Clinical trial NCT02999854
Conditions: Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome
Keywords: Haploidentical stem cell transplantation Graft-versus-host disease Immune reconstitution Alloreactive T-cells Photodynamic treatment Hematologic malignancy Transplant-related mortality Overall survival GRFS GVHD
Sponsor: Kiadis Pharma
Start date: 2017-11-29; Completion date: 2021-12-17
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to compare safety and efficacy of a haploidentical T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T cell replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy. An additional objective of the study is to compare the effect of the two treatments on quality of life.

Detailed description:
Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study comparing two parallel groups. After signing informed consent, a total of 250 patients will be randomized in a 1:1 fashion to receive either a T-cell depleted hematopoietic stem cell transplantation (HSCT; CD34 selection) from a related, haploidentical donor, followed by ATIR101 infusion, or a T-cell replete HSCT, followed by a high dose of post-transplant cyclophosphamide (PTCy).

Randomization will use minimization to balance treatment groups with respect to underlying disease (AML, ALL, or MDS), Disease Risk Index (DRI; intermediate risk, high risk, or very high risk) and center. A stochastic treatment allocation procedure will be used so that the treatment assignment is random for all patients entered in the study.

Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT. All patients will be followed up for at least 24 months post HSCT.

Arms: arm 1: T-cell depleted HSCT from a related, haploidentical donor, followed by IV infusion with ATIR101 at a single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT arm 2: T-cell replete HSCT from a related, haploidentical donor, followed by IV infusion of post-transplant cyclophosphamide (PTCy) 50 mg/kg/day at 3 and 4/5 days after the HSCT
Interventions: intervention 1: ATIR101 intervention 2: Cyclophosphamide intervention 3: T-cell depleted HSCT from a related, haploidentical donor intervention 4: T-cell replete HSCT from a related, haploidentical donor
Intervention descriptions: intervention 1: ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic treatment; single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT (intravenous infusion) intervention 2: High dose post-transplant cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT (powder for intravenous infusion) intervention 3: T-cell depleted graft prepared from peripheral blood stem cells using the CD34+ cell selection method; infused after a total body irradiation (TBI) or non-TBI conditioning regimen intervention 4: T-cell replete (full, non-manipulated) graft prepared from either bone marrow or peripheral blood stem cells; infused after a total body irradiation (TBI) or non-TBI conditioning regimen

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol: CR-AIR-009 
 
Study Title: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive 
treatment with ATIR101, a T-lymphocyte enriched leukocyte 
preparation depleted ex vivo of host alloreactive T-cells, versus a 
haploidentical HSCT with post-transplant cyclophosphamide in 
patients with a hematologic malignancy (HATCY study) 
 
Study Number: 
CR-AIR-009 
 
NCT Number: 
NCT02999854 
 
Study Phase: 
III 
 
Product Name: 
ATIR101 
 
EudraCT No: 
2016-004672-21 
 
Sponsor: 
Kiadis Pharma Netherlands B.V. 
 
 
 
Date 
Protocol version 
Original Protocol: 
23 November 2016 
1.0 
Amendment 1 (UK only): 
13 March 2017 
N/A 
Amendment 2 (UK only): 
14 July 2017 
N/A 
Amendment 3: 
26 September 2017 
2.0 
Amendment 4: 
23 August 2018 
3.0 
 
Confidentiality Statement 
Information contained in this document is the property of Kiadis Pharma Netherlands B.V., and is 
confidential. This information may not be disclosed to third parties without written authorization from 
Kiadis Pharma Netherlands B.V., except to obtain informed consent from those persons to whom the 
product will be administered, and to comply with legal regulations. No part of this document may be 
reproduced, stored in a retrieval system or transmitted in any form or by any means – electronic, 
mechanical, recording or otherwise – without the prior authorization of Kiadis Pharma Netherlands B.V. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF APPENDICES ............................................................................................................6 
LIST OF IN-TEXT TABLES ....................................................................................................6 
LIST OF IN-TEXT FIGURES...................................................................................................6 
STATEMENT OF COMPLIANCE ...........................................................................................7 
1 
PROTOCOL SUMMARY .................................................................................................8 
1.1 
Synopsis ...................................................................................................................8 
1.2 
Schema ...................................................................................................................10 
1.3 
Schedule of Activities ............................................................................................11 
2 
INTRODUCTION ...........................................................................................................14 
2.1 
Study Rationale ......................................................................................................14 
2.2 
Background ............................................................................................................14 
2.2.1 
Allogeneic Transplantations Using Haploidentical Donors ........................14 
2.2.1.1 
T-Cell Depleted (TCD) HSCT ...........................................................15 
2.2.1.2 
Post-Transplant Cyclophosphamide ..................................................15 
2.2.1.3 
GVHD-Free, Relapse-Free Survival (GRFS) Endpoint ....................16 
2.2.2 
Study Intervention ........................................................................................17 
2.2.2.1 
Relevant Nonclinical Findings ...........................................................18 
2.2.2.2 
Relevant Clinical Research ................................................................19 
2.3 
Risk/Benefit Assessment .......................................................................................22 
2.3.1 
Known Potential Risks .................................................................................22 
2.3.2 
Known Potential Benefits ............................................................................24 
2.3.3 
Assessment of Potential Risks and Benefits ................................................24 
3 
OBJECTIVES AND ENDPOINTS .................................................................................26 
3.1 
Objectives ..............................................................................................................26 
3.2 
Primary Endpoint ...................................................................................................26 
3.3 
Secondary Endpoints .............................................................................................27 
3.4 
Other Endpoints .....................................................................................................27 
4 
STUDY DESIGN.............................................................................................................29 
4.1 
Overall Design .......................................................................................................29 
4.2 
Scientific Rationale for Study Design....................................................................29 
4.3 
Justification for Dose .............................................................................................29 
4.4 
End of Study Definition .........................................................................................29 
5 
STUDY POPULATION ..................................................................................................31 
5.1 
Inclusion Criteria ...................................................................................................31 
5.2 
Exclusion Criteria ..................................................................................................31 
5.3 
Lifestyle Considerations ........................................................................................32 


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5.4 
Screen Failures .......................................................................................................32 
5.5 
Strategies for Recruitment and Retention ..............................................................32 
6 
STUDY INTERVENTION ..............................................................................................34 
6.1 
Study Interventions Administration .......................................................................34 
6.1.1 
Study Intervention Description ....................................................................34 
6.1.2 
Dosing and Administration ..........................................................................34 
6.2 
Preparation/ Handling/ Storage/ Accountability ....................................................35 
6.2.1 
Acquisition and Accountability ...................................................................35 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ...................................36 
6.2.3 
Product Storage and Stability.......................................................................36 
6.2.4 
Preparation ...................................................................................................36 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................................37 
6.4 
Study Intervention Compliance .............................................................................37 
6.5 
Concomitant Therapy.............................................................................................37 
6.5.1 
Rescue Medicine ..........................................................................................40 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................................41 
7.1 
Discontinuation of Study Intervention ...................................................................41 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................41 
7.3 
Lost to Follow-Up ..................................................................................................41 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................42 
8.1 
Efficacy Assessments.............................................................................................42 
8.1.1 
Standard of Care Study Procedures .............................................................42 
8.1.2 
Disease Assessment .....................................................................................44 
8.1.3 
Infection Assessment ...................................................................................44 
8.1.4 
CMV/EBV/Adenovirus Monitoring ............................................................45 
8.1.5 
Graft-Versus-Host Disease Assessment ......................................................46 
8.1.6 
Mortality ......................................................................................................46 
8.1.7 
Immunophenotyping ....................................................................................47 
8.1.8 
Peripheral Blood Sampling for Research Purposes .....................................47 
8.1.9 
Quality of Life..............................................................................................48 
8.2 
Safety and Other Assessments ...............................................................................48 
8.2.1 
Demographics ..............................................................................................48 
8.2.2 
Hematologic Malignancy .............................................................................48 
8.2.3 
Medical History ...........................................................................................48 
8.2.4 
Karnofsky Performance Status ....................................................................49 
8.2.5 
Physical Examination...................................................................................49 
8.2.6 
CT Scan Thorax or Chest X-ray ..................................................................49 


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8.2.7 
Echocardiogram or MUGA Scan .................................................................49 
8.2.8 
Pulmonary Function Test .............................................................................49 
8.2.9 
Creatinine Clearance ....................................................................................49 
8.2.10 
Vital Signs ....................................................................................................50 
8.2.11 
Engraftment..................................................................................................50 
8.2.12 
Chimerism ....................................................................................................50 
8.2.13 
Safety Laboratory Tests ...............................................................................50 
8.2.14 
Pregnancy Test .............................................................................................51 
8.2.15 
Auxiliary Scientific Studies .........................................................................51 
8.2.16 
Health Economics Data Collection ..............................................................51 
8.3 
Adverse Events and Serious Adverse Events ........................................................52 
8.3.1 
Definition of Adverse Events (AEs) ............................................................52 
8.3.2 
Definition of Serious Adverse Events (SAE) ..............................................52 
8.3.3 
Classification of an Adverse Event ..............................................................52 
8.3.3.1 
Severity of Event................................................................................52 
8.3.3.2 
Relationship to Study Intervention ....................................................53 
8.3.3.3 
Expectedness ......................................................................................54 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ............54 
8.3.5 
Adverse Event Reporting .............................................................................54 
8.3.6 
Serious Adverse Event Reporting ................................................................55 
8.3.7 
Reporting Events to Participants ..................................................................56 
8.3.8 
Events of Special Interest.............................................................................56 
8.3.9 
Reporting of Pregnancy ...............................................................................56 
8.4 
Unanticipated Problems .........................................................................................56 
8.4.1 
Definition of Unanticipated Problems (UPs) ...............................................56 
8.4.2 
Unanticipated Problem Reporting................................................................57 
8.4.3 
Reporting Unanticipated Problems to Participants ......................................57 
8.5 
Study Visits ............................................................................................................57 
8.5.1 
Screening (between Informed Consent & Confirmation Eligibility) ...........57 
8.5.2 
Pre-HSCT (between Confirmation Eligibility & HSCT).............................58 
8.5.3 
HSCT (Day 0) ..............................................................................................59 
8.5.4 
Week 1, 2, 3 .................................................................................................59 
8.5.5 
Week 4 .........................................................................................................60 
8.5.6 
Week 5, 6, 7, 8, 9, 10 ...................................................................................60 
8.5.7 
Month 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, 24 ....................................................61 
8.5.8 
Follow-up Beyond Month 24: Every 6 Months ...........................................62 
9 
STATISTICAL CONSIDERATIONS.............................................................................63 
9.1 
Statistical Hypotheses ............................................................................................63 


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9.2 
Sample Size Determination....................................................................................63 
9.3 
Populations for Analyses .......................................................................................63 
9.4 
Statistical Analyses ................................................................................................64 
9.4.1 
General Approach ........................................................................................64 
9.4.2 
Analysis of the Primary Efficacy Endpoint .................................................65 
9.4.3 
Analysis of the Secondary Endpoints ..........................................................65 
9.4.4 
Safety Analyses ............................................................................................66 
9.4.5 
Baseline Descriptive Statistics .....................................................................66 
9.4.6 
Planned Interim Analyses ............................................................................66 
9.4.7 
Sub-Group Analyses ....................................................................................67 
9.4.8 
Tabulation of Individual Participant Data....................................................67 
9.4.9 
Exploratory Analyses ...................................................................................67 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..68 
10.1 
Regulatory, Ethical, and Study Oversight Considerations.....................................68 
10.1.1 
Informed Consent Process ...........................................................................68 
10.1.1.1 
Consent/assent and Other Informational Documents Provided to 
Participants .........................................................................................68 
10.1.1.2 
Consent Procedures and Documentation ...........................................68 
10.1.2 
Study Discontinuation and Closure .............................................................69 
10.1.3 
Confidentiality and Privacy .........................................................................70 
10.1.4 
Future Use of Stored Specimens and Data ..................................................70 
10.1.5 
Key Roles and Study Governance ...............................................................71 
10.1.6 
Safety Oversight...........................................................................................72 
10.1.7 
Clinical Monitoring ......................................................................................72 
10.1.8 
Quality Assurance and Quality Control .......................................................72 
10.1.8.1 
ATIR101 Manufacturing ...................................................................72 
10.1.8.2 
Clinical Study.....................................................................................73 
10.1.9 
Data Handling and Record Keeping ............................................................73 
10.1.9.1 
Data Collection and Management Responsibilities ...........................73 
10.1.9.2 
Study Records Retention....................................................................74 
10.1.10 Protocol Deviations ......................................................................................75 
10.1.11 Publication and Data Sharing Policy ...........................................................75 
10.1.12 Conflict of Interest Policy ............................................................................76 
10.2 
Additional Considerations .....................................................................................76 
10.2.1 
Reporting of Serious Breaches.....................................................................76 
10.2.2 
Protocol Amendments ..................................................................................76 
10.3 
Abbreviations .........................................................................................................77 
11 REFERENCES ................................................................................................................81 


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12 APPENDICES .................................................................................................................86 
 
LIST OF APPENDICES 
Appendix 1 
Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndromes Risk .............................................................. 86 
Appendix 2 
Disease Risk Index (DRI) ........................................................................... 87 
Appendix 3 
EBMT Risk Score ....................................................................................... 88 
Appendix 4 
Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI)
 .................................................................................................................... 89 
Appendix 5 
Karnofsky Performance Status (KPS) Scale .............................................. 90 
Appendix 6 
Severity Grading of Graft-Versus-Host Disease ........................................ 91 
Appendix 7 
Calculation of Ideal Body Weight (IBW) and Adjusted Ideal Body Weight 
(AIBW) ....................................................................................................... 95 
Appendix 8 
Sponsor Signature ....................................................................................... 96 
Appendix 9 
Coordinating Investigator Signatures ......................................................... 97 
Appendix 10 
Principal Investigator Signature ................................................................. 99 
 
LIST OF IN-TEXT TABLES 
Table 1 
Kaplan-Meier estimates of OS and TRM at 6 and 12 months after HSCT 21 
Table 2 
Categories of acute and chronic GVHD ..................................................... 46 
Table 3  
List of safety laboratory tests...................................................................... 51 
Table 4 
Organ scoring of chronic GVHD ............................................................... 92 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Schematic overview of the ATIR101 procedure ........................................ 17 
Figure 2 
Survival curves of GRFS probability versus time after HSCT (data study 
CR-AIR-007 and external controls study CR-AIR-006) ............................ 22 
 


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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP E6[R2]), and applicable local laws and regulations. The 
principal investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the sponsor and documented approval from the 
institutional review board (IRB) or independent ethics committee (IEC), except where 
necessary to eliminate an immediate hazard to the study participants. All relevant personnel 
involved in the conduct of this study have completed ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB/IEC for review and approval. Approval of both the protocol and 
the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB/IEC before the changes are 
implemented to the study. All changes to the consent form will be IRB/IEC approved; 
a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 


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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Title: 
A Phase III, multicenter, randomized controlled study to compare safety and efficacy of a 
haploidentical HSCT and adjunctive treatment with ATIR101, a T-lymphocyte enriched 
leukocyte preparation depleted ex vivo of host alloreactive T-cells, versus a haploidentical 
HSCT with post-transplant cyclophosphamide in patients with a hematologic malignancy 
(HATCY study) 
Study Description: 
Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study 
comparing two parallel groups. After signing informed consent, a total of 250 patients will 
be randomized in a 1:1 fashion to receive either a T-cell depleted hematopoietic stem cell 
transplantation (HSCT; CD34 selection) from a related, haploidentical donor, followed by 
ATIR101 infusion, or a T-cell replete HSCT, followed by a high dose of post-transplant 
cyclophosphamide (PTCy). 
Randomization will use minimization to balance treatment groups with respect to 
underlying disease (AML, ALL, or MDS), Disease Risk Index (DRI; intermediate risk, 
high risk, or very high risk) and center. A stochastic treatment allocation procedure will be 
used so that the treatment assignment is random for all patients entered in the study. 
Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2.0×106 
viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the 
PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the 
HSCT. All patients will be followed up for at least 24 months post HSCT.  
Objectives:  
The primary objective of this study is to compare safety and efficacy of a haploidentical 
T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical 
T-cell replete HSCT with post-transplant administration of high dose cyclophosphamide 
(PTCy) in patients with a hematologic malignancy.  
An additional objective of the study is to compare the effect of the two treatments on 
quality of life. 
Endpoints: 
The primary endpoint of the study is GVHD-free, relapse-free survival (GRFS). GRFS is 
defined as time from randomization until grade III/IV acute graft-versus-host disease 
(GVHD), chronic GVHD requiring systemic immunosuppressive treatment, disease 
relapse, or death, whichever occurs first. This endpoint captures both safety and efficacy. 
Secondary endpoints: 
• Overall survival (OS)  
• Progression-free survival (PFS)  
• Relapse-related mortality (RRM) 
• Transplant-related mortality (TRM) 


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Other endpoints: 
• Immune reconstitution 
• Incidence and severity of acute and chronic GVHD  
• Incidence and severity of viral, fungal, and bacterial infections 
• Incidence and severity of adverse events 
• Quality of life: FACT-BMT, SF-36, MDASI, and EQ-5D-5L total scores  
 
Study Population: 
The study population consists of male or female patients aged 18-70 years with a 
hematologic malignancy (AML in remission, ALL in remission, or MDS) who are eligible 
for a haploidentical HSCT. The Karnofsky Performance Status (KPS) should be ≥ 70%. 
Each patient must have a related haploidentical donor aged 16-75 years available, who is 
eligible according to local requirements and regulations. Vulnerable participants such as 
pregnant women and children will not be enrolled in the study. 
In total, 250 patients are planned to be randomized. 
Phase: 
III 
Description of Sites Enrolling Participants: 
Approximately 50 sites globally are planned to enroll participants in the study. 
Description of Study Intervention: 
The advanced therapy medicinal product (ATMP) ATIR101 is a T-lymphocyte enriched 
leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic 
treatment (PDT) with the photosensitizing reagent TH9402. ATIR101 is presented as a 
“dispersion for infusion”. Patients in the ATIR101 group will be infused with ATIR101 
intravenously (IV) at a single dose of 2.0×106 viable T-cells/kg body weight between 28 
and 32 days after a CD34-selected HSCT (or later if required by the patient's medical 
condition). 
The drug cyclophosphamide, which is part of the control intervention, is presented as a 
lyophilized powder for IV infusion, which is commercially available for human use under 
various brand names. Patients in the PTCy group will be infused with cyclophosphamide 
50 mg/kg/day IV at 3 and 4/5 days after a non-manipulated, T-cell replete HSCT. 
Study Duration: 
The estimated time from start of enrolment until completion of the interim data analysis of 
the primary endpoint amounts to 29 months. The estimated time from start of enrolment 
until completion of the final data analyses amounts to approximately 38 months. 
Participant Duration: 
Each patient is planned to be in the study for at least approximately 26 months, i.e. from 
signing informed consent to visit at 24 months post HSCT. Patient follow-up beyond 
24 months post HSCT will be discontinued when a total number of 156 GRFS events has 
been reached. Each donor is planned to be in the study for approximately 1-2 months. 


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1.2 
Schema 
 
Obtain informed consent 
Assess expected patient eligibility 
Randomization 1:1 
ATIR101 
group 
PTCy  
group 
Apheresis patient/ 
donor for ATIR101 
manufacturing 
Collection of donor 
stem cell graft 
Collection of donor 
stem cell graft 
Conditioning + 
CD34-selected  
T-cell depleted HSCT  
[Day 0] 
Conditioning + 
non-manipulated T-cell 
replete HSCT  
[Day 0] 
ATIR101 infusion  
[Day 30 ± 2] 
Cyclophosphamide 
infusion  
[Day 3 and 4/5] 
Follow-up assessments of study endpoints and safety 
(see Section 1.3, Schedule of Activities) 
Confirmation patient 
eligibility 
Confirmation patient 
eligibility 


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1.3 
Schedule of Activities 
 
Screening 
(between informed 
consent & confir-
mation eligibility) 
Pre-
HSC
T 
HSCT 
(Day 0) 
Week  
1, 2, 3 
Week 4 
Week  
5, 6, 7, 8, 
9, 10 
Month  
3, 4, 5, 6, 8, 
10, 12, 15, 
18, 21, 24 
Follow-up 
beyond 
Month 24 
every 
6 months 
Informed consent patient/donor 
X 
 
 
 
 
 
 
 
Patient eligibility 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Apheresis patient and donor PBMCs 1 
 
X 2 
 
 
 
 
 
 
Collection donor PBSCs/bone marrow 
 
X 
 
 
 
 
 
 
Conditioning regimen 
 
X 
 
 
 
 
 
 
HSCT  
 
 
X 
 
 
 
 
 
ATIR101 infusion 3 
 
 
 
 
X 
 
 
 
Cyclophosphamide infusion 4 
 
 
 
X 5 
 
 
 
 
Demographics patient/donor 
X 
 
 
 
 
 
 
 
Hematologic malignancy 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
KPS 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 6 
X 6 
 
 
1  
For preparation of ATIR101; ATIR101 group only 
2  
Including measurement of patient weight 
3  
ATIR101 group only 
4  
PTCy group only 
5  
On Day +3 and Day +4/+5 
6  
Only at Week 6, Week 8, Week 10, Month 3, and Month 4 


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Screening 
(between informed 
consent & confir-
mation eligibility) 
Pre-
HSC
T 
HSCT 
(Day 0) 
Week  
1, 2, 3 
Week 4 
Week  
5, 6, 7, 8, 
9, 10 
Month  
3, 4, 5, 6, 8, 
10, 12, 15, 
18, 21, 24 
Follow-up 
beyond 
Month 24 
every 
6 months 
CT scan thorax/chest X-ray 
X 7 
 
 
 
 
 
 
 
Echocardiogram/MUGA scan 
X 7 
 
 
 
 
 
 
 
Pulmonary function test 
X 7 
 
 
 
 
 
 
 
Creatinine clearance 
X 8 
 
 
 
 
 
 
 
Vital signs 
X 9 
 
X 
X 
X 10 
X 
X 11 
 
Quality of life 
X 
 
 
 
 
 
X 12 
X 12 
Disease assessment 13 
X  
 
X 
X 
X 
X 
X 
X 
Infection assessment 
X 
X 
X 
X 
X 
X 
X 
 
CMV/EBV/adenovirus (PCR) 
X 
 
X 
X 
X 
X 
X 
 
Engraftment  
 
 
 
X 
X 16 
X 14 
 
 
Chimerism 
 
 
 
X 15 
X 16 
X 17 
X 17 
 
GVHD assessment 
 
 
 
X 
X 
X 
X 
X 
 
7  
If not already done within 6 weeks before signing informed consent 
8  
Calculated or measured, if not already done within 2 weeks before signing informed consent 
9  
Including measurement of patient height at screening only 
10  For all patients (in ATIR101 group before infusion of ATIR101); Additionally, following ATIR101 infusion, pulse rate and supine blood pressure will be 
assessed after 15 minutes, 1 hour, and 2 hours and continuous oxygen monitoring will be done if the patient has respiratory problems. 
11  Only at Month 3 and Month 4 
12  Only at Month 3, Month 6, Month 12, Month 24, Month 36, and Month 48 
13  Includes bone marrow biopsy/aspirate at Screening, Month 3, Month 6, Month 12, and Month 24 unless relapse has already been confirmed, and in case of 
suspected relapse 
14  In case of no neutrophil or platelet engraftment at Week 4, measurements are to be continued at weekly visits until engraftment. 
15  Only in case of suspected relapse 
16  For all patients (in ATIR101 group before infusion of ATIR101) 
17  Only at Week 10, Month 3, Month 6, Month 12, Month 24, and in case of suspected relapse post HSCT 


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Screening 
(between informed 
consent & confir-
mation eligibility) 
Pre-
HSC
T 
HSCT 
(Day 0) 
Week  
1, 2, 3 
Week 4 
Week  
5, 6, 7, 8, 
9, 10 
Month  
3, 4, 5, 6, 8, 
10, 12, 15, 
18, 21, 24 
Follow-up 
beyond 
Month 24 
every 
6 months 
Mortality assessment 
Continuous recording 
Hematology/biochemistry 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 18 
X 18 
 
Pregnancy test patient/donor (if 
applicable) 
X 
 
 
 
 
 
 
 
Viral testing patient/donor 
X 19 
 
 
 
 
 
 
 
HLA compatibility 
X 
 
 
 
 
 
 
 
ABO/Rhesus blood group 
X 
 
 
 
 
 
 
 
Immunophenotyping 
X 
 
 
X 20 
X 21 
X 
X 
X 
Peripheral blood sampling 22 
X 
 
 
 
 
X 23 
X 23 
 
Patient AEs (other) 
X 
X 
X 
X 
X 
X 
X 24 
X 24 
Donor AEs 
X 
X 25 
 
 
 
 
 
 
SAEs 
Continuous recording 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 26 
 
18  Only at Week 8, Month 3, and Month 4 
19  Viral testing to be done within one month before collection of PBMCs (for ATIR101 manufacturing) and within one month of collection of stem cells 
20  Only at Week 3 
21  For all patients (in ATIR101 group before infusion of ATIR101) 
22  For research purposes. At selected sites and patients.  
23  Only at Week 8, Month 4, Month 6, Month 8, Month 10, and Month 12; Additional sampling when a pre-specified GVHD event occurs in ATIR101-treated 
patients within the first year after HSCT (see Section 8.1.8). 
24  Only at Month 3, Month 4, Month 5, and Month 6. However, SAEs and AEs of special interest (Section 8.3.8) are to be recorded as AEs throughout study. 
25  Up to and including the collection of stem cells 
26  Excluding medications for the treatment of non-serious infections 


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2 INTRODUCTION 
2.1 
Study Rationale 
In this Phase III clinical study ATIR101 will be evaluated for its clinical benefit when used 
as adjunctive treatment after a haploidentical HSCT in patients with a hematologic 
malignancy (AML, ALL, or MDS). The dosing regimen of ATIR101 (single dose of 2.0×106 
viable T-cells/kg IV at 28-32 days post HSCT) has been well established in previous Phase 
I-II clinical studies. To reflect current practice of haploidentical transplants for hematologic 
malignancies, the patient population is limited to patient for whom no suitable HLA matched 
sibling or unrelated donor is available in a timely manner. 
The study is designed to confirm results obtained in Phase I-II clinical studies and to 
compare the outcomes of patients receiving ATIR101 post HSCT in a randomized setting to 
a control group of patients receiving a high dose of cyclophosphamide post HSCT, an 
upcoming treatment modality for patients in need of a haploidentical HSCT.  
2.2 
Background 
2.2.1 
Allogeneic Transplantations Using Haploidentical Donors 
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option 
for many malignant disorders. HSCT comprises the elimination of the patient’s bone marrow, 
usually by means of myeloablative conditioning involving high-dose chemotherapy and 
possibly total body irradiation, followed by transplantation of donor stem cells. Major 
complications of HSCT include graft-versus-host disease (GVHD) and other life-threatening 
complications such as graft rejection/failure and infection. Even with the use of 
immunosuppressive prophylaxis, 30 to 60% of patients will develop some level of acute 
GVHD (Abo-Zena and Horwitz 2002; Jagasia et al. 2012; Ruggeri et al. 2006).  
Use of a human leukocyte antigen (HLA) matched donor, ideally an HLA-identical sibling, 
will reduce the above-mentioned risks. Unfortunately, such an ideal donor will only be 
available for about 25% of the patients. A matched unrelated donor (MUD) from a donor 
registry can be an alternative. However, despite the establishment of worldwide donor 
registries, the probability of finding a MUD within a medically reasonable time (i.e. 2 to 3 
months) can be low. The probability of finding such a donor in the international registries 
ranges from 10% in poorly represented ethnic groups to 60% to 80% in Caucasians (Reisner 
et al. 2011). Even when a donor has been identified, he/she might not be able or willing to 
donate stem cells. Results from donor searches are available at a minimum of 6 weeks (if a 
match can be identified in the national registries) but usually it takes 2 to 4 months or longer 
(Heemskerk et al. 2005; Hirv et al. 2009). Overall, this option might not be viable for 
patients who urgently need a stem cell transplantation and many patients relapse while HLA 
typing is in progress or while waiting for the start of the transplant procedure. 
Interest in the use of haploidentical donors arises from the immediate availability of a one 
haplotype-matched family donor for virtually all patients, particularly those who urgently 
need transplantation (Aversa et al. 1998). In the last decade, the use of haploidentical donors 


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has emerged as an alternative when an HLA-identical sibling or MUD is not available 
(Passweg et al. 2015).  
The haploidentical transplant procedures have become feasible using methods to reduce or 
control GVHD, either by T-cell replete or T-cell deplete methods. In T-cell deplete strategies 
ex vivo graft manipulation with CD34-selection or selective T-cell depletion (CD3/CD19 and 
αβ/CD19 depletion) is applied. Most recently, T-cell replete strategies using high doses of 
post-transplant cyclophosphamide (PTCy) or extensive immunosuppression without prior 
graft manipulation have emerged as successful approaches to reduce GVHD. With both 
T-cell replete and T-cell deplete strategies, deficiencies in recovery of T- and B-cells remain, 
which are associated with increased rates of infections and disease relapse. 
2.2.1.1 
T-Cell Depleted (TCD) HSCT 
The recognition that GVHD is caused by donor derived T-cells led to the strategy of T-cell 
depletion in order to reduce the risk of GVHD (Aversa et al. 1998). Use of ex vivo T-cell 
depleted (TCD) grafts has significantly reduced the risk of GVHD without the need for post-
transplant immunosuppression (Devine et al. 2011). The most used approach for removal of 
T-cells from the graft has been the positive selection of CD34+ hematopoietic stem cells 
using immunomagnetic beads. A potential limitation of TCD grafts is a higher risk of graft 
rejection, as preclinical data has indicated that donor-derived T-cells facilitate engraftment. 
In the haploidentical HSCT setting this has been solved by profound in vivo and in vitro 
lymphodepletion and administering a mega dose of CD34+ cells with a small fraction of 
T-cells, and additionally the use of ATG in the conditioning regimen. Another limitation of 
TCD grafts is that higher rates of viral and invasive fungal infections, and Epstein-Barr virus 
(EBV) associated post-transplant lymphoproliferative disease (PTLD) have been noted with 
TCD HSCT as a consequence of impaired T-cell reconstitution (Goker et al. 2001). T-cell 
depletion has a marked effect on immune recovery with patients remaining severely 
immunocompromised for extensive periods of time after HSCT (up to 1 year or more), 
leading to a high risk of life-threatening (infectious) complications resulting in high 
transplant-related mortality (TRM) and low overall survival (OS) (Aversa et al. 1998; 
Handgretinger et al. 2001; Koh et al. 2007). Additionally, depleting T-cells from the graft 
could compromise the graft-versus-leukemia (GVL) effect, leading to an increase in relapse 
(Sehn et al. 1999). 
Re-introducing unmanipulated T-cells early after a TCD HSCT is a solution for the above 
given limitations, but the risk of inducing life-threatening GVHD would be significant 
(Lewalle et al. 2003). However, the adoptive transfer of selected, allo-depleted or genetically 
manipulated T-cells clearly is an alternative. Photodynamic treatment (PDT) is a method 
developed to allow elimination of alloreactive T-cells from a donor lymphocyte preparation, 
resulting in a DLI which can be given at higher doses, without causing severe GVHD 
(Bastien et al. 2010; Boumedine and Roy 2005). 
2.2.1.2 
Post-Transplant Cyclophosphamide 
High-dose cyclophosphamide is a potent immunomodulatory agent that has been used 
successfully for the prevention of GVHD after HLA-matched and –mismatched HSCT where 


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the full donor graft was administered. Preclinical studies had shown that administration of 
cyclophosphamide early after HSCT preferentially killed activated, cycling alloreactive 
T-cells while sparing resting, non-alloreactive T-cells, like human regulatory T-cells (Luznik 
et al. 2001). Initial clinical results of this approach using a high dose of cyclophosphamide 
on Day +3 and +4 post-transplant, with additional use of immunosuppressive agents like 
tacrolimus and mycophenolate mofetil, showed primary graft failure in 13% of patients and 
complete T-cell engraftment in the remaining patients by Day +28 (Luznik et al. 2008). 
Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 34% and 6%, 
respectively. Non-relapse mortality rate and relapse rate at 1 year were 15% and 51%, 
respectively. Actuarial OS at two years post HSCT was 36%. 
To date, haploidentical non-myeloablative and myeloablative transplantation with post-
transplant cyclophosphamide, commonly known as the Baltimore protocol, is being used 
widely in patients for whom no matched donor is available. Data from two BMT CTN 
sponsored Phase II studies (BMT CTN 0603 & 0604) were used to compare the outcome of 
haploidentical transplants in high-risk hematologic malignancies, using post-transplant 
cyclophosphamide, against transplants done using double umbilical cord blood (dUCB) 
grafts, without PTCy (Brunstein et al. 2011). This data showed that haploidentical HSCT 
with PTCy is at least as effective as dUCB transplants, with less non-relapse mortality after 
haplo-HSCT (7% versus 24%) and higher 1-year OS (62% versus 54%), but with an increase 
in relapse at 1 year post-transplant (45% versus 31%). Other studies have also shown 
comparable transplant outcomes of haploidentical HSCT, using PTCy, compared to HLA-
matched related and unrelated donor transplants (Bashey et al. 2013; Burroughs et al. 2008).  
A recent study evaluated the data from the CIBMTR database in patients with AML (Ciurea 
et al. 2015) who either received a haploidentical HSCT, using PTCy, or a matched unrelated 
HSCT. OS was comparable between the two transplant regimens, with 1-year OS of 65% in 
both patient groups. Patients receiving a haploidentical HSCT had less acute and chronic 
GVHD, with grade II-IV acute GVHD reported in 16% and chronic GVHD in 28%, 
compared to 33% and 45% in unrelated donor transplants. Non-relapse mortality was 
comparable, but relapse occurred more frequently in the first year post HSCT in patients who 
received a haplo-HSCT (41% versus 32%). The higher rate of relapse continues to be a 
challenge, in addition to the required immunosuppression that needs to be given to patients 
for a prolonged period of time after the transplant.  
2.2.1.3 
GVHD-Free, Relapse-Free Survival (GRFS) Endpoint 
A new composite endpoint has been introduced by the Blood and Marrow Transplant 
Clinical Trial Network (BMT CTN), to better define a successful transplant outcome. This 
GVHD-free, relapse-free survival (GRFS) endpoint is defined as freedom from grade III-IV 
acute GVHD, chronic GVHD requiring systemic treatment, relapse, and death (Holtan et al. 
2015). Data from a large, single center patient cohort was analyzed for GRFS among 531 
consecutive adult recipients of allogeneic transplantation (Solh et al. 2016). They found for 
the whole cohort that although 78% of patients are alive at 1 year post HSCT only 31% of 
transplant recipients survived 1 year without experiencing at least 1 GRFS event. For 
haploidentical donor transplants (n=128), done at this institute using the post-transplant 
cyclophosphamide approach, the reported 1-year GRFS rate was 33% (95% CI 25-41). 


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2.2.2 
Study Intervention 
ATIR101, an individualized advanced therapy medicinal product (ATMP), is a T-lymphocyte 
enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells (using 
photodynamic treatment). ATIR101 is being developed as adjunctive treatment to 
haploidentical HSCT for the reduction of morbidity and mortality due to infections, GVHD, 
and/or relapse in patients with hematologic malignancies. 
For manufacturing of ATIR101, donor and patient peripheral blood mononuclear cells 
(PBMCs) are collected by apheresis on the same day. For the patient this apheresis is done in 
advance of the conditioning regimen for the HSCT and for the donor this additional apheresis 
is done before the apheresis to collect the stem cell graft (PBSCs).  
 
Figure 1 
Schematic overview of the ATIR101 procedure 
The selective depletion of host alloreactive T-cells in ATIR101 is shown schematically in 
Figure 1. During processing patient and donor cells are co-cultured in a mixed lymphocyte 
reaction (MLR) to stimulate activation of host alloreactive T-cells (the patient cells are 
gamma irradiated prior to the MLR). In the MLR, donor lymphocytes are activated against 
the major discordant major histocompatibility complex (MHC) antigens of the irradiated 
patient’s cells. Those cells that are activated accumulate more light-sensitive TH9402 than 
non-activated cells and are consequently more susceptible to the effect of PDT.  


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2.2.2.1 
Relevant Nonclinical Findings 
TH9402 is a specifically designed derivative of rhodamine, a substance that is often used in 
cell biology to stain mitochondria in living cells because of its low toxicity and its specific 
attraction and retention in these organelles. Similarly, TH9402 binds to mitochondria. 
TH9402 absorbs light at a peak wavelength of 514 nm in the visible green spectrum and 
transfers the absorbed energy to oxygen, leading to the production of reactive oxygen species 
(mainly singlet oxygen) inside the cells. Subsequent oxidative reactions of these species with 
various biomolecules ultimately cause programmed cell death. TH9402 accumulates in cells 
with low P-glycoprotein (Pgp) pump activity such as activated lymphocytes. These target 
cells will accumulate significantly higher amounts of photosensitizer than resting cells and 
will be selectively depleted upon exposure to light.  
The light exposure device used in the manufacturing of ATIR101 is custom designed to 
deliver light of a specific wavelength range that results in the photo activation of TH9402 
molecules incorporated by cells. Special lamps with peak emission around 514 nm are 
positioned below the glass treatment surface of the device, delivering a tightly controlled 
light dose.  
T-cells in ATIR101 can be characterized as being sufficiently depleted of recipient-reactive 
T-cells that might cause severe acute GVHD while having maintained the general ability to 
become activated by other stimuli, like infectious epitopes and malignant cells, and are 
therefore expected to be able to fight infections and disease relapse in the human body 
(Bastien et al. 2012; Guimond et al. 2002; Mielke et al. 2008).  
In vitro assays have been developed to show that ATIR101 batches are indeed depleted of 
alloreactive cells while the remaining cells retain their reactivity to other stimuli. The various 
leukocyte subsets have been measured both in the original donor cells as well as in ATIR101. 
T-cells (CD3+), monocytes (CD14+), B-cells (CD19+), NK-cells (CD3- CD16/56+) are 
present in the original donor cells while ATIR101 is strongly enriched for T-cells (> 90%).  
The proliferation of the cells in ATIR101 and the original donor cells after stimulation with 
recipient cells and third-party cells have been compared using the CFSE-dilution based 
proliferation assay. A selective depletion of recipient-reactive cells is observed, while 
reactivity to third party cells is retained. Thus, alloreactive T-cells have been largely 
eliminated from ATIR101 with preservation of T-cell response to other antigenic stimuli.  
To better characterize the capacity of ATIR101 to fight infections, virus specific CD8+ cells 
against EBV and CMV were measured using a variety of HLA-multimers both in ATIR101 
and in original donor cells. Anti-viral T-cells are largely preserved in ATIR101. 
In a proof of concept study in a mouse stem cell transplantation model, PDT using TH9402 
ex vivo successfully eliminated foreign HLA-specific cytotoxic T-cells but did not eliminate 
resting anti-leukemia and anti-third-party T-lymphocytes. In particular, without a donor 
lymphocyte infusion (DLI), stem cell transplanted and BCL1 leukemia inoculated mice 
developed leukemia with 50% mortality at 100 days. Infusion of untreated DLIs prevented 
relapse, but resulted in 100% mortality due to GVHD. However, upon infusion of DLIs that 


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were depleted of host-alloreactive T-cells (by PDT/TH9402), 90% of mice survived > 100 
days without BCL1 tumors and GVHD. These data show that PDT/TH9402 treatment of 
donor lymphocytes prevents GVHD, while preserving third-party immune response and GVL 
effects (Chen et al. 2002). 
2.2.2.2 
Relevant Clinical Research 
Dose Ranging Study (CR-GVH-001)  
This was an open-label, single-arm, non-randomized, single-center study conducted in 
19 patients with severe hematological malignancies undergoing haploidentical peripheral 
blood stem cell transplantation with CD34+ cell selection and subsequent infusion of 
T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells 
(ATIR101). Adult patients with severe hematologic malignancies, who do not have the 
possibility of receiving an allogeneic transplant from a human leukocyte antigen (HLA) 
matched sibling donor were eligible to participate in this study.  
Cohorts of patients received an increasing dose of ATIR101 with the primary objective to 
determine the maximum tolerated dose (MTD) using the incidence of grade III-IV acute 
GVHD within 30 days after infusion as dose limiting toxicity (DLT). Secondary objectives 
were to evaluate the immune reconstitution following ATIR101 and its effect on the 
incidence and severity of infections and relapse.  
The haploidentical donor was mobilized with G-CSF and the peripheral blood stem cells 
(PBSCs) were collected and placed on a CD34 selection column to prepare the graft 
consisting of approximately 10×106 CD34+ cells/kg with a maximum of 3×104 CD3+ 
cells/kg. Patients were subject to a myeloablative conditioning regimen comprised of total 
body irradiation (TBI), thiotepa, rabbit ATG, fludarabine and methylprednisolone before 
transplantation. ATIR101 was infused IV 35 ± 7 days post transplant, once engraftment had 
been established. Seven dose levels of ATIR101 T-cells were tested in this study using the 
classic 3+3 design. 
Patients have been followed up for 5 years after ATIR101 infusion. The primary safety 
parameter of this study was the occurrence of GVHD. No patients developed grade III/IV 
acute GVHD. Therefore, the MTD, which was defined as the dose of T-cells at which DLT 
toxicity (acute GVHD grade III/IV within 30 days) occurs in 33% of the patients following 
ATIR101 infusion, has not been reached in this study with doses up to 5.0×106 viable T-
cells/kg body weight.  
The data of study CR-GVH-001 indicate that with the use of ATIR101, a high dose of T-cells 
can be infused safely to patients with hematologic malignancies following a (mismatched) 
haploidentical stem cell transplantation. The use of ATIR101 allowed early immune 
reconstitution while preventing grade III/IV acute GVHD. To boost immune reconstitution 
the goal is to administer the highest possible dose without the occurrence of grade III/IV 
acute GVHD. Since in dose cohort L7 (5.0×106 T-cells/kg) all patients developed GVHD, 
which required (extensive) immunosuppressive treatment, and the infection rate was 


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markedly higher compared to dose cohort L6 (2.0×106 T-cells/kg), the optimal dose of 
ATIR101 for further development was considered to be 2.0×106 T-cells/kg.  
Phase II Study (CR-AIR-007)  
This is an open-label, single-arm, non-randomized, multicenter study conducted in patients 
with hematological malignancies (AML, ALL, or MDS) undergoing haploidentical 
peripheral blood stem cell transplantation with CD34+ cell selection and subsequent single 
infusion of T-lymphocyte enriched leukocyte preparation depleted ex vivo of host 
alloreactive T-cells (ATIR101) (Roy and Mielke 2018). 
Study CR-AIR-007 is completed and has achieved its objective of treating 23 patients with 
ATIR101. Patient age ranged from 21 to 64 years (median: 41 years). The majority of 
patients had AML (16 patients, 70%), and 7 patients (30%) had ALL. At the time of 
transplant, 15 patients were in first remission (CR1) and 8 patients were in second or 
subsequent remission phase. The Disease Risk Index (DRI) (Armand et al. 2014) was high in 
57% of patients and intermediate in 43% of patients; the cytogenetic risk profile was 
intermediate for 39% and adverse for 61% of the patients. Patients received the graft most 
frequently from a sibling (39.1%) or child (39.1%) and less frequently from a parent (17.4%). 
Donors were generally 3/6 HLA matched (70%) or 4/6 HLA matched (26%). 
Patients underwent myeloablative conditioning, consisting of a] TBI (1200 cGy: n=11) or 
b] melphalan (120 mg/m2: n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 
5d) and ATG (2.5 mg/kg x 4d).  A CD34-selected stem cell graft from a haploidentical donor 
was given, containing a mean of 11×106 CD34+ cells/kg (range 4.7-24.4×106) and 0.29×104 
CD3+ cells/kg (range 0-1.8×104). In addition, donor lymphocytes from the same donor were 
processed using PDT technology, creating a donor lymphocyte infusion depleted of 
alloreactive T-cells (ATIR101). ATIR101 was infused at a median of 28 days (range 28-73) 
post HSCT at a fixed dose of 2.0×106 CD3+ cells/kg, without use of any post-transplant 
GVHD prophylaxis. 
At the end of the study, median follow-up of ATIR101-treated patients was 20 months post 
HSCT (range 3.6-24.4). All patients engrafted rapidly after transplantation, with neutrophil 
and platelet engraftment achieved at a median of 12 (range 8-34) and 11 (range 9-35) days, 
respectively. Overall, 10 patients (43.5%) died due to TRM and four patients (17.4%) due to 
disease relapse. At 2 years post HSCT, probabilities (based on Kaplan-Meier estimates) were 
48% for TRM, 25% for RRM, and 39% for OS. 
Within the first 12 months post HSCT, no acute GVHD grade III/IV occurred, while four 
grade II cases and three grade I cases were observed. Interestingly, these cases all had late 
onset (> 100 days post HSCT) except for two patients showing acute GVHD grade I and II, 
respectively, before ATIR101 infusion, thereby delaying the infusion until resolution of 
GVHD. Between 1 and 2 years after HSCT, GVHD grade III-IV was reported for three 
patients and severe chronic GVHD for one patient. Of note, all patients who developed acute 
GVHD grade III or IV had received an unmanipulated donor lymphocyte infusion (DLI) 
shortly before GVHD onset. One patient with acute GVHD grade I following ATIR101 
infusion progressed into severe chronic GVHD after > 12 months post HSCT. 


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In total, for four patients in the (M)ITT population disease relapse (or disease progression) 
was reported. Two patients relapsed early after HSCT (within 100 days) and two relapsed 
more than a year after HSCT. All four patients died due to RRM during the study.  
Data from study CR-AIR-007 were compared with data from the observational, non-
interventional cohort study CR-AIR-006. This study with 1-year follow-up included adult 
patients (18 to 65 years) with hematological malignancies (AML, ALL, both in complete 
remission, and MDS) who had received allogeneic TCD HSCT (CD34+ cell selection) from 
a haploidentical donor, or allogeneic HSCT from a fully matched or 1-locus mismatched 
unrelated donor (MUD/MMUD).  
In comparison to patients receiving TCD HSCT without additional donor lymphocytes 
(external control group of study CR-AIR-006; no head-to-head comparison), infusion of 
ATIR101 led to a marked, statistically significant reduction of TRM and improvement in OS 
(Table 1). TRM for ATIR101 patients in study CR-AIR-007 was 13% at 6 months and 32% 
at 12 months, compared with 37% and 70% in patients treated with TCD HSCT only in study 
CR-AIR-006 (these patients had received a CD34-selected graft from a haploidentical donor 
following a similar preparative regimen for the same disease conditions at the same 
transplant centers but did not receive ATIR101 post transplant). The OS probability was 83% 
at 6 months and 61% at 12 months in ATIR101-treated patients, vs. 63% and 20% in the 
Haplo without ATIR101 group of study CR-AIR-006. 
Table 1 
Kaplan-Meier estimates of OS and TRM at 6 and 12 months after HSCT 
 
OS 
TRM 
6 months 
12 months 
6 months 
12 months 
CD34-Haplo-HSCT + ATIR101   
CR-AIR-007 (n=23) 
83% 
61% 
13% 
32% 
CD34-Haplo-HSCT  (external control) 
CR-AIR-006 (n=35) 
63% 
20% 
37% 
70% 
p-value of difference between survival 
curves 
p=0.0029 
p=0.0065 
 
The GVHD-free, relapse-free survival (GRFS) for HSCT + ATIR101 is estimated to be 57% 
at 1-year post HSCT, which compares favorably to the TCD HSCT only control group 
(20%), and also against patients undergoing a MUD transplantation (41%), derived from the 
same centers (Figure 2). 


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Figure 2 
Survival curves of GRFS probability versus time after HSCT 
(data study CR-AIR-007 and external controls study CR-AIR-006) 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
Potential adverse reactions of the study intervention ATIR101 are: 
• Graft-versus-Host Disease 
Because ATIR101 contains mismatched donor lymphocytes and due to the possibility, 
that a small percentage of alloreactive T-cells could remain in ATIR101, a causal 
relationship between acute or chronic GVHD and ATIR101 administration cannot be 
ruled out. Data from previous ATIR101 studies show that GVHD serious adverse events 
probably, possibly, or certainly related to ATIR101 have been reported in nine patients. 
Therefore, acute and chronic GVHD are currently considered expected serious adverse 
reactions of ATIR101. 
• CMV and EBV related reactions 
CMV and EBV related reactions and reactivations have been observed in previous 
ATIR101 studies. Due to the immune-compromised state of the patient CMV and EBV 
may be transmitted from donor to recipient during stem cell transplantation or can 
originate from a de novo infection after HSCT. A previous CMV/EBV infection resulting 
in latent presence of the virus in lymphocytes may lead to reactivation due to the 


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immune-compromised state of the patient after HSCT. Because ATIR101 contains donor 
lymphocytes, the causal relationship between CMV/EBV related adverse events (AEs) 
and ATIR101 administration cannot be ruled out if the donor is positive for CMV/EBV at 
screening.  
• Post-transplant lymphoproliferative disease (PTLD) 
Because ATIR101 contains donor lymphocytes, the causal relationship between PTLD 
and ATIR101 administration cannot be ruled out if the donor is positive for EBV at 
screening. PTLD typically occurs with EBV infection. PTLD possibly related to 
ATIR101 according to the sponsor was reported in three patients in study CR-AIR-007. 
• Hypersensitivity to any of the excipients (including DMSO) 
Potential adverse reactions after the infusion could include allergic or hypersensitivity 
reactions to some of the constituents of ATIR101 (e.g. the excipient DMSO): immediate 
fever or chills, skin rash, bronchospasm, or anaphylactic shock, and delayed serum-
sickness-like reactions. Rash possibly related to ATIR101 has been reported in one 
patient in study CR-AIR-007. 
• Autoimmune hemolytic anemia (AIHA) 
AIHA was reported in five patients (19.2%) in study CR-AIR-007 and one patient (5.9%) 
in study CR-AIR-008. Based on the available literature and data from these patients it 
was preliminarily concluded that the observed cases of AIHA are most likely related to 
the TCD HSCT that the patients underwent. In AIHA, donor lymphocytes are believed to 
produce autoantibodies against donor antigens, leading to hemolysis. Although a direct 
relationship between AIHA and ATIR101 infusion does not seem to be likely at the 
moment, it cannot be excluded.  
 
The marketed drug cyclophosphamide, which is part of the control intervention, is associated 
with the following (very) commonly occurring adverse reactions (Baxter 2016): 
System organ class 
Preferred term 
Frequency * 
Infections and infestations 
Infections 
Common 
Blood and lymphatic system disorders 
Myelosuppression 
Very common 
 
Haemolytic uraemic syndrome 
Very common 
Immune system disorders 
Immunosuppression 
Very common 
Hepatobiliary disorders  
Hepatic function abnormal 
Common 
Skin and subcutaneous tissue disorders 
Alopecia 
Very common 
Renal and urinary disorders 
Cystitis 
Very common 
 
Microhematuria 
Very common 
 
Haemorrhagic cystitis 
Common 
 
Macrohematuria 
Common 
Reproductive system and breast disorders 
Impairment of spermatogenesis 
Common 
General disorders and administration site 
conditions 
Fever 
Very common 
 
Asthenia 
Common 
 
Mucosal inflammation 
Common 
* Very common: frequency ≥ 1/10; Common: frequency ≥ 1/100 and < 1/10 
 
As with all cytotoxic therapy, treatment with cyclophosphamide involves the risk of 
secondary tumours and their precursors as late sequelae. The risk of urinary tract cancer as 
well as the risk of myelodysplastic alterations, partly progressing to acute leukemia, is 


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increased. Other malignancies reported after use of cyclophosphamide include lymphoma, 
thyroid cancer, and sarcomas. In some cases, the secondary malignancy developed several 
years after cyclophosphamide treatment had been discontinued. 
Patients (in the ATIR101 group) and donors may experience adverse reactions from the 
apheresis procedure such as light-headedness/fainting due to temporary hypotension. tingling 
sensations around the mouth and fingers, and slight muscle cramps. 
The most common risks for the donor are associated with G-CSF administered for stem cell 
collection: fatigue, nausea, flu-like muscle soreness, bone pain, thrombocytopenia, and high 
WBC count. 
The most common risks for the patient are associated with the conditioning regimen, HSCT, 
and anti-viral and immunosuppressant regimen. These risks include infections, graft 
rejection, GVHD, disease relapse and adverse reactions to concomitant therapies (e.g., 
radiation therapy, chemotherapy, anti-viral drugs, and immunosuppressants in the PTCy 
group). 
2.3.2 
Known Potential Benefits 
For the majority of patients with high-risk hematologic malignancy, an allogeneic HSCT 
remains the only curative option. The use of a matched (related or unrelated) donor from the 
donor registries is considered standard of care for patients who are eligible for an HSCT. 
However, a significant number of patients do not receive this treatment, because a suitable 
HLA-matched related or unrelated donor cannot be found in a timely manner or cannot be 
found at all. This protocol offers patients in need of an HSCT, who lack a suitable HLA-
matched sibling or unrelated donor, the opportunity to receive a potentially life-saving 
treatment by the use of mismatched relatives, who are only partially HLA-matched to the 
patient, as stem cell donor (haploidentical donors). 
2.3.3 
Assessment of Potential Risks and Benefits 
This protocol offers patients in need of an HSCT, who lack a suitable HLA-matched sibling 
or unrelated donor, the opportunity to receive a potentially life-saving treatment by the use of 
mismatched relatives, who are only partially HLA-matched to the patient, as stem cell donor 
(haploidentical donors). Patients will receive either a TCD HSCT followed by ATIR101 
(study intervention) or a T-cell replete HSCT followed by a high dose of cyclophosphamide 
(control intervention). 
A T-cell replete haploidentical HSCT followed by a high dose of cyclophosphamide is an 
upcoming widely used treatment if no HLA-matched donor is available in a timely manner. 
Although the conditioning regimen, the transplant, and required medications involve certain 
risks (see above), these are definitely outweighed by the benefit of survival rates comparable 
to those of matched donor transplants. However, treatment with cyclophosphamide involves 
the risk of occurrence of secondary tumors, specifically urinary tract tumors and acute 
leukemias, even several years after cyclophosphamide treatment has been discontinued.  


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A TCD HSCT followed by ATIR101 is an investigational treatment in patients without the 
availability of a matched donor in a timely manner. This treatment modality is associated 
with some known risks (see above). Interestingly, Phase II studies showed promising 
outcome rates with regard to overall survival, disease relapse and GVHD. Therefore, the 
clinical benefit of this treatment is expected to outweigh the risk for the patient.  
Furthermore, all patients will contribute to increasing the knowledge on the efficacy and 
safety of a haploidentical HSCT and adjunctive ATIR101 treatment compared to the widely 
used T-cell replete HSCT followed by a high dose of cyclophosphamide (Baltimore 
protocol), which might be of benefit for future patients. In conclusion, the overall benefit/risk 
ratio for patients participating in the study is positive. 


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3 OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
The primary objective of this study is to compare safety and efficacy of a haploidentical 
T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T-cell 
replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in 
patients with a hematologic malignancy. An additional objective of the study is to compare 
the effect of the two treatments on quality of life. 
Most of the study endpoints are times to event. Unless specified otherwise, summary 
statistics (cumulative incidences or proportion of patients free of the event of interest) will be 
presented for time to event endpoints at 3 months, 6 months, 12 months and 24 months. 
Some endpoints clearly capture the efficacy of ATIR101, some clearly capture the safety of 
ATIR101, and some provide a combined assessment of efficacy and safety. 
3.2 
Primary Endpoint 
The primary endpoint of the study is GVHD-free, relapse-free survival (GRFS). GRFS is 
defined as time from randomization until grade III/IV acute GVHD, chronic GVHD 
requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs 
first (Holtan et al. 2015). This endpoint captures both safety and efficacy. 
Composite endpoints acknowledge that both survival and rates of other critical events are 
important when testing new therapies. Recently, the Blood and Marrow Transplant Clinical 
Trials Network recognized the potential utility of the novel composite endpoint of GRFS in 
trials of allogeneic HSCT. Each of the GRFS components (grade III/IV acute GVHD, 
chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, and death) 
is clinically meaningful. GRFS therefore represents ideal recovery from HSCT and a 
measure of cure without ongoing morbidity. Using a cohort of 628 adult patients with 
hematological malignancies who underwent reduced intensity conditioning (RIC) and HSCT 
between 2006 and 2009 followed by GVHD prophylaxis with tacrolimus and methotrexate, 
data from the Center for International Blood and Marrow Transplant Research determined 
that the 1-year probability of GRFS was 23% (95% CI 20-26). Thus, only approximately 
one-quarter of adult patients transplanted for malignant disease survived without at least one 
of these major complications during the first 12 months after HSCT (Bolaños-Meade et al. 
2015).  
Data from a large, single center patient cohort was analyzed for GRFS among 531 
consecutive adult recipients of allogeneic transplantation (Solh et al. 2016). They found that 
although 78% of patients are alive at 1 year post HSCT only 31% of transplant recipients 
survived 1 year without experiencing at least 1 GRFS event and only 24% survive it 2 years 
post-transplant without 1 GRFS event. These findings are in line with a recent report from 
the University of Minnesota that showed a 1-year survival rate of 63% and a 1-year GRFS 
rate of 31% (Holtan et al. 2015). 


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The Blood and Marrow Transplant Clinical Trials Network has incorporated this composite 
endpoint into new prospective trials of allogeneic HSCT. It is believed to better assess a 
successful transplant because it incorporates survival and freedom from relapse as well as the 
occurrence of clinically significant GVHD with its well-recognized effects on quality of life. 
3.3 
Secondary Endpoints 
Overall survival (safety and efficacy) 
Overall survival (OS) is defined as the time from randomization until death from any cause. 
Progression-free survival (efficacy) 
Progression-free survival (PFS) is defined as the time from randomization until relapse, 
disease progression, or death, whichever occurs first. 
Relapse-related mortality (efficacy) 
Relapse-related mortality (RRM) is defined as the time from randomization to death due to 
disease relapse or disease progression. 
Transplant-related mortality (safety and efficacy) 
Transplant-related mortality (TRM) is defined as the time from randomization to death due to 
causes other than disease relapse or disease progression. 
3.4 
Other Endpoints 
Immune reconstitution (efficacy) 
• Time to T-cell reconstitution, defined as the time to CD3+ > 0.2×109/l in peripheral blood 
(at two consecutive measurements; time to first measurement) 
 
Incidence and severity of acute and chronic GVHD (safety) 
Acute and chronic GVHD will be diagnosed, classified, and graded according to NIH criteria 
(see Section 8.1.5). The following endpoints are assessed: 
• Cumulative incidence of grade II-IV and grade III-IV acute GVHD 
• Cumulative incidence of moderate and severe chronic GVHD 
• Cumulative incidence of chronic GVHD requiring systemic immunosuppressive 
treatment 
• Duration of acute and chronic GVHD episodes 
 
Incidence and severity of viral, fungal, and bacterial infections (efficacy) 
• Cumulative incidence of NCI CTCAE grade 2-5 and grade 3-5 infections 
 


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Incidence and severity of adverse events (safety) 
• Cumulative incidence of NCI CTCAE grade 3-5 adverse events 
 
Quality of life 
• FACT-BMT, SF-36, MDASI, EQ-5D-5L total scores (change from screening) 
 


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4 STUDY DESIGN 
4.1 
Overall Design 
Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study 
comparing two parallel groups. After signing informed consent, a total of about 250 patients 
will be randomized in a 1:1 fashion to receive either a TCD HSCT (CD34 selection) from a 
related, haploidentical donor, followed by ATIR101 infusion, or a T-cell replete HSCT, 
followed by a high dose of PTCy.  
Randomization will use minimization to balance treatment groups with respect to underlying 
disease (AML, ALL, or MDS), DRI (intermediate risk, high risk, or very high risk) and 
center. A stochastic treatment allocation procedure will be used so that the treatment 
assignment is random for all patients entered in the study. 
Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2.0×106 
viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the PTCy 
group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT. All 
patients will be followed up for at least 24 months post HSCT. Patient follow-up beyond 
24 months post HSCT will be discontinued when a total number of 156 GRFS events has 
been reached. 
4.2 
Scientific Rationale for Study Design 
The study is designed to confirm results obtained in Phase I-II clinical studies and to 
compare the outcomes of patients receiving ATIR101 post HSCT in a randomized setting to 
a control group of patients receiving a high dose of cyclophosphamide post HSCT, an 
upcoming treatment modality for patients in need of a haploidentical HSCT. The study aims 
at showing superiority in the ATIR101 group compared to the PTCy group. 
4.3 
Justification for Dose 
In study CR-GVH-001 the optimal dose of ATIR101 for further development was considered 
to be 2.0×106 viable T-cells/kg. Data of studies CR-AIR-007 and CR-AIR-006 show 
significant improvement of TRM and OS after ATIR101 treatment at a dose of 2.0×106 
viable T-cells/kg compared to patients who did not receive ATIR101. 
The dose of cyclophosphamide of 50 mg/kg/day at 3 and 4/5 days after the HSCT is based on 
published data of the Baltimore protocol, which showed comparable outcomes of 
haploidentical HSCT followed by PTCy and matched (un)related donor transplants (Bashey 
et al. 2013; Burroughs et al. 2008), 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases 
of the study and a total number of 156 GRFS events has been reached. After study 
completion, patients treated with ATIR101 who consented will be enrolled in the 


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observational patient registry CR-REG-001, involving passive follow-up until 5 years after 
the HSCT. 
A donor is considered to be in the study up to and including collection of the stem cells for 
the HSCT. 
The end of the study is defined as the date at which the last data point from the last patient is 
received globally. 


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5 STUDY POPULATION 
5.1 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study: 
1. Any of the following hematologic malignancies: 
- 
Acute myeloid leukemia (AML) in first cytomorphological remission (with < 5% 
blasts in the bone marrow) with Disease Risk Index (DRI) intermediate or above, or 
in second or higher cytomorphological remission (with < 5% blasts in the bone 
marrow) 
- 
Acute lymphoblastic leukemia (ALL) in first or higher remission (with < 5% blasts in 
the bone marrow) 
- 
Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one 
transfusion per month), or intermediate or higher IPSS-R risk group) 
2. Clinical justification of allogeneic stem cell transplantation where a suitable HLA 
matched sibling or unrelated donor is unavailable in a timely manner.  
3. Availability of a related haploidentical donor with one fully shared haplotype and 2 to 4 
mismatches at the HLA-A, -B, -C, and -DRB1 loci of the unshared haplotype, as 
determined by high resolution HLA-typing 
4. Karnofsky Performance Status (KPS) ≥ 70% 
5. Male or female, age ≥ 18 years and ≤ 70 years 
Patients aged ≥ 65 years must have a Sorror score ≤ 3 
6. Patient weight ≥ 25 kg and ≤ 130 kg 
7. Availability of a donor aged ≥ 16 years and ≤ 75 years who is eligible according to local 
requirements and regulations. Donors aged < 16 years are allowed if they are the only 
option for an HSCT, if they are permitted by local regulations, and if the IRB/IEC 
approves participation in the study. 
8. For females of childbearing potential27 who are sexually active and males who have 
sexual contact with a female of childbearing potential: willingness to use reliable 
methods of contraception (oral contraceptives, intrauterine device, hormone implants, 
contraceptive injection or abstinence) during study participation 
9. Given written informed consent (patient and donor) 
 
5.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Diagnosis of chronic myelomonocytic leukemia (CMML) 
2. Availability of a suitable HLA-matched sibling or unrelated donor in a donor search 
3. Prior allogeneic hematopoietic stem cell transplantation 
4. Diffusing capacity for carbon monoxide (hemoglobin corrected DLCO) < 50% predicted 
5. Left ventricular ejection fraction < 45% (evaluated by echocardiogram or MUGA scan) 
6. AST and/or ALT > 2.5 × ULN (CTCAE grade 2) 
 
27  A female is considered of childbearing potential following menarche and until becoming post-menopausal 
unless permanently sterile. 


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7. Creatinine clearance < 50 ml/min (calculated or measured) 
8. Positive pregnancy test or breastfeeding of patient or donor (women of childbearing age 
only)  
9. Estimated probability of surviving less than 3 months 
10. Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) 
11. Known hypersensitivity to cyclophosphamide or any of its metabolites 
12. Any contraindication for GVHD prophylaxis with mycophenolate mofetil, 
cyclosporine A, or tacrolimus 
13. Known presence of HLA antibodies against the non-shared donor haplotype 
14. Positive viral test of the patient or donor for HIV-1, HIV-2, HBV28, HCV28, Treponema 
pallidum, HTLV-1 (if tested), HTLV-2 (if tested), WNV (if tested), or Zika virus (if 
tested) 
15. Any other condition that, in the opinion of the investigator, makes the patient or donor 
ineligible for the study 
 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently entered in the study. This might include patients who have been 
randomized but for whom eligibility cannot be confirmed (see Section 6.3). A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Participants who do not meet the criteria for enrolment in this study (screen failure) may be 
rescreened. If rescreening is needed due to laboratory assessments, physical examination or 
other diagnostic assessments being out of protocol defined ranges, the out of protocol 
assessment(s) may be repeated once within four weeks of initial screening. If rescreening 
indicates that the participant is still not eligible, the patient cannot continue. A total 
rescreening needs to be done if more than four weeks have passed since the initial screening. 
Rescreened participants should be assigned the same participant number as for the initial 
screening. 
5.5 
Strategies for Recruitment and Retention 
Patients will be approached for participation in the study after the decision to proceed with a 
transplantation has been made and if no suitable matched related or unrelated donor is 
available in due time following a donor search and a suitable haploidentical donor has been 
 
28  HBV/HCV: Only patients with active infection or infection history and donors with active infection are 
excluded. 


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identified. A transplant physician will verify patient eligibility criteria for enrolment in the 
study and ineligible patients will proceed off study without further follow-up. Patient 
recruitment will not exclude women and members of minority groups in accordance with the 
NIH Policy on Inclusion of Women and Minorities as Participants in Research Involving 
Human Subjects. Vulnerable participants such as pregnant women and children will not be 
enrolled in the study. 
The required sample size is 250 patients, and 156 events are required for the final analysis of 
the primary endpoint considering two specific types of study withdrawal, i.e. patients not 
reaching HSCT and patients for whom ATIR101 could not be produced. The sample size 
calculation additionally assumes that 10% of patients will be lost to follow-up at 1 year post 
HSCT in each treatment group.  
In this multinational study approximately 50 transplant centers are anticipated to participate. 
The screening target is four to six patients per transplant center. The accrual duration forecast 
is 30 months and the estimated time to get a sufficient number of events for final analysis of 
the primary endpoint is 38 months. 


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6 STUDY INTERVENTION 
6.1 
Study Interventions Administration 
6.1.1 
Study Intervention Description 
Patients in the ATIR101 group will receive a single ATIR101 dose, which is an ATMP 
manufactured on an individual basis. For ATIR101 manufacturing donor and patient 
peripheral blood mononuclear cells (PBMCs) as well as donor plasma are collected by 
apheresis on the same day according to the procedure described in the Product Handling & 
Shipping Manual as well as Kiadis Pharma-defined specifications for cell content. For the 
patient this apheresis is done in advance of the conditioning regimen for the HSCT (see 
Section 8.1.1) and for the donor this additional apheresis is done in general 0.5-3 weeks 
before the apheresis for the stem cell graft. Donation, collection and testing of human tissues 
and cells will be done in compliance with relevant local regulations (e.g., Directive 
2004/23/EC). The apheresis materials will be prepared for temperature-controlled shipment 
and shipped to the manufacturing facility according to the procedure that is described in the 
Product Handling & Shipping Manual. ATIR101 will be manufactured by a contract 
manufacturing organization under responsibility of Kiadis Pharma.  
For each patient batch, one 20-ml unit (bag) of ATIR101 will be prepared containing 2.0×106 
viable T-cells/kg, and if sufficient cells are available at the time of formulation, an additional 
unit (rescue dose) will be prepared containing at least 1.0×106 viable T-cells/kg. Each batch 
of ATIR101, manufactured for the individual patient, will be tested on key quality attributes, 
of which depletion of alloreactivity while preserving third party reactivity is crucial. The 
units are frozen and stored. After formal release, the frozen ATIR101 unit will be shipped to 
the clinical site just before ATIR101 infusion is required.  
Patients in the PTCy group will be given cyclophosphamide, which is a marketed drug 
supplied by the hospital pharmacy. 
6.1.2 
Dosing and Administration 
Patients in the ATIR101 group will be infused IV with ATIR101 at a single dose of 
2.0×106 viable T-cells/kg body weight between 28 and 32 days after the HSCT (or later if 
required by the patient's medical condition; see below). The actual dose of ATIR101 (number 
of viable T-cells) will be based on the patient’s body weight at screening. When the patient’s 
body weight at the time of ATIR101 administration differs from the patient’s body weight at 
screening, the dose should not be adjusted. 
In exceptional cases a second (rescue) dose of ATIR101 might be considered in the ATIR101 
group, if available. See Section 6.5.1 for details. 
ATIR101 will not be infused at the time of the planned infusion if: 
• The patient is suffering from active GVHD (any grade), and/or 
• The patient is receiving steroid-based immunosuppressive therapy (excluding topical 
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Once the symptoms of GVHD have been resolved and no steroid-based immunosuppression 
is used any more, the investigator can decide to infuse ATIR101 at the pre-specified dose. 
However, if there are clear signs of T-cell reconstitution (CD3+ > 0.05×109 cells/l) at the 
time of the delayed administration, ATIR101 should not be administered without consent of 
the sponsor. 
In the event the patient fails to demonstrate hematologic engraftment (see Section 8.2.11), 
bone marrow aspirate or biopsy might be performed and on a case by case basis it will be 
decided whether to infuse ATIR101 or not, after discussion between one of the coordinating 
investigators, Kiadis Pharma, and the investigator of the respective site. 
If the ATIR101 infusion is delayed or a rescue dose is given, extra visits should be performed 
to achieve at least a weekly patient follow-up for six weeks after ATIR101 infusion. The 
extra visits will be recorded as unscheduled visits in the eCRF. At these visits the same 
assessments as after a Week 4 ATIR101 infusion will be performed. 
Patients in the PTCy group will be given cyclophosphamide 50 mg/kg/day IV for 2 days on 
Day +3 and Day +4/+5. Prior to administration of cyclophosphamide, patients must receive 
appropriate hydration and mesna according to institutional standards.  
6.2 
Preparation/ Handling/ Storage/ Accountability 
6.2.1 
Acquisition and Accountability 
ATIR101 will be shipped frozen to the clinical sites in a dry shipper saturated with liquid 
nitrogen guaranteeing a temperature < -135 °C for at least 7 days. ATIR101 will remain 
stored in the dry shipper until infusion. If infusion will not be done within the maximum 
storage time of the dry shipper (approx. 7 days), the product can either be shipped back to the 
manufacturing facility or stored locally (details are given in the Product Handling & 
Shipping Manual). 
Drug accountability of ATIR101 will be documented at the study centers. In accordance with 
international guidelines, both Kiadis Pharma and the manufacturing facilities will maintain 
records of all ATIR101 products dispensed worldwide. After the completion of the study, the 
manufacturing facilities will take a full account of the product and provide it to Kiadis 
Pharma. All waste materials that have been used for the preparation and/or administration of 
ATIR101 at the manufacturing facility and at the study site will be destroyed according to 
local regulations on an ongoing basis. 
Traceability of ATIR101 
In this study traceability of ATIR101 is defined as the ability to locate and identify each 
individual unit of blood cells/plasma during any step from apheresis, through processing, 
testing and storage, to distribution of ATIR101 to the patient or disposal and vice versa. This 
also implies the ability to identify the donor, the ability to identify the patient at the study site 
and the ability to locate and identify all relevant data relating to products and materials 
coming into contact with those blood cells/plasma. 


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Traceability of patients and donors is ensured by documenting the identity of patients and 
donors including their donor/patient number at the study site. Both patient and donor 
identities are protected and are only identified by code numbers that can be linked at the 
study site to their full identity. 
Traceability of blood cells/plasma from apheresis until distribution of ATIR101 is ensured by 
the procedures of the manufacturing facility. Traceability of ATIR101 at the study site is 
ensured by maintaining an accountability log. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
The study intervention ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted 
ex vivo of host alloreactive T-cells using PDT with the photosensitizing reagent TH9402. 
ATIR101 is presented as a “dispersion for infusion”. The cell suspension contains 2.5-
13×106 viable T-cells/ml (for a patient weight range of 25-130 kg), 10% dimethylsulfoxide 
(DMSO), and 30% donor plasma in saline 0.9%. The total volume of a unit is 20 ml (dose 
2.0×106 viable T-cells/kg) or in case of a rescue dose (see Section 6.5.1) 10-20 ml (dose 
1.0-2.0×106 viable T-cells/kg). It is packed in a cryopreservation bag. Labels are designed 
according to local regulations. 
Cyclophosphamide, which is part of the control intervention, is presented as a lyophilized 
powder for intravenous infusion, which is commercially available for human use under 
various brand names. It is supplied in vials for single dose use. 
6.2.3 
Product Storage and Stability 
ATIR101 must be stored in liquid nitrogen (vapor phase) until infusion. The current shelf life 
is 18 months. 
Unopened cyclophosphamide vials must be stored below 25°C (77°F). The reconstituted 
solution for administration must be used immediately. 
6.2.4 
Preparation 
The frozen ATIR101 product should be thawed in approx. 2 minutes and the entire unit 
should be infused intravenously immediately (i.e. when last ice crystals are dissolved). In 
general, the time from the moment ATIR101 has been thawed (i.e. temperature 0°C/32°F 
without any ice crystals) until infusion of the entire unit (including rinsing the infusion bag 
with saline) should not take more than 20 minutes. Detailed instructions on the thawing and 
infusion process are provided in the ATIR101 Product Handling & Shipping Manual. 
Cyclophosphamide must be reconstituted using 0.9% sodium chloride for injection or water 
for injection and can be further diluted according to the instructions of the manufacturer. 
Cyclophosphamide should be handled and disposed in a manner consistent with other 
cytotoxic drugs. To minimize the risk of dermal exposure, gloves must always be worn when 
handling vials containing cyclophosphamide.  


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6.3 
Measures to Minimize Bias: Randomization and Blinding 
Patients expected to comply with the inclusion and exclusion criteria as judged by the 
investigator will be randomized in a 1:1 fashion to either the ATIR101 group or the PTCy 
group. Before randomization each and every patient must sign informed consent and 
demographics, details of the hematologic malignancy, vital signs, and DRI will be recorded. 
Randomization will be performed by applying a stochastic minimization technique with a 
minimization probability parameter of 0.80 (Pocock and Simon 1975), to balance treatment 
groups with respect to underlying disease (AML, ALL, or MDS), DRI (intermediate risk, 
high risk, or very high risk) and center. Randomization will be carried out by using an 
interactive web response system (IWRS). 
After randomization, patient eligibility will be confirmed by checking compliance with all 
inclusion and exclusion criteria. In case of non-compliance with one or more inclusion and 
exclusion criteria the patient will be regarded as a screening failure and will not be enrolled 
in the study. Based on experiences with previous ATIR101 studies it is anticipated that 
eligibility will be confirmed for almost all randomized patients. 
6.4 
Study Intervention Compliance 
Administration of ATIR101 and cyclophosphamide will be performed and documented by 
study site personnel.  
6.5 
Concomitant Therapy 
All concomitant prescription medications used during the study, in addition to the study 
intervention (ATIR101) or control intervention, will be considered concomitant. The 
following concomitant medications should be recorded in the electronic case report form 
(eCRF): 
• Medication for the treatment of GVHD 
• Medication for the treatment of infections 29 
• Prophylactic or preemptive use of anti-infective medication 
• Medication for the treatment of disease relapse 
• Medication for the treatment of other reported AEs 
• Post-transplant prophylactic use of immunosuppressive medication 
• Medication for prophylaxis against cyclophosphamide-induced hemorrhagic cystitis 
• Additional hematopoietic stem cell grafts 
• Additional lymphocyte infusions 
• Hematopoietic growth factors 
• Vaccinations 
• Medication for the treatment of veno-occlusive disease 
 
 
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Immunosuppressive Medication 
Post-transplant prophylaxis against GVHD will not be permitted in the ATIR101 group 
unless discussed with and approved by the sponsor. 
Post-transplant immunosuppressive therapy (e.g. corticosteroids) in the absence of GVHD 
should be avoided in the ATIR101 group unless medically indicated. The use of 
immunosuppressives shortly before infusion of ATIR101 or thereafter will inhibit the effects 
of ATIR101. 
In addition to cyclophosphamide, patients in the PTCy group will receive 
immunosuppressive medications for GVHD prophylaxis (e.g. mycophenolate mofetil, 
cyclosporine A, tacrolimus) based on institutional guidelines. 
G-CSF 
Post-transplant G-CSF treatment should be avoided within a week prior to ATIR101 
infusion, unless medically indicated. The use of post-transplant G-CSF after ATIR101 
infusion will be at the discretion of the investigator after consultation of the sponsor. 
Mesna and Hydration 
Prior to administration of cyclophosphamide, patients must receive appropriate hydration and 
mesna according to institutional standards to prevent cyclophosphamide-induced 
hemorrhagic cystitis (see Section 6.1.2). 
CMV 
If the patient is cytomegalovirus (CMV) positive, it is strongly recommended to use a CMV 
positive donor. All patients (ATIR101 and PTCy group) will be subject to regular 
quantitative quantitative polymerase chain reaction (PCR) monitoring. If quantified viral 
DNA levels exceed the institutional threshold for treatment of CMV (as established for each 
study center), patients should be treated pre-emptively with ganciclovir or valganciclovir 
according to institutional guidelines. 
ATIR101 group: 
To prevent infections with CMV, patients in the ATIR101 group who are CMV positive or 
have a CMV positive donor must be given prophylactic treatment including ganciclovir and 
foscarnet. The following dosing schedule is recommended (Day 0 is the day of HSCT): 
• From Day -9 through Day -2: ganciclovir 5 mg/kg IV q12h. 
• From Day 4 through Day 20: foscarnet 90 mg/kg IV q24h. 
• From Day 21 until Day 100: valganciclovir 900 mg PO daily 5 days a week, or 
ganciclovir 5 mg/kg IV q24h 5 days a week. 
• Dosage is to be adjusted depending on renal function. 
 


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EBV 
To prevent PTLD, all patients will be subject to regular quantitative PCR monitoring for 
Epstein-Barr virus (EBV) followed by adequate (pre-emptive) treatment if indicated. If 
quantified viral DNA levels exceed the institutional threshold for treatment of EBV (as 
established for each study center), patients should be treated with rituximab. It is also 
recommended to start rituximab if a patient who was EBV positive in the past, demonstrates 
enlarged lymph nodes, even if PCR for EBV is low or negative. 
The following schedule is recommended: 
• Immediately after the rise in EBV DNA is detected, rituximab (anti-CD20) 375 mg/m2 IV 
is started once weekly, until PCR for EBV becomes negative.  
• If PTLD is suspected on the basis of clinical symptoms, CT scans of thorax, abdomen 
and pelvis, as well as bone marrow aspiration and biopsy, and -when possible- lymph 
node extraction should be conducted. If results of the CT scan, bone marrow 
examinations, and lymph nodes demonstrate PTLD, rituximab is repeated weekly for at 
least 2 weeks. 
 
Adenovirus 
To prevent infections with adenovirus, patients will be subject to regular quantitative PCR 
monitoring followed by adequate treatment. If quantified viral DNA levels exceed the 
institutional threshold for treatment of adenovirus (as established for each study center), 
patients should be treated according to local institutional guidelines. 
Toxoplasma 
Patients with a positive serology test for toxoplasma gondii at screening or with a toxoplasma 
gondii positive donor will receive prophylaxis with trimethoprim-sulfamethoxazole (or 
alternatively atovaquone) per local institutional guidelines. 
HSV and VZV 
Patients tested positive for herpes simplex virus (HSV) or varicella zoster virus (VZV) at 
screening must receive prophylaxis with acyclovir or valacyclovir (in the absence of 
foscarnet) per local institutional guidelines for at least one year or until the CD4+ 
lymphocyte count has normalized. 
Other viral, fungal and bacterial prophylaxis will be given according to local institutional 
guidelines. 
Participation in Other Clinical Studies 
Participation in another clinical study is to be discussed between the investigator and Kiadis 
Pharma. 


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6.5.1 
Rescue Medicine 
It is not recommended to treat patients with a non-manipulated DLI for any reason, as the 
risk of developing life-threatening GVHD is extremely high. If a DLI is indicated due to 
impending relapse or uncontrolled infection, a rescue dose of ATIR101 might be considered 
in the ATIR101 group, if available. The investigator can request Kiadis Pharma for shipment 
of an ATIR101 unit containing a rescue dose. This request should be supported by a clinical 
rationale for the infusion of a rescue dose. 
GVHD is treated based on institutional standards. Limited GVHD of the skin should be 
treated locally only (steroid cream). Advanced stages and confirmed gut or liver GVHD 
require treatment according to institutional policy (e.g. IV steroids 0.5 mg/kg prednisolone, 
four times daily). 


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7 STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
If a patient relapses before the HSCT, the patient is not necessarily discontinued from the 
study. The investigator may decide to keep the patient in the study without any follow-up 
visits until at a later stage, treatment with an HSCT followed by ATIR101 or PTCy may be 
beneficial. After re-assessment of patient eligibility, the study schedule may be resumed if 
deemed clinically relevant. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
The patient and donor are free to withdraw from participation in the study at any time upon 
request. 
The investigator may terminate participation in the study for any of the following reasons:  
• The patient relapsed before collection of PBMCs for the manufacturing of ATIR101 or 
before HSCT, and did not achieve remission upon additional chemotherapy, 
• The ATIR101 batch is not suitable for patient administration, 
• The stem cell graft is not suitable for patient administration, 
• The patient is unwilling or unable to comply with study requirements,  
• The patient is lost to follow-up, or 
• Any other reason which, in the opinion of the investigator, justifies discontinuation of the 
patient from the study. 
 
For any patient who is discontinued from the study, the reason must be recorded in the 
electronic case report form (eCRF) as end-of-active study follow-up information. Adverse 
events ongoing at study discontinuation will be followed up for outcome information until 
resolution or stabilization, if possible (see Section 8.3.4). Patients prematurely discontinued 
from the study will not be replaced. 
When an eligible patient (see Section 6.3) is discontinued from active study follow-up after 
randomization, every effort will be made to collect data on disease status, GVHD, and 
mortality at 12, 24, and if applicable at 36 and 48 months after the HSCT (or in case of no 
HSCT, at 12, 24, and if applicable at 36 and 48 months after randomization).  
If a patient is discontinued from the study after ATIR101 or PTCy infusion, every effort will 
be made to report SAEs until at least 3 months after ATIR101 or PTCy infusion. 
7.3 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she fails to return for two scheduled 
visits and cannot be contacted by the study site staff. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Efficacy Assessments 
8.1.1 
Standard of Care Study Procedures  
Eligible patients are randomized to either the ATIR101 group or the PTCy group. Patients in 
both groups will undergo a conditioning regimen followed by an HSCT as part of regular 
standard of clinical care. In this section the conditioning regimens and HSCT procedures are 
described.  
For patients who weigh less than 125% of their ideal body weight (IBW), dosing of all drugs 
specified in this section should be based on actual body weight. For patients who weigh 
greater than or equal to 125% of their IBW, dosing should be based on the adjusted ideal 
body weight (AIBW). Calculation of IBW and AIBW is described in detail in Appendix 7. 
Conditioning Regimens 
All patients will undergo a conditioning regimen, either using a total body irradiation (TBI) 
regimen (Champlin et al. 2002) or a non-TBI based regimen. In order to balance the 
regimens between both treatment groups as much as possible, one of the following 
conditioning regimens must be used for both the ATIR101 group and the PTCy group (day 
numbers are relative to the day of HSCT). However, in the PTCy group, no thiotepa will be 
given in the TBI regimen. Both conditioning regimens for the PTCy group are in accordance 
with published data (Bacigalupo et al. 2015; Gaballa et al. 2016; Solomon et al. 2015). 
Minor scheduling deviations from these conditioning regimens are to be discussed between 
the investigator and Kiadis Pharma. 
TBI REGIMEN 
• Fractionated TBI 200 cGy twice daily for 3 days on Day -10 to -8 (1200 cGy in 
6 fractions) 
• Fludarabine 30 mg/m2 IV once daily for 5 days on Day -7 to -3 (150 mg/m2) 
• ATIR101 group only: Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 (10 mg/kg) 
 
NON-TBI REGIMEN 
• Fludarabine; 30 mg/m2 IV once daily for 5 days on Day -8 to -4 (150 mg/m2) 
• Thiotepa; 5 mg/kg IV twice daily for 1 day on Day -7 (10 mg/kg) 
• Melphalan; 60-70 mg/m2 IV once daily for 2 days on Day -2 and -1 (120-140 mg/m2) * 
 
* At the discretion of the investigator, melphalan can be given at 60 or 70 mg/m2 depending on the patient's 
condition. 
 


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Hematopoietic Stem Cell Transplantation (HSCT) 
Patients randomized to the ATIR101 group will receive a TCD graft from the donor, using 
the CD34+ cell selection method. Patients randomized to the PTCy group will receive a 
non-manipulated (full, T-cell replete) graft from the donor, either using bone marrow or 
peripheral blood stem cells (PBSCs) 
ATIR101 Group 
Patients randomized to the ATIR101 group will receive a TCD graft from the donor, using 
the CD34+ cell selection method. The collection and preparation of the donor stem cell graft 
is performed according to institutional procedures at the study center. The study centers will 
mobilize peripheral blood stem cells (PBSCs) from the donor with granulocyte colony-
stimulating factor (G-CSF) administered subcutaneously at a dose of approx. 8 µg/kg twice 
daily for approx. 4 to 7 days. The PBSCs will be collected by apheresis. According to the 
Perugia protocol for haploidentical transplants, the CD34-selected stem cell graft is targeted 
to contain at least 5×106 CD34+ cells/kg but if possible 8-11×106 CD34+ cells/kg with a 
maximum of 3×104 CD3+ cells/kg as assessed by flow cytometry (Champlin et al. 2002). To 
ensure a consistently highly purified stem cell graft, clinical sites will use the CliniMACS® 
CD34 isolation system (Miltenyi Biotec) as part of their institutional procedures for 
preparing the stem cell graft. To achieve the target CD34+ cell dose, more than one stem cell 
graft may be given. 
Prior to the transplant all patients in the ATIR101 group will be given rabbit anti-thymocyte 
globulin (ATG; Thymoglobulin®). The recommended dose of rabbit ATG is 2.5 mg/kg IV 
once daily for 4 days on Day -5 to -2, as a continuous IV infusion for 4-8 hours (10 mg/kg 
total dose); during the course of ATG, patients will receive methylprednisolone 1-2 
mg/kg/day IV. Scheduled deviations from this recommended ATG dosing schedule are to be 
discussed between the principal investigator and Kiadis Pharma. 
PTCy Group 
Patients randomized to the PTCy group will receive a non-manipulated (full) T-cell replete 
graft from the donor, either using bone marrow or PBSCs. The collection and preparation of 
the donor stem cell graft is performed according to institutional procedures at the study 
center. The study centers will mobilize PBSCs from the donor with granulocyte colony-
stimulating factor (G-CSF) or will use bone marrow as source of stem cells, depending on the 
center’s preference and experience. Donor bone marrow harvest will be done under 
anesthesia and the graft will not be manipulated, except for removal of red blood cells. The 
recommended target of mononuclear cells in bone marrow to be infused is 4×108 cells/kg 
body weight. The recommended target of PBSCs to be infused is 5×106 CD34+ cells/kg body 
weight. To achieve the target CD34+ cell dose, more than one stem cell graft may be given. 
Viral Testing 
Viral testing will be performed at the local laboratory, and if required by local regulations the 
tests will also be done on a separate blood sample at the manufacturing facility. 


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Blood of the patient and the donor will be tested for the presence of the following viruses 
(and other micro-organisms) in accordance with local regulatory requirements and 
regulations: EBV, CMV, HIV-1, HIV-2, HBV, HCV, Treponema pallidum, Toxoplasma 
gondii, herpes simplex virus (HSV), varicella zoster virus (VZV), HTLV-I (if applicable), 
HTLV-II (if applicable), WNV (if applicable), and Zika virus (if applicable). This viral 
testing must be done on samples obtained within one month before collection of PBMCs. If 
the patient is CMV positive, it is strongly recommended to use a CMV positive donor.  
HLA Compatibility 
Mismatches at the HLA-A, -B, -C, and -DRB1 loci (and if possible at the HLA–DQB1 locus) 
of the unshared haplotype will be assessed at the local laboratory by high resolution HLA-
typing. 
Blood Group 
ABO and Rhesus blood group of patient and donor will be assessed at the local laboratory. 
8.1.2 
Disease Assessment 
The status of the hematologic disease will be assessed regularly. Details of relapse or disease 
progression will be recorded on the Relapse/Disease Progression AE page of the eCRF. 
A bone marrow biopsy must be performed at fixed visits unless relapse has already been 
confirmed (Screening, Month 3, Month 6, Month 12, and Month 24 post HSCT) and in case 
of suspected relapse. In case a bone marrow biopsy cannot be obtained, it may be replaced by 
a bone marrow aspirate. If a bone marrow aspirate and/or biopsy had already been obtained 
within 2 weeks prior to signing informed consent (or start of re-screening) or 6 weeks prior to 
a scheduled visit (from Month 3 onwards), the assessment does not need to be repeated. 
In addition, in case of suspected relapse post HSCT, chimerism will be assessed to support 
the diagnosis. 
A test for the presence of minimal residual disease (MRD) can be done locally at the study 
center as per institutional standards and the results will be recorded in the eCRF. 
8.1.3 
Infection Assessment 
In this study an infection is defined as a clinically apparent infectious disease with symptoms 
or detectable viral reactivation, especially of CMV, EBV, or adenovirus. Details of all 
infections will be recorded on the Infection AE page of the eCRF, including type of 
infection, infection site, start date, stop date, NCI CTCAE severity grade (see Section 8.3.3), 
outcome, and action taken. Whenever an infectious episode is suspected, appropriate 
diagnostic measures need to be taken, including blood cultures to allow assessment of the 
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8.1.4 
CMV/EBV/Adenovirus Monitoring 
Patients will be monitored for CMV, EBV, and adenovirus, using PCR assays at the local 
laboratory. 
CMV 
Weekly CMV monitoring by quantitative PCR will be performed until Week 10 after the 
HSCT, monthly until Month 6, every 2 months until Month 12, and every 3 months until 
Month 24. More frequent monitoring for CMV is recommended depending on the patient's 
CMV status at baseline and the investigator's judgment, according to local, institutional 
guidelines. 
Guidelines for prophylactic medications and treatments against CMV are provided in Section 
6.5. 
EBV 
Weekly EBV monitoring by quantitative PCR will be performed until Week 10 after the 
HSCT, monthly until Month 6, every 2 months until Month 12, and every 3 months until 
Month 24. More frequent monitoring for EBV is recommended depending on the patient's 
EBV status at baseline and the investigator's judgment, according to local, institutional 
guidelines. 
Guidelines for pre-emptive medications and treatments against EBV are provided in Section 
6.5. 
Adenovirus 
Weekly adenovirus monitoring by quantitative PCR will be performed until Week 10 after 
the HSCT, monthly until Month 6, every 2 months until Month 12, and every 3 months until 
Month 24. More frequent monitoring for adenovirus is recommended depending on the 
patient's adenovirus status at baseline and the investigator's judgment, according to local, 
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8.1.5 
Graft-Versus-Host Disease Assessment 
GVHD events will be diagnosed and classified based on the NIH criteria (Filipovich et al. 
2005) as summarized in Table 2. 
Table 2 
Categories of acute and chronic GVHD 
Category 
Time of 
symptoms after 
HSCT or DLI 
Presence of 
acute GVHD 
features 
Presence of 
chronic GVHD 
features 
Acute GVHD 
Classic acute GVHD 
Persistent, recurrent, or 
late-onset acute GVHD 
 
≤ 100 days 
> 100 days 
 
 
Yes 
Yes 
 
No 
No 
Chronic GVHD 
Classic chronic GVHD 
Overlap syndrome 
 
No time limit 
No time limit 
 
No 
Yes 
 
Yes 
Yes 
 
Acute GVHD will be graded according to the Glucksberg scale (Harris et al. 2016) (see 
Appendix 6). Chronic GVHD will be graded according to NIH criteria (Filipovich et al. 
2005; Jagasia et al. 2015) (see Appendix 6). Whenever deemed possible, tissue biopsies will 
be obtained to confirm the GVHD diagnosis and to assess its severity. However, acute and 
chronic GVHD remain clinical diagnoses, which are considered present when diagnosed and 
treated, even in the absence of biopsy confirmation.  
Details of all GVHD events will be recorded on the GVHD AE page of the eCRF, including 
start date, stop date, NCI CTCAE severity grade (see Section 8.3.3), GVHD grade, outcome, 
and action taken. For chronic GVHD events it will also be recorded whether they require 
systemic immunosuppressive treatment. The start date of the GVHD event is defined as the 
date of initiation of GVHD treatment or the date of biopsy confirmation of GVHD, 
whichever is earlier. Resolution of the GVHD event is defined as complete response, i.e. 
resolution of all signs and symptoms according to the treating investigator. Early symptoms 
before diagnosis not treated as GVHD and flares after resolution of the GVHD event will be 
reported as separate AEs. 
8.1.6 
Mortality 
If a patient dies, the following information must be recorded in the eCRF: 
• Date of death 
• Cause of death (specification) 
• Investigator classification of cause of death into: 
• Disease relapse/progression 


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• Transplant-related mortality (TRM) defined as death due to causes other than disease 
relapse or disease progression 
 
All death cases will be subject to independent adjudication (see Section 8.3.3). 
8.1.7 
Immunophenotyping 
Immunophenotyping on peripheral blood samples by means of flow cytometry assessment of 
immune subsets at the local laboratory according to local practice should be done if the 
absolute lymphocyte count is higher than 0.1×109/l.  
Immunophenotyping assessments are planned at screening, at 3, 4, 5, 6, 7, 8, 9, and 10 weeks 
after the HSCT, as well as at 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, and 24 months post HSCT (and 
if applicable every 6 months thereafter). 
The following cell markers/cell marker combinations are to be measured: 
• CD3+ identifying T-cells 
• CD3+ CD8+ identifying cytotoxic T-cells 
• CD3+ CD4+ identifying helper T-cells 
• CD3- CD56+ identifying natural killer (NK)-cells 
• CD19+ identifying B-cells 
 
8.1.8 
Peripheral Blood Sampling for Research Purposes 
Sampling for GVHD Research Project 
Patients treated with HSCT plus ATIR101, who develop acute GVHD (grade III-IV) or 
chronic GVHD requiring systemic immunosuppressive treatment within the first year after 
stem cell transplantation, will be asked to donate a peripheral blood sample at a volume of 
35 ml for further research including genetic testing, focused solely on exploring the nature of 
the GVHD adverse event. Samples will be obtained only from patients, who gave their 
permission for an additional blood collection in case of GVHD. Participants who do not wish 
to donate peripheral blood samples for research purposes may still participate in the study. 
The peripheral blood samples should preferably be collected before steroid treatment. The 
samples will be handled according to the provided laboratory manual and subsequently sent 
to the laboratory of the sponsor. 
Sampling for General Immune Reconstitution 
At selected study sites, peripheral blood samples for further research of immune 
reconstitution will be collected from a subgroup of patients who signed a separate informed 
consent. These blood samples will be collected at a volume of 35 ml at screening, 8 weeks 
post HSCT, as well as at 4, 6, 8, 10 and 12 months post HSCT. Additional samples, also at a 
volume of 35 ml, will be taken when any of those patients develops a viral infection NCI 
grade 3/4 (sample to be taken preferably before treatment starts or in case of disease 


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progression despite of treatment). Participants who do not wish to donate peripheral blood 
samples for research purposes may still participate in the study. 
The samples will be handled according to the provided laboratory manual and subsequently 
sent to the laboratory of the sponsor where they will be used for ancillary assays of immune 
reconstitution and immune cell characterization. 
8.1.9 
Quality of Life 
The Foundation for the Accreditation of Cellular Therapy – Bone Marrow Transplantation 
questionnaire (FACT-BMT, version 4), the Short Form 36-item health survey (SF-36, 
version 2), the MD Anderson Symptom Inventory (MDASI), and the EQ-5D-5L will be 
scored at Screening, Month 3, Month 6, Month 12, and Month 24 (and if applicable 
Month 36 and Month 48), provided that validated translations in local language are available. 
8.2 
Safety and Other Assessments 
8.2.1 
Demographics 
Year of birth, gender, race30, and ethnicity30 of patient and donor will be recorded as well as 
the family relation between donor and patient. 
8.2.2 
Hematologic Malignancy 
WHO classification (Arber et al. 2016) and FAB classification of the hematologic 
malignancy, cytogenetic and molecular abnormalities, date of first diagnosis, and presence of 
minimal residual disease (if assessed) will be recorded. 
The DRI will be assessed according to Armand (Armand et al. 2014). See Appendix 2 for 
details. 
The EBMT risk score will be assessed according to Gratwohl (Gratwohl 2012). See 
Appendix 3 for details. 
All prior relapses and treatments of the hematologic malignancy will be recorded, including 
treatments that led to previous remissions if applicable. 
8.2.3 
Medical History 
All existing medical conditions at the time of screening and other relevant medical history 
including information on previous other malignancies will be recorded.  
Comorbidity will be assessed according to the items of the hematopoietic cell 
transplantation-specific comorbidity index (HCT-CI) (Sorror et al. 2005) (see Appendix 4).  
 
30 Unless recording of race and ethnicity is not allowed by local regulations. 


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8.2.4 
Karnofsky Performance Status 
Performance status will be assessed as a percentage (0-100%) according to the Karnofsky 
Performance Status (KPS) scale (Schag et al. 1984) (see Appendix 5). 
8.2.5 
Physical Examination 
At least the following body systems will be examined: skin, ears/nose/throat (ENT), 
respiratory, cardiovascular, abdomen (including liver and spleen), and lymph nodes. All 
abnormal findings will be recorded. 
8.2.6 
CT Scan Thorax or Chest X-ray 
A high-resolution CT scan of the thorax or a chest X-ray will be used to assess the presence 
of any generalized lung disease. This assessment may have been done within 6 weeks before 
signing informed consent (or start of re-screening). 
8.2.7 
Echocardiogram or MUGA Scan 
An echocardiogram or MUGA scan will be used to assess the patient's cardiac function. This 
assessment may have been done within 6 weeks before signing informed consent (or start of 
re-screening). 
8.2.8 
Pulmonary Function Test 
A pulmonary function test measuring the DLCO will be used to assess the functional status 
of the lungs. This assessment may have been done within 6 weeks before signing informed 
consent (or start of re-screening). The hemoglobin (Hb) corrected DLCO will be calculated 
with one of the following formulas (Macintyre et al. 2005) and can be compared with the 
DLCO predicted value: 
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀:  𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑓𝑓𝑓𝑓𝑓𝑓 𝐻𝐻𝐻𝐻 = 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 
(1.7 × 𝐻𝐻𝐻𝐻 [𝑔𝑔/𝑑𝑑𝑑𝑑] / (10.22 + 𝐻𝐻𝐻𝐻 [𝑔𝑔/𝑑𝑑𝑑𝑑]) 
𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹:  𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑓𝑓𝑓𝑓𝑓𝑓 𝐻𝐻𝐻𝐻 = 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 
(1.7 × 𝐻𝐻𝐻𝐻 [𝑔𝑔/𝑑𝑑𝑑𝑑] / (9.38 + 𝐻𝐻𝐻𝐻 [𝑔𝑔/𝑑𝑑𝑑𝑑]) 
 
8.2.9 
Creatinine Clearance 
To assess renal function creatinine clearance will be either calculated or measured: 
• Calculation by using the Cockcroft-Gault formula (Cockcroft and Gault 1976) 
 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 [ml/min] = (140 −𝐴𝐴𝐴𝐴𝐴𝐴) × 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 [𝑘𝑘𝑘𝑘] × 0.85[𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓]
72 × 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 [mg/dl]
 


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• Measurement by collecting 24-hour urine 
 
Creatinine clearance [ml/min] = 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 [𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑] × 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 [𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚]
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 [mg/dl]
  
 
Serum creatinine and urine creatinine will be assessed at the local laboratory. These 
assessments may have been done within 2 weeks before signing informed consent (or start of 
re-screening). 
8.2.10 
Vital Signs 
The following vital sign parameters will be measured for the patient at regular intervals: 
respiration rate or oxygen saturation, pulse rate, temperature, weight, height (at screening 
only), and supine blood pressure after 5 minutes of rest. In addition, following ATIR101 
infusion, pulse rate and supine blood pressure will be assessed after 15 minutes, 1 hour, and 2 
hours. Continuous oxygen monitoring will be done if the patient has respiratory problems 
after ATIR101 infusion. 
Weight and height of donors for patients in the ATIR101 group will be recorded pre HSCT. 
8.2.11 
Engraftment 
Neutrophil engraftment is defined as neutrophil count ≥ 0.5×109/l for 3 consecutive days and 
platelet recovery is defined as platelets ≥ 20×109/l for 3 consecutive days, without 
transfusion. The first days of occurrence of both criteria will be recorded. 
Primary graft failure is defined as lack of initial engraftment of donor cells. The patient never 
recovers from neutropenia (neutrophil count < 0.5×109/l), resulting in pancytopenia and an 
urgent need for re-transplantation. Secondary graft failure is defined as loss of donor cells 
after initial engraftment. In this case autologous recovery is common; however, marrow 
aplasia and pancytopenia may also develop. 
8.2.12 
Chimerism 
A blood sample for assessment of chimerism will be collected at Week 4 (before ATIR101 
infusion, if applicable), at Week 10, Month 3, Month 6, Month 12, Month 24, and in case of 
suspected relapse. Chimerism will be assessed in peripheral blood lymphocytes and 
polynuclear cells (neutrophils) by PCR amplification at the local laboratory. 
8.2.13 
Safety Laboratory Tests 
Patients will be in a seated or supine position during blood collection. Safety laboratory tests 
will include hematology, blood chemistry, and urinalysis tests (see Table 3). Safety 
laboratory tests will be performed at the local laboratory. 


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Table 3  
List of safety laboratory tests 
Hematology: 
- 
Hematocrit  
- 
Hemoglobin (Hb) 
- 
Mean corpuscular volume (MCV) 
- 
Platelet count 
- 
Red blood cell (RBC) count  
- 
White blood cell (WBC) count 
- 
Lymphocytes 
- 
Monocytes 
- 
Basophils 
- 
Eosinophils 
- 
Absolute neutrophil count (ANC) 
 
Urinalysis:  
- 
Bilirubin 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Leukocytes 
Blood Chemistry: 
- 
Albumin 
- 
Alkaline phosphatase (AP) 
- 
Alanine aminotransferase (ALT) 
- 
Aspartate aminotransferase (AST) 
- 
(Corrected) calcium (Ca) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Magnesium (Mg) 
- 
Phosphorus (P) 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Total protein 
- 
Urea or blood urea nitrogen (BUN) 
 
 
8.2.14 
Pregnancy Test 
At screening, a pregnancy test (serum or urine β-HCG test) will be performed in female 
patients and donors unless they are diagnosed as postmenopausal or if surgically sterilized. 
8.2.15 
Auxiliary Scientific Studies 
Patients in selected centers may be offered participation in auxiliary scientific studies based 
on approval by the local ethical committee and the sponsor such as special immune 
reconstitution studies and human artificial skin models for the prediction of residual GVHD. 
These studies are regarded separate studies and require independent informed consent from 
the patient. 
8.2.16 
Health Economics Data Collection 
Data will be collected on the cost of medication and/or treatments given during the entire 
study period for health economics assessment of both transplant regimens used in this study. 


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8.3 
Adverse Events and Serious Adverse Events 
8.3.1 
Definition of Adverse Events (AEs)  
A pre-treatment AE is defined as any untoward medical occurrence in a clinical investigation 
patient who has participated in the pre-treatment period of the study but prior to 
administration of the investigational product. 
A treatment-emergent AE is defined as any untoward medical occurrence in a clinical 
investigation patient administered an investigational product or procedure and which does 
not necessarily have to have a causal relationship with study participation. A treatment-
emergent AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or procedure, whether or not considered related to the medicinal product 
or procedure. 
8.3.2 
Definition of Serious Adverse Events (SAE)  
An SAE is any untoward medical occurrence or effect that at any dose:  
• Results in death; 
• Is life threatening (at the time of the event); 
• Requires hospitalization or prolongation of existing inpatients’ hospitalization; 
In this study, the following hospitalizations will not lead to reporting of an SAE: 
- 
Elective hospitalization for a pre-existing condition that has not worsened 
- 
Hospitalization for logistical reasons 
- 
Hospitalization for study procedures 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is an important medical event that satisfies any of the following: 
- 
May require intervention to prevent the items listed before 
- 
Is likely to affect the safety of the patient, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization. 
 
8.3.3 
Classification of an Adverse Event  
8.3.3.1 
Severity of Event  
The severity grade of an AE provides a qualitative assessment of the extent or intensity of an 
AE, as determined by the investigator or as reported by the patient. The severity grade does 
not reflect the clinical seriousness of the event, only the degree or extent of the affliction or 
occurrence (e.g. severe nausea, mild seizure).  
The severity grade should be recorded in the eCRF according to the grading below. Severity 
grades of specific AEs will be evaluated using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 5.0 (NCI et al. 2017). 


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1 = Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 = Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
3 = Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living. 
4 = Grade 4: Life-threatening consequences; urgent intervention indicated. 
5 = Grade 5: Death related to adverse event 
8.3.3.2 
Relationship to Study Intervention 
All AEs will be examined to determine any relationship to ATIR101 or post-transplant 
cyclophosphamide using the WHO-UMC system for standardized case causality assessment. 
The assessment criteria are listed below: 
Certain: 
• An event or laboratory test abnormality, with plausible relationship to 
administration of the investigational product. 
• The event cannot be explained by the disease or other drugs. 
• Response to withdrawal is plausible (pharmacologically, pathologically). 
• Event definitive pharmacological or phenomenological (i.e. an objective and 
specific medical disorder or a recognized pharmacological phenomenon). 
• Re-challenge satisfactory, if needed. 
 
Probable: 
• An event or laboratory test abnormality, with reasonable time relationship to 
administration of the investigational product. 
• Unlikely to be attributed to the disease or other drugs. 
• Response to withdrawal clinically reasonable. 
• Re-challenge not required. 
 
Possible: 
• An event or laboratory test abnormality, with reasonable time relationship to 
administration of the investigational product. 
• Could also be explained by the disease or other drugs. 
• Information on drug withdrawal may be lacking or unclear. 
 


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Unrelated/Unlikely: 
• Event or laboratory test abnormality, with a time to administration of the 
investigational product that makes a relationship improbable (but not impossible). 
• Disease or other drugs provide plausible explanations. 
 
8.3.3.3 
Expectedness  
The Medical Monitor will be responsible for determining whether an SAE is expected or 
unexpected. An SAE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the list of expected adverse reactions included in the 
Reference Safety Information section of the Investigator’s Brochure. 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up  
The time period for AE reporting starts when the ICF is signed. For the donor, all AEs will 
be reported until and including the collection of the stem cells. For the patient, infections 
(including viral activations) will be reported until two years after the HSCT. Relapse/disease 
progression, GVHD, AEs of special interest (Section 8.3.8), and SAEs (see Section 8.3.6) 
will be reported throughout the study. Other AEs including local and systemic reactions not 
meeting SAE criteria will be reported until 6 months after the HSCT. 
Events will be followed for outcome information until resolution or stabilization. If required 
by local regulations, evaluation of donor AEs will be done by a sub-investigator (physician) 
who is independent from the investigator evaluating the patient. 
8.3.5 
Adverse Event Reporting  
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit. The occurrence of an AE or SAE may come to the attention of study personnel 
during study visits and interviews of a patient presenting for medical care, or upon review by 
a study monitor. All AEs, whether spontaneously reported by the patient, discovered during 
general questioning by the investigator, or detected through physical examination, laboratory 
test or other means will be recorded on the appropriate eCRF. 
AEs will be captured on the appropriate eCRF. Information to be collected includes event 
description, time of onset, investigator’s assessment of severity, relationship to study 
intervention, actions taken, and time of resolution/stabilization of the event. All AEs must be 
documented appropriately regardless of relationship. 
Each event should be recorded as a single diagnosis. Accompanying signs (including 
abnormal laboratory values and electrocardiogram [ECG] findings) or symptoms should not 
be recorded as additional AEs. However, if the diagnosis is unknown or uncertain, signs and 
symptoms must be recorded.  


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Within this study, GVHD (see Section 8.1) will be recorded separately from the other AEs in 
the eCRF. 
Any medical condition that is present at the time that the patient is screened will be 
considered as baseline and not reported as an AE but as medical history. However, if the 
patient’s medical condition deteriorates at any time during the study, it will be recorded as an 
AE. Investigators should ensure that the event term recorded captures the change in the 
condition (e.g., “worsening of…”).  
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
8.3.6 
Serious Adverse Event Reporting  
All SAEs at any time during the study through the last follow-up visit required by the 
protocol must be reported by the investigator within 24 hours of knowledge of their 
occurrence to the sponsor or representative, independent of the circumstances or suspected 
cause. The report must be completed on the SAE report form in English and must include a 
relationship assessment. Information about every SAE will be collected and recorded on the 
SAE report form as well as simultaneously in the applicable eCRF pages, including at least 
data on screening, HSCT, ATIR101/PTCy infusion, AEs and concomitant medications.  
The SAE report form should be sent by e-mail or fax to ProPharma Group (St. Paul MN, 
USA). 
E-mail addresses: 
 
 
saereports@drugsafety.biz and saereporting@kiadis.com 
SAE fax number: 
 
 
+1 919-844-6948 
Backup fax number:  
 
+1 919-882-8337 
The original SAE report form, together with the fax confirmation sheet (if applicable), must 
be kept at the study site. If the initial report is made verbally or by telephone, a written 
confirmation via e-mail or fax must follow within 24 hours. The investigator will be 
requested to supply detailed information regarding the event at the time of the initial report. 
Each SAE should be recorded as a single diagnosis on the SAE report form. Accompanying 
signs (including abnormal laboratory values and ECG findings) or symptoms should not be 
recorded as additional SAEs. However, if the diagnosis is unknown, signs and symptoms 
should be recorded. As soon as the diagnosis causing the signs and symptoms is known, the 
event terms will be adjusted to the final diagnosis. 
For all SAEs occurring during the study, the investigator must submit follow-up reports to 
the sponsor or representative regarding the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes (in the case of persistent impairment), or the patient 
dies. In the event that a patient dies, an autopsy report (if available) must be forwarded to the 
sponsor or its representative. The timelines and procedure for follow-up reports are the same 


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as those for the initial report. The form and fax confirmation sheet must be retained by the 
site. 
All suspected unexpected serious adverse reactions (SUSARs) will be subject to expedited 
reporting to the regulatory authorities by the sponsor or its representative. The sponsor will 
also prepare expedited reports for other safety issues that might materially alter the current 
benefit-risk assessment of the investigational product. 
8.3.7 
Reporting Events to Participants 
Not applicable. 
8.3.8 
Events of Special Interest 
In this study the following AEs are regarded events of special interest: 
• PTLD 
• Infusion reactions 
• AIHA 
• Secondary malignancies 
• Hemorrhagic cystitis 
• Veno-occlusive disease 
 
Events of special interest (serious or non-serious) must be reported throughout the study on 
the eCRF. 
8.3.9 
Reporting of Pregnancy 
Pregnancies occurring during participation in the study after randomization, including 
pregnancies of partners of male patients, will be reported as an AE and will be followed up. 
The competent authority and IEC/IRB will be informed on these pregnancies. 
8.4 
Unanticipated Problems 
8.4.1 
Definition of Unanticipated Problems (UPs) 
Unanticipated problems (UPs) involving risks to participants are defined as any incident, 
experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IEC/IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 


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• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
8.4.2 
Unanticipated Problem Reporting 
In general, an AE observed during the conduct of a study should be considered an 
unanticipated problem (UP) involving risk to human subjects, and reported to the involved 
IECs/IRBs, only if it were unexpected, serious, and would have implications for the conduct 
of the study (e.g., requiring a significant, and usually safety-related, change in the protocol 
such as revising inclusion/exclusion criteria or including a new monitoring requirement, 
informed consent, or investigator’s brochure). An individual AE occurrence ordinarily does 
not meet these criteria because, as an isolated event, its implications for the study cannot be 
understood. 
The UP report to be sent to the IEC/IRB will include the following information: 
• Protocol identifying information: protocol title and number, name principal investigator, 
and the IEC/IRB project number 
• A detailed description of the event, incident, experience, or outcome 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
 
Changes in the conduct of the study as a result of an UP, will be submitted for approval to the 
competent authority as a substantial amendment. 
8.4.3 
Reporting Unanticipated Problems to Participants 
If applicable, the investigator will inform participants about UPs that may be relevant to the 
patient’s consent or may influence the patient’s willingness to continue participation in the 
study. 
8.5 
Study Visits 
A schedule of activities by study visit in tabular form is displayed in Section 1.3. 
8.5.1 
Screening (between Informed Consent & Confirmation Eligibility) 
• Informed consent patient/donor 
• Patient eligibility 
• Randomization 
• Demographics patient/donor 
• Hematologic malignancy; including WHO/FAB classification, cytogenetic and molecular 
abnormalities, DRI, EBMT risk score, date of first diagnosis, and prior treatments/ 
relapses 


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• Medical history; including comorbidity (HCT-CI) 
• KPS 
• Physical examination 
• CT scan thorax or chest X-ray; if not already done within 6 weeks before signing 
informed consent (or start of re-screening) 
• Echocardiogram or MUGA scan; if not already done within 6 weeks before signing 
informed consent (or start of re-screening) 
• Pulmonary function test; if not already done within 6 weeks before signing informed 
consent (or start of re-screening) 
• Creatinine clearance; calculated or measured, if not already done within 2 weeks before 
signing informed consent (or start of re-screening) 
• Vital signs; respiration rate or oxygen saturation, pulse rate, temperature, weight, height, 
and supine blood pressure after 5 minutes of rest 
• Quality of life; FACT-BMT, SF-36, MDASI, and EQ-5D-5L (if available in local 
language) 
• Disease assessment; including bone marrow biopsy or aspirate if not already obtained 
within 2 weeks before signing informed consent (or start of re-screening) 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 
• Hematology/biochemistry 
• Urinalysis 
• Pregnancy test patient/donor (if applicable) 
• Viral testing patient/donor; EBV, CMV, HIV-1, HIV-2, HBV, HCV, Treponema 
pallidum, adenovirus, Toxoplasma gondii, HSV, VZV, HTLV-I (if applicable), HTLV-II 
(if applicable), WNV (if applicable), or Zika virus (if applicable). This viral testing must 
be done on samples obtained within one month before collection of PBMCs. 
• HLA compatibility; mismatches at the HLA-A, -B, -C, and -DRB1 loci (and if possible at 
the HLA–DQB1 locus) of the unshared haplotype 
• Immunophenotyping if the absolute lymphocyte count > 0.1×109/l 
• At selected sites and patients: peripheral blood sampling for research purposes 
• Patient AEs (other) 
• Donor AEs 
• Concomitant medications 
 
8.5.2 
Pre-HSCT (between Confirmation Eligibility & HSCT) 
• Apheresis patient and donor PBMCs for ATIR101 manufacturing including measurement 
of patient weight (ATIR101 group only)  
• Collection of donor stem cell graft (PBSCs or bone marrow) 
• Conditioning regimen 
• Infection assessment 
• Patient AEs (other) 
• Donor AEs; up to and including the collection of stem cells 
• Concomitant medications 
 


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8.5.3 
HSCT (Day 0) 
• HSCT; either TCD CD34-selected (ATIR101 group) or T-cell replete (PTCy group) 
• Physical examination 
• Vital signs; respiration rate or oxygen saturation, pulse rate, temperature, weight, and 
supine blood pressure after 5 minutes of rest 
• Disease assessment 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 
• Hematology/biochemistry 
• Patient AEs (other) 
• Concomitant medications 
 
8.5.4 
Week 1, 2, 3 
Visits must be performed within the following windows: 
• Week 1: 1 week ± 2 days after the HSCT 
• Week 2: 2 weeks ± 2 days after the HSCT 
• Week 3: 3 weeks ± 2 days after the HSCT 
 
Activities: 
• Cyclophosphamide infusion; on Day +3 and Day +4/+5 (PTCy group only) 
• Physical examination 
• Vital signs; respiration rate or oxygen saturation, pulse rate, temperature, weight, and 
supine blood pressure after 5 minutes of rest 
• Disease assessment 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 
• Engraftment  
• Chimerism; only in case of suspected relapse 
• GVHD assessment 
• Immunophenotyping if the absolute lymphocyte count is higher than 0.1×109/l; only at 
Week 3 
• Hematology/biochemistry 
• Patient AEs (other) 
• Concomitant medications 
 


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8.5.5 
Week 4 
The visit must be performed within 28-32 days after the HSCT. 
Activities: 
• ATIR101 infusion (ATIR101 group only), unless the patient's medical condition requires 
that ATIR101 is infused later, e.g. because the patient is suffering from acute GVHD. 
• Physical examination 
• Vital signs; respiration rate or oxygen saturation, pulse rate, temperature, weight, and 
supine blood pressure after 5 minutes of rest (in ATIR101 group before infusion of 
ATIR101). Additionally, following ATIR101 infusion, pulse rate and supine blood 
pressure will be assessed after 15 minutes, 1 hour, and 2 hours, and continuous oxygen 
monitoring will be done if the patient has respiratory problems. 
• Disease assessment 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 
• Engraftment (in ATIR101 group before infusion of ATIR101) 
• Chimerism (in ATIR101 group before infusion of ATIR101) 
• GVHD assessment 
• Hematology/biochemistry 
• Urinalysis 
• Immunophenotyping if the absolute lymphocyte count is higher than 0.1×109/l (in 
ATIR101 group before infusion of ATIR101) 
• Patient AEs (other) 
• Concomitant medications 
 
8.5.6 
Week 5, 6, 7, 8, 9, 10 
Visits must be performed within the following windows: 
• Week 5: 5 weeks ± 3 days after the HSCT 
• Week 6: 6 weeks ± 3 days after the HSCT 
• Week 7: 7 weeks ± 3 days after the HSCT 
• Week 8: 8 weeks ± 3 days after the HSCT 
• Week 9: 9 weeks ± 3 days after the HSCT 
• Week 10: 10 weeks ± 3 days after the HSCT 
 
Activities: 
• Physical examination; only at Week 6, Week 8, and Week 10 
• Vital signs; respiration rate or oxygen saturation, pulse rate, temperature, weight, and 
supine blood pressure after 5 minutes of rest 
• Disease assessment 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 


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• Engraftment; in case of no neutrophil or platelet engraftment at Week 4, measurements 
are to be continued at weekly visits until engraftment 
• Chimerism; only at Week 10 and in case of suspected relapse 
• GVHD assessment 
• Hematology/biochemistry 
• Urinalysis; only at Week 8 
• Immunophenotyping if the absolute lymphocyte count is higher than 0.1×109/l 
• At selected sites and patients: peripheral blood sampling for research purposes; only at 
Week 8; additional sampling when a pre-specified GVHD event occurs in ATIR101-
treated patients (see Section 8.1.8). 
• Patient AEs (other) 
• Concomitant medications 
 
8.5.7 
Month 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, 24 
Visits must be performed within the following windows: 
• Month 3 after HSCT: 12 weeks ± 1 week after the HSCT 
• Month 4 after HSCT: 16 weeks ± 1 week after the HSCT 
• Month 5 after HSCT: 5 months ± 1 week after the HSCT 
• Month 6 after HSCT: 6 months ± 1 week after the HSCT 
• Month 8 after HSCT: 8 months ± 2 weeks after the HSCT 
• Month 10 after HSCT: 10 months ± 2 weeks after the HSCT 
• Month 12 after HSCT: 12 months ± 2 weeks after the HSCT 
• Month 15 after HSCT: 15 months ± 2 weeks after the HSCT 
• Month 18 after HSCT: 18 months ± 2 weeks after the HSCT 
• Month 21 after HSCT: 21 months ± 2 weeks after the HSCT 
• Month 24 after HSCT: 24 months ± 2 weeks after the HSCT 
 
Activities: 
• Physical examination; only at Month 3 and Month 4 
• Vital signs; only at Month 3 and Month 4; respiration rate or oxygen saturation, pulse 
rate, temperature, weight, and supine blood pressure after 5 minutes of rest 
• Quality of life; FACT-BMT, SF-36, MDASI, and EQ-5D-5L (if available in local 
language); only at Month 3, Month 6, Month 12, and Month 24;  
• Disease assessment (at all visits);  
Including bone marrow biopsy; only at Month 3, Month 6, Month 12, and Month 24, and 
in case of suspected relapse 
• Infection assessment 
• CMV/EBV/adenovirus monitoring (PCR) 
• Chimerism; only at Month 3, Month 6, Month 12, Month 24, and in case of suspected 
relapse 
• GVHD assessment 
• Hematology/biochemistry 


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• Urinalysis; only at Month 3 and Month 4 
• Immunophenotyping if the absolute lymphocyte count is higher than 0.1×109/l 
• At selected sites and patients: peripheral blood sampling for research purposes; only at 
Month 4, Month 6, Month 8, Month 10, and Month 12; additional sampling when a pre-
specified GVHD event occurs in ATIR101-treated patients (see Section 8.1.8). 
• Patient AEs (other); only at Month 3, Month 4, Month 5, and Month 6. 
However, SAEs and AEs of special interest (Section 8.3.8) are to be recorded as AEs 
throughout the study. 
• Concomitant medications 
 
8.5.8 
Follow-up Beyond Month 24: Every 6 Months 
Visits must be performed within the following windows until a total number of 156 GRFS 
events has been reached: 
• Month 30 after HSCT: 30 months ± 4 weeks after the HSCT 
• Month 36 after HSCT: 36 months ± 4 weeks after the HSCT 
• Month 42 after HSCT: 42 months ± 4 weeks after the HSCT 
• Month 48 after HSCT: 48 months ± 4 weeks after the HSCT 
• Etc. 
 
Activities: 
• Quality of life; FACT-BMT, SF-36, MDASI, and EQ-5D-5L (if available in local 
language); only at Month 36 and Month 48 
• Disease assessment;  
Including bone marrow biopsy in case of suspected relapse 
• GVHD assessment 
• Hematology/biochemistry 
• Immunophenotyping if the absolute lymphocyte count is higher than 0.1×109/l 
• Patient SAEs and AEs of special interest (Section 8.3.8) are to be recorded as AEs 
throughout the study. 
• Concomitant medications (excluding medications for the treatment of non-serious 
infections) 
 
When a total number of 156 GRFS events has been reached, the remaining patients who are 
in follow-up beyond Month 24 will be contacted by telephone for the following end-of-study 
assessments: 
• Disease assessment 
• GVHD assessment 
• Patient SAEs and AEs of special interest 
• Concomitant medications 


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9 STATISTICAL CONSIDERATIONS 
The planned analyses are summarized below. Any deviations from these analyses will be 
justified in the clinical study report. Details of the planned analyses will be described in the 
statistical analysis plan (SAP).  
9.1 
Statistical Hypotheses 
For the primary endpoint GRFS, interest focuses on whether the hazard rate in the ATIR101 
group significantly differs from that in the PTCy group. Hence the null and alternative 
hypotheses are: 
H0  
Hazard ratio ATIR101/PTCy = 1 
H1  
Hazard ratio ATIR101/PTCy ≠ 1 
9.2 
Sample Size Determination 
For the primary endpoint, GRFS, data from previous trials suggest that the 12-month GRFS 
will be equal to 52.2% in the ATIR101 group versus 36% in the control group (a hazard ratio 
equal to 0.636). These 12-month GRFS rates allow for two specific types of study 
withdrawal, i.e. patients not reaching HSCT and patients in whom ATIR101 could not be 
produced. The sample size calculation additionally assumes that 10% of patients will be lost 
to follow-up at 1 year in each treatment group. A power of 0.8 will be required for this 
magnitude of treatment effect, and a two-tailed significance level equal to 0.05. An interim 
analysis will be performed at two-thirds information time, using a spending function close to 
an O’Brien-Fleming type boundary. 
Based on these assumptions, the sample size required is 250 patients, and 156 events are 
required for the final analysis of GRFS to take place. If the 12-month GRFS rates are close to 
the assumed values, the interim analysis should take place towards the end of the accrual 
period, and the final analysis about 8 months later. The overall 12-month GRFS rate will be 
monitored for both treatment arms combined. If the overall 12-month GRFS rate is 
substantially lower than anticipated, the sponsor may decide to increase the sample size by 
maximum 20% (i.e. to 300 patients) so that the timing of the interim and final analysis is not 
unduly postponed. The percentage of the two types of study withdrawal described in the 
paragraph above will also be monitored. If the percentage of protocol deviations is 
substantially larger than anticipated, the Sponsor may decide to increase the sample size by 
maximum 20% (i.e. to 300 patients) so that the power of the study is protected. 
9.3 
Populations for Analyses 
All enrolled patients who were randomized will be included in the analyses. The following 
analysis datasets will be discerned: 


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Intention-to-treat (ITT) population 
The ITT population consists of all randomized patients. The ITT population is the primary 
efficacy dataset for the primary and secondary endpoints. 
Modified intention-to-treat (MITT) population 
The MITT population consists of all randomized patients who received an HSCT and 
ATIR101 (ATIR101 group) or at least one dose of post-transplant cyclophosphamide 
(PTCy group). 
Per protocol (PP) population 
Prior to locking the database, the sponsor will define a PP population as a subset of the MITT 
population of patients without major protocol deviations. The PP population will be used to 
(1) shed light on potential reasons why the primary analysis of the ITT population may have 
failed to reach significance, or (2) investigate how major protocol deviations may have had 
an impact on the magnitude of the treatment benefit. The definition of “major” protocol 
deviations will be agreed upon, and all cases of such major deviations adjudicated prior to 
database lock, by a team blinded to treatment allocation. 
Safety population 
The safety population consists of all patients who received an HSCT. 
9.4 
Statistical Analyses 
9.4.1 
General Approach  
For time to event endpoints, standard statistical methods will be used, including Kaplan-
Meier curves, the logrank test and the Cox proportional hazards model. The assumption of 
proportional hazards will be tested. All analyses will be stratified by underlying disease and 
Disease Risk Index (DRI). 
For binary endpoints, treatment groups will be compared through the Cochran-Mantel-
Haenszel test, stratified by underlying disease and DRI. The impact of prognostic factors 
upon these endpoints will be assessed through logistic regression models. 
Unless specified otherwise, descriptive statistics (cumulative incidences or proportion of 
patients free of the event of interest) will be presented for time to event endpoints at 
3 months, 6 months, 12 months, and yearly thereafter. The 95% confidence intervals will be 
calculated for the treatment contrast. 
The following missing data handling strategies for primary efficacy endpoint and secondary 
endpoints will be used: 
• There will be no imputation of missing values. 


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• There will be no “administrative” censoring for any reason, i.e. all events will be used in 
the analyses. The only censored observations will be for patients who have not 
experienced the event of interest. For instance, patients who died due to disease relapse or 
disease progression will be censored in the analysis of time to TRM. 
 
9.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint of the study is GRFS, treated as a time to event variable. The primary 
approach for the primary efficacy analysis will be a randomization test to reflect the 
treatment allocation procedure. The randomization test will be based on a large number of 
simulated trials, say S, in which the treatments are re-allocated to the patients actually entered 
in the study (in the same order of entry) using the same minimization algorithm. Each 
simulated trial uses a different seed for the random number generator. The test statistic, say 
∆, is calculated for the actual trial (∆obs) and for each simulated trial (∆i , i = 1, . . . , S). The 
significance probability (P-value) of the randomization test is calculated directly from the 
empirical distribution of ∆ under the null hypothesis. Let s be the number of ∆I’s for which 
|∆i| ≥ |∆obs|. The two-sided randomization P-value is equal to s/S. The number of simulated 
trials S will be chosen to ensure that the P-value is estimated correctly to the second 
significant digit (Buyse 2010). 
Standard times to event analyses described in Section 9.4.1 will be considered supportive 
analyses of the primary efficacy endpoint. 
9.4.3 
Analysis of the Secondary Endpoints 
Secondary endpoints will be tested for significance using a Hochberg procedure. The 
procedure works as follows: let p1, p2, p3 and p4 be the p-values of the tests for each of the 
four secondary endpoints, with p1 ≥ p2 ≥ p3 ≥ p4. Let α be the significance level (e.g. 5%) 
appropriate for the analysis. If p1 ≤ α, all four secondary endpoints show a significant 
treatment effect. If p1 > α and p2 ≤ α/2, the endpoints corresponding to p2, p3 and p4 show a 
significant treatment effect. If p1 > α and p2 > α/2 and p3 ≤ α/3, the endpoints corresponding 
to p3 and p4 show a significant treatment effect. If p1 > α and p2 > α/2 and p3 > α/3 and 
p4 ≤ α/4, the endpoint corresponding to p4 shows a significant treatment effect. If p1 > α and 
p2 > α/2 and p3 > α/3 and p4 > α/4, no secondary endpoint shows a significant treatment 
effect. 
Of note, the assumption of independence or positive correlation between the test statistics is 
required for the Hochberg procedure to preserve the type I error when one-sided testing is 
used (Dmitrienko et al. 2009). Two-sided testing will be used throughout and will not be at 
risk of an inflated type I error. 
Standard times to event analyses described in Section 9.4.1 will be considered supportive 
analyses of the secondary endpoints. 
A competing risk analysis will be performed for the following events that are considered 
failures for the primary endpoint and for some of the secondary endpoints: grade III/IV acute 
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systemic immunosuppressive treatment, disease relapse/progression (including disease-
related death), and death from all causes other than GVHD or disease relapse/progression. 
Gray’s test will be used to compare the randomized treatment arms for the competing risks, 
and the Fine-Gray proportional hazards model will be used to adjust these comparisons for 
covariates of interest (Fine and Gray 1999; Gray 1988). 
9.4.4 
Safety Analyses 
Safety variables include the reported AEs, SAEs, laboratory tests, vital signs and physical 
examination. 
AEs will be coded and evaluated for severity using NCI-CTCAE and will be summarized by 
MedDRA system organ class and preferred term. Separate summaries will be generated for 
the following: 
• All AEs 
• Severe AEs (Grade 3 or higher) 
• SAEs 
 
Listings will be provided of: 
• SAEs 
• AEs leading to treatment discontinuation 
• AEs resulting in death 
• AEs listed according to maximum severity 
 
The frequency of AEs will be tabulated by grade. Adverse events will be compared using χ² 
tests or, for low counts, using Fisher’s exact test. In view of the anticipated large number of 
statistical tests, P-values will not be interpreted in the usual sense but will be used as a 
“flagging device” to highlight differences worth further scrutiny. 
Laboratory tests: Summary statistics for baseline, each post-baseline measurement, and 
change from baseline for each post-baseline measurement will be presented for hematology, 
blood chemistry, and urinalysis parameters. 
Other safety data (e.g., vital signs) will be tabulated and listed, notable values will be 
flagged, and any other information collected will be listed as appropriate. 
9.4.5 
Baseline Descriptive Statistics 
The two treatment groups will be compared on baseline characteristics, using descriptive 
statistics and inferential statistics. 
9.4.6 
Planned Interim Analyses  
An interim analysis will be conducted when at least 105 GRFS events have occurred. The 
IDMC will review the results of the interim analysis. The sponsor will remain blinded to 


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these results, except if significance is reached at the time of the interim analysis (P < 
0.01246), with a treatment effect greater than anticipated (hazard ratio of 0.61 or better). At 
the time of the final analysis, significance will be reached (P < 0.04613) with a treatment 
effect lower than anticipated, but still clinically worthwhile (hazard ratio of 0.73 or better). 
9.4.7 
Sub-Group Analyses 
Subgroup analyses will be carried out by underlying disease, DRI, age, sex, and race/ 
ethnicity. Forest plots will be presented with a descriptive intent. Interaction tests will be 
carried out to investigate potential modulation of the treatment effect by baseline patient 
characteristics, but the trial is neither planned nor powered to detect interactions. Further 
sub-group analyses will be specified in the SAP. 
9.4.8 
Tabulation of Individual Participant Data 
Individual participant data will be listed by measure and time point. 
9.4.9 
Exploratory Analyses 
Exploratory analyses will be specified in the SAP. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to 
starting study intervention. In this study the following consent forms are available: 
• Informed consent for the patient 
• Informed consent for the donor 
• Informed assent for the minor donor (aged 16 or 17 years; only if allowed according to 
local requirements and regulations) 
• Informed consent for the parents/legal guardians of the minor donor (aged 16 or 17 years; 
only if allowed according to local requirements and regulations) 
• Informed consent for the patient for peripheral blood sampling for further research of 
immune reconstitution, if applicable 
 
10.1.1.2 
Consent Procedures and Documentation 
• The informed consent forms and any other written study materials provided to the 
patients and donors have to be approved by an IEC/IRB before patient enrollment. 
• The investigator/sub-investigator is responsible for explaining the nature and purpose of 
the study as well as other study-related matters to patients and donors, using the written 
information, and for obtaining their full understanding and written consent to participate 
in the study at their own free will. If required by local regulations, the informed consent 
procedure of the donor will be done by a sub-investigator who is independent from the 
investigator evaluating the patient. 
• The investigator or other responsible personnel who provided explanations to the patient 
and the donor (including collaborators who gave supportive information, if applicable), 
should sign and date the written information. 
• In case of a donor under age, the donor as well as his/her legal representative should be 
informed about the study and must sign and date the written information. 
• Informed consent must be obtained prior to the first observations/examinations of the 
screening period are performed (use of assessments which were performed before signing 
informed consents is subject of informed consent).  
• The investigator or other responsible personnel must give a copy of the signed consent 
form to the patient and the donor and store the original. 
• The process and communication of the consent should be documented on medical records 
of the patient and donor.  
• The investigator or other responsible personnel should note the following when obtaining 
consent from patients and donors: 


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- 
No patient/donor may be subjected to undue influence, such as compulsory 
enrollment into a study. 
- 
The language and expressions used in the written information should be as plain and 
understandable as possible. Patients should be given the opportunity to ask questions 
and receive satisfactory answers to the inquiry and should have adequate time to 
decide whether or not to participate in the study. Written information should not 
contain any language or contents that causes the patient to waive or appears to waive 
any legal rights, or that releases/mitigates or appears to release/mitigate the study site, 
the investigator/sub-investigator, collaborators, or the sponsor from liability for 
negligence. 
 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor, and auditor upon request. 
Supply of new and important information influencing the patient’s consent and revision of 
the written information 
• The investigator/sub-investigator should immediately inform the patient orally whenever 
new information becomes available that may be relevant to the patient’s consent or may 
influence the patient’s willingness to continue participation in the study (e.g., report of 
serious adverse drug reactions). The communication should be documented on medical 
records, for example, and it should be confirmed whether the patient is willing to remain 
in the study or not.  
• If the investigator or the sponsor recognizes the necessity to revise the written 
information in the terms and conditions applicable to the first point, the written 
information should be revised immediately based on the newly available information and 
be re-approved by the IEC/IRB.  
• The investigator/sub-investigator should obtain written informed consent to continue 
participation with the revised written information defined in the previous bullet even if 
patients are already informed of the relevant information orally. The investigator or other 
responsible personnel who provided explanations and the patient and donor should sign 
and date the informed consent form. The investigator or other responsible personnel 
should give a copy of the signed informed consent form to the patient and donor who had 
given consent with the written information and store the original appropriately as done 
for the first informed consent.  
 
10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the sponsor to the investigators and regulatory authorities. If 
the study is prematurely terminated or suspended, the principal investigator will promptly 
inform the IEC/IRB and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• Determination of unexpected, significant, or unacceptable risk to participants  


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• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements  
• Data that are not sufficiently complete and/or evaluable  
• Determination of futility  
 
The study may resume once concerns about safety, protocol compliance and/or data quality 
are addressed and satisfy the sponsor, IEC/IRB and/or the competent authority. 
In case it will be decided that the study will be prematurely terminated or suspended, all 
patients who are still in the study should at least complete the visit at Month 4 post HSCT. 
After premature termination of the study, efforts will be made to follow up patients for the 
occurrence of serious adverse events (SAEs) until 3 months after ATIR101 or 
cyclophosphamide administration. 
10.1.3 
Confidentiality and Privacy 
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted below is strictly prohibited. Upon the 
patient’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her medical welfare.  
Kiadis Pharma will use the information obtained during the conduct of this study for the 
development of ATIR101. The study investigator is obliged to provide Kiadis Pharma with 
complete test results and all data developed in this study, as described in this protocol. This 
information may be disclosed to appropriate competent authorities. 
Access to stored samples will be limited. Samples and data will be stored using codes 
assigned by the investigators. The code key linking the participant name to the research 
record will be kept by the investigator and may not be released outside the study site. The 
coded data does not include any identifying information of the participant, such as name or 
address. Data will be kept in password-protected computers. Only investigators, the sponsor 
and affiliates or contracted parties will have access to the coded samples and data. 
Even though individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to patients’ privacy due to direct access to source 
documents, or from other sources, they may not disclose the contents to third parties.  
Data generated by this study must be available for inspection upon request by representatives 
of the EMA, the FDA, Health Canada, any other competent authority, IECs/IRBs (if 
appropriate), and Kiadis Pharma. 
10.1.4 
Future Use of Stored Specimens and Data 
The blood and urine samples that are taken for efficacy and safety analyses will be analyzed 
by the local laboratory at the hospital soon after collection and destroyed after this analysis.  
In a subgroup of patients at selected study sites only and after consent of the patient, 
peripheral blood samples will be obtained for research purposes (see Section 8.1.8).  


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Samples and data collected under this protocol will be used to study the efficacy and safety 
of ATIR101. During the manufacturing of ATIR101, mandatory samples are taken for 
manufacturing testing. It is possible that some of these samples will not be used for the 
standard tests. If the study participant consents, these remaining samples may also be used 
for research to increase knowledge on ATIR101 and to improve ATIR101 manufacturing and 
treatment with ATIR101. These samples will not be used for genetic research purposes. 
All remaining samples will be destroyed after ATIR101 has become an accepted treatment or 
after the company has stopped development of ATIR101. Study participants who request 
destruction of samples will be notified of compliance with such request and all supporting 
details will be maintained for tracking.  
Data collected for this study will be analyzed and stored at a delegated contract research 
organization (CRO) for data management. After the study is completed, the de-identified, 
archived data will be stored, under the supervision of the sponsor.  
10.1.5 
Key Roles and Study Governance 
Coordinating 
Investigators: 
Prof. Denis Claude Roy, MD  
Research Center and Cellular Therapy Laboratory 
Maisonneuve-Rosemont Hospital (Montreal, Canada) 
 
Prof. Stephan Mielke, MD 
Centre for Allogeneic Stem Cell Transplantation 
Karolinska University Hospital (Stockholm, Sweden) 
Sponsor Contact: 
Annelies Legters, MSc 
Senior Director Clinical Operations 
Kiadis Pharma (Amsterdam-Zuidoost, The Netherlands) 
Phone +31 20 240 5250 
E-mail  a.legters@kiadis.com 
Medical Monitor: 
Bernd-Jan Sanson, MD 
Head of Clinical and Medical Affairs EU 
Kiadis Pharma (Amsterdam-Zuidoost, The Netherlands) 
Phone +31 20 240 5250 
E-mail  b.sanson@kiadis.com 
Study Monitoring 
CTI Clinical Trial Services, Inc (Covington, KY, USA) 
Data Management: 
IDDI (Louvain-la-Neuve, Belgium) 
Statistician: 
Marc Buyse 
IDDI (Louvain-la-Neuve, Belgium) 
Safety Management: 
ProPharma Group (St. Paul MN, USA) 
 


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10.1.6 
Safety Oversight 
Safety oversight under the direction of an independent data monitoring committee (IDMC) 
composed of individuals with the appropriate expertise will be established to monitor the 
safety of the patients in study CR-AIR-009. The members of the IDMC are responsible for 
safeguarding the interests of the patients by reviewing the safety and mortality data during 
the study. They are not affiliated to the sponsor. The IDMC will serve as an independent 
advisory group to the sponsor and is required to provide recommendations about continuing 
(with or without modifications) or stopping the study. The IDMC will meet regularly to 
assess safety and efficacy on each arm of the study, including the results of the interim 
analysis. 
Procedures to be used for the IDMC, including composition and roles and responsibilities of 
its members, will be described in detail in the IDMC charter.  
In addition, a Medical Monitor of the sponsor will advise the study investigators and will 
monitor participant safety. The role of the Medical Monitor is to 1) review all AEs on a 
regular basis throughout the study; 2) be available to advise the investigators on study-related 
medical questions or problems, and 3) evaluate cumulative participant safety data and make 
recommendations regarding the safe continuation of the study. 
10.1.7 
Clinical Monitoring 
Kiadis Pharma is responsible for monitoring the clinical study to ensure that patients’ human 
rights, safety, and well-being are protected, that the study is properly conducted in adherence 
to the current protocol, to GCP ICH E6(R2), and to applicable regulatory requirements, and 
that study data reported by the investigator/sub-investigator are accurate and complete and 
that they are verifiable with study-related records such as source documents. The sponsor 
will determine the extent and nature of the monitoring and assign clinical monitors who are 
(sponsor independent) GCP-trained. The sponsor will provide the monitor(s) with adequate 
training on the study protocol. The study will be monitored in accordance with the clinical 
trial monitoring plan, which specifies the monitoring tasks. 
10.1.8 
Quality Assurance and Quality Control 
10.1.8.1 
ATIR101 Manufacturing 
ATIR101 will be manufactured as individualized patient batches at manufacturing facilities, 
under supervision of Kiadis Pharma. Before start of the study, Kiadis Pharma Quality 
Assurance (QA) will qualify each manufacturing facility including its quality system. The 
qualification program includes site visit(s), verification audit(s), and the generation of a 
quality agreement between Kiadis Pharma and the manufacturing facility.  
Kiadis Pharma will train personnel from the manufacturing facility in the optimized process 
to be used in study CR-AIR-009. Manufacturing will only start after the technology transfer 
is completed and the manufacturing process has been qualified by successful qualification 
runs. The manufacturing batch records will be subject of a separate training by experts from 
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Quality Control (QC) testing of ATIR101, the raw (starting) materials and intermediates will 
be performed at the manufacturing facility, contract laboratories, and/or the Kiadis Pharma 
R&D laboratory. Contract laboratories will be qualified by Kiadis Pharma QA prior to the 
start of ATIR101 manufacturing. 
Because ATIR101 is manufactured as individualized patient batches and for every patient a 
different patient-donor combination is used, there is a chance that a batch fails to meet the 
acceptance criteria for administration within this study protocol. These cases will be 
discussed and trended in Quality Review Meetings, during which appropriate follow-up 
measures will be initiated. 
10.1.8.2 
Clinical Study 
Procedures relevant to the clinical management of this study are either described in the 
applicable standard operating procedures (SOPs), or in the management and oversight plan. 
The purpose of the management and oversight plan is to describe all procedures which have 
not been covered in the SOPs. If new SOPs are generated or updated during the course of the 
study, the management and oversight plan will be updated and reference will be made to the 
new SOP. 
Kiadis Pharma will not allow any waivers to the applicable protocol throughout the conduct 
of the study. An unplanned excursion from the protocol not implemented or intended as a 
systematic change, which could not be justified as necessary to protect the safety, rights, or 
welfare of the subjects, will be reported and followed up according to the local IEC/IRB 
requirements.  
The investigator and the study site must accept monitoring and auditing by Kiadis Pharma or 
their representatives as well as inspections from the IEC/IRB and relevant regulatory 
authorities. In these instances, they must provide all study-related records, such as source 
documents when they are requested by the monitors and auditors, the IEC/IRB, or regulatory 
authorities. The confidentiality of the patients’ identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access. In 
accordance with Kiadis Pharma procedures, this study may be subject to an independent QA 
GCP audit and/or a sponsor-initiated inspection at the study sites. 
10.1.9 
Data Handling and Record Keeping 
10.1.9.1 
Data Collection and Management Responsibilities 
The investigator or designee must enter all protocol-required data in the available electronic 
case report form (eCRF). An eCRF will be developed for both the patient and the donor. In 
the interest of collecting data in the most efficient manner, the investigator or designee 
should enter data (including laboratory values) into the eCRF as soon as possible after the 
patient’s visit. The eCRFs and any supporting documents should be available for retrieval at 
any given time. The monitor should verify the data in the eCRFs with source documents and 
confirm that there are no inconsistencies between them. If the monitor finds no 
inconsistencies, the appropriate eCRF parts are electronically signed. If any inconsistency is 
detected on the eCRFs, the monitor must query the investigator and the investigator should 


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make corrections/additions in the eCRF or provide an explanation within the eCRF system. 
The monitor should verify the corrected data with source documents to confirm that there are 
no inconsistencies between them, and also check that appropriate records on the 
corrections/additions of data are maintained. 
For screening failures, defined as patients who signed informed consent (and may have been 
randomized) but were not eligible for study participation, the minimum demographic data 
(year of birth and gender) and reason for withdrawal will also be collected in an eCRF. 
The investigator is responsible to ensure that all data in the eCRFs are accurate and complete, 
and that all entries are verifiable with source documents. Source data must be available at the 
site to document the existence of the study patients and donors, and to substantiate the 
integrity of study data collected. In case a patient is prematurely discontinued, the reason for 
discontinuation must be documented in the source documents. 
In order to obtain objective clinical GVHD and mortality data two adjudication committees 
will be established: 
• To ensure an objective approach for the classification and severity grading of GVHD 
events, Kiadis Pharma will request an independent GVHD adjudication committee to 
review each (possible) GVHD case and to come to a final assessment for GVHD 
classification and severity grading. This final assessment will be recorded on a 
separate CRF page and will be added to the clinical database. Procedures to be used 
for the GVHD adjudication committee will be described in detail in a separate 
charter. 
• To ensure an objective assessment of the classification of the cause of death, Kiadis 
Pharma will request an independent death adjudication committee to review each 
death case and to provide a final assessment for the cause of death. This final 
assessment will be recorded on a separate CRF page and will be added to the clinical 
database. Procedures to be used for the death adjudication committee will be 
described in detail in a separate charter. 
 
Data management will be coordinated by a delegated CRO, in accordance with their SOPs 
for data management. All study specific processes and definitions will be described in the 
data management plan. Coding of medical terms will be performed using the Medical 
Dictionary for Regulatory Activities (MedDRA) and medications will be coded with the 
WHO Drug Dictionary (WHO-DD). 
10.1.9.2 
Study Records Retention 
ICH guidelines for Good Clinical Practice require that all records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including eCRFs, 
consent forms, laboratory tests, and medication inventory records, must be retained by the 
Investigator until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 


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region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents must be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement 
with Kiadis Pharma. It is the responsibility of Kiadis Pharma to inform the Investigator as to 
when these documents no longer need to be retained. 
ATIR101 traceability records must be kept for a minimum of 30 years after the expiry date of 
the product. 
10.1.10 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, GCP, or 
requirements in other procedures. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly. These practices are 
consistent with ICH E6:  
• 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, Section 5.1.1  
• 5.20 Noncompliance, Sections 5.20.1 and 5.20.2.  
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in study source documents. Protocol deviations must be 
sent to the local IEC/IRB per their guidelines. The site principal investigator/study staff is 
responsible for knowing and adhering to their IEC/IRB requirements. If required by local 
guidelines, protocol deviations will also be reported to and assessed by the competent 
authorities. 
10.1.11 Publication and Data Sharing Policy 
Publication policy 
The sites and the principal investigators shall have the right to publish and present results of 
the study following submission to Kiadis Pharma Netherlands B.V. for review of the 
manuscript, abstract or presentation intended for publication or presentation at least 70 days 
prior to the date of submission for publication or presentation. Kiadis Pharma Netherlands 
B.V. shall complete its review within 60 days of receipt of the submitted manuscript, abstract 
or presentation. Kiadis Pharma Netherlands B.V. may request that the principal investigators 
or the sites delete from the manuscript, abstract or presentation any confidential information. 
At the end of the 60-day period, the sites and the principal investigators will have the right to 
publish and present the material, abstract and presentation. However, single site data may not 
be published and/or presented prior to the publication of the multicenter data from the overall 
study. 


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Disclosure policy 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study. 
10.1.12 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the study. 
10.2 Additional Considerations 
10.2.1 
Reporting of Serious Breaches 
Serious breaches are defined as breaches of the conditions and principles of GCP in 
connection with the study, that are likely to affect, to a significant degree, the safety or 
physical or mental integrity of the participants in the study or the scientific value of the 
study. The sponsor shall notify the competent authorities concerned about a serious breach 
according to local laws and regulations. 
10.2.2 
Protocol Amendments 
After the start of the clinical study, the sponsor may make amendments to the protocol. If 
those amendments are substantial and are likely to have an impact on the safety of the study 
participants or to change the interpretation of the scientific documents in support of the 
conduct of the study, or if they are otherwise significant, the sponsor shall submit these to the 
competent authorities and IECs/IRBs together with a rationale for the changes. The changes 
will only be implemented after approval from both the competent authority and the IEC/IRB 
has been obtained. 


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10.3 Abbreviations 
AE 
adverse event 
AIHA 
autoimmune haemolytic anaemia 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
ATG 
anti-thymocyte globulin 
ATMP 
advanced therapy medicinal product 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
BUN 
blood urea nitrogen 
cGy 
centigray 
CFSE 
carboxyfluorescein succinimidyl ester 
CI 
confidence interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CMML 
chronic myelomonocytic leukemia 
CMV 
cytomegalovirus 
CR 
complete remission 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLI 
donor lymphocyte infusion 
DLT 
dose-limiting toxicity 
DMSO 
dimethylsulfoxide 
DNA 
deoxyribonucleic acid 
DRI 
Disease Risk Index 


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dUCB 
double umbilical cord blood 
EBMT 
European Society for Blood and Marrow Transplantation 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ENT 
ears, nose, throat 
EQ-5D-5L 
EQ-5D 5-level version 
FAB 
French-American-British 
FACT-BMT 
Foundation for the Accreditation of Cellular Therapy – Bone Marrow 
Transplantation questionnaire 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GRFS 
GVHD-free, relapse-free survival 
GVHD 
graft-versus-host disease 
GVL 
graft-versus-leukemia 
Hb 
hemoglobin 
HBV 
hepatitis B virus 
HCT-CI 
hematopoietic cell transplantation-specific comorbidity index 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HSCT 
hematopoietic stem cell transplantation 
HSV 
herpes simplex virus 
HTLV 
human T-lymphotropic virus 
ICH 
International Conference on Harmonization 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
Ig 
immunoglobulin 


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IPSS-R 
Revised International Prognostic Scoring System 
IRB 
institutional review board 
ITT 
intention-to-treat 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
MCV 
mean corpuscular volume 
MDASI 
MD Anderson Symptom Inventory 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex 
MITT  
modified intention-to-treat 
MLR 
mixed lymphocyte reaction 
MMUD 
mismatched unrelated donor 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MUD 
matched unrelated donor 
MUGA 
multiple gated acquisition 
N/A 
not applicable 
NCI 
National Cancer Institute 
NCT 
National Clinical Trial 
NHI 
National Institutes of Health 
NK 
natural killer (cells) 
OS 
overall survival 
PBSC 
peripheral blood stem cell 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PDT 
photodynamic treatment 


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PFS 
progression-free survival 
Pgp 
P-glycoprotein 
PO 
orally 
PP 
per protocol 
PTCy 
post-transplant cyclophosphamide 
PTLD 
post-transplant lymphoproliferative disease 
q12h 
each 12 hours 
q24h 
each 24 hours 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
red blood cell 
RRM 
relapse-related mortality 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 
Short Form 36-item health survey 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TBI 
total body irradiation 
TCD 
T-cell depleted 
TRM 
transplant-related mortality 
ULN 
upper limit of normal 
UP 
unanticipated problem 
VZV 
varicella zoster virus 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
WHO-UMC 
World Health Organization Uppsala Monitoring Centre 
WNV 
West Nile virus 
 


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Bastien JP, Roy J, Roy DC. Selective T-cell depletion for haplotype-mismatched allogeneic 
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Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related 
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Buyse M. Generalized pairwise comparisons of prioritized outcomes in the two-sample 
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Champlin R, Hesdorffer C, Lowenberg B, Martelli MF, Mertelsmann RH, Reisner Y, et al. 
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Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. 
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
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Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and 
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Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing 
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Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
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12 APPENDICES 
Appendix 1 
Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndromes Risk 
IPSS-R cytogenetic risk groups 
Cytogenetic prognostic subgroups 
Cytogenetic abnormalities 
Very good 
-Y, del(11q) 
Good 
normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
del(7q), +8, +19, i(17q), any other single or double 
independent clones 
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 
3 abnormalities 
Very poor 
Complex: >3 abnormalities 
 
 
IPSS-R prognostic score values 
Prognostic 
variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very good 
 
Good 
 
Intermediate 
Poor 
Very poor 
BM blast, % 
≤ 2 
 
> 2-< 5 
 
5-10 
> 10 
 
Hemoglobin, g/dl 
≥ 10 
 
8-< 10 
< 8 
 
 
 
Platelets, ×109/l 
≥ 100 
50-<100 
< 50 
 
 
 
 
ANC, ×109/l 
≥ 0.8 
< 0.8 
 
 
 
 
 
Risk score is obtained by adding scores of these five prognostic variables 
 
 
IPSS-R prognostic risk categories and scores 
Risk category 
Risk score 
Very low 
≤ 1.5 
Low 
> 1.5-3 
Intermediate 
> 3-4.5 
High 
> 4.5-6 
Very high 
> 6 
 
Source: (Greenberg et al. 2012) 


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Appendix 2 
Disease Risk Index (DRI) 
 
DRI group 
Disease (stage) 
 
LOW 
AML favorable cytogenetics CR 
INTERMEDIATE 
AML intermediate cytogenetics CR 
ALL CR1 
Low-risk MDS§ adverse cytogenetics (early stage) 
Low-risk MDS§ intermediate cytogenetics (early or advanced 
stageª) 
High-risk MDS* intermediate cytogenetics (early stage) 
HIGH 
AML favorable cytogenetics (advanced stageª) 
AML adverse cytogenetics CR 
AML intermediate cytogenetics (advanced stageª) 
ALL CR2  
ALL CR3 
High-risk MDS* intermediate cytogenetics (advanced stageª) 
High-risk MDS* adverse cytogenetics (early or advanced stageª) 
Low-risk MDS§ adverse cytogenetics (advanced stageª) 
VERY HIGH 
AML (advanced stageª) 
AML adverse cytogenetics (advanced stageª) 
CR = complete remission 
§ Low-risk MDS refers to MDS with ≤ 5% blasts (refractory anemia with or without ringed sideroblasts and refractory 
cytopenia with multilineage dysplasia) 
* High-risk MDS refers to MDS with > 5% blasts (refractory anemia with excess blasts [RAEB-1 and RAEB-2]) 
a Advanced stage refers to induction failure or active relapse 
AML cytogenetics Favorable: Inv(16);  Intermediate: Normal, All other abn.; Adverse: Complex (≥4 abn.) 
MDS cytogenetics Favorable: Del(5q), Del(20q), Monosomy Y, Normal; Intermediate: Trisomy 8, All other abn.; 
Adverse: Abnormal 7, Complex (≥3 abn.)   
Source: (Armand et al. 2010; Armand et al. 2014; Armand et al. 2012) 
 


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Appendix 3 
EBMT Risk Score 
 
EBMT risk score = sum of the scores for each of the five risk factors  
 
 
Risk factor 
0 points 
1 point 
2 points 
Age (yr) 
< 20 
20 - 40 
> 40 
Disease stage * 
Early 
Intermediate 
Late 
Time interval from diagnosis 
to transplantation (months) 
< 12  
(any time interval 
for patients in 
early disease 
stage) 
> 12 
(only applies to 
patients in 
intermediate or 
late disease stage) 
- 
Donor type 
HLA- identical 
sibling 
Unrelated donor, 
other 
- 
Donor recipient sex 
combination 
Any other 
combination 
Female donor, 
male recipient 
- 
 
 
* Classification of disease stage for calculation of EBMT risk score 
Disease stage 
ALL, AML 
MDS 
Early 
In first complete remission 
Untreated or in first complete remission 
Intermediate 
In second complete remission 
In second complete remission or in 
partial remission 
Late 
In all other disease stages 
In all other disease stages 
 
Source: (Gratwohl 2012) 


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Appendix 4 
Hematopoietic Cell Transplantation-specific Comorbidity Index 
(HCT-CI) 
Comorbidity 
Definition of comorbidities 
HCT-CI 
weighted 
score 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias 
1 
Cardiac 
Coronary artery disease*, congestive heart failure, myocardial 
infarction, or EF 
50% 
1 
Inflammatory bowel disease Crohns disease or ulcerative colitis 
1 
Diabetes 
Requiring treatment with insulin or oral hypoglycemics but not diet 
alone 
1 
Cerebrovascular disease 
Transient ischemic attack or cerebrovascular accident 
1 
Psychiatric disturbance 
Depression or anxiety requiring psychiatric consult or treatment 
1 
Hepatic, mild 
Chronic hepatitis, bilirubin > ULN to 1.5 x ULN, or AST/ALT > 
ULN to 2.5 x ULN 
1 
Obesity 
Patients with a body mass index > 35 kg/m2 
1 
Infection 
Requiring continuation of antimicrobial treatment after Day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 
2 
Peptic ulcer 
Requiring treatment 
2 
Moderate/severe renal 
Serum creatinine > 2 mg/dl, on dialysis, or prior renal transplantation 
2 
Moderate pulmonary 
DLCO and/or FEV1 66%-80% or dyspnea on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient's past history, excluding 
nonmelanoma skin cancer 
3 
Heart valve disease 
Except mitral valve prolapse 
3 
Severe pulmonary 
DLCO and/or FEV1 
65% or dyspnea at rest or requiring oxygen 
3 
Moderate/severe hepatic 
Liver cirrhosis, bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN 
3 
*One or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass graft. 
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythmatosis; RA, rheumatoid 
arthritis; CTD, connective tissue disease; DLCO, diffusion capacity of carbon monoxide. 
 
HCT-CI summary score is based on the sum of the HCT-CI weighted scores (Sorror et al. 
2005). 


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Appendix 5 
Karnofsky Performance Status (KPS) Scale  
Performance Status 
(%) 
Condition 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his 
personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death not 
imminent. 
20 
Very sick; hospital admission necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 
 


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Appendix 6 
Severity Grading of Graft-Versus-Host Disease 
 
ACUTE GRAFT-VERSUS-HOST DISEASE (Harris et al. 2016) 
GVHD Target Organ Staging 
Skin 
Stage 0  no active (erythematous) GVHD rash 
Stage 1  maculopapular rash involving < 25% of the body surface 
Stage 2  maculopapular rash involving 25-50% of the body surface 
Stage 3  maculopapular rash involving > 50% of the body surface 
Stage 4  generalized erythroderma (> 50% of the body surface) plus bullous formation and 
desquamation (> 5% of the body surface) 
 
Liver 
Stage 0  bilirubin < 2 mg/dl 
Stage 1  bilirubin 2-3 mg/dl 
Stage 2  bilirubin 3.1-6 mg/dl 
Stage 3  bilirubin 6.1-15 mg/dl 
Stage 4  bilirubin > 15 mg/dl 
 
Upper Gastrointestinal (GI) 
Stage 0  no or intermittent nausea, vomiting, or anorexia 
Stage 1  persistent nausea, vomiting or anorexia 
 
Lower GI (diarrhea stool output/day for adults) 
Stage 0  < 500 ml/day or < 3 episodes/day 
Stage 1  500-999 ml/day or 3-4 episodes/day 
Stage 2  1000-1500 ml/day or 5-7 episodes/day 
Stage 3  > 1500 ml/day or > 7 episodes/day 
Stage 4  severe abdominal pain with or without ileus or grossly bloody stool (regardless of 
stool volume) 
 
Overall grading of acute GVHD (based on most severe target organ involvement) 
Grade 
Skin 
Liver 
Lower GI 
Upper GI 
I 
Stage 1-2 
Stage 0 
Stage 0 
Stage 0 
II 
Stage 3 and/or 
Stage 1 and/or 
Stage 1 and/or 
Stage 1 
III 
Stage 0-3 
Stage 2-3 and/or 
Stage 2-3 
Stage 0-1 
IV 
Stage 4 and/or 
Stage 4 and/or 
Stage 4 
Stage 0-1 
 


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CHRONIC GRAFT-VERSUS-HOST DISEASE 
The global scoring system for chronic GVHD (Filipovich et al. 2005; Jagasia et al. 2015) 
reflects the clinical effect of chronic GVHD on the patient’s functional status. Eight organs 
or sites (skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint and fascia, and genital 
tract) are considered for calculating global score. Elements included in the proposed global 
scoring include both the number of organs or sites involved and the severity score within 
each affected organ. Performance status scoring is not incorporated into the global scoring 
system. The global descriptions of mild, moderate, and severe were chosen to reflect the 
degree of organ impact and functional impairment due to chronic GVHD. Note that the 
global scoring system can be applied only after the diagnosis of chronic GVHD is confirmed 
by either (1) the presence of a diagnostic feature or, if a diagnostic feature is not present, 
(2) at least 1 distinctive manifestation of chronic GVHD with the diagnosis supported by 
histologic, radiologic, or laboratory evidence of GVHD from any site.  
• Mild chronic GVHD: 
1 or 2 organs involved with no more than score 1 plus lung score 0 
• Moderate chronic GVHD: 
3 or more organs involved with no more than score 1 OR 
at least 1 organ (not lung) with a score of 2 OR 
lung score 1  
• Severe chronic GVHD: 
At least 1 organ with a score of 3 OR 
lung score of 2 or 3 
 
Table 4 shows the scoring system for individual organs. 
Table 4 
Organ scoring of chronic GVHD 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
PERFORMANCE 
SCORE  
 
KPS, ECOG or LPS 
Asymptomatic and 
fully active 
(ECOG 0; KPS or 
LPS 100%) 
Symptomatic, fully 
ambulatory, 
restricted only in 
physically 
strenuous activity 
(ECOG 1, KPS or 
LPS 80-90%) 
Symptomatic, 
ambulatory, 
capable of self 
care, >50% of 
waking hours out 
of bed (ECOG 2, 
KPS or LPS 
60-70%) 
Symptomatic, 
limited self-care, 
>50% of waking 
hours in bed 
(ECOG 3-4, KPS 
or LPS <60%) 
SKIN† 
Score % BSA 
GVHD features to be 
scored by BSA:  
Maculopapular 
rash/erythema 
Lichen planus-like 
features  
Papulosquamous 
lesions or ichthyosis 
Keratosis pilaris-like 
 
No BSA involved 
 
1-18% BSA  
 
19-50% BSA  
 
>50% BSA  


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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
GVHD  
 
Skin features 
Other GVHD 
features (not scored 
by BSA):  
Hyperpigmentation  
Hypopigmentation  
Poikiloderma  
Severe or generalized 
pruritus  
Hair involvement 
Nail involvement  
 
No sclerotic 
features 
 
Superficial 
sclerotic features 
“not hidebound” 
(able to pinch) 
Deep sclerotic 
features  
“Hidebound” 
(unable to pinch)  
Impaired mobility 
Ulceration 
MOUTH 
Lichen planus-like 
features present 
No symptoms 
Mild symptoms 
with disease signs 
but not limiting 
oral intake 
significantly 
Moderate 
symptoms with 
disease signs with 
partial limitation 
of oral intake 
Severe symptoms 
with disease signs 
on examination 
with major 
limitation of oral 
intake 
EYES  
 
Keratoconjunctivitis 
sicca (KCS) 
confirmed by 
ophtalmologist 
No symptoms 
Mild dry eye 
symptoms not 
affecting ADL 
(requirement of 
lubricant eye drops 
≤3 x per day) 
Moderate dry eye 
symptoms 
partially affecting 
ADL (requiring 
lubricant eye 
drops >3 x per day 
or punctal plugs),  
WITHOUT 
vision impairment 
due to KCS 
Severe dry eye 
symptoms 
significantly 
affecting ADL 
(special eyeware to 
relieve pain) OR 
unable to work 
because of ocular 
symptoms OR loss 
of vision due to 
KCS 
GI TRACT 
 
Esophageal web/ 
proximal  stricture or 
ring 
Dysphagia 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss ≥ 5% 
Failure to thrive 
No symptoms 
Symptoms without 
significant weight 
loss* (<5%) 
Symptoms 
associated with 
mild to moderate 
weight loss* 
(5-15%) OR 
moderate diarrhea 
without significant 
interference with 
daily living 
Symptoms 
associated with 
significant weight 
loss* >15%, 
requires nutritional 
supplement for 
most calorie needs 
OR esophageal 
dilation OR severe 
diarrhea with 
significant 
interference with 
daily living 
LIVER 
Normal total 
bilirubin and ALT 
or AP <3 x ULN 
Normal total 
bilirubin with ALT 
≥3 to 5 x ULN or 
AP ≥3 x ULN 
Elevated total 
bilirubin but 
≤3 mg/dl or ALT 
>5 x ULN 
Elevated total 
bilirubin >3 mg/dl 


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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
LUNGS ** 
Symptom score 
 
 
 
No symptoms  
 
Mild symptoms 
(shortness of 
breath after 
climbing one flight 
of steps)  
 
Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground)  
 
Severe symptoms 
(shortness of 
breath at rest; 
requiring O2)  
Lung score 
% FEV1 
FEV1 ≥80% 
FEV1 60-79% 
FEV1 40-59% 
FEV1 ≤39% 
JOINTS AND 
FASCIA 
P-ROM score 
Shoulder (1-7) 
Elbow (1-7) 
Wrist/finger (1-7) 
Ankle (1-4) 
No symptoms 
Mild tightness of 
arms or legs, 
normal or mild 
decreased range of 
motion (ROM) 
AND not affecting 
ADL 
Tightness of arms 
or legs OR joint 
contractures, 
erythema thought 
due to fasciitis, 
moderate decrease 
ROM AND mild 
to moderate 
limitation of ADL 
Contractures 
WITH significant 
decrease of ROM 
AND significant 
limitation of ADL 
(unable to tie 
shoes, button 
shirts, dress self 
etc.) 
GENITAL TRACT 
Currently sexually 
active 
No symptoms 
Mild signs‡ and 
females with or 
without discomfort 
on exam  
Moderate signs‡ 
and may have 
symptoms with 
discomfort on 
exam  
Severe signs‡ with 
or without 
symptoms 
OTHER INDICATORS, CLINICAL FEATURES OR COMPLICATIONS RELATED TO CHRONIC 
GVHD  
(check all that apply and assign a score to its severity (0-3) based on functional impact where applicable 
(none-0, mild-1, moderate-2, severe-3)  
Pericardial effusion___  
 
 
 
 
 
 
Pleural effusion(s)___  
Ascites (serositis)___  
 
 
 
 
 
 
Nephrotic syndrome___  
Peripheral neuropathy___   
 
 
 
 
 
Myasthenia gravis___  
Eosinophilia >500/μL___   
 
 
 
 
 
Polymyositis___  
Platelets <100,000/μL ___  
 
 
 
 
 
Weight loss* >5% without GI symptoms ___ 
Others (specify):__________ 
ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; LPS, Lansky 
Performance Status; BSA, body surface area; ADL, activities of daily living; AP, alkaline phosphatase; ALT, 
alanine aminotransferase; ULN, upper limit of normal; P-ROM, Photographic range of motion; FEV1, forced 
expiratory volume in 1 second. *Weight loss within 3 months. †Skin scoring should use both percentage of 
BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the 
percentage of BSA score and the skin feature score, OR if superficial sclerotic features are present (Score 2), 
but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin 
scoring. ‡To be completed by specialist or trained medical providers. **Lung scoring should be performed 
using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring 
where there is discrepancy between symptoms and FEV1 scores. 
 


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Appendix 7 
Calculation of Ideal Body Weight (IBW) and Adjusted Ideal Body 
Weight (AIBW) 
For patients who weigh less than 125% of their ideal body weight (IBW), dosing of all drugs 
part of the conditioning regimen should be based on actual body weight. For patients who 
weigh greater than or equal to 125% of their IBW, dosing should be based on the adjusted 
ideal body weight (AIBW). 
 
Calculation of IBW (Peterson et al. 2016) 
US version: height measured in inches: 
Males:  
 
𝐼𝐼𝐼𝐼𝐼𝐼 [𝑘𝑘𝑘𝑘] = 50.0 + 2.3 × (ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 [𝑖𝑖𝑖𝑖] −60) 
Females:   
𝐼𝐼𝐼𝐼𝐼𝐼 [𝑘𝑘𝑘𝑘] = 45.5 + 2.3 × (ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 [𝑖𝑖𝑖𝑖] −60) 
Metric version: height measured in cm: 
Males:  
 
𝐼𝐼𝐼𝐼𝐼𝐼 [𝑘𝑘𝑘𝑘] = 50.0 + 0.91 × (ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 [𝑐𝑐𝑐𝑐] −152) 
Females:   
𝐼𝐼𝐼𝐼𝐼𝐼 [𝑘𝑘𝑘𝑘] = 45.5 + 0.91 × (ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 [𝑐𝑐𝑐𝑐] −152) 
 
Calculation of AIBW (Hicks et al. 2012) 
Males and females: 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴=  𝐼𝐼𝐼𝐼𝐼𝐼+ 0.25 × (𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡−𝐼𝐼𝐼𝐼𝐼𝐼) 
 


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Appendix 8 
Sponsor Signature 
Study Title: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive 
treatment with ATIR101, a T-lymphocyte enriched leukocyte 
preparation depleted ex vivo of host alloreactive T-cells, versus a 
haploidentical HSCT with post-transplant cyclophosphamide in 
patients with a hematologic malignancy (HATCY study) 
Study Number: 
CR-AIR-009 
Original Protocol: 
Version 1.0 (23 November 2016) 
Amendment 1-3: 
Version 2.0 (26 September 2017) 
Amendment 4: 
Version 3.0 (23 August 2018) 
 
 
This clinical study protocol has been approved by the sponsor.  
 
 
 
Signed: 
 
 
Date:  
 
Andrew Sandler, MD 
Chief Medical Officer 
Kiadis Pharma Netherlands B.V. 


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Appendix 9 
Coordinating Investigator Signatures 
Study Title: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive 
treatment with ATIR101, a T-lymphocyte enriched leukocyte 
preparation depleted ex vivo of host alloreactive T-cells, versus a 
haploidentical HSCT with post-transplant cyclophosphamide in 
patients with a hematologic malignancy (HATCY study) 
Study Number: 
CR-AIR-009 
Original Protocol: 
Version 1.0 (23 November 2016) 
Amendment 1-3: 
Version 2.0 (26 September 2017) 
Amendment 4: 
Version 3.0 (23 August 2018) 
 
 
This clinical study protocol has been approved by the coordinating investigator.  
 
 
 
Signed: 
 
 
Date:  
 
Prof. Denis Claude Roy, MD  
Research Center and Cellular Therapy Laboratory 
Maisonneuve-Rosemont Hospital (Montreal, Canada) 
 
 


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Study Title: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive 
treatment with ATIR101, a T-lymphocyte enriched leukocyte 
preparation depleted ex vivo of host alloreactive T-cells, versus a 
haploidentical HSCT with post-transplant cyclophosphamide in 
patients with a hematologic malignancy (HATCY study) 
Study Number: 
CR-AIR-009 
Original Protocol: 
Version 1.0 (23 November 2016) 
Amendment 1-3: 
Version 2.0 (26 September 2017) 
Amendment 4: 
Version 3.0 (23 August 2018) 
 
 
This clinical study protocol has been approved by the coordinating investigator.  
 
 
 
Signed: 
 
 
Date:  
 
Prof. Stephan Mielke, MD 
Centre for Allogeneic Stem Cell Transplantation 
Karolinska University Hospital (Stockholm, Sweden) 
 


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Version 3.0; 23 August 2018 
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Appendix 10 Principal Investigator Signature 
Study Title: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive 
treatment with ATIR101, a T-lymphocyte enriched leukocyte 
preparation depleted ex vivo of host alloreactive T-cells, versus a 
haploidentical HSCT with post-transplant cyclophosphamide in 
patients with a hematologic malignancy (HATCY study) 
Study Number: 
CR-AIR-009 
Original Protocol: 
Version 1.0 (23 November 2016) 
Amendment 1-3: 
Version 2.0 (26 September 2017) 
Amendment 4: 
Version 3.0 (23 August 2018) 
 
 
I have read all pages of this clinical study protocol for which Kiadis Pharma Netherlands 
B.V. is the sponsor. I agree that it contains all the information required to conduct this study. 
I agree to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with the ICH 
GCP guidelines (ICH E6[R2]) and the provisions of the Helsinki Declaration. I will also 
ensure that all relevant members of my staff have access to copies of this protocol, the ICH 
GCP guidelines and the Helsinki Declaration to enable them to work in accordance with the 
provisions of these documents.” 
 
 
 
 
Signed: 
 
 
Date:  
 
 
Printed name: ………………………………………………………………………. 
Address: ……………………………………………………………………………. 
……………………………………………………………………………………… 
……………………………………………………………………………………… 
 

SAP_001.pdf: 
Signature Page for KIADIS_CR_AIR_009_ASAP
Study CR-AIR-009 v2.0
Signature Page for KIADIS_CR_AIR_009_ASAP
Study CR-AIR-009 v2.0
eSignature for Approval
Johan Hettinga
Sponsor
13-Dec-2021 09:34:03 GMT+0000
eSignature for Approval
Kun Wang
Author
13-Dec-2021 10:35:29 GMT+0000
eSignature for Approval
Emmanuel Quinaux
IDDI Statistician
13-Dec-2021 11:01:29 GMT+0000
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TPL N°: eTPL SA-02-01 
TPL Version: 06 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
 
Abbreviated Statistical Analysis Plan 
 
SPONSOR:  
Kiadis Pharma 
 
PROTOCOL TITLE: 
A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive treatment 
with ATIR101, a T-lymphocyte enriched leukocyte preparation 
depleted ex vivo of host alloreactive T-cells, versus a haploidentical 
HSCT with post-transplant cyclophosphamide in patients with a 
hematologic malignancy (HATCY study) 
 
STUDY CODE: 
CR-AIR-009 
 
 
Summary: 
The undersigned certify that they have read, reviewed and approved the updates to this 
document to include the addition to the plan for Long-term Follow-up data: addition of 
Section 8.13 Additional Analyses with of LTFU Data (p15); tables 14.02.02.03, 14.02.03.03, 
14.02.04.03, 14.02.05.03, 14.03.04.04, 14.03.04.05; figures 14.02.01.03, 14.02.02.03, 14.02.03.03, 
14.02.04.03 and listings 16.2.7.1, 16.2.7.2, 16.2.7.3, 16.2.7.4. 
 
Signature: 
 
For IDDI: 
Kun Wang - Senior Biostatistician 
Emmanuel Quinaux, Director Biostatistics  
 
For Sponsor: 
Johan Hettinga, Senior Data Manager 
Jenny Martin, Head, Kiadis Clinical Operations 
 
 
 
 
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TPL N°: eTPL SA-02-01 
TPL Version: 06 
Of SOP SA-02.08 
TPL Effective Date: 31 Mar 2016 
 
Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 3 
2. 
INTRODUCTION ........................................................................................... 5 
3. 
STUDY DESIGN AND CHANGES FROM THE PROTOCOL .................................. 5 
4. 
GENERAL ANALYSIS CONVENTIONS AND DEFINITIONS .............................. 6 
4.1 
Definition of Populations ........................................................................... 7 
4.1.1 
Intention-To-Treat (ITT) Population ..................................................... 7 
4.1.2 
Safety Population .............................................................................. 7 
4.1.3 
Modified Safety Population ................................................................. 7 
4.1.4 
Per Protocol (PP) Population ............................................................... 7 
4.2 
Definition of Endpoints ............................................................................. 7 
4.3 
Calculated Variables ................................................................................. 8 
4.4 
Partial Dates ........................................................................................... 8 
4.5 
Missing Data ........................................................................................... 8 
5. 
STUDY PATIENTS ......................................................................................... 8 
5.1 
Disposition of Patients .............................................................................. 8 
5.2 
Protocol Deviations .................................................................................. 9 
5.3 
Inclusion and Exclusion Criteria ................................................................. 9 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................... 9 
7. 
CONCOMITANT TREATMENT ....................................................................... 10 
8. 
SAFETY AND EFFICACY EVALUATION ......................................................... 10 
8.1 
Incidence and severity of acute and chronic GVHD ..................................... 10 
8.2 
Incidence and severity of viral, fungal, and bacterial infections .................... 10 
8.3 
Adverse Events ...................................................................................... 11 
8.4 
Deaths and Serious Adverse Events ......................................................... 11 
8.5 
Events of Special Interest ....................................................................... 12 
8.6 
Clinical Laboratory Determination ............................................................ 12 
8.7 
CMV/EBV .............................................................................................. 13 
8.8 
Vital Signs, Physical Findings and Other Observations Related to Safety ....... 13 
8.9 
Extent of Exposure / Details of Different Study Procedures .......................... 14 
8.10 
Bone Marrow Biopsy / Aspirate ................................................................ 14 
8.11 
Engraftment and Chimerism .................................................................... 14 
8.12 
Efficacy Endpoints .................................................................................. 14 
8.13 
Additional Analyses of LTFU Data ............................................................. 15 
9. 
APPENDICES .............................................................................................. 17 
9.1 
Schedule of Activities (original)................................................................ 17 
9.2 
Schedule of Activities After Stopping Study (ATIR101 patients) ................... 20 
9.3 
List of Tables/Graphs/Listings .................................................................. 22 
9.3.1 
List of Statistical Tables ................................................................... 22 
9.3.2 
List of Graphs ................................................................................. 24 
9.3.3 
List of Derived Data Listings ............................................................. 25 
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APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
1. List of Abbreviations and Definition of Terms 
 
Abbreviation 
Term 
AE 
adverse event 
AIHA 
autoimmune hemolytic anemia 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ALL 
acute lymphoblastic leukemia 
AP 
alkaline phosphatase 
ASAP 
Abbreviated statistical analysis plan 
AST 
aspartate aminotransferase 
ATG 
anti-thymocyte globulin 
Ca 
calcium 
CD 
cluster of differentiation 
Cl 
chloride 
CMV 
cytomegalovirus 
CT 
computed tomography 
CTC 
Common Terminology Criteria 
DLP 
Data lock point 
DRI 
Disease Risk Index 
EBV 
Epstein-Barr virus 
EBMT 
European Society for Blood and Marrow Transplantation 
ECG 
electrocardiogram 
ENT 
ears, nose, throat 
FACT-BMT 
Foundation for the Accreditation of Cellular Therapy – Bone Marrow 
Transplantation questionnaire 
GCP 
Good Clinical Practice 
GRFS 
GVHD-free, relapse-free survival 
GVHD 
graft-versus-host-disease 
HBV 
hepatitis B virus 
HCT-CI 
hematopoietic cell transplantation-specific comorbidity index 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HSCT 
hematopoietic stem cell transplantation 
HTLV 
human T-lymphotropic virus 
ICH 
International Conference on Harmonization 
Ig 
immunoglobulin 
ITT 
intention-to-treat 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LTFU 
Long-term follow-up 
MCV 
mean corpuscular volume 
MDASI 
MD Anderson Symptom Inventory 
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APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
magnesium 
MITT 
modified intention-to-treat 
MRD 
minimal residual disease 
MUGA 
multiple gated acquisition 
NCI 
National Cancer Institute 
NK 
natural killer (cells) 
OS 
overall survival 
P 
phosphorus 
PBMC 
peripheral blood mononuclear cells 
PFS 
progression-free survival 
PP 
per protocol 
PT 
preferred term 
PTCy 
post-transplant cyclophosphamide 
PTLD 
post-transplant lymphoproliferative disease 
QoL 
quality of life 
RBC 
red blood cell 
RRM 
relapse-related mortality 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical analysis system 
SF-36 
Short Form 36-item health survey 
SOC 
system organ class 
TEAE 
Treatment emergent adverse event 
TRM 
transplant-related mortality 
WBC 
white blood cell 
WHO 
World Health Organization 
WNV 
West Nile virus 
 
 
 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 5 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
2. Introduction 
This document is an Abbreviated Statistical Analysis Plan (ASAP) designed to outline 
the planned analysis required to satisfy the abbreviated Clinical Study Report (CSR) of 
the HATCHY study (A Phase III, multicenter, randomized controlled study to compare 
safety and efficacy of a haploidentical HSCT and adjunctive treatment with ATIR101, a 
T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-
cells, versus a haploidentical HSCT with post-transplant cyclophosphamide in patients 
with a hematologic malignancy). Study CR-AIR-009 was terminated early for futility 
since it was unlikely that the study would meet the primary endpoint. Therefore, only 
an abbreviated Clinical Study Report will be written.  
The International Conference on Harmonization (ICH) guideline E3 “Structure and 
Content of Clinical Study Reports”, and the FDA guideline for abbreviated reports 
“Guidance for Industry. Submission of abbreviated reports and synopses in support of 
marketing applications” were used as a guide to the writing of this ASAP. 
This ASAP outlines the analyses specified in the Protocol (Version 3.0, dated 23th 
August 2018) that are required to be reported in the abbreviated CSR. 
An addendum to the ASAP has been added in section 8.13 to describe the additional 
analyses of the additional data collected during the long-term-follow-up (LTFU) period.   
3. Study Design and Changes from the Protocol 
This is a randomized (1:1), multicenter, open-label, controlled, Phase III clinical trial 
evaluating the efficacy and safety of a haploidentical HSCT and adjunctive treatment 
with ATIR101, a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host 
alloreactive 
T-cells, 
versus 
a 
haploidentical 
HSCT 
with 
post-transplant 
cyclophosphamide (PTCy) in approximately 250 patients with a hematologic 
malignancy (Acute lymphoblastic leukemia [ALL] in remission, acute myeloblastic 
leukemia [AML] in remission, and myelodysplastic syndrome [MDS]). 
Randomization will use minimization to balance treatment groups with respect to 
underlying disease (AML, ALL, or MDS), DRI (intermediate risk, high risk, or very high 
risk) and center. A stochastic treatment allocation procedure will be used so that the 
treatment assignment is random for all patients entered in the study.  
Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 
2.0×106 viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized 
in the PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4 or 5 days 
after the HSCT.  
Due to early termination of the study, patients will be followed for safety and efficacy 
for at least four (4) months post-HSCT. Patients who were not yet past the 4-month 
visit post-HSCT, will have the following schedule: 
• 
For ATIR101 treated patients:  
o 
1-week, 1-month, 3-month post-ATIR101 infusion (i.e. 4-month visit 
post-HSCT) 
• 
For PTCy treated patients:  
o 
1-week, 1-month post-PTCy infusion and 4-month visit post-HSCT  
 
Completion of the Month-4 Visit will be the End of Active Study Follow-up.  
 
For patients who have already completed the Month-4 visit, follow-up visits will be 
performed until last patient last 4 month visit, also defined as data lock point (DLP).  
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 6 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
 
All patients will be followed for at least 4 months post-HSCT for the following safety 
and efficacy endpoints: 
 
• 
incidence and severity of adverse events (AEs) (safety) 
• 
incidence and severity of acute (a) and chronic (c) graft-versus-host-disease 
(GVHD) (safety) 
• 
incidence and severity of viral, fungal and bacterial infections (safety and 
efficacy) 
• 
transplant-related mortality (TRM) (safety and efficacy) 
• 
GVHD-free, relapse-free survival (GRFS) (efficacy) 
• 
overall survival (OS) (safety and efficacy) 
• 
progression-free survival (PFS) (efficacy) 
• 
relapse-related mortality (RRM) (efficacy) 
• 
Quality of life (QoL) 
In addition, data on immune reconstitution, laboratory tests, vital signs and physical 
examination will be available for all patients up to the time of study termination.  
Due to the early termination of the trial, the classification of primary and secondary 
endpoints will not be applied, and a number of pre-specified analyses will not be 
performed. However, by-patient listings will be generated for all data collected for this 
study. 
4. General Analysis Conventions and Definitions 
Data will be analyzed using SAS (Version 9.3 or later). Figures will be created in R. 
No tests of significance will be carried out to compare treatment arms on baseline data 
because any observed differences between them most likely be attributed to chance. 
No tests of significance will be carried out on efficacy data due to early study 
termination. 
Descriptive statistics will be tabulated as follows:  
• 
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages. 
• 
Continuous data will be summarized using number of non-missing values 
(n), mean, standard deviation, median, minimum and maximum values. 
Time-to-event endpoints will be estimated using Kaplan-Meier (KM) techniques. When 
appropriate, the median along with associated 95% confidence interval (CI) will be 
estimated based on Brookmeyer and Crowley methodology (using log-log 
transformation for constructing the CI). Rates at fixed time points will be derived from 
the KM estimate along with their corresponding log-log transformed CI. KM curves will 
also be presented. No formal test (log-rank test) will be performed to compare the 
treatment groups for time-to-event distributions. 
For time-to-event endpoints subject to competing risks, i.e. relapse-related mortality 
(RRM) and transplant-related mortality (TRM), cumulative incidence curves will be 
produced. No formal test (Gray’s test) will be performed to compare the treatment 
groups. 
The output tables will include two columns (ATIR101, PTCy) and will be created by 
time point. The ‘All’ column will be presented only if particularly specified. All data will 
be presented in the form of listings sorted by treatment group and patient ID. 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 7 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
4.1 
Definition of Populations 
All enrolled patients who were randomized will be included in the analyses. The 
following analysis populations will be discerned: 
4.1.1 
Intention-To-Treat (ITT) Population  
The Intention-To-Treat (ITT) population consists of all randomized patients. This 
population will be used for all the data listings and efficacy evaluation. 
4.1.2 
Safety Population  
The safety population will include all patients who received an HSCT. The safety 
population is the primary population for safety and efficacy evaluation. 
Note: For abbreviated CSR, the safety population will not be analyzed. 
4.1.3 
Modified Safety Population  
The Modified Safety population consists of all randomized patients who received an 
HSCT and ATIR101 (ATIR101 group) or at least one dose of post-transplant 
cyclophosphamide (PTCy group). The modified safety population defined in this ASAP 
has the identical definition as the Modified Intention-To-Treat (MITT) population 
defined in the protocol. Hence the MITT population will not be used for any pre-
specified analyses covered by this statistical analysis plan. The Modified Safety 
population is the primary population for safety and efficacy evaluation. 
4.1.4 
Per Protocol (PP) Population 
The Per Protocol (PP) population is a subset of the safety population, i.e. patients 
without major protocol deviations, defined by the sponsor prior to locking the database. 
The definition of “major” protocol deviations will be agreed upon, and all cases of such 
major deviations adjudicated prior to database lock, by a team blinded to treatment 
allocation.  
Note: For abbreviated CSR, PP population will not be derived. 
4.2 
Definition of Endpoints 
• 
GVHD-free, relapse-free survival (GRFS): defined as time from randomization 
until grade III/IV acute graft-versus-host disease (GVHD), chronic GVHD 
requiring systemic immunosuppressive treatment, disease relapse, or death, 
whichever occurs first.  
• 
Overall survival (OS): defined as the time from randomization until death 
from any cause  
• 
Progression-free survival (PFS): defined as the time from randomization until 
relapse, disease progression, or death, whichever occurs first  
• 
Relapse-related mortality (RRM): defined as the time from randomization to 
death due to disease relapse or disease progression 
• 
Transplant-related mortality (TRM): defined as the time from randomization 
to death due to causes other than disease relapse or disease progression 
 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 8 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
4.3 
Calculated Variables 
• 
Day 0: defined as the day of HSCT procedure according to protocol conventions. 
• 
Baseline: The baseline for each variable is defined as the last available 
assessment before HSCT. 
• 
For time-to-event data, event time is calculated as follows: 
Event time = [Event date – date of randomization] 
• 
Event durations (e.g. AE duration) are calculated as follows:  
Duration = [end date – start date +1] 
• 
Time intervals (e.g. days from HSCT to ATIR101) are calculated as follows:  
Time interval = [end date – start date] 
4.4 
Partial Dates 
If part of the starting or ending dates of an adverse event (AE) is missing, the following 
convention will be used: 
• 
For a missing day in an AE ‘start date’, the missing day is replaced by the first 
day of the month (e.g. UKMAY2003 -> 01MAY2003) 
• 
For a missing day in an AE ‘end date’, the missing day is replaced by the last 
day of the month (e.g. UKMAR2003 -> 31MAR2003) 
4.5 
Missing Data 
Any missing baseline values will not be imputed. If a subject has a missing baseline 
value that is required for a particular analysis, then the subject will be excluded from 
the statistical analysis. 
Missing values will not be imputed for any time related endpoints. For patients who 
have not experienced the specific endpoints/events, the last known date of visit will be 
used as censoring time. 
Missing AE severity will not be imputed. Such AEs will be included in summaries by 
including a category of “missing” in the tables. If the assessment of the relationship of 
the AE to study medication is missing, we will assume that the AE is possibly related 
to study medication.  
There will be no imputation of missing laboratory, vital sign, or electrocardiogram 
(ECG) data. 
5. Study Patients 
5.1 
Disposition of Patients 
The number of screened patients (who provide informed consent to the trial), the 
number of randomized patients, the number of patients fulfilling inclusion and 
exclusion criteria, the number of screen failures (including reason for screen failure), 
the number of patients who received an HSCT, the number of patients who received 
ATIR101/ PTCy, the number of patients that discontinued before HSCT, between HSCT 
and ATIR101/ PTCy, and after ATIR101/ PTCy (including reason for discontinuation) will 
be summarized.  
Individual patient disposition information will be listed additionally including details of 
‘other reason’ if applicable, time from randomization to PBMC apheresis (in case of 
ATIR101), time from PBMC apheresis to HSCT (in case of ATIR101), time from 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 9 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
randomization to HSCT (in case of PTCy), time from diagnosis (of first occurrence of 
hematologic malignancy) to HSCT, time from HSCT to ANC and Platelet engraftment, 
time from HSCT to ATIR101 infusion or PTCy treatment, and time from PBMC apheresis 
to ATIR101 infusion. 
5.2 
Protocol Deviations 
All protocol deviations will be assessed and identified prior to the database lock. The 
details will be provided in a data listing by the Sponsor. 
5.3 
Inclusion and Exclusion Criteria 
All inclusion criteria that were not met and all exclusion criteria that were met will be 
provided in a data listing by patient. 
6. 
Demographic and other Baseline Characteristics 
Descriptive statistics with respect to patient and donor characteristics at baseline will 
be displayed for the Modified Safety population and the ITT population.  
The variables to be summarized for patients are: 
• 
Demographics: age, gender, race and ethnicity 
• 
Hematologic malignancy and disease status: indications (AML, ALL, MDS), 
AML/ALL/MDS WHO classification level 1 and 2, FAB classification, disease 
status, number of previous remissions, EBMT risk score, Karnofsky score and 
hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (“Sorror 
score”) 
Patient cytogenetic abnormalities, molecular abnormalities, previous therapies as well 
as relevant medical history will be listed only. 
The variables to be summarized for donors are: 
• 
Demographics: age, gender, race and ethnicity; family relation between donor 
and patient  
• 
Human leukocyte antigen (HLA) compatibility: matches at the HLA-A, -B, C and 
-DRB1 loci (and if available at the DQB1 locus) of the unshared haplotype will 
be assessed.  
• 
A table with percentage of x/8 and x/10 matches based on HLA A, B, DRB1, C 
and if available DQB1 types will be made. HLA-typing will be performed by high 
resolution. All four digits must be identical in order to be a match. When one 
allele of an HLA type matches, it is called a haploid match. When two alleles 
match, it is called diploid match. The calculated x/8 and x/10 scores will be 
added to the listing with patient and donor demographic information (i.e. age, 
gender, patient-donor relationship, HLA typing outcome and 2 scores). 
A by patient-listing with the following information will be provided: results of computed 
tomography (CT) scan of the thorax/chest X-ray (if applicable), echocardiogram or 
multiple-gated acquisition (MUGA) scan results (if applicable), results of pulmonary 
function test (if applicable), creatinine clearance results (if applicable), pregnancy test 
results (if applicable) and human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B 
virus (HBV), hepatitis C virus (HCV), Treponema pallidum, human T-lymphotropic virus 
(HTLV)-I (if tested), HTLV-II (if tested), West Nile virus (WNV) (if tested).  
In an additional listing the following donor data will be depicted: pregnancy test results 
(if applicable), HIV-1, HIV-2, HBV, HCV, Treponema pallidum, HTLV-I (if tested), HTLV-
II (if tested), WNV (if tested) results. 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 10 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
7. 
Concomitant Treatment 
All concomitant treatments related to AEs will be summarized for the modified safety 
population by WHO Drug Dictionary code 2018, version 1 (using ATC classification) 
and listed.  
8. 
Safety and Efficacy Evaluation  
Safety and efficacy evaluation will be performed on the Modified Safety population. 
Efficacy evaluation will be also performed on the ITT population. 
8.1 
Incidence and severity of acute and chronic GVHD 
The following datapoints will be analysed using descriptive statistics: 
• 
Cumulative incidence of grade II-IV and grade III-IV acute GVHD  
• 
Cumulative incidence of moderate and severe chronic GVHD 
• 
Cumulative incidence of chronic GVHD requiring systemic 
immunosuppressive treatment 
• 
Duration of acute and chronic GVHD episodes 
Incidence and severity of acute or chronic GVHD will be summarized for the whole 
active study follow-up period, and by time period. Time periods are defined as follows: 
- HSCT to 1 month post HSCT 
- 1 month to 4 months post HSCT 
- Follow-up beyond 4 months post HSCT 
In order to allocate a GVHD event to the correct time period, the start date of the event 
will be used. When two GVHD episodes occurred one after the other (i.e. start date of 
the second GVHD is the stop date of the first GVHD or the day after the stop date of 
the first GVHD), they will be considered a single GVHD event. This event will have the 
start date of the first record and will be counted with the highest grade throughout the 
whole event. This rule will be applied separately for acute and chronic GVHD events. 
8.2 
Incidence and severity of viral, fungal, and bacterial infections  
Cumulative incidence of NCI CTCAE grade 2-5 and grade 3-5 infections will be 
summarized separately, for the whole active study follow-up period, and by time 
period. Time periods are defined as follows: 
- Randomization to HSCT 
- HSCT to 1 month post HSCT 
- 1 month post HSCT to 4 months post HSCT 
- Follow-up beyond 4 months post HSCT 
In order to allocate an infection to the correct time period, the start date of the event 
is taken.  When two infections are directly one after the other (i.e. start date of the 
second infection is the stop date of the first infection or the day next to the stop date 
of the first infection) it should be considered one infection. This case will have the start 
date of the first record and will be counted with highest grade throughout the whole 
event. This rule will be applied separately for grade 2-5 and grade 3-5 infections. 
 
 
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 11 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
8.3 
Adverse Events 
Adverse events (AE) will be coded using MedDRA (Version 21.0), and evaluated for 
severity using NCI-CTCAE.  
The safety analyses on AEs will be based on the treatment-emergent adverse events 
(TEAEs). A TEAE is defined as any untoward medical occurrence in a clinical 
investigation patient administered an investigational product or procedure and which 
does not necessarily have to have a causal relationship with study participation. In this 
study, an adverse event is treatment emergent if it is first observed or worsens on or 
after the date of HSCT. In case of missing start date, the adverse event will be 
considered as treatment emergent.  
Adverse events will be summarized by MedDRA system organ class (SOC) and 
preferred term (PT). SOCs will be ordered by frequency (highest frequency first). PTs 
will be ordered alphabetically per SOC. Patients will only be counted once for each PT. 
In case that a patient experienced the same event more than once, the worst severity 
will be presented.  
Tabulations of the number of patients who experienced AEs will be presented by 
treatment. The frequency of AEs will also be tabulated by grade.  
Separate summaries will be generated for the following:  
• 
All TEAEs 
• 
TEAEs by severity 
• 
ATIR101/PTCy related TEAEs 
• 
Severe TEAEs (NCI CTCAE grade 3 or higher) 
 
• 
Severe TEAEs (NCI CTCAE grade 3 or higher) related to ATIR101/PTCy 
• 
GVHD TEAEs 
• 
Infection TEAEs 
In addition, a summary table presenting an overview of all AEs by AE type (i.e. 
Infection, Relapses/disease progression, GVHD, Other) will be provided.  
All AEs, including non-treatment-emergent AEs will be included in individual patient 
data listings. The following specific AE listings will also be provided: 
• 
GVHD AEs  
• 
Infection AEs (including type of infection, severity, seriousness, causality, 
details organism, start since HSCT/ATIR101/PTCy, outcome, duration). 
The GVHD AE listing will contain the following detailed information: type, severity, 
organ involved (and score), number of days between start of GVHD and HSCT, number 
of days between start of GVHD and ATIR101, duration of GVHD in days, relation to 
ATIR101, action taken and outcome. 
For donors, all AEs will be summarized by SOC and PT and Severity. The details of AEs 
will be provided in a data listing. 
8.4 
Deaths and Serious Adverse Events  
Serious adverse events (SAEs) will be summarized by system organ class and preferred 
term for: 
• 
All SAEs 
• 
SAEs related to ATIR101/PTCy 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 12 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
Separate listings will detail all serious adverse events, graft failures / graft rejections 
and deaths, including number of days since HSCT, date and cause of death together 
with investigator classification and adjudicator classification of cause of death, during 
the study. 
The number of deaths will be tabulated together with the primary cause of death. 
8.5 
Events of Special Interest 
In this study, the following AEs are regarded events of special interest: 
• 
Post-transplant lymphoproliferative disease (PTLD) 
• 
Infusion reactions 
• 
Autoimmune hemolytic anemia (AIHA) 
• 
Secondary malignancies 
• 
Hemorrhagic cystitis 
• 
Veno-occlusive disease  
Incidence of AEs of special interest will be summarized by MedDRA SOC and PT.  
8.6 
Clinical Laboratory Determination 
Summary statistics for baseline, each post-baseline measurement, and change from 
baseline for each post-baseline measurement will be presented for hematology, blood 
chemistry, and urinalysis parameters. 
Hematology, blood chemistry and urinalysis parameters will be listed as follows: by 
patient, parameters per category in columns and visits in rows. Unscheduled visit 
results will be inserted based on the unscheduled visit’s date. Results will be presented 
as, e.g. 300 unit*(L) or 850 unit**(H).  
*: abnormal not clinically significant;  
**: abnormal clinically significant;  
L: if value below or equal to lower limit;  
H: if value above or equal to higher limit.  
For urinalysis only abnormal results are presented (result is abnormal based on the 
question (abnormal clinically (non-)significant?) or if outcome is not negative i.e. 
positive, traces, +, ++, etc.). 
An overview of hematology, serum chemistry and urinalysis is presented in Table 1 
below: 
 
 
 
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 13 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
Table 1: List of safety laboratory tests 
Hematology: 
 
• 
Hematocrit  
• 
Hemoglobin  
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count 
• 
Lymphocytes 
• 
Monocytes 
• 
Basophils 
• 
Eosinophils 
• 
Absolute neutrophil count (ANC) 
 
Urinalysis:  
 
• 
Bilirubin 
• 
Glucose 
• 
Ketones 
• 
Nitrite  
• 
Blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Leukocytes 
 
Blood Chemistry: 
 
• 
Albumin 
• 
Alkaline phosphatase (AP) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
(Corrected) Calcium (Ca) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Magnesium (Mg) 
• 
Phosphorus (P) 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Total protein 
• 
Urea 
 
An additional listing presenting per patient and per parameter (hematology, blood 
chemistry, urinalysis) abnormal clinically significant values will also be made. 
8.7 
CMV/EBV 
CMV and EBV results will be summarized in format of cross table (separate table for 
CMV and EBV). Overall (i.e. for all timepoints combined including unscheduled visits), 
for 
the 
donor/patient 
combinations 
with 
positive/positive, 
positive/negative, 
negative/positive and negative/negative baseline result, the percentage of patients 
with CMV/EBV outcome above the CMV/EBV detection limit at a minimum of one 
timepoint and below the CMV/EBV detection limit for all visits is presented. 
In a listing, both for patient and donor, baseline CMV/EBV results are presented. In an 
additional patient listing both for CMV and EBV and at each timepoint, the CMV/EBV 
result is presented. In the listing it is also presented how many times a patient has an 
outcome above the detection limit (over all timepoints combined). The CMV/EBV 
detection limit is also presented in the listing. 
8.8 
Vital Signs, Physical Findings and Other Observations Related 
to Safety 
Vital signs (respiration rate or oxygen saturation, temperature, weight, pulse rate, and 
supine blood pressure after 5 minutes of rest) and physical examination data (skin, 
ears/nose/throat (ENT), respiratory, cardiovascular, abdomen (including liver and 
spleen), and lymph nodes) will be listed. 
 
 
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 14 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
8.9 
Extent of Exposure / Details of Different Study Procedures 
Summary statistics will be provided for the patient conditioning regimen, HSCT 
procedure and adjunctive treatment.  
Data listings will be provided presenting for each patient: details on patient 
conditioning regimen, HSCT, ATIR101 infusion/PTCy treatment.  
For ATIR101 group: total amount of viable CD3+ cells/kg(x104) and total amount of 
viable CD34+ cells/kg(x106) given to the patient, amount of ATIR101 infused.  
For PTCy group: source of stem cells (‘G-CSF mobilized blood’ or ‘bone marrow’) and 
Total mononuclear cells given to the patient (x108) 
An additional table summarizing time from enrolment to apheresis, time from diagnosis 
to HSCT, time from apheresis to HSCT, time from HSCT to ANC and platelet 
engraftment, time from HSCT to ATIR101 infusion / PTCy will be made. 
8.10 
Bone Marrow Biopsy / Aspirate 
A table will summarize at the relevant timepoints (baseline, week 4, 3 months, 4 
months, and unscheduled visits) the amount and percentage of patients with 
myeloblasts <5% (Y/N) and the actual value of myeloblasts (in %). The presence of 
minimal residual disease (MRD) if available will also be summarized at the relevant 
timepoints. 
A listing providing all details (including both blasts abd myeloblast) on bone marrow 
aspirate / biopsy will also be made.  
8.11 
Engraftment and Chimerism 
Engraftment is defined as neutrophil count ≥ 0.5x109/L for 3 consecutive days and 
platelets ≥ 20x109/L for 3 consecutive days, without transfusion. The first days of 
occurrence of both criteria will be recorded. Time to absolute neutrophil count (ANC) 
engraftment and platelet engraftment (from HSCT) will be summarized according to 
the schedule of activities (see Section 9.1). 
Chimerism results (i.e., total number of cells analyzed, percentage (%) of donor cells, 
assessment done prior to ATIR101Y/N) will be listed (including unscheduled visits). 
8.12 
Efficacy Endpoints 
Due to the early study termination, the efficacy evaluation has been limited to the 
following endpoints as defined in this abbreviated SAP (section 4.2): 
• 
GRFS, OS, PFS, RRM, and TRM 
These endpoints will be analyzed as time-to-event variables when feasible, i.e., if there 
are sufficient number of events. For GRFS, OS and PFS, the corresponding KM curves 
will be presented along with median and 95% CI. For RRM and TRM, cumulative 
incidence curves will be produced. 
• 
Quality of life (QoL) 
The raw QoL data from the Foundation for the Accreditation of Cellular Therapy – Bone 
Marrow Transplantation questionnaire (FACT-BMT), the Short Form 36-item health 
survey (SF-36), the MD Anderson Symptom Inventory (MDASI) will be transferred into 
the following scores (if applicable) following the relevant scoring guidelines: 
➢ FACT-BMT (McQuellon et al., 1997): 
- 
Physical well-being (PWB) subscale score 
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 15 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
- 
Social/family well-being (SWB) subscale score 
- 
Emotional well-being (EWB) subscale score 
- 
Functional well-being (FWB) subscale score 
- 
Bone marrow transplant subscale (BMT) subscale score 
- 
FACT-G total score 
- 
FACT-BMT total score 
➢ SF-36 (Maruish ME (Ed.), 2011) : 
- 
PF health domain T score 
- 
RP health domain T score 
- 
BP health domain T score 
- 
GH health domain T score 
- 
VT health domain T score 
- 
SF health domain T score 
- 
RE health domain T score 
- 
MH health domain T score 
- 
HT health domain T score 
- 
Physical component summary (PCS) T score 
- 
Mental component summary (MCS) T score 
➢ MDASI (Charles S. Cleeland, 2009): 
- 
Mean core symptom severity subscale score 
- 
Mean interference subscale score 
QoL endpoints will be analyzed descriptively. The quantitative QoL scores and changes 
from Baseline will be summarized by visit.  
Other efficacy data, e.g. immune reconstitution, will be provided in data listings. 
8.13 
Additional Analyses of LTFU Data 
Enrollment into the study was terminated early for futility, visit schedules were 
modified and database was locked on 22Apr2020, after all patients had reached the 
Month 4 Visit. Data were collected after the data lock point for long term safety and 
efficacy information through 2 years following HSCT. Additional analyses for the long-
term safety and efficacy evaluations are to be performed on the Modified Safety 
population. All data (not limited to the LTFU period) will be included. The endpoints to 
be analyzed are  as follows: 
• 
Cumulative Incidence of TRM 
• 
Kaplan Meier Estimates of GRFS 
• 
Kaplan Meier Estimates of OS 
• 
Kaplan Meier Estimates of PFS 
The same analysis method as described in Section 8.12 will be used. 
• 
Incidence of Treatment Emergent SAEs   
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 16 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
• 
Incidence of Treatment Emergent SAEs related to ATIR101/PTCy    
Serious adverse events (SAEs) will be summarized by system organ class and preferred 
term. 
All relevant data for individual patients will be provided in data listings.  
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 17 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
9. Appendices 
9.1 
Schedule of Activities (original) 
  
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 18 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
 
  
 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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Kiadis – CR-AIR-009 - ASAP                                                                                                                Page 19 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
  
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 20 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
9.2 
Schedule of Activities After Stopping Study (ATIR101 patients) 
 
 
Time after HSCT 
 
Week 4 
Week 5 
Week 8 
Month 4 
ATIR101 infusion  
X 
 
 
 
Physical examination 
X 
X 
X 
X 
Vital signs 
X 1 
X 
X 
 
Disease assessment 2 
X 
X 
X 
X 
Infection assessment 
X 
X 
X 
X 
CMV/EBV/adenovirus (PCR) 
X 
X 
X 
 
Engraftment  
X 3 
X 
X 
 
Chimerism 
X 3 
X 
 
 
GVHD assessment 
X 
X 
X 
X 
Mortality assessment 
Continuous recording 
Hematology/biochemistry 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
Patient AEs (other) 
X 
X 
X 
X 
SAEs 
Continuous recording 
Concomitant medications4 
X 
X 
X 
X 
                                           
1  
Before infusion of ATIR101; Additionally, following ATIR101 infusion, pulse rate and supine blood pressure will be assessed after 15 
minutes, 1 hour, and 2 hours and continuous oxygen monitoring will be done if the patient has respiratory problems. 
2  
Bone marrow biopsy/aspirate only in case of suspected relapse 
3  
Before infusion of ATIR101 
4  
For AE/SAE related medication only 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 21 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
Schedule of Activities after stopping study (PTCy patients) 
 
 
Time after HSCT 
 
Week 1 
Week 2 
Week 5 
Month 4 
Cyclophosphamide infusion 
X 5 
 
 
 
Physical examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
 
Disease assessment 6 
X 
X 
X 
X 
Infection assessment 
X 
X 
X 
X 
CMV/EBV/adenovirus (PCR) 
X 
X 
X 
 
Engraftment  
X 
X 
X 
 
Chimerism 
X 7 
X 7 
 
 
GVHD assessment 
X 
X 
X 
X 
Mortality assessment 
Continuous recording 
Hematology/biochemistry 
X 
X 
X 
X 
Urinalysis 
 
 
 
X  
Patient AEs (other) 
X 
X 
X 
X 
SAEs 
Continuous recording 
Concomitant medications8 
X 
X 
X 
X 
 
 
 
                                           
5  
On Day +3 and Day +4/+5 
6  
Bone marrow biopsy/aspirate only in case of suspected relapse 
7  
Only in case of suspected relapse 
8  
For AE/SAE related medication only 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 22 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
9.3 
List of Tables/Graphs/Listings 
9.3.1 
List of Statistical Tables 
Number 
Description 
Population 
Table 14.01.01.01-02 
Patient disposition 
All patients 
Table 14.01.02.01-02  
Patient demographics 
Modified Safety, ITT 
Table 14.01.03.01-02 
Patient baseline disease characteristics 
Modified Safety, ITT 
Table 14.01.04.01-02  
Donor demographics 
Modified Safety, ITT 
Table 14.01.05.01-02  
Matching score based on HLA typing patient - donor 
Modified Safety, ITT 
Table 14.01.06.01-02 
Concomitant medications 
Modified Safety, ITT 
Table 14.01.07.01-02 
Summary of durations 
Modified Safety, ITT 
Table 14.02.01.01-02 
Summary of Relapse/Disease Progression, Graft failure, TRM, GVHD  
Modified Safety, ITT 
Table 14.02.02.01-02 
KM estimates of GRFS  
Modified Safety, ITT 
Table 14.02.02.03 
KM estimates of GRFS - LTFU 
Modified Safety 
Table 14.02.03.01-02 
KM estimates of OS  
Modified Safety, ITT 
Table 14.02.03.03 
KM estimates of OS - LTFU 
Modified Safety  
Table 14.02.04.01-02 
KM estimates of PFS  
Modified Safety, ITT 
Table 14.02.04.03 
KM estimates of PFS - LTFU 
Modified Safety  
Table 14.02.05.01-02 
Cumulative incidence of TRM (cumulative incidence function) 
Modified Safety, ITT 
Table 14.02.05.03 
Cumulative incidence of TRM (cumulative incidence function) - LTFU 
Modified Safety 
Table 14.02.06.01-02 
Cumulative incidence of RRM (cumulative incidence function)  
Modified Safety, ITT  
Table 14.02.07.01-02 
Incidence and severity of viral, fungal, and bacterial infections by time 
period 
Modified Safety, ITT 
Table 14.02.08.01-02 
Cumulative incidence of NCI CTCAE grade 2-5 and grade 3-5 for viral, 
fungal, and bacterial infections 
Modified Safety, ITT 
Table 14.02.09.01-02 
Incidence and severity of acute or chronic GVHD by time period  
Modified Safety, ITT 
Table 14.02.10.01-02 
Cumulative incidence of grade II-IV and grade III-IV acute GVHD  
Modified Safety, ITT 
Table 14.02.11.01-02 
Cumulative incidence of moderate and severe chronic GVHD  
Modified Safety, ITT 
Table 14.02.12.01-02 
Cumulative incidence of chronic GVHD requiring systemic 
immunosuppressive treatment  
Modified Safety, ITT 
Table 14.02.13.01-02 
Duration of acute and chronic GVHD episodes  
Modified Safety, ITT 
Table 14.02.14.01-02 
FACT-BMT: summary of scores and changes from Baseline 
Modified Safety, ITT 
Table 14.02.15.01-02 
SF-36: summary of scores and changes from Baseline 
Modified Safety, ITT 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 23 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
Table 14.02.16.01-02 
MDASI: summary of scores and changes from Baseline 
Modified Safety, ITT 
Table 14.03.01.01   
Study procedures 
Modified Safety 
Table 14.03.01.02 
Bone marrow biopsy/aspirate 
Modified Safety 
Table 14.03.02 
Summary of MRD 
Modified Safety 
Table 14.03.03.01  
Summary of treatment-emergent adverse events  
Modified Safety 
Table 14.03.03.02 
Incidence of treatment-emergent adverse events by SOC and PT 
Modified Safety 
Table 14.03.03.03 
Incidence of treatment-emergent adverse events related to ATIR101/PTCy 
by SOC and PT 
Modified Safety 
Table 14.03.03.04 
Incidence of treatment-emergent adverse events by SOC, PT and severity 
Modified Safety 
Table 14.03.03.05 
Incidence of treatment-emergent severe adverse events (grade 3-5) by 
SOC and PT 
Modified Safety 
Table 14.03.03.06 
Incidence of treatment-emergent severe adverse events (grade 3-5) related 
to ATIR101/PTCy by SOC and PT 
Modified Safety 
Table 14.03.03.07 
Incidence of GVHD treatment-emergent adverse events by SOC and PT 
Modified Safety 
Table 14.03.03.08 
Incidence of treatment-emergent Infection adverse events by SOC and PT 
Modified Safety 
Table 14.03.04.01  
Summary of treatment-emergent serious adverse events  
Modified Safety 
Table 14.03.04.02  
Incidence of treatment-emergent serious adverse events by SOC and PT 
Modified Safety 
Table 14.03.04.03  
Incidence of treatment-emergent serious adverse events related to 
ATIR101/PTCy by SOC and PT 
Modified Safety 
Table 14.03.04.04  
Incidence of treatment-emergent serious adverse events by SOC and PT - 
LTFU 
Modified Safety 
Table 14.03.04.05  
Incidence of treatment-emergent serious adverse events related to 
ATIR101/PTCy by SOC and PT - LTFU 
Modified Safety 
Table 14.03.05  
Summary of deaths 
Modified Safety 
Table 14.03.06.01  
Summary of adverse events of special interest 
Modified Safety 
Table 14.03.06.02  
Incidence of adverse events of special interest by SOC and PT 
Modified Safety 
Table 14.03.07.01 
Donor adverse events by SOC and PT 
Modified Safety 
Table 14.03.07.02 
Donor adverse events by SOC, PT and severity 
Modified Safety 
Table 14.03.08 
CMV/EBV summary 
Modified Safety 
 
 
 
 
Note: If a table needs to be made on several populations e.g. ITT, the table numbering is as follows:  
Table 14.xx.xx.01 and Table 14.xx.xx.02. 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 24 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
9.3.2 
List of Graphs 
Number 
Description 
Population 
Figure 14.02.01.01-02   Kaplan-Meier curve of GRFS 
Modified Safety, ITT 
Figure 14.02.01.03   
Kaplan-Meier curve of GRFS - LTFU 
Modified Safety  
Figure 14.02.02.01-02   Kaplan-Meier curve of OS 
Modified Safety, ITT 
Figure 14.02.02.03   
Kaplan-Meier curve of OS - LTFU 
Modified Safety  
Figure 14.02.03.01-02   Kaplan-Meier curve of PFS 
Modified Safety, ITT 
Figure 14.02.03.03   
Kaplan-Meier curve of PFS - LTFU 
Modified Safety  
Figure 14.02.04.01-02 
Cumulative incidence curve of TRM 
Modified Safety, ITT 
Figure 14.02.04.03 
Cumulative incidence curve of TRM - LTFU 
Modified Safety  
Figure 14.02.05.01-02 
Cumulative incidence curve of RRM 
Modified Safety, ITT 
 
 
 
 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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                            Page 25 of 26 
 
APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
9.3.3 
List of Derived Data Listings 
 
Number 
Description 
Population 
Listing 16.2.1.1 
Patient disposition 
All enrolled patients 
Listing 16.2.1.2  
In- and exclusion criteria not met 
ITT 
Listing 16.2.1.3  
Patient and donor demographics 
ITT 
Listing 16.2.1.4 
Patient and donor baseline CMV/EBV 
ITT 
Listing 16.2.1.5  
Patient baseline disease characteristics 
ITT 
Listing 16.2.1.6 
Additional patients baseline disease characteristics (CT, ECG, pulmonary, 
creatinine, pregnancy, virology) 
ITT 
Listing 16.2.2.1 
Durations (including time to engraftment) 
ITT 
Listing 16.2.2.2 
Patient cytogenetic abnormalities 
ITT 
Listing 16.2.2.3 
Patient molecular abnormalities 
ITT 
Listing 16.2.2.4 
Patient previous therapies 
ITT 
Listing 16.2.2.5 
Patient medical history 
ITT 
Listing 16.2.2.6 
Concomitant medications 
ITT 
Listing 16.2.3.1 
Time to event data: GRFS, OS, PFS, RRM, TRM, T-cell reconstitution 
ITT 
Listing 16.2.3.2 
FACT-BMT scores 
ITT 
Listing 16.2.3.3 
SF-36 scores 
ITT 
Listing 16.2.3.4 
MDASI scores 
ITT 
Listing 16.2.4.1 
Details of patient conditioning regimen 
ITT 
Listing 16.2.4.2 
Details of HSCT procedure 
ITT 
Listing 16.2.4.3 
Details of ATIR101/PTCy 
ITT 
Listing 16.2.4.4 
Bone marrow aspirate 
ITT 
Listing 16.2.4.5 
Chimerism 
ITT 
Listing 16.2.5.1  
GVHD adverse events (patients) 
ITT 
Listing 16.2.5.2 
All adverse events (patients) 
ITT 
Listing 16.2.5.3 
Serious adverse events (patients) 
ITT 
Listing 16.2.5.4 
All adverse events (donors) 
ITT 
Listing 16.2.5.5 
Deaths   
ITT 
Listing 16.2.6.1  
Graft failures / graft rejections 
ITT 
Listing 16.2.6.2 
Immune reconstitution (immunophenotyping and immunoglobulins) 
ITT 
Listing 16.2.6.3 
Laboratory data for hematology 
ITT 
Kiadis - CR-AIR-009                                                                   Version: 2.0
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APP N°: TPL SA-02-01 
APP Version: 06 
of SOP SA-02.07 
APP Effective Date: 31 Mar 2016 
Listing 16.2.6.4  
Laboratory data for serum chemistry 
ITT 
Listing 16.2.6.5 
Urinalysis data 
ITT 
Listing 16.2.6.6 
Per patient listing with clinically significant abnormal lab values (hematology, 
blood chemistry, urinalysis) 
ITT 
Listing 16.2.6.7 
Patient CMV/EBV 
ITT 
Listing 16.2.6.8 
Vital signs 
ITT 
Listing 16.2.6.9 
Physical examinations 
ITT 
Listing 16.2.7.1 
Time to event data: GRFS, OS, PFS, TRM 
Modified Safety 
Listing 16.2.7.2 
Serious adverse events (patients) 
Modified Safety 
Listing 16.2.7.3 
Deaths   
Modified Safety 
Listing 16.2.7.4 
Patient disposition 
Modified Safety 
 
Kiadis - CR-AIR-009                                                                   Version: 2.0
Approved in Vault: 13 Dec 2021