note: Patients who have received AUTO2 and have discontinued or completed the study may 
continue to be monitored for AUTO2 treatment-related SAEs and AEs until they enrol onto 
the long-term follow-up study (AUTO-LT1) and the End of Study visit will be delayed. 
9.2 
DETAILS OF STUDY ASSESSMENTS 
9.2.1 
Demographic and Baseline Assessments 
The following will be collected at screening to determine eligibility and baseline status of the 
patient. Baseline safety assessments will also be performed as detailed in Section 9.2.2. 

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9.2.1.1 
Demographic Data and Baseline Variables 
Demographic data will include self-reported race/ethnicity, age, gender, and height at 
screening visit prior to leukapheresis. 
9.2.1.2 
Medical/Multiple Myeloma History 
Medical history includes clinically significant diseases, surgeries, MM history (including all 
prior cancer therapies and procedures), and all medications (e.g. prescription drugs, 
over-the-counter drugs, herbal/homeopathic remedies, and nutritional supplements) used by 
the patient. Histological confirmation of disease diagnosis will be obtained (pathology report) 
and results of cytogenetic markers analysis will be collected. 
9.2.1.3 
Pregnancy Test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing will be performed for 
women of childbearing potential at the screening visit and will be repeated as described in the 
Schedule of Assessments. 
9.2.2 
Safety Evaluations 
All patients who receive AUTO2 will be considered evaluable for toxicity assessment. Any 
clinically relevant changes occurring during the study must be recorded on the AE section of 
the eCRF. Safety assessments will be based on medical review of AE reports and the results 
of vital sign measurements, ECGs, physical examinations, clinical laboratory tests and ECOG 
performance status at specified time points as described in the Schedule of Events. 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; details regarding the SEC are provided in 
Section 10.5. The study will include the following evaluations of safety and tolerability 
according to the time points provided in the Schedule of Assessments. 
9.2.2.1 
Adverse Events 
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 10.3. 
Toxicity will be graded using the NCI CTCAE Version 4.03 criteria. The incidence of AEs 
will be tabulated and reviewed for potential significance and clinical importance. 
9.2.2.2 
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 AUTO2 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. Screening laboratory results must 
be available to the Investigator for evaluation before AUTO2 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 16. 

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Table 16: 
Clinical Laboratory Tests 
Assessment 
Description 
Haematology 
Haemoglobin, red blood cell count, platelet count, white blood cell count with 
differential (neutrophils, eosinophils, lymphocytes, monocytes, and basophils). 
Coagulation 
Prothrombin time, international normalised ratio, activated PTT, fibrinogen. 
Biochemistry 
Sodium, phosphate, potassium, ALT, AST, creatinine, CPK, lactate dehydrogenase, 
total bilirubin, calcium, total protein, albumin, glomerular filtration rate and 
creatinine clearance performed only at screening. 
CRP and Ferritin 
Ferritin and C-reactive protein. 
Pregnancy test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing for women of 
childbearing potential. 
Serology  
 
Human immunodeficiency virus antibody. 
 
Hepatitis B core antibody: if positive, further testing (deoxyribonucleic acid 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 
RNA PCR) should be performed to rule out active infection. 
 
Anti-human T-lymphotropic virus-1. 
 
Anti-human T-lymphotropic virus-2. 
 
Syphilis Serology. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; PCR=polymerase chain 
reaction; PTT=partial thromboplastin time; RNA=ribonucleic acid. 
9.2.2.3 
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 
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 
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. 
9.2.2.4 
Echocardiogram (ECHO) or Multiple Gated Acquisition (MUGA) 
Echocardiogram is the preferred method to assess cardiac ejection fraction and cardiac valve 
abnormalities; MUGA is an acceptable alternative. Assessments should be performed at 
screening and should include an evaluation for left ventricular ejection fraction and both 
right- and left-sided valvular lesions. Additional ECHO/MUGA assessments may be 
performed as clinically indicated. Generally, for a patient, the same procedure should be 
performed at screening and at any follow-up assessment to allow direct comparison. 
9.2.2.5 
Vital Signs 
Vital signs will include temperature, pulse/heart rate, respiratory rate, blood pressure [systolic 
and diastolic] and weight. Blood pressure and pulse/heart rate measurements should be 
recorded with the patient in a seated position. Multiple time points (minimum of 3) will be 

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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 a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
9.2.2.6 
Physical Examination 
A complete physical examination will be conducted at screening as per the institutional 
standard practice. Thereafter, a symptom-directed physical examination will be conducted at 
subsequent visits if indicated. From Day 0 onwards, only clinically significant observations 
will be recorded and reported as AEs as appropriate. The schedule for physical examinations 
is provided in the Schedule of Assessments. 
9.2.2.7 
ECOG Performance Status 
The ECOG scale provided in Appendix 2 will be used to grade changes in the patient’s daily 
living activities. The frequency of ECOG assessments is provided in the Schedule of 
Assessments. 
9.2.3 
Pharmacodynamics and Biomarker Evaluation 
Blood-based pharmacodynamics biomarkers will be evaluated in all patients as described in 
the Schedule of Assessments. Peripheral and bone-marrow biomarkers may be assessed pre- 
and post-treatment with AUTO2. Assessment at additional or fewer parameters and/or time 
points may be performed based on emerging data. 
9.2.3.1 
Evaluation of AUTO2 Persistence in Peripheral Blood 
Validated assays will be used to measure the expansion/persistence of RQR8/APRIL CAR T 
cells in the peripheral blood following agreed Standard Operating Procedures at time points 
indicated in the Schedule of Assessments. Flow cytometry will be used to measure the 
frequency of RQR8/APRIL CAR T cells per microliter of whole blood and/or a qPCR assay 
will be used to quantify the number of copies of the RQR8/APRIL CAR transgene per 
100 cells in peripheral whole blood. Sample analysis may cease when the results of 
2 consecutive tests are negative. Thereafter, if the patient has not experienced disease 
progression, samples will be collected and stored. Please refer to the AUTO2-MM1 
laboratory manual for the handling and storage of samples. 
9.2.3.2 
Evaluation of RCR in Peripheral Blood 
As per health authorities’ guidelines, tests will be performed to evaluate and monitor the 
presence of replication competent retrovirus by qPCR in whole blood. Please refer to the 
AUTO2-MM1 laboratory manual for the handling and storages of samples. 
9.2.3.3 
Insertional Mutagenesis 
Insertional mutagenesis leading to oncogenesis is a recognised safety concern of vector-based 
therapy. Samples will be stored and archived with the intent to be analysed for insertional 
mutagenesis, should a patient develop a new malignancy. The result will allow a potential 
relationship between AUTO2 treatment and the development of any new malignancy to be 
established. 

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9.2.3.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
9.2.3.5 
 
 
 
 
 
 
 
 
  
9.2.4 
Efficacy Evaluation 
Response evaluations for the primary endpoint/final analysis will be based on assessments, 
using 2016 IMWG Guidelines.  

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9.2.4.1 
Response Categories 
Disease evaluations must be performed at screening, on the day of AUTO2 administration 
and then at visits as outlined in the Schedule of Assessments. Disease evaluation assessments 
will be performed by a local laboratory until disease progression. This study will use the 
IMWG consensus recommendations for MM treatment response criteria (Durie 2006, 
Rajkumar et al. 2011, Kumar et al. 2016). New abnormalities or changes from screening 
assessments should be recorded in the patient’s medical notes and should also be recorded on 
the corresponding eCRF page. 
Disease response: The International Myeloma Working Group uniform response criteria for 
MM will be employed for documenting disease response, as presented in Appendix 1. 
Disease progression must be consistently documented across clinical study sites using the 
criteria in Appendix 1. It is important that instances and evidence of disease progression 
(diagnosis and documentation) be reported to the Sponsor as soon as possible. The medical 
monitor will review the data to confirm that the IMWG 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. If the medical monitor considers that the IMWG criteria for 
disease progression have not been met, then the Sponsor will contact the Investigator to 
discuss the patient. For continuation in the study, the IMWG response will be determined on 
an ongoing basis by the Investigator. 
Serum free light chain assay test results will be analysed by the local laboratory for the 
assessment of sCR, according to the most recently published IMWG criteria (Durie 2006). 
 
 
9.2.4.2 
Myeloma Protein Measurements in Serum and Urine 
Blood and 24-hour urine samples for M-protein measurements will be analysed by the local 
laboratory. Only one serum and one 24-hour urine sample per time point are required to 
perform the following tests: 
 
Serum quantitative immunoglobulins (QIgs): All patients will be evaluated for IgG, IgA, 
IgM at screening. To be repeated as clinically indicated. 
 
Serum M-protein quantitation by serum protein electrophoresis (SPEP) at screening 
visits, on Day 0 and then repeated at every visit from the end of the DLT period onwards. 
 
Serum immunofixation at Screening and thereafter when a CR is suspected. 
 
Serum free light chain assay: This test will be performed at screening visits, on Day 0 
and then repeated at every visit from the end of the DLT period onwards for patients who 
are serum free light chain positive i.e. light chain positive MM or when CR is suspected 
or maintained.  
 
Twenty-four hour-urine M-protein quantitation by urine protein electrophoresis (UPEP) 
at screening visits, on Day 0 and then repeated at every visit from the end of the DLT 
period onwards.  
 
Urine immunofixation at Screening and thereafter when a CR is suspected. 
Blood and 24-hour urine samples will be collected as specified in the Schedule of 
Assessments until the development of confirmed disease progression. Serum and urine 
immunofixation test and serum free light chain assay will be performed at Screening and 

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thereafter when a CR is suspected (when serum or 24-hour urine M-protein electrophoresis 
[by SPEP or UPEP] are 0 or non-quantifiable). For patients with light chain MM, both serum 
and urine immunofixation test and serum free light chain assay will be performed routinely. 
9.2.4.3 
Serum Calcium Corrected for Albumin 
Blood samples for calculating serum calcium corrected for albumin will be collected and 
analysed locally, as specified in the Schedule of Assessments, until the development of 
confirmed disease progression. Development of hypercalcemia (corrected serum calcium 
>11.5 mg/dL or 2.8 mmol/L) can indicate disease progression or relapse if it is not 
attributable to any other cause (Appendix 1). Calcium binds to albumin and only the unbound 
(free) calcium is biologically active; therefore, the serum calcium level must be adjusted for 
abnormal albumin levels (“corrected serum calcium”). If blood is analysed at a local 
laboratory, measurement of free ionised calcium is an acceptable alternative to corrected 
serum calcium for determining hypercalcemia. Free ionised calcium levels greater than the 
ULN (local laboratory reference ranges) are considered to be hypercalcaemic for this study. 
9.2.4.4 
β2-microglobulin and Albumin 
Blood samples for β2 microglobulin and albumin are to be collected at screening and will be 
analysed by the local laboratory.  
9.2.4.5 
 
 
 
 
 
 
 
 
 
9.2.4.6 
Fluorodeoxyglucose PET/CT Imaging 
A PET-CT assessment of skull, ribs, upper limbs, femurs, pelvis and spine will be completed 
at baseline to accurately assess osteolytic lesions and the extent of hypermetabolic activity in 
intramedullary and extramedullary sites during screening. 
Positron emission tomography-computerised tomography scans may be repeated when 
clinically indicated to document response or progression. Computerised tomography (CT) or 
MRI is an acceptable method for evaluation of bone disease, and may be included at the 
discretion of the Investigator. 
Disease progression may be manifested by pain related to osteolytic bone disease. Therefore, 
disease progression may be documented, in these cases, by appropriate radiological 
investigations. If the diagnosis of disease progression is obvious by radiographic 
investigations, then no repeat confirmatory radiography is necessary. In instances where 
changes may be more subtle, repeat radiology at an appropriate time point may be required. 
9.2.4.7 
Documentation of Extramedullary Plasmacytomas 
Sites of known extramedullary plasmacytomas must be documented at screening. Clinical 
examination or cross-sectional imaging (MRI, CT, PET-CT) may be used to document 

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extramedullary sites of disease. The modality used for follow-up scans for disease response 
assessment should be consistent with initial/baseline techniques used. Positron emission 
tomography-computerised tomography is recommended for functional assessment, however, 
MRI (spine and/or pelvis) and CT may be used according to local practice. 
Extramedullary plasmacytomas should be assessed for all patients with a history of 
plasmacytomas or if clinically indicated at screening by radiological imaging, and repeated as 
clinically indicated during treatment to confirm response or disease progression. If 
assessment can only be performed radiologically, then evaluation of extramedullary 
plasmacytomas may be done every 12 weeks. 
For every patient, the methodology used for evaluation of each disease site should be 
consistent across all visits. Irradiated or excised lesions will be considered unmeasurable, and 
will be monitored only for disease progression.  
To qualify for PR or MR, the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have decreased by at least 50% or 25%, respectively, 
and new plasmacytomas must not have developed (see Appendix 1). To qualify for disease 
progression, either the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have increased by at least 50%, or a new plasmacytoma 
must have developed. In the cases where not all existing extramedullary plasmacytomas are 
reported, but the sum of products of the perpendicular diameters of the reported 
plasmacytomas have increased by at least 50%, this will also qualify as disease progression. 
9.2.5 
Blood Volume Collections 
The total estimated volume of blood collected for safety, biomarkers and immunological 
assessments (with the exception of the leukapheresis procedure) across the entire study will 
not normally exceed 665 mL. The maximum volume of blood collected on any 1 day will 
unlikely exceed 50 mL. No more than 300 mL of blood will be collected in any 28-day 
period. Additional samples may be collected as required to ensure the safety of the patient, or 
for additional cytokine measurements, which are not included in these estimates. Refer to the 
laboratory manual for the handling and storages of samples. 

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10 
SAFETY MANAGEMENT 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of patients, investigators, and the Sponsor, and are 
mandated by regulatory agencies worldwide. The Investigator or site staff will be responsible 
for detecting, documenting and reporting events that meet the definition of an AE or SAE. 
10.1 
ADVERSE EVENTS DEFINITIONS 
10.1.1 
Adverse Event 
According to the International Conference on Harmonisation (ICH) guideline for Good 
Clinical Practice (GCP), an AE is any untoward medical occurrence in a clinical investigation 
patient administered a pharmaceutical product, regardless of causal attribution. An AE can 
therefore be any of the following: 
 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition). 
 
Recurrence of an intermittent medical condition (e.g. headache) not present at baseline. 
 
Any deterioration in a laboratory value or other clinical test that is considered clinically 
relevant, may lead to a change in concomitant medication or management, or leads to a 
change in study treatment, concomitant treatment or discontinuation from the study. 
 
Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g. pre-conditioning or screening invasive 
procedures such as biopsies). 
Events that do NOT meet the definition of an AE include: 
 
Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
The disease/disorder being studied (i.e. MM), or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than expected for the 
patient’s condition.  
10.1.2 
Adverse Reactions 
An adverse reaction is defined as any untoward and unintended responses to an 
investigational medicinal product related to any dose administered.  
An unexpected adverse reaction is an adverse reaction in which the nature or severity of 
which is not consistent with the Investigator Brochure for AUTO2. 

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10.1.3 
Serious Adverse Events 
An SAE is any AE that meets any of the following criteria: 
 
Fatal (i.e. the AE actually causes or leads to death). Death due to disease progression will 
not be considered as an SAE. 
 
Life threatening (i.e. the AE, in the view of the Investigator, places the patient at 
immediate risk of death). This does not include any AE that, had it occurred in a more 
severe form, or was allowed to continue, might have caused death. 
 
Requires inpatient hospitalisation (other than pre-planned hospitalisation including any 
hospitalisation for study treatment and hospitalisation for disease progression) or 
prolongation of existing hospitalisation due to an AE.  
 
Results in persistent or significant disability/incapacity (i.e. the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 
 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
study drug. 
 
It is a suspected transmission of any infectious agent via a medicinal product. 
 
Significant medical event in the Investigator's judgment (e.g. may jeopardise the patient 
or may require medical/surgical intervention to prevent 1 of the outcomes listed above). 
Protocol-specific SAEs are as follows: 
 
Grade 4 CRS. 
 
Any new primary cancers. 
 
Significant cardiac dysfunction such as Grade 3 or higher decrease in left ventricular 
ejection fraction. 
Serious AEs are required to be reported by the Investigator to the Sponsor immediately 
(i.e. no more than 24 hours after learning of the event; see Section 10.3.2 for reporting 
instructions). 
Events NOT considered as SAEs are hospitalisations for: 
 
A procedure for protocol/disease-related investigations (e.g. surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow 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 10 days following 
AUTO2 infusion for general management purposes or until resolution of AEs, or if it is 
standard process for the management of underlying disease (including the re-admission 
for close monitoring in a setting such as an increase or expansion of RQR8/APRIL 
CART cells). 
 
Hospitalisation for administration of pre-conditioning chemotherapy or conducting study 
procedures. 
 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 

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 
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. 
 
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 Case Report Form (CRF). 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 CRF 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.  
10.1.4 
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, even if it is a component of 
the study endpoint (e.g. all-cause mortality). 
10.1.5 
Adverse Events of Special Interest 
The following are AEs of special interest. 
 
Grade 2 to 5 CRS. 
 
Grade 2 to 5 neurotoxicity (including depressed level of consciousness, dysphagia, 
ataxia, seizures, and cerebral oedema). 
AEs of special interest that are ≥Grade 3 should be reported to the sponsor within 24 hours of 
becoming aware of the event. (see Section 10.3.2 for reporting instructions). Additional 
information may be gathered about these AEs. Based on emerging data, additional AEs may 
be classified as AEs of special interest.  
10.2 
ADVERSE EVENTS ASSESSMENT 
Adverse event information will be collected at study visits. Patients will be instructed to call 
study site personnel to report any abnormalities during the intervals between study visits, and 
to come to the study site if medical evaluation is needed and the urgency of the situation 
permits. Adverse events will be assessed by the Investigator, or appropriately qualified 

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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 Table 17. 
10.2.1 
Severity of Adverse Events 
The severity of AEs will be graded based upon the patient’s symptoms according to the NCI 
CTCAE (Version 4.03). 
Adverse events that are not defined in the NCI CTCAE should be evaluated for severity 
according to the following scale. 
Table 17: 
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. 
Note: 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 10.2.1. Seriousness, not 
severity, serves as a guide for defining regulatory obligations. 
10.2.2 
Assessment of Relationship 
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 that are classed 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 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 
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Relationship assessments that are classed 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 suspected of being related to a comparator, ancillary, or additional 
study drug that has not been manufactured or provided by the Sponsor, please provide the 
name of the manufacturer when reporting the event. 
10.3 
ADVERSE EVENTS REPORTING PROCEDURES 
10.3.1 
All Adverse Events 
All AEs, both those observed by study site personnel and those spontaneously reported by the 
patient, will be recorded in the eCRF. All AEs, irrespective of seriousness, severity, or 
relationship to study drug, must be recorded using medical terminology that accurately 
reflects the event. Whenever possible, diagnoses should be given 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 source document and reported according in the eCRF as per eCRF completion 
guidelines. 
Note: Grade 1 to 2 haematology laboratory abnormalities can be frequent in this patient 
population and are not subject to reporting unless felt to be clinically significant by the 
investigator. 
The reporting period for all AEs is described in Table 18. 
Table 18: 
Reporting Period for All AEs 
From: Informed consent form signature  
Until: Day 60 post last AUTO2 infusiona 
From: Day 60 post last AUTO2 infusion  
Until: End of studya 
 All AEs from Day -7 
 AEs related to study procedure only for 
48 hours following the procedure 
(e.g. leukapheresis, bone marrow biopsy)  
 All SAEs from Day -7 
 Treatment-related Grade 3 to 5 AEs  
 AEs of special interest (Section 10.3.3) 
 AEs related to study procedure (e.g. bone marrow 
biopsy) 
 Treatment-related SAEs 
AE=adverse event; SAE=serious adverse event. 
a 
Or until withdrawal whichever occurs first. 
Adverse events related to intervening/bridging non-study related anti-cancer therapy 
administered prior to pre-conditioning or AEs associated with disease progression during the 
same period will not be reported as AEs. These events will be recorded as an update to the 
medical history of the patient (since signing consent). Please refer to eCRF completion 
guidelines. 

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The Investigator should follow each AE until the event has resolved to baseline or Grade 1, 
the event is assessed as stable by the Investigator, the patient is lost to follow-up or the 
patient withdraws consent. 
In the event that a drug-related AE and/or any SAE is ongoing at the time of proposed 
completion of the study (2 years after dosing or at progression, whichever happens first) then 
the event will be further followed up until the AEs are resolved or stabilised for a maximum 
of 6 months, or death, withdrawal of consent, start of new treatment or until patient contact 
discontinues, whichever happens first (extended end of study). During the extended 
follow-up period, the following will be collected: 
 
Resolution information for ongoing AEs from the study treatment period 
 
New treatment related AEs only  
10.3.2 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the appropriate Sponsor contact 
person by study-site personnel within 24 hours of their knowledge of the event. Additional or 
follow-up information on a SAE must also be reported immediately (i.e. within 24 hours of 
awareness of the SAE). This timeframe also applies to additional new information 
(follow-up) on previously forwarded SAEs. Should the FDA or other regulatory authority 
require that the Sponsor submit additional data on the event, the Investigator will be asked to 
provide those data to the Sponsor in a timely fashion.  
Information to be Provided by the Investigator for an SAE: 
Information regarding an SAE will be transmitted to the Sponsor using the Serious Adverse 
Event Form, which must be completed and signed by a physician from the study site, and 
transmitted to the Sponsor within 24 hours. The Sponsor or designee will require all of the 
following information about the patient and the event: 
 
Investigator identification 
 
Patient identification code 
 
Information on study treatment (e.g. start/stop date, dose and frequency of study 
treatment administered) 
 
Description of event 
In addition to the above information, the Sponsor will require the Investigator’s assessment of 
the following: 
 
Severity of the SAE 
 
Relationship of the SAE to the study treatment 
 
Outcome of the SAE  
The SAE report form should be completed and faxed or emailed to the relevant toll-free fax 
number or email address (fax numbers and email address are listed on the form and in the 
SAE form completion guidelines). 
Follow-up Information on an SAE: 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted. Serious AEs must be followed up to resolution by the 
Investigator, even if this extends beyond the study reporting period. Resolution of an SAE is 

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defined as the return to baseline status, Grade 1, or stabilisation of the condition with the 
expectation that it will remain chronic. For all SAEs, the Investigator is obligated to pursue 
and provide information to the Sponsor. In addition, an Investigator may be requested by the 
Sponsor to obtain specific information in an expedited manner. This information may be 
more detailed than that captured on the SAE form. In general, this will include a description 
of the AE in sufficient detail to 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. 
After the initial SAE report, the Investigator is required to follow each patient proactively and 
to report new significant follow-up 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 
There should be routine follow-up as clinically appropriate until the event resolves or 
stabilises or end of study as per criteria described above. The Medical Monitor may specify a 
longer period of time, if required to assure the safety of the patient. 
At the end of study, or following discontinuation, any new toxicities related to the study 
treatment or any events listed below will be reported and followed up under the long-term 
follow up protocol: 
 
All AEs designated as special interest 
 
Serious AEs related to the study drug and the following:  
 
New malignancies 
 
Incidence/exacerbation of pre-existing neurologic disorder 
 
New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
 
Others designated special interests 
 
New incidence of a haematological disorder designated of special interest. 
The Investigator should report these events to the Sponsor Drug Safety Provider in writing (if 
the study database has not yet been closed on the AE eCRF page). 
Medical Review and Reporting by the Sponsor: 
The Sponsor (or designee) will determine expedited reporting requirements for each reported 
SAE according to local requirements based upon: 
 
Causality  
 
Expectedness  
The current IB Section “Reference Safety Information” will be used as the reference for 
determination of expectedness and risk assessment of AUTO2 related AEs. 

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Any Serious Adverse Reaction associated with the use of cyclophosphamide and fludarabine 
used as pre-conditioning will be notified to the appropriate manufacturer. 
Sponsor Responsibility for Expedited Safety Reports: 
The Sponsor (or designee) will notify Investigators of all reportable SAEs. This notification 
will be in the form of an expedited safety report. Upon receiving such notices, the 
Investigator must review and retain the notice with other study-related documentation. 
The Sponsor will ensure that SAEs are reported to the IEC/IRB(s) and regulatory 
authority(ies) according to local requirements. 
Suspected unexpected adverse reactions and other significant safety issues reported from the 
investigational product development program shall be reported to the relevant competent 
health authorities in all concerned countries according to local regulations (either as 
expedited safety reports and/or in aggregate reports), by the Sponsor (or designee). 
10.3.3 
Adverse Events of Special Interest 
Adverse events of special interest that are ≥Grade 3, including neurotoxicity and CRS, should 
be reported to the sponsor within 24 hours of becoming aware of the event. 
10.3.4 
Management of Pregnancy 
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. The pregnancy report form should be 
completed and faxed or emailed to the relevant toll-free fax number or email address (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. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs and must be reported using the SAE 
Form to the Sponsor immediately (i.e. no more than 24 hours after learning of the event). 
The Investigator should 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. The pregnancy report form should be completed and 
faxed or emailed to the relevant toll-free fax number (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 need to sign an authorisation for use and disclosure of pregnancy health information to 
allow for follow-up on her pregnancy. The Investigator may provide information on the risks 

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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 
learning of the event 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 10.3.2. 
 
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, without regard 
to causality, as SAEs.  
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to the study drug should also be reported to the 
Sponsor’s Drug Safety Group within 24 hours of the Investigator’s knowledge of the event by 
faxing or emailing a copy of the Pregnancy Report Form to the Sponsor Pharmacovigilance 
Provider. 
10.3.5 
Other Significant Events Reporting 
Safety events of interest on a Sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
 
Overdose of a Sponsor study drug 
 
Suspected abuse/misuse of a Sponsor study drug 
 
Inadvertent or accidental exposure to a Sponsor study drug 
 
Medication error involving a Sponsor product (with or without subject/patient exposure 
to the Sponsor study drug, e.g. name confusion) 
A study drug overdose is the accidental or intentional use of AUTO2 in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not an 
AE unless it results in untoward medical effects. Any AUTO2 overdose or incorrect 
administration of AUTO2 should be noted on the corresponding CRF page. All AEs 
associated with an overdose or incorrect administration of AUTO2 should be recorded on the 
AE CRF page. If the associated AE fulfils serious criteria, the event should be reported to the 
Sponsor immediately (i.e. no more than 24 hours after learning of the event; see 
Section 10.3.2). 
10.3.6 
Reporting Exemptions 
Relapse or disease progression that does not worsen in terms of time-course or severity of the 
disease expected in that patient is considered an efficacy outcome measure and will not be 
reported as an AE. Tumour-related signs and symptoms will only be recorded as AEs if they 

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worsen in severity or increase in frequency beyond that normally expected for disease 
progression as determined by the Investigator. 
Hospitalisation due solely to the progression of underlying malignancy will NOT be 
considered an SAE. Death as a result of disease progression is not an SAE. 
10.4 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL 
The study could be stopped by the SEC or IDMC upon occurrence of any of the following 
events: 
 
Unexpected and related SAE that exposed patients participating to the study to 
unacceptable risk of harm. 
 
Uncontrolled SAEs related to identified risks. 
 
The occurrence of Grade 4 toxicity in 3 patients, unless, in the opinion of the IDMC, is 
considered manageable with the institution of appropriate supportive care or dose 
modification.  
 
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 relevant regulatory 
authorities and ethics committees. 
10.5 
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 medical monitor and details of membership is 
described in the SEC charter. The team will meet at regular frequencies throughout study 
conduct; during dose escalation, the SEC will meet after the 1st and 3rd patient in each cohort 
have completed the DLT evaluation period. Additional ad hoc meetings will be instituted if 
safety stopping criteria is met or as clinically necessary based on merging data. 
Documentation of meeting outcomes will be maintained by the Sponsor. 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 an RP2D is determined. The SEC may stop further enrolment into 1 or more of the 
cohorts if treatment-emergent toxicity is determined to result in an unfavourable change in 
patient risk/benefit. In Phase II, cumulative safety data will be assessed by the SEC after 
10 patients are treated and on a periodic basis not exceeding 3 to 6 months. Decisions and/or 

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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. 
10.6 
INDEPENDENT DATA MONITORING COMMITTEE 
An IDMC consisting of two independent physicians and one 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 the SEC: 
 
When any safety stopping criteria (Section 10.4) is met 
 
Prior to opening Phase II 
 
At the interim analysis of Phase II (after 10 patients have been treated) 
 
Annually (6 monthly during active enrolment) during Phase II to review cumulative 
safety data 
Throughout the trial, information regarding all SAEs and DLTs as well as dose escalation 
meeting minutes will be sent to the IDMC members. 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. 
When a RP2D decision is made by the SEC, the decision will need to be reviewed and 
endorsed by the IDMC prior to opening Phase II. 
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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11 
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. 
11.1 
SAMPLE SIZE ESTIMATION 
Approximately 80 patients will be enrolled into the study and up to 72 patients will be 
treated. 
 
Phase I: Dose escalation: up to 42 patients in total (up to 6 per dose cohort and up to 12 
at a RP2D). 
 
Phase II: Dose expansion: up to 30 patients in total.  
In the dose escalation phase, an accelerated titration design will be used for the first cohort, 
with 1 patient being recruited into the lowest dose level. However, if Grade 2 or higher 
toxicity is observed during the DLT observation period, the design will transition into a 
standard 3+3 design. All subsequent cohorts will follow a 3+3 design.  
Phase II of the study will follow Simon’s 2-stage optimal design. The null hypothesis that the 
true response rate is 10% will be tested against a 1-sided alternative. In the first stage, 
10 evaluable patients will be accrued (6 weeks post treatment of 10th evaluable patient). If 
there are 1 or fewer responses in these 10 evaluable patients, the study will be stopped. 
Otherwise, 19 additional evaluable patients will be accrued for a total of 29. The null 
hypothesis will be rejected if 6 or more responses are observed in 29 evaluable patients. This 
design yields a type I error rate of 5% and power of 80% when the true response rate is 30%. 
11.2 
DESCRIPTION OF ANALYSIS DATASETS 
11.2.1 
Full Analysis Set 
The full analysis set will consist of all patients enrolled into the study. 
11.2.2 
Safety Analysis Set for the Study and for Study Treatment 
All patients who have started pre-conditioning therapy of cyclophosphamide and fludarabine 
will be included in the safety analysis set for the study. A patient who has pre-conditioning 
therapy but not AUTO2 therapy will not be excluded from the safety analysis set for the 
study. 
All patients who receive at least 1 dose (complete or partial dose) of AUTO2 therapy will be 
included in the safety analysis set for the Study treatment. 
11.2.3 
Efficacy Analysis Set 
All patients who receive at least 1 dose (complete or partial dose) of AUTO2 therapy will be 
included in the efficacy analysis set. 
11.3 
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 

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variables. Time to event endpoints will be summarised using Kaplan-Meier method. 
Summary statistics will be presented for baseline characteristics. 
11.3.1 
Primary Endpoints 
The primary endpoints of the study are as follows: 
 
Phase 1: Safety (to determine the MTD and RP2D) 
 
Incidence of Grade 3 to 5 toxicity occurring within the DLT period (28 days post 
AUTO2 infusion). 
 
Frequency of DLT and the persistence of AUTO2. 
 
Phase II: Safety and Anti-tumour Effect 
 
Best overall response post-AUTO2 infusion.  
11.3.1.1 
Phase I: Safety 
Safety associated with AUTO2 administration (only those who received AUTO2). 
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 
AUTO2 up to 60 days after the last infusion, any event that is considered drug-related 
regardless of the start date of the event, or any event that is present at baseline and continues 
after the first dose of study treatment but worsens in intensity. 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 
according to NCI CTCAE Version 4.03, and the baseline and worst post-baseline values 
within 3 months from the AUTO2 administration observed for each patient will be 
summarised. 
Adverse events of special interest will be analysed in greater depth, including the time to 
onset and time to resolution where appropriate. 
11.3.1.2 
Phase I: Recommended Part 2 Dose and Maximum Tolerated Dose 
At the end of the Phase I dose escalation phase, the RP2D will be identified based on the 
safety data and evaluation of the activity data collected in the dose escalation phase. 
11.3.1.3 
Phase II: Anti-tumour Effect 
The primary endpoints for Phase II (efficacy) will be assessed as follows: 
 
Best Overall response (sCR+CR+VGPR+PR) rate, following treatment with AUTO2 
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11.3.2 
Secondary Endpoints 
Feasibility of AUTO2 manufacture in this patient population (all patients) 
Feasibility of product generation will be examined by assessing the number of AUTO2 
successfully manufactured as a fraction of the number of patients undergoing leukapheresis 
(all patients registered).  
Clinical efficacy of AUTO2 
 
Determine the clinical benefit (sCR+CR+VGPR+PR+MR) rate following treatment with 
AUTO2. 
 
Evaluate clinical outcomes including duration of response, time to disease progression, 
PFS, and OS. 
 
Duration of response will be calculated from the date of first observation of sCR, 
CR, VGPR or PR to the date of disease progression, relapse or death, for patients 
who are considered as responders (achieved at least PR). Patients who have not 
progressed, relapsed or died will be censored at the last adequate disease assessment. 
 
Clinical benefit (sCR+CR+VGPR+PR+MR) rate following treatment with AUTO2 
cells. 
 
Time to Progression will be calculated from the date of AUTO2 treatment to the date 
of progression. Patients who have not progressed, relapsed or died without 
progression/relapse will be censored at the last adequate disease assessment. 
 
Progression-Free Survival will be calculated from the date of AUTO2 treatment to 
the date of progression or death. Patients who have not progressed or relapsed will 
be censored at the last adequate disease assessment. 
 
Overall Survival will be calculated from the date of AUTO2 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).  
 
Time to response will be calculated from the start date of treatment to the date of first 
observation of sCR, CR, VGPR or PR, for patients who are considered as responders. 
Biomarker and pharmacodynamic effects of AUTO2 
The following analyses on the pharmacodynamic effects of AUTO2 will be performed for 
patients who received AUTO2: 
 
Expansion and persistence of RQR8/APRIL CAR positive T cells in the peripheral blood 
as determined by qPCR and flow cytometry will be summarised using the appropriate 
statistical methods: 
 
Expansion is defined as the maximum level of RQR8 expression in both qPCR 
(copies/μg genomic deoxyribonucleic acid) and flow cytometry (cells/µL) assays 
during follow-up. Engraftment is defined as detection of any level of RQR8 
expression in circulating T cells (i.e. PBMC) by qPCR (viral insertions per genome) 
and/or flow cytometry following infusion (cells/µL).  
 
Persistence is defined as the duration of detectability, from infusion to the first 
negative result. 

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11.3.3 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
11.3.4 
Immunogenicity Data 
Analyses of immunogenicity data will be documented in the Statistical Analysis Plan. 
11.3.5 
Pharmacokinetics 
Not applicable. 
11.3.6 
Other Analyses 
Not applicable. 
11.3.7 
Interim Analysis 
In the Phase II part of the study, an interim analysis will be performed after 10 patients are 
enrolled and considered evaluable in Phase II (6 weeks post treatment of 10th evaluable 
patient). The study will be stopped in this first stage if no more than 1 response (as per 
IMWG) has been observed. If the response rate has exceeded interim analysis stopping 
criteria prior to 10 evaluable patients having been enrolled, then the study will continue to 
full enrolment. A formal interim analysis will still be performed after the 10th evaluable 
patient. 

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12 
DATA QUALITY CONTROL AND ASSURANCE 
12.1 
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/favourable opinion, as soon as possible. The deviation or 
change will be submitted to: 
 
IEC/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 informed consent form 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 contact from new patients prior to enrolment. 
If the revision is an administrative letter, investigators must inform their IEC(s)/IRB(s). 
12.2 
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.  
12.3 
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 CRF 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 the medical monitor (e.g. pathology reports, imaging reports, cancer treatment history), 
this may help to better understand a patient’s general condition, emerging safety issues, 
effectiveness of their management and the efficacy of treatment. 
The Sponsor must be informed immediately of any change in the personnel involved in the 
conduct of the trial. 
12.4 
AUDITS AND SITE INSPECTIONS 
Authorised personnel from domestic and foreign regulatory authorities and the Sponsor 
Quality Assurance (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. 

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13 
DATA HANDLING AND RECORD KEEPING 
13.1 
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 
CRFs should be reviewed and electronically signed and dated by the Investigator or a 
designee. The eCRF system will be FDA Code of Federal Regulations 21 Part 11 compliant. 
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 
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 
Organization 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. 
13.2 
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, informed consent forms, 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. 

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14 
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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15 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
ETHICS COMMITTEE REVIEW AND APRROVAL 
The final study protocol, including the final version of the written patient information sheet, 
informed consent form and any other relevant patient facing material, must be approved or 
given a favourable opinion in writing by an IEC/IRB as appropriate.  
15.2 
REGULATORY AUTHORITY REVIEW AND APPROVAL 
The study will not commence before approval from the regulatory authority 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.  
15.3 
INVESTIGATOR RESPONSIBILITIES 
15.3.1 
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 Good Clinical Practice: 
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 (IND), 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”. 
15.3.2 
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 of 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. 
15.3.3 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from patients 
prior to conducting any study-related procedures. All consent documentation must be in 
accordance with applicable regulations and ICH GCP. Each patient is requested to sign and 

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date the informed consent form after she/he has received and read the patient information 
sheet 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 will be given adequate time to evaluate the information given to 
them before signing and dating the informed consent form. It will also be explained to the 
patients that they are free to refuse entry into the study at any time and without prejudice to 
future treatment. The informed consent form must also be signed and dated by the person 
obtaining consent. The original signed informed consent form for each patient will be 
retained on file by the Investigator and the second signed original given to the patient. 
Informed consent 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 form during the study, the Investigator must 
always use the most current IEC/IRB approved form for documenting written informed 
consent. 
15.3.4 
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. 
15.3.5 
Communication with Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) 
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 informed consent form, any written information to the patients, patients’ recruitments 
procedures (e.g. advertisement if applicable), Investigator’s brochure, 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 the ATIMP 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, 
informed consent form changes or revisions of other documents originally submitted for 
review; 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 will submit the informed consent to the Sponsor for approval prior to 
submitting to the IEC/IRB.  

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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. 
15.3.6 
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 Informed Consent Form.  
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 Informed Consent Form signed by the patient, unless 
permitted or required by law. 
15.4 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL 
FUTURE RESEARCH 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to further understand AUTO2, 
to understand advanced cancers, to understand differential drug responders, and to develop 
tests/assays related to AUTO2 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. Patients may withdraw their consent for their samples to 
be stored for research. 

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16 
STUDY COMPLETION 
All materials or supplies provided by the Sponsor will be returned to the Sponsor upon study 
completion. The study will be considered complete when the last patient completes their final 
follow-up visit and all the data clarification forms have been resolved. A final Clinical Study 
Report will be provided to the relevant authorities within 12 months after the completion 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 
according to 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 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 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Section 801 of the FDA Amendments Act mandates the registration with ClinicalTrials.gov 
of certain clinical trials of drugs (including biological products) and medical devices subject 
to 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 protocol, CRFs 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 the 
ATIMP. 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 CRFs 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 suggested publication and/or its timing (at the Sponsor’s 
discretion). 
In addition, if requested by the Sponsor, the Investigator shall withhold publication an 
additional 6 months to allow for filing a patent application or taking such other 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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18 
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. 
Attal, M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. (1996). A 
prospective, randomized trial of autologous bone marrow transplantation and chemotherapy 
in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335(2):91-97. 
Berdeja, JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA, Jr., et al. (2017). Phase 
II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of 
patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J 
Haematol 177(2):254-262. 
Brentjens, RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, et al. (2003). 
Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-
stimulated by CD80 and interleukin-15. Nat Med 9(3):279-286. 
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 and Kochenderfer JN (2016). Toxicities of chimeric antigen receptor T cells: 
recognition and management. Blood 127(26):3321-3330. 
Brudno, JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, et al. (2018). T Cells 
Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen 
Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J Clin 
Oncol:Jco2018778084. 
Carpenter, RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. (2013). B-
cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. 
Clinical Cancer Research: An Official Journal of the American Association for Cancer 
Research 19(8):2048-2060. 
Child, JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. (2003). High-dose 
chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 
348(19):1875-1883. 
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. 
Claudio, JO, Masih-Khan E, Tang H, Goncalves J, Voralia M, Li ZH, et al. (2002). A 
molecular compendium of genes expressed in multiple myeloma. Blood 100(6):2175-2186. 
Cooper, LJN, Topp MS, Serrano LM, Gonzalez S, Chang W-C, Naranjo A, et al. (2003). T-
cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-
versus-B-lineage leukemia effect. Blood 101(4):1637-1644. 
CRUK 
(2014). 
Myeloma 
Statistics. 
Retrieved 
June 
2016 
from 
http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-
type/myeloma. 

AUTOLUS LTD 
 
AUTO2-MM1 
Version 7.0, 27 June 2018 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
 PAGE 109 OF 120 
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. 
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. Journal of Clinical Oncology: Official Journal of the 
American Society of Clinical Oncology 26(32):5233-5239. 
Durie, BGM (2006). International uniform response criteria for multiple myeloma. 
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, 
U.K 20(10):1-7. 
Enblad, G, Karlsson H, Wikstrom K, Essand M, Savoldo B, Brenner MK, et al. (2015). Third 
Generation CD19-CAR T Cells for Relapsed and Refractory Lymphoma and Leukemia 
Report from the Swedish Phase I/IIa Trial. Blood 126(23):1534. 
Fan, F, Zhao W, Liu J, He A, Chen Y, Cao X, et al. (2017). Durable remissions with BCMA-
specific 
chimeric 
antigen 
receptor 
(CAR)-modified 
T 
cells 
in 
patients 
with 
refractory/relapsed multiple myeloma. Journal of Clinical Oncology 35(18_suppl):LBA3001-
LBA3001. 
FDA (2017). YESCARTA Prescribing Information. Retrieved 19 December 2017 from 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/App
rovedProducts/UCM581226.pdf. 
FDA (Undated). KYMRIAH Prescribing Information. Retrieved 19 December 2017 from 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/App
rovedProducts/UCM573941.pdf. 
Frisen, L (1982). Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg 
Psychiatry 45(1):13-18. 
Fry, EE (2016). CD22 CAR Update and Novel Mechanisms of Leukemic Resistance. 
American Association for Cancer Research, New Orleans, Louisiana. 
Fry, TJ, Stetler-Stevenson M, Shah NN, Yuan CM, Yates B, Delbrook C, et al. (2015). 
Clinical Activity and Persistence of Anti-CD22 Chimeric Antigen Receptor in Children and 
Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL). Blood 
126(23):1324-1324. 
Garcia-Carmona, Y, Cols M, Ting AT, Radigan L, Yuk FJ, Zhang L, et al. (2015). 
Differential induction of plasma cells by isoforms of human TACI. Blood 125(11):1749-
1758. 
Gardner, R, Leger KJ, Annesley CE, Summers C, Rivers J, Gust J, et al. (2016). Decreased 
Rates of Severe CRS Seen with Early Intervention Strategies for CD19 CAR-T Cell Toxicity 
Management. Blood 128(22):586-586. 
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. The New England 
Journal of Medicine 373(11):1040-1047. 
Gargett, T, Fraser CK, Dotti G, Yvon ES and Brown MP (2015). BRAF and MEK inhibition 
variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro. 
Journal of Immunotherapy (Hagerstown, Md.: 1997) 38(1):12-23. 

AUTOLUS LTD 
 
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 PAGE 110 OF 120 
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. 
Goebeler, M-E, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. (2016). Bispecific T-
Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With 
Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study. Journal 
of Clinical Oncology 34(10):1104-1111. 
Hallek, M (2013). Chronic lymphocytic leukemia: 2013 update on diagnosis, risk 
stratification and treatment. Am J Hematol 88(9):803-816. 
Harousseau, JL and Moreau P (2009). Autologous hematopoietic stem-cell transplantation for 
multiple myeloma. N Engl J Med 360(25):2645-2654. 
Helton, KJ, Patay Z and Triplett BM (2013). Fludarabine-induced severe necrotizing 
leukoencephalopathy in pediatric hematopoietic cell transplantation. Bone Marrow 
Transplantation 48(5):729-731. 
Hoyos, V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, et al. (2010). 
Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance 
their anti-lymphoma/leukemia effects and safety. Leukemia 24(6):1160-1170. 
Jakubowiak, A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, et al. (2016). 
Randomized 
phase 
2 
study: 
elotuzumab 
plus 
bortezomib/dexamethasone 
vs 
bortezomib/dexamethasone for relapsed/refractory MM. Blood 127(23):2833-2840. 
Jensen, MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. (2010). 
Antitransgene rejection responses contribute to attenuated persistence of adoptively 
transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol 
Blood Marrow Transplant 16(9):1245-1256. 
Kenderian, SS, Porter DL and Gill S (2017). Chimeric Antigen Receptor T Cells and 
Hematopoietic Cell Transplantation: How Not to Put the CART Before the Horse. Biol Blood 
Marrow Transplant 23(2):235-246. 
Kershaw, MH, Teng MWL, Smyth MJ and Darcy PK (2005). Supernatural T cells: genetic 
modification of T cells for cancer therapy. Nature Reviews. Immunology 5(12):928-940. 
Kimberley, FC, van der Sloot AM, Guadagnoli M, Cameron K, Schneider P, Marquart JA, et 
al. (2012). The design and characterization of receptor-selective APRIL variants. The Journal 
of Biological Chemistry 287(44):37434-37446. 
Klebanoff, CA, Khong HT, Antony PA, Palmer DC and Restifo NP (2005). Sinks, 
suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor 
immunotherapy. Trends in Immunology 26(2):111-117. 
Klinger, M, Benjamin J, Kischel R, Stienen S and 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. Journal of Clinical Oncology 34(15_suppl):LBA3010-LBA3010. 

AUTOLUS LTD 
 
AUTO2-MM1 
Version 7.0, 27 June 2018 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
 PAGE 111 OF 120 
Kochenderfer, JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. (2012). 
B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a 
clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119(12):2709-
2720. 
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):540-549. 
Kochenderfer, JN, Yu Z, Frasheri D, Restifo NP and 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. 
Kocoglu, M and Badros A (2016). The Role of Immunotherapy in Multiple Myeloma. 
Pharmaceuticals 9(1). 
Kumar, S, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. (2012). Risk of 
Progression and Survival in Multiple Myeloma Relapsing After Therapy with IMiDs and 
Bortezomib: A Multicenter International Myeloma Working Group Study. Leukemia 
26(1):149-157. 
Kumar, S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. (2016). 
International Myeloma Working Group consensus criteria for response and minimal residual 
disease assessment in multiple myeloma. Lancet Oncol 17(8):e328-e346. 
Kyle, RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. (2003). Review of 
1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78(1):21-33. 
Kyle, RA and Rajkumar SV (2004). Multiple myeloma. N Engl J Med 351(18):1860-1873. 
Kyle, RA and Rajkumar SV (2009). Criteria for diagnosis, staging, risk stratification and 
response assessment of multiple myeloma. Leukemia 23(1):3-9. 
Kyle, RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. (2007). American 
Society of Clinical Oncology 2007 clinical practice guideline update on the role of 
bisphosphonates in multiple myeloma. J Clin Oncol 25(17):2464-2472. 
Laubach, JP, Mitsiades CS, Mahindra A, Schlossman RL, Hideshima T, Chauhan D, et al. 
(2009). Novel therapies in the treatment of multiple myeloma. J Natl Compr Canc Netw 
7(9):947-960. 
Laubach, JP, Voorhees PM, Hassoun H, Jakubowiak A, Lonial S and Richardson PG (2014). 
Current strategies for treatment of relapsed/refractory multiple myeloma. Expert review of 
hematology 7(1):97-111. 
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. Journal of Immunotherapy (Hagerstown, Md.: 1997) 33(7):723-734. 
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):517-528. 

AUTOLUS LTD 
 
AUTO2-MM1 
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Clinical Study Protocol 
 
CONFIDENTIAL 
 
 PAGE 112 OF 120 
Lee, L, Bounds D, Paterson J, Herledan G, Sully K, Seestaller-Wehr LM, et al. (2016). 
Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated 
cytotoxicity in multiple myeloma. British Journal of Haematology:n/a-n/a. 
Liu, Y, Chen Z, Wei R, Shi L, He F, Zixiao S, et al. (2018). Remission observed from a phase 
1 clinical study of CAR-T therapy with safety switch targeting BCMA for patients with 
relapsed/refractory multiple myeloma. ASCO Poster, Abstract: 8020. 
Lonial, S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. (2016). Daratumumab 
monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-
label, randomised, phase 2 trial. Lancet (London, England) 387(10027):1551-1560. 
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. 
Moreaux, J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, et al. (2005). The level of 
TACI gene expression in myeloma cells is associated with a signature of microenvironment 
dependence versus a plasmablastic signature. Blood 106(3):1021-1030. 
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? 
Nature Clinical Practice. Oncology 3(12):668-681. 
NCT02064387 (2014). Dose Escalation Study to Investigate the Safety, Pharmacokinetics, 
Pharmacodynamics, Immunogenicity and Clinical Activity of GSK2857916. Retrieved 15 
August 
2017 
from 
https://clinicaltrials.gov/ct2/show/NCT02064387?term=NCT02064387&rank=1. 
NCT02215967 (2014). Study of T Cells Targeting B-Cell Maturation Antigen for Previously 
Treated 
Multiple 
Myeloma. 
 
from 
https://clinicaltrials.gov/ct2/show/NCT02215967?term=NCT02215967&rank=1. 
NCT02348216 (2016). A Phase 1-2 Multi-Center Study Evaluating KTE-C19 in Subjects 
With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1) - Full Text View - 
ClinicalTrials.gov. 
Retrieved 
11 
April 
2017 
from 
https://clinicaltrials.gov/ct2/show/NCT02348216. 
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. 
NCT02546167 (2015). CART-BCMA Cells for Multiple Myeloma. Retrieved 15 August 
2017 from https://clinicaltrials.gov/ct2/show/NCT02546167?term=NCT02546167&rank=1. 
NCT02658929 (2016). Study of bb2121 in Multiple Myeloma. Retrieved 15 August 2017 
from https://clinicaltrials.gov/ct2/show/NCT02658929?term=NCT02658929&rank=1. 
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). Journal of Clinical Oncology 
34(15_suppl):7559-7559. 
Neelapu, SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. (2017). 
Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev 
Clin Oncol. 

AUTOLUS LTD 
 
AUTO2-MM1 
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Clinical Study Protocol 
 
CONFIDENTIAL 
 
 PAGE 113 OF 120 
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):649-655. 
Palumbo, A and Anderson K (2011). Multiple myeloma. The New England Journal of 
Medicine 364(11):1046-1060. 
Philip, B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, et al. (2014). A highly 
compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 
124(8):1277-1287. 
Porter, DL, Levine BL, Kalos M, Bagg A and June CH (2011). Chimeric antigen receptor-
modified T cells in chronic lymphoid leukemia. The New England Journal of Medicine 
365(8):725-733. 
Raje, NS, Berdeja JG, Lin Y, Munshi NC, DiCapua Siegel DS, Liedtke M, et al. (2018). 
bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple 
myeloma: Updated results from a multicenter phase I study. J Clin Oncol 36 (suppl; abstr 
8007). 
Rajkumar, SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. (2011). 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 117(18):4691-4695. 
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. 
Ruella, M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, et al. 
(2017). Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 
chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31(1):246-248. 
San-Miguel, JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. 
(2014). Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib 
and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a 
multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15(11):1195-1206. 
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):1822-1826. 
Simon, R, Freidlin B, Rubinstein L, Arbuck SG, Collins J and Christian MC (1997). 
Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 
89(15):1138-1147. 
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):1282-1295. 
Spear, P, Barber A and 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 and 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. 

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 PAGE 114 OF 120 
Tai, Y-T and Anderson KC (2015). Targeting B-cell maturation antigen in multiple myeloma. 
Immunotherapy. 
Tarte, K, De Vos J, Thykjaer T, Zhan F, Fiol G, Costes V, et al. (2002). Generation of 
polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant 
plasmablasts. Blood 100(4):1113-1122. 
Tarte, K, Zhan F, De Vos J, Klein B and Shaughnessy J, Jr. (2003). Gene expression profiling 
of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell 
differentiation. Blood 102(2):592-600. 
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):2123-2138. 
Wrzesinski, C and Restifo NP (2005). Less is more: lymphodepletion followed by 
hematopoietic 
stem 
cell 
transplant 
augments 
adoptive 
T-cell-based 
anti-tumor 
immunotherapy. Current Opinion in Immunology 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. 

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19 
APPENDICES 
Appendix 1: International Myeloma Working Group (IMWG) response criteria for 
multiple myeloma for documenting disease response 
Response 
Category* 
IMWG Criteria 
Stringent 
clinical 
response 
Complete response as defined below plus normal free light chain (FLC) ratio and absence of 
clonal cells in bone marrow by immunohistochemistry or immunofluorescence a. 
Complete 
response 
(CR) 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomasb and <5% plasma cells in bone marrow c. 
Very good 
partial 
response 
(VGPR) 
Serum and urine monoclonal protein (M-protein) detectable by immunofixation but not on 
electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level 
<100 mg/24 hours. 
Partial 
response 
≥50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by ≥90% or 
to <200 mg/24 hours. 
If the serum and urine M-protein are unmeasurable a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria. 
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measurable, ≥50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was ≥30%. 
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of 
soft tissue plasmacytomas (SPD) is also required.b 
Minimal 
Response 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 
50 to 89%. 
If present, a 25% to 49% reduction in the size of soft tissue plasmacytomas is also required.b 
No 
change/Stable 
disease 
Not meeting criteria for CR, VGPR, partial response, minimal response or progressive 
disease. 
Progressive 
diseased,e 
Increase of ≥25% from lowest response value in any 1 or more of the following: 
Serum M-component and/or (the absolute increase must be ≥0.5 g/dL)  
Serum M-component increases of ≥1 g/dL are sufficient to define relapse if starting M-
component is ≥5 g/dL 
Urine M-component and/or (the absolute increase must be ≥200 mg/24 hours) 
Only in patients without measurable serum and urine M-protein levels; the difference 
between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. 
Bone marrow plasma cell percentage; the absolute percentage must be ≥10%f  
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% 
increase in the longest diameter of a previous lesion >1 cm in short axisb 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only 
measure of disease. 
Clinical 
Relapse 
Clinical relapse requires 1 or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (Calcium elevation, 
Renal insufficiency, Anaemia and Bone abnormalities). It is not used in calculation of time to 
progression or progression-free survival] but is listed here as something that can be reported 
optionally or for use in clinical practice. 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not 
constitute progression). 

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Response 
Category* 
IMWG Criteria 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is 
defined as a 50% (and at least 1 cm) increase as measured serially by the SPD of the 
measurable lesion. 
Hypercalcaemia (>11 mg/dL); 
Decrease in haemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related 
conditions; 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to 
myeloma;  
Hyperviscosity related to serum paraprotein 
Relapse from 
CR d (To be 
used only if 
the end point 
studied is 
disease free 
survival) g 
Any 1 or more of the following: 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis. 
Development of ≥5% plasma cells in the bone marrow f 
Appearance of any other sign of progression (i.e. new plasmacytoma, lytic bone lesion, or 
hypercalcaemia). 
CR=complete response; FLC=free light chain; M-protein=monoclonal protein; PR=partial response; SPD=sum of the 
products of the maximal perpendicular diameters; VGPR=very good partial response. 
*All response categories require two consecutive assessments made any time before starting any new therapy 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by 
serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed 
above. Very good partial response in such patients is defined as a >90% decrease in the difference between involved and 
uninvolved FLC levels. 
a 
Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal 
ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2. 
b 
Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans 
where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler 
c 
Confirmation with repeat bone marrow biopsy not needed. 
d 
All relapse categories require 2 consecutive assessments made at any time before classification as relapse or disease 
progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for 
progressive disease shown here to be classified as progressive disease for the purposes of calculating time to progression 
and progression-free survival. The definitions of clinical relapse, relapse from CR and relapse from MRD are not to be 
used in calculation of time to progression or progression-free survival.  
e 
In the case where a value is felt to be a spurious result per physician discretion (e.g., a possible laboratory error), that 
value will not be considered when determining the lowest value. 
f 
Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
g 
For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using 
criteria listed above for progressive disease. 

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Appendix 2: 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 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken et al. 1982). 

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Appendix 3: 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 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 methods 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. 
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) 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. 
Highly effective methods of birth control 
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: 
 
Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
o 
oral 
o 
intravaginal 
o 
transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 1:  
o 
oral 
o 
injectable 
o 
implantable2 
 
Intrauterine device2 
 
Intrauterine hormone-releasing system2 
 
Bilateral tubal occlusion2 
 
Vasectomised partner2, 3 
 
Sexual abstinence4 
1 
Hormonal contraception may be susceptible to interaction with the advanced therapy investigational 
medicinal product, which may reduce the efficacy of the contraception method.  
2 
Contraception methods that in the context of this guidance are considered to have low user dependency.  
3 
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the women of child bearing potential trial participant and that the vasectomised partner has 
received medical assessment of the surgical success.  
4 
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 

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The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. 
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 spermicide5  
 
Cap, diaphragm or sponge with spermicide5  
5 
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. 
Birth control methods which are considered UNACCEPTABLE in clinical trials  
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods)  
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhoea methods are not acceptable methods of contraception.  
 
Female condom and male condom should not be used together. 
Acceptable methods of birth control in clinical trials: 
 
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. 
 
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. 
 
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. 
 
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. 
 
Use of IUDs are excluded due to increased risks of infection and bleeding in this 
population. 
 
In case of use of oral contraception, women must be stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women 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, salpingectomy, and/or bilateral oophorectomy) are eligible without requiring 

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the use of contraception. Acceptable documentation includes written or oral documentation 
communicated by clinician or clinician's staff of one of the following: 
 
Demographics show age <11 years. 
 
Physical examination indicates Tanner Stage 1. 
 
Physician report/letter. 
 
Operative report or other source documentation in the patient record. 
 
Discharge summary. 
 
Follicle stimulating hormone measurement elevated into the menopausal range.