Clinical trial NCT02065869
Conditions: Acute Lymphoblastic Leukemia Leukemia, Acute Myeloid (AML), Child Lymphoma, Non-Hodgkin Myelodysplastic Syndrome Primary Immunodeficiency Anemia, Aplastic Osteopetrosis Hemoglobinopathies Cytopenia Fanconi Anemia Diamond Blackfan Anemia Thalassemia Anemia, Sickle Cell
Keywords: ALL AML hematologic neoplasms hematologic malignancies primary immune deficiences hemoglobinopathy congenital cytopenia anemia
Sponsor: Bellicum Pharmaceuticals
Start date: 2014-04-01; Completion date: 2021-09-07
Enrollment: 187 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate pediatric patients with malignant or non-malignant blood cell disorders who are having a blood stem cell transplant depleted of T cell receptor (TCR) alfa and beta cells that comes from a partially matched family donor. The study will assess whether immune cells, called T cells, from the family donor, that are specially grown in the laboratory and given back to the patient along with the stem cell transplant can help the immune system recover faster after transplant. As a safety measure these T cells have been programmed with a self-destruct switch so that they can be destroyed if they start to react against tissues (Graft versus host disease).

Detailed description:
This is a Phase I/II study evaluating the safety and feasibility of BPX-501 T cells infused after partially mismatched, related, TCR alpha beta T cell depleted hematopoietic stem cell transplant (HSCT) in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with hematologic disorders, with the potential for reducing the severity and duration severe acute graft versus host disease (GvHD).

The trial will also evaluate the treatment of GvHD by the infusion of dimerizer drug (AP1903/rimiducid) in those subjects who present with GVHD who progress or do not respond to standard of care treatment.

Arms: arm 1: TCR alpha beta depleted graft infusion with addback of BPX-501 T cells (rivogenlecleucel).

Rimiducid/AP1903: Dimerizer drug administered to subjects who develop Grade III-IV acute GVHD, Grade II gut/liver acute GVDH or Grade I/II skin-only acute GvHD which is non-responsive after 7 days of standard of care treatment
Interventions: intervention 1: BPX-501 T cells intervention 2: Rimiducid
Intervention descriptions: intervention 1: 1x10E6 cells/kg infused on Day 0 intervention 2: 0.4mg/kg administered IV to treat GVHD

Protocol documents:
Prot_000.pdf: 
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Phase II extension study of CaspaCIDe T cells (BPX-501) from an HLA-partially 
matched family donor after negative selection of TCR αβ+T cells in pediatric 
patients affected by hematological disorders 
Protocol Number: 
BP-004 
Combination Product: 
BPX-501 – Donor T cells genetically modified with BPZ-1001 
retroviral vector containing the iCasp suicide gene 
AP1903 (Rimiducid) (Dimerizer drug)  
Principal Investigators and Institutions: 
Principal Investigator  
Prof. Franco Locatelli 
IRCCS Ospedale Pediatrico Bambino Gesù 
Piazzale Sant’Onofrio, 4 
00161 Roma, Italy  
Tel: (+00 39) 06 6859 2678 
E-mail: franco.locatelli@opbg.net 
 
Co-Principal Investigators 
Dr. Waseem Qasim 
Institute of Child Health & Great Ormond Street Hospital 
30 Guilford Street 
London, WC1N 1EH 
E-mail: w.qasim@ucl.ac.uk 
 
Dr. Mary Slatter 
Queen Victoria Rd,  
Newcastle upon Tyne, NE1 4LP, UK  
E-mail:  Mary.Slatter@nuth.nhs.uk 
 
Trial Sponsor: 
Bellicum Pharmaceuticals, Inc. 
2130 W. Holcombe Blvd, Suite 800 
Houston, TX 77030 
ClinicalTrials.Gov / EudraCT Number: NCT02065869 / 2014-000584-41 
Version Number: 
11.0 Italy 
Date: 
29 October 2018 
Confidentiality Statement 
This document contains information confidential to Bellicum Pharmaceuticals, Inc. and it may not be disclosed to anyone 
other than recipient study staff and members of Institutional Review Board (IRBs) and Ethical Committees (ECs). This 
information cannot be used for any purpose other than either evaluation or conduct of the clinical study described here without 
prior written consent from Bellicum Pharmaceuticals, Inc. 
 
 


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Investigator’s Agreement 
 
I have read this protocol and agree to comply with all provisions set forth in this protocol, including all 
statements regarding confidentiality, and to complete the study within the time designated. 
I assume responsibility for the conduct of this study at my study site. I will ensure that I have sufficient 
resources allocated to this project such that the safety of my patients is protected at all times and that I 
complete my obligations to the Sponsor according to the agreed timelines. I will delegate responsibilities 
only to those who are qualified by training and experience. I will ensure the integrity of the data generated 
by my team and that all team members are familiar with the study protocol and the study medication. 
I agree that I will grant access to the applicable records, my staff allocated to the conduct of this protocol 
and my facilities for the purposes of monitoring, auditing and any required inspections associated with 
the conduct of this clinical trial. 
I agree to comply with the ICH Guideline on Good Clinical Practice, applicable EMA regulations and 
applicable FDA guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
Confidential information contained in the protocol document will not be used for any other purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent of the 
Sponsor.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
Printed Name 
Investigator 
 
 




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TABLE OF CONTENTS 
 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ............................................................. 3 
SYNOPSIS ................................................................................................................................................. 7 
LIST OF ABBREVIATIONS AND TERMS .......................................................................................... 20 
1 INTRODUCTION ............................................................................................................................. 23 
1.1 Haplo-identical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) ................................ 23 
1.2 Potential Role of the Cells Remaining in the Graft ..................................................................... 25 
1.3 Clinical Outcomes after αβ TCR T Cell and CD19+ Cell Depletion .......................................... 26 
1.4 Selective αβ TCR T Cell and CD19 Depletion ............................................................................ 26 
1.5 BPX-501: Genetically Modified T Cells With Suicide Safety Switch ........................................ 28 
1.6 Evaluation of Benefits/Risks........................................................................................................ 30 
2 OBJECTIVES OF THE STUDY ....................................................................................................... 31 
2.1 Primary Objectives....................................................................................................................... 31 
3 PATIENT POPULATION AND SELECTION ................................................................................ 32 
3.1 ELIGIBILITY .............................................................................................................................. 33 
3.2 Patient Discontinuation/Withdrawal Criteria ............................................................................... 35 
4 DESIGN AND CONDUCT OF THE STUDY .................................................................................. 36 
4.1 Trial Rationale ............................................................................................................................. 36 
4.2 Trial Design ................................................................................................................................. 36 
4.3 Patient Enrollment, Registration and Assignment to Treatment ................................................. 37 
5 TREATMENTS ADMINISTERED .................................................................................................. 37 
5.1 Screening...................................................................................................................................... 37 
5.2 Donor Screening Investigation .................................................................................................... 38 
5.3 T Cell Apheresis for T Cell Manufacture at Bellicum Pharmaceuticals ..................................... 38 
 
5.5 Rimiducid Dimerizer Drug Packaging, Labeling and Storage .................................................... 40 


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5.6 Donor Peripheral Stem Cells Mobilization .................................................................................. 40 
5.7 Stem Cell Apheresis Procedure ................................................................................................... 41 
 
5.9 Conditioning Regimen ................................................................................................................. 42 
5.10 Infusion of BPX-501 Cells........................................................................................................... 44 
5.11 Infusion of Rimiducid .................................................................................................................. 44 
5.12 Monitoring ................................................................................................................................... 46 
5.13 Management of Experimental Drugs ........................................................................................... 46 
5.14 Concomitant Therapies ................................................................................................................ 47 
5.15 Transfusion Requirements ........................................................................................................... 47 
6 EVALUATION CRITERIA .............................................................................................................. 47 
6.1 Clinical Assessment ..................................................................................................................... 47 
6.2 Laboratory Investigations ............................................................................................................ 48 
6.3 Radiological Investigations .......................................................................................................... 48 
6.4 Microbiological Investigations .................................................................................................... 48 
6.5 Definition of Engraftment ............................................................................................................ 48 
7 SAFETY REPORTING ..................................................................................................................... 48 
7.1 Parameters of safety, assessment of AE and SAE ....................................................................... 48 
7.2 End of Study ................................................................................................................................ 52 
7.3 Recording of Data ........................................................................................................................ 53 
7.4 Data quality Assurance ................................................................................................................ 53 
7.5 Data Management ........................................................................................................................ 53 
7.6 Statistical Methods ....................................................................................................................... 54 
7.7 Safety Analysis ............................................................................................................................ 58 
7.8 Adverse Events (AEs) .................................................................................................................. 58 
7.9 Deaths and Serious Adverse Events (SAE), AEs Leading to Treatment Discontinuation .......... 59 


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7.10 Reporting of Deviations to the Protocol ...................................................................................... 59 
8 ETHICAL ISSUES/CONSIDERATIONS ........................................................................................ 59 
8.1 Institutional and Ethical Review .................................................................................................. 59 
8.2 Investigator's Responsibilities ...................................................................................................... 59 
9 REFERENCES .................................................................................................................................. 61 
Appendix A:  Performance Status Criteria .............................................................................................. 64 
Appendix B:  Acute GvHD Grading Scale by Organ .............................................................................. 65 
Appendix C:  Chronic GvHD Grading Scale ........................................................................................... 69 
Appendix D:  AE Grading and Toxicity .................................................................................................. 74 
Appendix E:  Eligibility for Allotransplantation ..................................................................................... 75 
Appendix F:  ATG Pharmacokinetics and Dosing .................................................................................. 76 
Appendix G:  Standard Institutional Donor Mobilization, Clinical Concomitant Care, Lab and 
Microbiological Monitoring..................................................................................................................... 78 
Appendix H:  Laboratory Tests................................................................................................................ 80 
Appendix I:  Conditioning Regimens ...................................................................................................... 82 
Appendix J: Assessments Associated with Rimiducid in Treatment of GVHD ...................................... 84 
Appendix K:  Guidelines for Monitoring & Management of Neurotoxicity ........................................... 85 
 
 
 
 


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SYNOPSIS 
Background 
Over the last 4 decades, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an 
HLA-matched donor, either related or unrelated, has been increasingly used to treat patients affected by 
several malignant or non-malignant disorders. However, only 25% of patients who need or could benefit 
from an allograft have an HLA-identical sibling and fewer than 60% of remaining patients can be matched 
with suitable HLA-compatible, unrelated donors (Rocha 2008). In the absence of an HLA-matched donor, 
alternative donor/sources of hematopoietic stem cells such as HLA-haploidentical relatives are being 
increasingly used. While mature donor T cells present in the graft facilitate T-cell reconstitution, in the 
context of increased immune genetic disparity between patient and donor, the T cells are also responsible 
for the occurrence of graft-versus-host disease (GVHD), a severe, sometimes fatal, immune complication, 
which also impairs patient’s immune reconstitution. 
Strategies to prevent GVHD after HLA-haploidentical allo-HSCT based on either pharmacological 
immunosuppression or T-cell depletion of the graft have been developed. The physical elimination of T 
cells from the graft has been shown to be highly effective to prevent both acute and chronic GVHD. 
However, with T-cell depletion of the graft, the patient does not receive the adoptive transfer of donor-
derived memory T lymphocytes, which are mainly responsible for protection from severe infections 
during the state of profound immune deficiency that usually lasts for at least 4-6 months after 
transplantation. Overall, HLA-haploidentical allo-HSCT is associated with a higher incidence of graft 
rejection, and both viral and fungal infections, resulting in high transplantation-related mortality (TRM).  
Recent data has shown that not only adaptive immunity, but also innate immunity, such as natural killer 
(NK) cells, influence the patient’s outcome (Locatelli 2013). Therefore, transplantation of mobilized 
peripheral blood stem cells (PBSCs) selectively depleted of TCR αβ T-lymphocytes offers potential 
advantages over the use of positively selected CD34+ hematopoietic stem cells because of the presence 
of other ancillary non-stem cells, including NK and TCRγδ T cells. 
Clinical Outcomes after TCR αβ T Cell and CD19+ Cell Depletion 
Locatelli and colleagues started the program of T-cell depleted haplo-HSCT using the negative selection 
of αβTCR T-cells in November 2010. The study is officially registered at the clinicaltrials.gov website as 
NCT01810120. More than 100 patients with either hematological malignancies or with non-malignant 
disorders received transplants depleted of αβTCR T cells. The data collected to date demonstrates that 


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depletion of αβTCR+ and CD19+ cells led to an approximate 4.1-log and 3.1-log depletion of αβ TCR T 
cells and B cells, respectively. The residual T-cell content was below the previously published safe 
threshold (i.e. 1x105/kg recipient body weight) for HLA-haploidentical HSCT.  Patients did not receive 
any post-transplant immune suppression. 
The outcome of children with acute leukemia given αβ TCR T-cell and B-cell depleted haplo-HSCT 
demonstrated a transplant-related mortality of less than 10% and a 20% risk of malignant disease 
recurrence (Locatelli 2012; Bertaina 2014). There has been no reported acute GvHD with either 
gastrointestinal or liver involvement, and skin-only Grade I-II GvHD was observed in approximately 30% 
of patients, without chronic GvHD.  
Despite the positive patient outcome results in terms of leukemia-free survival (75%), reconstitution of 
adaptive immunity was still sub-optimal. Until 2 months after transplantation, the proportion of 
circulating αβTCR+ mature T cells is lower than that of γδ TCR+ immature T-cells. The delayed immune 
reconstitution resulted in a high probability of serious infections, and the cumulative incidence of CMV, 
adenovirus or aspergillus infections approached 50% (Figure 1). 
 
 


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Figure 1: Correlation Between T Cell Subset Distribution and Likelihood of Viral and Fungal 
Infections 
 
 
 
 
 
 
 
 
Immune reconstitution remains a challenge since T cell engraftment and expansion can take up to 180 
days; therefore, the addition of mature T cells which exhibit a broad repertoire of T cell immunity against 
viral antigens, and potentially against cancer antigens, might provide a clinical benefit. However, the 
potential occurrence of acute graft-versus-host disease (aGVHD) is an expected side effect due to these 
mature T cells. The use of a suicide gene switch which would trigger the initiation of the apoptosis 
(programmed cell death) of the alloreactive T cells by the infusion of dimerizer drug (rimiducid) would 
represent a potential means for restoring early immunity with a built in “safety switch” against GvHD side 
effects. 
Study Rationale 
This is a Phase II extension study evaluating the safety and feasibility of BPX-501 T cells infused after 
partially matched, related, T cell-depleted HSCT in pediatric patients. The purpose of this clinical trial is 
to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with 
hematologic disorders, with the potential for reducing the severity and duration of severe acute GvHD, 
thereby improving overall survival. The trial will also evaluate the treatment of GvHD by the infusion of 
dimerizer drug (Rimiducid/AP1903) in those subjects who present with GvHD who do not respond to 
standard of care treatment. 
Study Type 
Interventional Study 
 


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Study Design 
Allocation: Non-Randomized 
Endpoint Classification:  Efficacy/ Safety 
Intervention Model: Single Group Assignment 
Masking: Open Label 
Primary Purpose: Treatment 
Estimated Enrollment: up to 175 evaluable patients treated with BPX-501 
Phase I Dose Escalation Summary 
Nine subjects were treated according to a 3+3 dose escalation design. Cohorts 1-3 subjects received 
0.2 x106 BPX-501 T cells/kg, 0.5 x 106 BPX-501 T cells/kg, and 1 x 106 BPX-501 T cells/kg, respectively. 
No DLTs were observed and the study then continued at the highest tested dose, namely 1 x 106 BPX-501 
T cells/kg.  No related AEs or SAEs were reported. All 9 subjects showed evidence of BPX-501 T cells. 
Subjects experienced Grade II skin-only GvHD which resolved without treatment with rimiducid. These 
preliminary results support further dose escalation in the malignant disease indications in the attempt to 
further the Graft versus Leukemia effect (GvL) in these high-risk patients.  
Therefore, subjects with malignant diseases were evaluated at two higher dose levels: 2x106 or 4x106 
cells/kg. No DLTs have been noted at either 2x106 or 4x106 cells/kg doses, so a true MTD was not 
determined. The Phase II extension study will evaluate the 1x106 BPX-501 T cells/kg dose for both 
malignant and non-malignant diseases. 
Phase II Primary End-Points 
Event-Free-Survival at 180 days (events include TRM (or NRM for malignant patients), severe GvHD 
(acute Grade 2-4 organ or extensive chronic GvHD) and life threatening infections (Grade 4).  
Phase II Secondary End-Points 
1. 
TRM (non-malignant) or NRM (malignant) at 100 and 180 days  
2. 
Cumulative incidence and severity of acute (grade 2-4) and chronic GvHD at 180 days; 
3. 
Time to resolution of acute or chronic GvHD after administration of rimiducid 
4. 
Immune reconstitution as determined by T cell subsets at day 180 
a. 
Absolute CD3 count 


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b. 
Absolute CD4 count 
c. 
Absolute CD8 count  
 
5. 
Time to immune reconstitution 
6. 
Disease Free/cGvHD survival at 180 days 
7. 
Disease status of each specific disease indication at 180 days: 
a. 
Primary immune disorders as determined by CD3 T cell count >500 cells/ul and lower 
normal levels of IgA and IgM at 180 days 
b. 
Haemoglobinopathies as determined by incidence of RBC transfusion dependence and 
untransfused haemoglobin of >8.5 g/dL at 180 days 
c. 
Fanconi Anemia as determined by RBC >3,000,000 cells/ul, neutrophil count determined 
by 1500 cells/ul and >150,000 platelet counts at 180 days 
d. 
Leukemia as determined by PFS at 180 days 
ELIGIBILITY 
Subject Inclusion Criteria 
1. 
Age < 18 years and > 1 month (< 1 month upon approval by Sponsor) 
2. 
Life expectancy > 10 weeks 
3. 
Patients deemed clinically eligible for allogeneic stem cell transplantation. 
4. 
Patients may have failed a prior allograft 
5. 
Patients with life-threatening acute leukemia (high-risk ALL in 1st CR, ALL in 2nd CR, high-risk 
AML in 1st CR, AML in 2nd CR) or myelodysplastic syndromes. Morphological CR must be 
documented and minimal residual disease measurement before transplantation is recommended. 
6. 
Non-malignant disorders deemed curable by allogeneic transplantation: 
a. 
Primary immune deficiencies,  
b. 
Severe aplastic anemia not responding to immune suppressive therapy,  
c. 
Osteopetrosis  
d. 
Selected cases of erythroid disorders, such as β0 β0 thalassemia major, sickle cell 
disease, Diamond-Blackfan anemia 
e. 
Congenital/hereditary cytopenia, including Fanconi Anemia before any clonal malignant 
evolution (MDS, AML). 


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Note: Subjects will be eligible if they meet either item 5 OR item 6. 
7. Lack of suitable conventional donor (HLA identical sibling or HLA phenotypically identical 
relative or 10/10 unrelated donor evaluated using high resolution molecular typing) or presence of 
rapidly progressive disease not permitting time to identify an unrelated donor 
8. A minimum genotypic identical match of 5/10 is required.  
9. The donor and recipient must be identical, as determined by high resolution typing, on at least one 
allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA- DRB1 and 
HLA-DQB1. 
10. Lansky/Karnofsky score  > 50 
11. Signed informed consent by the patient or the patient’s parent or guardian for patients who are 
minors 
Subject Exclusion Criteria 
1. Greater than active Grade II acute GvHD or chronic extensive GvHD due to a previous allograft 
at the time of screening 
2. Patient receiving an immunosuppressive treatment for GvHD treatment due to a previous allograft 
at the time of screening 
3. Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or 
of renal function (creatinine clearance <30ml/min/1.73m2) 
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure 
or left ventricular ejection fraction < 40%) 
5. Current uncontrolled clinically active infectious disease (including positive HIV serology or viral 
RNA) 
6. Serious concurrent uncontrolled medical disorder 
7. Pregnant or breast feeding female patient 
8. Lack of parents’/guardian’s informed consent for children who are minors. 
Donor Inclusion Criteria 
1. Eligible donors include 5/10 HLA identical relative, including but not limited to biological 
parents, siblings, or half-siblings. Matching will be determined by class I and class II DNA 
typing. The donor of the BPX-501 T cells must be the HSCT donor. 


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2. Donor age must be > 18 and < 65 years. 
3. The donor should be sufficiently healthy not to be at increased risk from the mobilization 
procedure. 
4. Should more than one “equally” MHC compatible donor be identified, other selection criteria 
may include natural killer cell (NK) alloreactivity, NK cell KIR-Haplotype, B-content for B-
haplotype donors, size of the NK alloreactive subset, gender, age, CMV status, health status and 
body weight of donor. The physician treating the subject will make the final decision. 
5. Donors must meet the selection criteria as defined by the European Directive 2006/17/CE) and 
according to the FACT-JACIE International Standards and local regulations for donor selection.  
6. The donor must have been informed of the investigational nature of the BPX-501 product and 
have signed an informed consent form that they will undergo a second apheresis procedure. Donor 
must have adequate peripheral venous access for leukapheresis or must agree to placement of a 
central venous catheter. 
7. The collection of donor T cells to be transduced with the suicide gene will be performed before 
the mobilization procedure with G-CSF in order to avoid any potential negative influence of this 
cytokine on function of genetically modified T cells. 
8. Signed informed consent 
Donor Exclusion Criteria 
1. Evidence of active infection (including urinary tract infection, or upper respiratory tract infection) 
or viral hepatitis exposure (on screening), unless HBs Ab+ and HBV DNA negative. 
2. Factors which place the donor at increased risk for complications from leukapheresis or 
mobilization therapy (e.g., autoimmune disease, symptomatic sickle cell trait, symptomatic 
coronary artery disease requiring therapy, previous thrombotic events). 
3. Pregnancy at the time of normal leukapheresis for the T cells and at the time of the mobilization 
for the stem cell allograft collection. 
4. Breastfeeding at the time of mobilization 
 
 


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Trial Design 
This is a Phase II extension, multi-center, open label study. The trial will be completed at the 1x106 
cells/kg dose for both malignant and non-malignant patients. In the event that the target dose cannot be 
manufactured, the subject will receive any available cells. 
The study will evaluate event-free survival for all evaluable patients at 180 days (6 months) after 
transplantation (active period). There will be an efficacy and safety analysis at the end of the 180-day 
active period with active long term follow-up for up to 2 years on a follow-on protocol (BP-404), with 
gene therapy safety follow-up for a total of 15 years. 
Clinical Schema 
 
The diagram above describes the steps and timing of manufacture and infusion of BPX-501 T cells 
following the TCR αβ depleted HSCT. 
Acute GVHD treatment 
There is the potential for patients to experience both acute and chronic graft vs. host disease (aGVHD 
and cGVHD) due to their allogeneic transplantation for their underlying disease (primary 
immunodeficiency or malignancy). The BPX-501 T cells are intended to: aid in engraftment, promote 
immune reconstitution, enhance allogeneic graft-vs-leukemia (GvL) effects in malignant recipients, and 


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can be eliminated upon infusion of rimiducid (AP1903) for potential mitigation of allo-reactive side 
effects.  
Acute GvHD grading should be conducted in accordance with the Modified Keystone Staging Schema 
(Appendix B)  Refer to guidelines for management of aGvHD provided in (Appendix B) . 
When possible, considering patient weight, blood samples will be drawn within 4 hours prior to the 
initiation of rimiducid infusion; 30 mins after initiation of the infusion; at 2 hours (< 5 min prior to end 
of the rimiducid infusion), 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after the initiation of the 
infusion. Each sample collected out to 24 hours should be split for separate processing. Approximately 
0.5 to 1 mL of blood should be processed to plasma and stored at -80 C for later PK analysis of rimiducid. 
The remaining samples, at least 0.3 mL of blood, should be used for prompt CD3+CD19+ T cell analysis. 
Additional samples (at least 0.3 mL) will be drawn at 48 hours and 7 days after the start of each rimiducid 
infusion, and 14 days, 21 days, and 28 days after the final dose of rimiducid (in the event multiple doses 
are administered) and evaluated for T cell responses only.  
Chronic GvHD Treatment 
Chronic GvHD (cGvHD) typically occurs 100 days or later after HSCT.  Chronic GvHD can often present 
with a sicca-like syndrome with thickened skin, lichen planus, papules, cholestatic jaundice, scleroderma-
like skin, eye and GI lesions. Chronic GvHD patients can also develop obstructive pulmonary disease 
symptoms. 
Chronic GvHD is typically classified into mild (i.e., localized skin involvement, with/or without liver 
dysfunction) or moderate to severe (i.e., generalized skin involvement or localized skin and/or hepatic 
dysfunction, plus liver histology showing hepatitis/necrosis/cirrhosis, eye involvement, salivary gland 
involvement, or effects on other organs).  Moderate to severe cGvHD usually involves more than one 
organ with an organ severity score of moderate or greater (or mild or greater for lungs). Management 
guidelines for cGvHD are shown in Appendix C. 
Response should be assessed per Appendix C.  Three general categories of overall response are used in 
clinical trials: complete response (CR), partial response (PR), and lack of response (unchanged, mixed 
response, progression). Complete response is defined as resolution of all manifestations in each organ or 
site, and PR is defined as improvement in at least 1 organ or site without progression in any other organ 
or site. The 2014 NIH Consensus Working Group recommends that skin, mouth, liver, upper and lower 


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GI, esophagus, lung, eye, and joint/fascia be considered in evaluating overall response. Genital tract and 
other manifestations are not included due to lack of validated response measures. 
Partial response in a specific organ requires an improvement of 1 or more points on a 4 to 7-point scale 
or an improvement of 2 or more points on a 10 to 12-point scale. The overall category of PR requires the 
absence of progression in any organ. 




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least 0.3 mL) will be drawn at 48 hours and 7 days (after each rimiducid dose), then at 14 days, 21 days, and 28 days after the final 
dose of rimiducid (in the event multiple doses are administered) and evaluated for T cell responses only. 
1 Screening activities shall occur after consenting. Screening refers to the period prior to conditioning. Historical assessments can be used to determine eligibility if 
performed within 42 days prior to the day of conditioning, except vital signs, complete blood count (CBC) with differential and platelet count (PLT), performance 
score, and serum chemistry panel which should be within 1 week prior to the day conditioning begins. HLA testing can be within 6 months prior to the day conditioning 
begins. Visit windows up to Day 60 are ± 3 days. Visit windows for from Day 100 to Day 180 are ± 7 days.  
2 Bone marrow evaluation is for subjects with hematological malignancies or non-malignant disorders such as congenital/hereditary cytopenia, including Fanconi 
Anemia and severe aplastic anemia. Disease evaluations for hematological malignancies such as acute leukemia and MDS include a bone marrow aspirate and biopsy. 
Cytogenetics, molecular, or other institutional assessment to determine Minimal Residual Disease (MRD) can be recorded at Baseline. Bone marrow aspirate for 
pathology and cytogenetics will be performed at Day 30, Day 100 and Day 180. Additional assessment can be performed if clinically indicated. 
3 Donor/host chimerism analyses shall be performed according to standard practice in the hospital. The same method shall be used for the same subject. 
4 The immune reconstitution flow panel includes CD3+ cells, alpha/beta CD3+ cells, gamma/delta CD3+ cells, CD4+ cells, CD8+ cells, NK cells and B cells, CD45RA, 
CD45RO, CD62L and CCR7. After BPX-501 infusion, the flow panel will expand to include CD3+/CD19+ cells, CD3+/CD19+/CD4+ cells and CD3+/CD19+/CD8+ 
cells. Baseline samples shall be collected within 10 days prior to Day 0. See Appendix H. Data from flow panel will be used to assess immune reconstitution.  Samples 
should be analyzed locally whenever possible. 
5 For clinical assessment and management of neurotoxicity refer to Appendix K. 
6 Vital signs include blood pressure, heart rate, respiratory rate and temperature. Before, during and after infusion of CD34+ stem cells and BPX-501 T cells, vital 
signs shall be collected 1 hour prior to starting infusion and at 15, 30 and 120 minutes after start of infusion. 
7 Viral monitoring may include CMV, HHV6, EBV and/or other viral studies as deemed necessary by the treating physician which may be monitored more frequently 
than the stated timepoints to monitor reactivation and viral status. 
8 According to standard practice in the hospital, blood counts and differentials will be performed at least 3 times per week after transplant until the neutrophil count 
reaches 0.5 x 109/L. Thereafter, at least 2 times per week until the neutrophil count is > 1.0 x 109/L and platelets > 100 x 109/L. GvHD assessments will be performed 
according to standard practice in the hospital. Subjects will receive GvHD assessment daily for 7 days after the initiation of the first rimiducid infusion and then resume 
the GvHD assessments per the schedule in the protocol. Refer to Appendix B and Appendix C. 
9 Concomitant Medication: The protocol will be conducted during the routine clinical care of the patients. All treatments such as transfusions and critical medications, 
defined below shall be collected in the EDC database: 
• 
Drugs and radiation treatment in conditioning regimens, including most recent chemotherapy regimen and G-CSF  
• 
Treatment for GvHD 
• 
Prophylaxis and/or treatment for infectious complications  
• 
Treatments in association with SAEs or AEs of special interest such as febrile neutropenia and anaphylaxis 
Standard supportive care treatments, non-prescription medications/OTCs, NSAIDs, laxatives/stool softeners, vitamins, and herbal supplements will not be collected 
if they are not protocol-mandated. 
10 Research blood samples collected in association with rimiducid infusion should be assessed locally(see Appendix H). Refer to Appendix J for the processing of 
samples for pPK testing. Additional details are provided in the laboratory manual.  


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11 BPX-501 T cell post-dose levels samples should be sent to Bellicum and the post systemic corticosteroids administration should be analyzed locally, similar to 
rimiducid sample. 
 
 
 
 


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LIST OF ABBREVIATIONS AND TERMS 
ALL 
Acute lymphoblastic leukemia 
ABW 
Adjusted Body Weight 
AE 
Adverse Event 
aGvHD 
Acute Graft Versus Host Disease 
Allo-HSCT 
Allogeneic hematopoietic stem cell transplantation 
AML 
Acute Myeloid leukemia 
APC 
Antigen presenting cells 
BFU-E 
Burst-forming units erythroid 
BM 
Bone marrow 
BMT 
Bone Marrow Transplantation 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
CB 
Cord blood 
CFU-GM 
Colony-forming units granulocytes macrophage 
CFU-M 
Colony-forming units macrophage 
cGvHD 
Chronic Graft Versus Host Disease 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CMV 
Cytomegalovirus 
CR 
Complete Remission 
CRF 
Case Report Forms 
CRO 
Contract Research Organization 
CTL 
Cytotoxic T Lymphocytes 
CTN 
Clinical Trials Network 
DFS 
Disease-free survival 
DLT 
Dose Limiting Toxicity 
EBMT 
European Group for Blood and Marrow Transplantation 
EBV 
Epstein Barr Virus 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 


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EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GMP 
Good medical practice 
GTP 
Good Tissue Practice 
GvHD 
Graft-Versus-Host Disease 
GvL 
Graft-versus-leukemia 
HAMA 
Human Anti-Mouse Antibody 
Haplo-HSCT 
HLA-haplo-identical hematopoietic stem cell transplantation 
HCT 
Hematopoietic Cell Transplantation 
HIPAA 
(US) Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes Simplex Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
KIR 
Killer immunoglobulin-like receptor 
LFS 
Leukemia-free survival 
LN2 
Liquid Nitrogen 
LPDs 
Lymphoproliferative Diseases 
LVEF 
Left Ventricular Ejection 
MACS 
Magnetically Activated Cell Sorting 
MDS 
Myelodysplastic Syndrome 
MHC 
Major Histocompatibility Complex 
MMSE 
Mini-Mental Status Examination 
mMMSE 
Modified Mini Mental Status Examination 
MTD 
Maximum Tolerated Dose 


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NCI CTCAE 
National Cancer Institute Common Terminology for Adverse Events 
NCR 
Natural cytotoxicity receptor 
NK 
Natural Killer 
NKR 
Natural killer receptor 
NOD 
Non-obese diabetic 
NR 
No Response 
NRM 
Non-Relapse Mortality 
OPBG 
Ospedale Pediatrico Bambino Gesù 
OS 
Overall survival 
PAgs 
Non-peptide Phosphoantigens 
PB-HSCT 
Peripheral blood hematopoietic stem cell transplantation 
PBMC 
Peripheral Blood Mononuclear Cell 
PBSC 
Peripheral Blood Stem Cell 
PK 
Pharmacokinetics 
PD 
Progressive Disease 
PR 
Partial Response 
RCR 
Replication Competent Retrovirus 
SAE 
Serious Adverse Event 
SCID 
Severe combined immunodeficiency 
SDV 
Source Data Verification 
TBI 
Total Body Irradiation 
TCR 
T-Cell Receptor 
TNC 
Total Nuclear Cell 
TNF 
Tumor necrosis factor 
TPHA 
Treponema pallidum haemagglutination test 
TRM 
Transplant-Related Mortality 
UCBT 
Umbilical cord blood transplantation 
VNTR 
Variable Number of Tandem Repeats 
WHO 
World Health Organization 
 
 


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1 
INTRODUCTION 
1.1 
Haplo-identical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) 
Over the last 4 decades, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an 
HLA-matched donor, either related or unrelated, has been increasingly used to treat patients affected 
by several malignant or non-malignant disorders. Thanks to this procedure, thousands of subjects 
have been cured of their original disease (Copelan 2006). The total number of allo-HSCT performed 
in Europe in 2008 was 11,408 (corresponding to an increase of 7%) and 1,426 in Italy according to 
the 2008 EBMT activity survey. However, only 25% of patients who need or could benefit from an 
allograft have an HLA-identical sibling and fewer than 60% of remaining patients can be matched 
with suitable HLA-compatible, unrelated donors (Rocha 2008). Moreover, the median time to locate 
a suitable unrelated donor is in the order of 3-4 months. In the absence of an HLA-matched donor, 
alternative donor/sources of hematopoietic stem cells (HSC), such as unrelated umbilical cord blood 
(UCB) and HLA-haploidentical relatives, are being increasingly used (Gluckman 2006; Locatelli 
2009). In particular, the majority of patients have a family member, identical for one HLA haplotype 
and fully mismatched for the other (i.e. haploidentical), who could immediately serve as HSC donor 
(Martelli 2002). Thus, HSCT from an HLA-haploidentical relative (haplo-HSCT) offers an 
immediate transplant treatment for those patients lacking a matched donor or a suitable UCB unit. 
Mature donor T cells present in the graft facilitate T-cell reconstitution, but are also responsible for 
the development of graft-versus-host disease (GvHD), a severe, sometimes fatal, immune 
complication, which also impairs the patient’s immune reconstitution.  
Strategies to prevent GvHD after HLA-haploidentical allo-HSCT based on either pharmacological 
immunosuppression or T-cell depletion of the graft have been developed. A milestone in the history 
of haplo-HSCT was the demonstration that an efficient T-cell depletion of the graft is able to prevent 
both acute and chronic graft-versus-host disease (GvHD) even when using a related donor differing 
at the three major HLA loci (Reisner 1983). The benefits of T-cell depleted haplo-HSCT were first 
demonstrated in children with severe combined immunodeficiency (SCID) and it can now be 
estimated that hundreds of SCID patients have been transplanted worldwide using an HLA-
haploidentical related donor, with a high rate of long-term, partial or complete immune reconstitution 
(Antoine 2003). However, the infusion of BM cells obtained from an HLA-haploidentical relative 
has been reported to be associated with a high incidence of graft failure in patients with acute 
leukemia. Indeed, due to the extensive T-cell depletion of the donor’s graft, the balance between 


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competing host and donor T cells shifted in favor of the unopposed host-versus-graft reaction 
(Bachar-Lustig 1995; Reisner 1999). The use of “megadoses” of G-CSF-mobilized peripheral blood 
donor HSC has been shown to overcome the barrier of HLA incompatibility in the donor/recipient 
pair and to elude the residual anti-donor cytotoxic T-lymphocyte activity of the recipient.  
An effective translation of this approach into the clinical setting was first reported in a pilot study 
performed in adults with acute leukemia by a group in Perugia. In that study, Aversa et al harvested 
“megadoses” of G-CSF–mobilized peripheral blood HSC, and transplanted them after T-cell-
depletion cells using the soybean agglutination and E-rosetting technique, without any subsequent 
pharmacological GvHD prophylaxis. The engraftment rate was above 90%, with a cumulative 
incidence of both Grade II-IV acute and chronic GvHD below 10%. Subsequently, the same group 
has adopted a more standardized method of T-cell depletion based on the positive selection of CD34 
cells from peripheral blood by magnetic beads using the CliniMACS (Miltenyi) system. The clinical 
trials performed using this approach of T-cell depletion have confirmed that sustained engraftment 
of donor hematopoietic stem cells, without the occurrence of GvHD, can be obtained in the majority 
of adult patients and that a substantial proportion of them, especially those affected by acute myeloid 
leukemia (AML) or myelodysplastic syndromes (MDS), became long-term survivors. The feasibility 
and efficacy of haplo-HSCT was reproduced in children with acute leukemia and documented in 
several pilot studies enrolling a limited number of patients. A larger study was performed by The 
Acute Leukemia and Pediatric Working Parties of the European Blood and Marrow Transplantation 
(EBMT) Group which analyzed the outcome of a large cohort of children with acute lymphoblastic 
leukemia (ALL) given T-cell depleted haplo-HSCT. This study showed that the 5-year leukemia-free 
survival (LFS) for children transplanted in complete remission was about 30%, indicating that haplo-
HSCT is a useful treatment for patients in morphological remission of this disease. Furthermore, this 
study showed that the stem cell dose infused in haplo-HSCT is crucial, as patients receiving a dose 
of CD34+ cells greater than 12x106 progenitors/kg have a better clinical outcome (Klingebiel 2010).  
More recently, the group at OPBG analyzed the outcome of 72 pediatric patients given a T-cell 
depleted PB-HSCT for the treatment of ALL (42 cases), AML (21 cases) or MDS (9 cases). Most 
children with acute leukemia were beyond 1st complete remission. The patients were given CD34+ 
cells positively selected using the one-step CliniMacs device (Miltenyi Biotech, Germany) with a 
median number of CD34+ cells infused of 20x106/kg (range 9-41) and no post-transplantation 
pharmacologic immune suppression. The 5-year estimate of disease-free survival (DFS) for the whole 


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cohort was 55%; it was 61% in ALL, 33% in AML and 78% in MDS patients (p<0.01) (Bernardo 
2011). 
Thus, in leukemia patients, the combination of a myeloablative conditioning regimens with the 
infusion of large numbers of highly purified peripheral blood CD34+ cells could guarantee: 1) the 
successful and sustained engraftment of donor hematopoietic stem cells across the HLA barrier; and 
2) a very low incidence of Grade II–IV acute GvHD without the need for any post-transplantation 
immune suppression. 
One disadvantage of this procedure is that the elimination of mature T cells from the graft means that 
recipients cannot benefit from the adoptive transfer of donor memory T lymphocytes that are 
primarily responsible for protection from severe infections during the first months after 
transplantation. Indeed, a state of profound immune deficiency has been documented to last for at 
least 4-6 months after haplo-HSCT and it translates into an increased risk of TRM, mainly attributable 
to infectious complications (Aversa 1998; Aversa 2005). Moreover, the absence of the T cell-
mediated graft-versus leukemia (GvL) effect has also been thought to render the recipients of a T-cell 
depleted allograft more susceptible to leukemia relapse. 
The clinical results only partly confirmed these expectations and showed that not only adaptive 
immunity, but also innate immunity plays a crucial role in the outcome of the transplant. Indeed, adult 
patients transplanted from a donor displaying NK cell alloreactivity were found to have a lower risk 
of leukemia recurrence, especially if affected by AML and when transplanted in morphological 
remission (Moretta 2011). 
1.2 
Potential Role of the Cells Remaining in the Graft 
NK cells represent an important component of the innate immunity and are of fundamental 
importance in limiting or eradicating pathogens during the early phases of a primary infection, (before 
T and B cells can mount efficient responses). Indeed, NK cells and phagocytes do not require clonal 
expansion and can enter and defend a tissue almost as soon as it becomes infected.  
Other potentially beneficial cells infused with the graft are γδ T lymphocytes. These lymphocytes 
have been termed non-conventional, innate-like or transitional T cells, owing to several 
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Total median % recovery yield of CD19- TCRαβ- cells in the graft after selection is 98% (70 – 130%). 
The remaining allograft composition for the reported leukemia patients is listed in Table 1 below. 
Table 1: TCR Depleted Graft Composition per kg Recipient Body Weight 
Total Nucleated Cell Count 
1.1 (0.35-3.27) X 109/kg 
CD34+ Cells 
14.6 (4.8-27.9) X 106/kg 
CD3+ cells 
8 (1-10) X 106/kg 
NK Cells 
31.7 (14-105) X 106/kg 
Tαβ 
4 (1-10) X104/kg 
Tγδ 
7.8 (0.9-14) X 106/kg 
The outcome of children with acute leukemia given αβ TCR T-cell and B-cell depleted haplo-HSCT 
demonstrated a transplant-related mortality of less than 10% and a 20% risk of malignant disease 
recurrence (Locatelli 2012; Bertaina 2014). There has been no reported acute GvHD with either 
gastrointestinal or liver involvement, and skin-only Grade I-II GvHD was observed in approximately 
30% of patients, without chronic GVHD (Bertaina 2015). Despite these positive patient outcome 
results, reconstitution of adaptive immunity was still sub-optimal. Until 2 months after 
transplantation, the proportion of circulating αβ T cells is lower than that of γδ cells. The delayed 
immune reconstitution resulted an increased probability of experiencing serious infections, with the 
cumulative incidence of CMV, adenovirus or aspergillus infection approaching 50% (Figure 3). 
Figure 3: Correlation between T Cell Subset Distribution and Likelihood of Viral and Fungal 
Infections. 
 


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Since immune reconstitution remains a challenge with T cell engraftment taking up to 180 days, the 
addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral antigens, 
as well as cancer antigens, might provide a clinical benefit. However, an expected side effect of the 
presence of T cells is the potential occurrence of aGvHD. The use of a suicide gene switch which 
would trigger the initiation of the apoptosis (killing) of the alloreactive T cells by the infusion of 
dimerizer drug (RUMIDUCID/AP1903) would represent the potential means for restoring early 
immunity with a built in “safety switch” against GvHD side effects. 
The delayed reconstitution of CD4+ cells and impaired recovery of T cell receptor (TCR) diversity 
may predispose recipients of T cell depleted HSCT to opportunistic infections for months to years 
after transplantation. Several studies demonstrate a higher probability of reactivation of viruses such 
as CMV and EBV (van Burik 2007), and increased risk for EBV-associated lymphoproliferative 
disorders (EBV-LPDs) after T cell depleted transplantation (Zutter 1988). Therefore, recipients of T 
cell depleted allografts often require ongoing surveillance for opportunistic viral pathogens. 
1.5 
BPX-501: Genetically Modified T Cells With Suicide Safety Switch 
1.5.1 iCasp9 Suicide Gene 
Unmodified donor T cell infusion is potentially an effective strategy for conferring anti-viral and anti-
tumor immunity following allogeneic stem cell transplantation (Di Stasi 2011). However, the 
administration of greater than 105 cells/kg unmodified donor T cells to recipients of haploidentical 
stem cell transplantation has been associated with increased incidence of GvHD. It has been 
previously demonstrated that administration of up to 107 cells/kg of CD25+ allo-depleted donor T 
cells after haploidentical transplantation for hematological malignancies could be administered safely 
and that the addition of these T cells was effective in controlling viral disease (Amrolia 2006). 
However, mortality due to disease relapse remained high, presumably due to the fact that the estimated 
frequency of tumor-reactive precursors is 1 to 2 logs lower than the frequency of virus- reactive 
precursors.  
The use of higher numbers of allodepleted T cells containing an inducible caspase 9 suicide gene in 
order to treat the potential increase in GVHD was then evaluated. The caspase recruiting domain of 
the human caspase 9 was modified with a drug binding domain, permitting T cell elimination after 
administration of a chemical dimerization drug, rimiducid. Administration of rimiducid dimerizes and 


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activates caspase 9 which activates downstream caspases, leading to apoptosis potentially within 
minutes to hours (Di Stasi 2011; Tey 2007). 
The gamma retrovirus, SFG.iCaspase9.2A.DeltaCD19 (BPZ-1001), consists of inducible caspase 9 
(iCasp9) linked, via a 2A-like sequence, to truncated human CD19 (DeltaCD19). The iCasp9 genetic 
modification, unlike the HSV-TK based suicide gene, is human derived and therefore likely to be less 
immunogenic. Moreover, pre-clinical and clinical studies show that killing occurs with much greater 
rapidity (within 3 hours) than with HSV-TK. Further advantages of the iCasp9 system are that killing 
induced by the dimerizer drug is primarily restricted to activated/proliferating cells, thus targeting 
donor alloreactive T cells active in GvHD, but sparing anti-viral donor T cells and potentially anti-
tumor specific T cells. Additionally, administration of the commonly used drug, ganciclovir, is not 
precluded. 
1.5.2 Rimiducid Dimerizer Drug 
Rimiducid is a member of a new class of lipid-permeable compounds termed activating, or dimerizer, 
drugs that act by inducing clustering of engineered proteins inside cells. RUMIDUCID- inducible 
activation of the Caspase 9 suicide gene is achieved by expressing a chimeric protein (iCasp9), fused 
to a drug-binding domain derived from human FK506-binding protein (FKBP). This chimeric protein 
is quiescent inside cells until administration of rimiducid, which cross-links the FKBP domains, 
initiating iCasp9 signaling. This signaling induces apoptosis of the gene modified cells. 
 
 
1.5.3 CASPALLO Trial   
In a Phase I study, ten patients between the ages of 3 and 17 years who had undergone stem-cell 
transplantation for relapsed acute leukemia were treated with the genetically modified T cells. 
The cells were detected in peripheral blood and increased in number over time, despite their 
constitutive transgene expression. A single dose of dimerizing drug, rimiducid, given to the patients 
in whom GvHD developed, eliminated more than 90% of the modified T cells within 30 minutes 
after administration and a greater than 90% reduction in CD19+ (i.e. transduced) T cells within 30 
minutes of drug administration, and a further log reduction within 24 hours without any reports of 
infusion related toxicity. Moreover, acute GvHD of the skin in all three subjects, and of the liver 
disease in one subject, completely resolved after 24 hr. (Di Stasi 2011). The patients who developed 


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GvHD received rimiducid. None of the 10 patients developed chronic GVHD. Six of the 10 patients 
are alive to date, with relapse as the primary cause of death in the other 4 patients (Zhou 2014). 
The residual iCasp9 gene modified T cell population expanded over the next 4-14 days and continued 
to help repopulate the subjects’ immune systems. The transduced cells were further shown to contain 
virus and fungal-peptide specific precursor cells which had not caused further GVHD. When 
examined ex vivo, these non-alloreactive iCasp9 T cells remained susceptible to apoptosis following 
exposure to rimiducid. The authors concluded that a single dose of dimerizer drug could eliminate the 
subpopulation of T cells causing GVHD but could spare viral specific CTLs. 
The iCasp9 gene is most highly expressed in activated and proliferating T cells, such as those causing 
GVHD. If cells are not activated, due to lack of viral stimulation for example, expression of the 
transgene is lower and in a minority of these cells, iCasp9 levels are insufficient to induce apoptosis 
after single rimiducid dose exposure, allowing subsequent re-expansion (Berger 2004). This 
hypothesis was supported by the CASPALLO clinical data showing activation- dependent induction 
of iCasp9 in T lymphocytes and enhanced susceptibility to dimerizer drug in activated versus resting 
T cells. 
1.6 
Evaluation of Benefits/Risks 
The direct benefit for the patient will be to improve his clinical outcome in terms of successful 
eradication of disease, modulation of GvHD and speed of both hematopoietic and immune recovery. 
The benefit for the community will be to potentially improve the clinical outcome of patients 
receiving a haplo-HSCT for the treatment of hematological disorders in terms of: promoting 
engraftment, lowering TRM and reducing the risk of disease recurrence, thus rendering the procedure 
more widely applicable. 
The potential risk undertaken in this study is to increase the incidence of GVHD in patients receiving 
a TCRαβ depleted graft as compared with patients receiving a positive selected CD34+ cells graft 
from an HLA-partially matched family donor. To decrease this risk, the efficiency of the depletion 
of TCRαβ+ T cells will be checked before the infusion of the graft.  
The benefits of infusing a TCRαβ T cell-depleted graft instead of a positive selected CD34+ cells 
graft from an HLA-partially matched family donor, would be the potential to decrease the incidence 


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of bacterial, viral or invasive fungal infection, to promote engraftment and to reduce the risk of 
recurrence of the disease in case of malignant disorders.  
There is a potential risk of neurotoxicity in patients undergoing HSCT and receiving BPX-501 cells. 
Neurologic complications are not uncommon after allogeneic HSCT and occur in 6-19% of patients 
depending on the type of transplant, the underlying disease (such as immune deficiency disorders) 
and prior treatments. They are the cause of death in 10-15% of children undergoing allogeneic HSCT. 
These events can be a result of agents used in the conditioning regimen, drug related toxicities, 
infections, or immune-mediated reactions such as GVHD. To date, 7 events of neurotoxicity (3%) in 
241 patients treated with BPX-501 after TCR αβ depleted HSCT (pediatric and adult) have been 
reported. Three had an identified viral infection (CMV or HHV6), one patient had an unidentified 
infection but responded to anti-viral, anti-fungal and anti-bacterial treatment. One patient had acute 
disseminated encephalitis (ADEM) as a potential late complication of GVHD. Two cases of 
encephalitis or encephalopathy were of unknown cause. BPX-501 cells have been documented to 
enter the central nervous system. Two patients experienced a complete resolution of encephalopathy 
after treatment with corticosteroids, rimiducid, and anti-infective agents. 
Patients will undergo a daily neurologic examination and mini-mental status examination (MMSE) 
(Folstein 1975) while inpatient and as part of all routine clinical follow-up examinations during each 
outpatient visit while patients are being treated on BPX-501 clinical trials.   
The sponsor assesses the risk-benefit status at this time to be favorable.  The potential risks of 
BPX-501 T cells, including potential immune-mediated events such as GvHD or encephalopathy, at 
this time do not appear to outweigh the benefits of enhanced immune reconstitution, relapse 
prevention, or the ability to treat GvHD with rimiducid.   
2 
OBJECTIVES OF THE STUDY 
2.1 
Primary Objectives 
This is a Phase II extension study evaluating the safety and feasibility of BPX-501 T cells infused 
after partially matched, related, T cell-depleted HSCT in pediatric patients. The purpose of this 
clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those 
patients with hematologic disorders, with the potential for reducing the severity and duration of severe 
acute GvHD, thereby improving overall survival. The trial will also evaluate the treatment of GVHD 


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by the infusion of dimerizer drug rimiducid (AP1903), activating the suicide gene, in those subjects 
who present with GVHD who do not respond to standard of care treatment. 
2.1.1 Phase II primary end-points 
Event-Free -Survival at 180 days (events include TRM (or NRM for malignant patients), severe 
GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life threatening infections (Grade 4).  
2.1.2 Phase II secondary end-points 
1. TRM (non-malignant) or NRM (malignant) at 100 and 180 days  
2. Cumulative incidence and severity of acute (grade 2-4) and chronic GVHD at 180 days; 
3. Time to resolution of acute or chronic GvHD after administration of rimiducid 
4. Immune reconstitution as determined by T cell subsets at day 180 
a. Absolute CD3 count 
b. Absolute CD4 count 
c. Absolute CD8 count  
 
5. Time to immune reconstitution 
6. Disease Free/cGVHD survival at 180 days 
7. Disease status of each specific disease indication at 180 days: 
a. Primary immune disorders as determined by CD3 T cell count >500 cells/ul and 
lower normal levels of IgA and IgM at 180 days 
b. Haemoglobinopathies as determined by incidence of RBC transfusion dependence 
and untransfused haemoglobin of >8.5 g/dL at 180 days 
c. Fanconi Anemia as determined by RBC >3,000,000 cells/ul, neutrophil count 
determined by 1500 cells/ul and >150,000 platelet counts at 180 days 
d. Leukemia as determined by PFS at 180 days 
3 PATIENT POPULATION AND SELECTION 
This study will enroll any infant (1 month -24 months), child (2-11 years) or teenager (12-18 years) 
with malignant hematological disorders in complete morphological remission or non-malignant 
hematological disorders eligible for an allogeneic transplantation and lacking either a related or 
unrelated HLA-matched donor or whose disease status does not allow the extensive wait for an 
unrelated donor. 
• Estimated Enrollment: Approximately 175 evaluable patients treated by BPX-501.  


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3.1 
ELIGIBILITY 
3.1.1 Subject inclusion criteria 
1. Age < 18 years and > 1 month (< 1 month upon approval by Sponsor) 
2. Life expectancy > 10 weeks 
3. Patients deemed clinically eligible for allogeneic stem cell transplantation. 
4. Patients may have failed prior allograft 
5. Patients with life-threatening acute leukemia (high-risk ALL in 1st CR, ALL in 2nd CR, high-
risk AML in 1st CR, AML in 2nd CR.) or myelodysplastic syndromes. Morphological CR must 
be documented and minimal residual disease measurement before transplantation is 
recommended. 
6. Non-malignant disorders deemed curable by allogeneic transplantation: 
a. primary immune deficiencies,  
b. severe aplastic anemia not responding to immune suppressive therapy,  
c. osteopetrosis  
d. selected cases of erythroid disorders such as β0 β0 thalassemia major, sickle cell 
disease, Diamond-Blackfan anemia. 
e. congenital/hereditary cytopenia, including Fanconi Anemia before any clonal 
malignant evolution (MDS, AML). 
Note: Subjects will be eligible if they meet either item 5 OR item 6. 
7. Lack of suitable conventional donor (HLA identical sibling or HLA phenotypically identical 
relative or 10/10 unrelated donor evaluated using high resolution molecular typing) or presence 
of rapidly progressive disease not permitting time to identify an unrelated donor 
8. A minimum genotypic identical match of 5/10 is required.  
9. The donor and recipient must be identical, as determined by high resolution typing, on at least 
one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA- DRB1 and 
HLA-DQB1. 
10. Lansky/Karnofsky score  > 50 
11. Signed informed consent by the patient or the patient’s parent or guardian for patients who 
are minors 


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3.1.2 Subject exclusion criteria 
1. Greater than active Grade II acute GvHD or chronic extensive GvHD due to a previous 
allograft at the time of screening 
2. Patient receiving an immunosuppressive treatment for GvHD treatment due to a previous 
allograft at the time of screening 
3. Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), 
or of renal function (creatinine clearance <30ml/min/1.73m2) 
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart 
failure or left ventricular ejection fraction < 40%) 
5. Current uncontrolled clinically active infectious disease (including positive HIV serology or 
viral RNA) 
6. Serious concurrent uncontrolled medical disorder 
7. Pregnant or breast feeding female patient 
8. Lack of parents’/guardian’s informed consent for children who are minors. 
3.1.3 Donor inclusion criteria 
1. Eligible donors include 5/10 HLA identical relative, including but not limited to biological 
parents, siblings, or half-siblings. Matching will be determined by class I and class II DNA 
typing. The donor of the BPX-501 T cells must be the HSCT donor. 
2. Donor age must be > 18 and < 65 years. 
3. The donor should be sufficiently healthy not to be at increased risk from the mobilization 
procedure. 
4. Should more than one “equally” MHC compatible donor be identified, other selection criteria 
may include natural killer cell (NK) alloreactivity, NK cell KIR-Haplotype, B-content for B-
haplotype donors, size of the NK alloreactive subset, gender, age, CMV status, health status 
and body weight of donor. The physician treating the subject will make the final decision. 


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5. Donors must meet the selection criteria as defined by the European Directive 2006/17/CE) 
and according to the FACT-JACIE International Standards and local regulations for donor 
selection.  
6. The donor must have been informed of the investigational nature of the BPX-501 product and 
have signed an informed consent form that they will undergo a second apheresis procedure. 
Donor must have adequate peripheral venous access for leukapheresis or must agree to 
placement of a central venous catheter. 
7. The collection of donor T cells to be transduced with the suicide gene will be performed before 
the mobilization procedure with G-CSF in order to avoid any potential negative influence of 
this cytokine on function of genetically modified T cells. 
8. Signed informed consent 
Donor exclusion criteria 
1. Evidence of active infection (including urinary tract infection, or upper respiratory tract 
infection) or viral hepatitis exposure (on screening), unless HBs Ab+ and HBV DNA 
negative. 
2. Factors which place the donor at increased risk for complications from leukapheresis 
or mobilization therapy (e.g., autoimmune disease, symptomatic sickle cell trait, 
symptomatic coronary artery disease requiring therapy, previous thrombotic events). 
3. Pregnancy at the time of normal leukapheresis for the T cells and at the time of 
mobilization for the stem cell allograft collection. 
4. Breastfeeding at the time of mobilization 
Sponsor will be notified of any AEs (infections, etc.) occurring in the donor between the 
leukapheresis and stem cell apheresis. 
3.2 
Patient Discontinuation/Withdrawal Criteria 
Patients and/or parent(s) or legal guardian(s) are free to discontinue participation or withdraw consent 
from the study at any time, for any reason, and without prejudice to further treatment. Patients who 
discontinue/withdraw from the study will receive treatment as deemed appropriate by their treating 
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A patient's participation in the study also may be discontinued at any time at the discretion of the 
investigator. The following may be justifiable reasons for the investigator to remove a patient from 
the study: 
- The patient was erroneously included in the study 
- The patient has developed an exclusion criterion or concurrent disease after having been 
considered eligible for the trial but before the start of the preparative regimen 
- The patient experiences an adverse event that is considered intolerable by the patient or the 
investigator 
Data of patients withdrawn from the study will be collected, stored and, whenever indicated, 
analyzed. These patients will be monitored in terms of outcome with regard to survival and, in case 
of malignancies, risk of recurrence. 
4 
DESIGN AND CONDUCT OF THE STUDY 
4.1 
Trial Rationale 
Previously, Aversa (2008) reported that a dose of 2x105 residual CD3+ cells after T cell depletion 
of a peripheral blood stem cell graft administered to haploidentical patients resulted in an incidence 
of Grade II-IV aGvHD of 18%. The occurrence of aGvHD reported by Di Stasi et al after a donor 
lymphocyte infusion (DLI) of gene modified T cells provides a basis for calculating the initial 
probability of toxicity. Ten patients who had undergone haploidentical stem-cell transplantation for 
relapsed acute leukemia were treated with DLI of T cells genetically modified with the iCasp9 suicide 
gene. Four patients who developed aGvHD (40%) and received a single dose of dimerizing drug, 
rimiducid, eliminated more than 90% of the modified T cells within 30 minutes after administration 
and the GvHD resolved in all four patients without recurrence (0% GvHD after rimiducid infusion). 
The probability of aGvHD in this clinical protocol is dependent on the number of T cells remaining 
in the T cell depleted stem cell graft, as well as the BPX-501 T cell dose. The onset of aGvHD will 
depend on interplay between a broad array of host and donor factors, including the presence, 
phenotype and precise specificity of residual major and minor histocompatibility antigen reactive T 
cells, and the numbers and functionality of T regulatory cells in the stem cell graft and the infused 
BPX-501 T cells. 
4.2 
Trial Design 
This is a Phase II extension multi-center, open label study.  


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Phase I dose escalation summary 
Nine subjects were treated according to a 3+3 dose escalation design. Cohorts 1-3 subjects received 
0.2x106 BPX-501 T cells/kg, 0.5x106 BPX-501 T cells/kg, and 1x106 BPX-501 T cells/kg, 
respectively. No DLTs were observed and the study then continued at the highest tested dose, that of 
1x106 BPX-501 T cells/kg.  No related AEs or SAEs were reported. All 9 subjects showed evidence 
of BPX-501 T cells. Subjects experienced Grade II skin-only GvHD, which resolved without 
treatment with rimiducid. These preliminary results support further dose escalation in the malignant 
disease indications in the attempt to further the Graft versus Leukemia effect (GvL) in these high-risk 
patients. Therefore, subjects with malignant diseases were evaluated at two higher dose levels: 2x106 
or 4x106 cells/kg. No DLTs have been noted at either 2x106 or 4x106 cells/kg doses, so a true MTD 
was not determined.   
Patients in the Phase II extension trial will be enrolled at the at the dose of 1x106 cells/kg dose 
regardless of disease (malignant or non-malignant) and the study follow-up for each patient will be 
180 days. Subjects will be enrolled in a long-term follow-up protocol (BP-404) for up to 2-years post-
transplant, with gene therapy follow-up for a total of 15 years. 
4.3 
Patient Enrollment, Registration and Assignment to Treatment 
Informed consent will be obtained from each patient/guardian and donor after the nature of the study 
is explained and prior to the performance of any study-specific procedures. 
Prior to enrollment into the study, a preliminary eligibility determination will be conducted for each 
patient. The investigator or designee shall complete the Patient Registration Form and submit for 
initial approval in the EDC system. Following confirmation that all appropriate forms have been 
completed, Bellicum will approve the subject assignment number in the EDC system. Before the 
starting of conditioning, the site shall confirm the subject eligibility and complete the subject 
enrollment.  
5 
TREATMENTS ADMINISTERED 
5.1 
Screening 
Screening activities shall occur after consenting. Historical assessments can be used to determine 
eligibility if performed within 42 days prior to the day of conditioning, except vital signs, complete 
blood count (CBC) with differential and platelet count (PLT), performance score, and serum 
chemistry panel which should be within 1 week prior to the day conditioning begins.  


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5.2 
Donor Screening Investigation 
Infectious disease monitoring per the established local regulatory guidelines will be performed, and 
per local regulations. Any or all of the following tests may be performed as required per donor 
selection guidelines:  
anti-HIV-1; anti-HIV-2; HIV-antigen, anti-HTLV I/II; HBs-antigen; anti-HBc; anti-HCV; 
CMV status; EBV status; TPHA 
Positive HIV, Hepatitis B and C DNA and TPHA serology are contra-indications to stem cell 
donation. Positive results will be discussed with the donor. Selected virology screening will be 
repeated at the time of leukapheresis for the BPX-501 (CaspaCIDe) T cells  
5.3 
 T Cell Apheresis for T Cell Manufacture at Bellicum Pharmaceuticals 
Prior to the non-mobilized T cell leukapheresis, the donor will be evaluated per the local guidelines. 
Leukocyte fraction will be collected using standardized continuous flow centrifugation. The donor 
will be monitored during apheresis. A standard apheresis procedure of up to approximately 2 blood 
volumes will be processed per institutional standard procedures. The volume processed and the 
duration of leukapheresis will be documented and recorded. If less than 5x109 mononuclear cells are 
collected, the Medical Monitor or Sponsor representative must be consulted immediately. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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5.4.3 Shipping and Storage 
Cryopreserved BPX-501 will be shipped in liquid nitrogen vapor phase to clinical sites in a validated 
shipping container. The receiving cell processing laboratory will store the product at or below -130oC 
until time of infusion. At that time, the product will be thawed at 37°C + 2°C per instructions for 
infusion to the recipient. Depending on the day of shipment timing may be longer than 1 day. 
5.5 
Rimiducid Dimerizer Drug Packaging, Labeling and Storage 
5.5.1 Packaging and Formulation 
The rimiducid for Injection is packaged in Type 1 clear glass serum vials. 
Each vial is stoppered with a Teflon©coated serum stopper and flip-off seal.
5.5.2 Labeling 
The primary product label (applied directly to the vial) for the rimiducid for Injection will contain at 
a minimum the following information: product name, rimiducid; the manufacturers’ lot 
number; product concentration, 5 mg/mL; volume of solution available in the vial; total RIMIDUCID 
contents of the vial. The product will be labeled according to the requirement of each competent 
authority. 
5.5.3 Storage 
The rimiducid for injection vials must be stored at 5°C ± 3°C (41°F ± 5°F) in a limited 
access, qualified refrigerator, preferably without light. 
5.5.4 Preparation for Treatment 
For use, the rimiducid will be diluted prior to administration. The rimiducid is administered via I.V. 
infusion at a dose of 0.4mg/kg diluted in normal saline with volume as appropriate for age of patient 
to be administered over 2 hours, using a DEHP-free saline bag and solution set. 
5.6 
Donor Peripheral Stem Cells Mobilization 
The selected donor will receive recombinant G-CSF (Neupogen®), as per site SOP by daily 
subcutaneous injection beginning from day –5 from the leukapheresis procedure. For a representative 
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ATG is recommended to be administered at a dose of 12-15 mg/kg over 3 days. Rituximab will be 
given for preventing the occurrence of EBV-related post-transplant lymphoproliferative disease 
(PTLD). Seizure prophylaxis will be administered per institutional guidelines while on busulfan.  
5.10 Infusion of BPX-501 Cells  
The BPX-501 T cell infusion should be administered 14 days (+4 days) after completion of the stem 
cell allograft infusion. The BPX-501 T cell product will be thawed in a 37 °C water bath, diluted with 
50 ml Plasmalyte (or NS), 35 ml initially, then 15 ml to “rinse” the bag, and administered over 30 
minutes (or as appropriate for patient weight). The patient will be pretreated with diphenhydramine 
and acetaminophen or equivalent per institutional standards. All treatments administered will be 
documented. No additional pharmacological GvHD prophylaxis will be administered after 
transplantation and during the period of the study. 
In the event of primary graft failure, the patient may receive additional conditioning prior to receiving 
the BPX-501 infusion. In the event of secondary graft failure, after additional immunosuppressive 
conditioning, an additional lot of BPX-501 may be manufactured from the donor. 
5.11 Infusion of Rimiducid 
5.11.1 GVHD Treatment 
5.11.1.1 Acute GvHD Treatment 
There is the potential for patients to experience both acute and chronic graft vs. host disease (aGVHD 
and cGVHD) due to their allogeneic transplantation for their underlying disease (primary 
immunodeficiency or malignancy). The BPX-501 T cells are intended to: aid in engraftment, promote 
immune reconstitution, enhance allogeneic graft-vs-leukemia (GvL) effects in malignant recipients, 
and can be eliminated upon infusion of rimiducid for potential mitigation of allo-reactive side effects.  
Acute GvHD grading should be conducted in accordance with the Modified Keystone Grading 
Schema (Appendix B). Refer to guidelines for management of aGVHD provided in Appendix B:  
Acute GvHD Grading Scale by Organ 
Vital signs are recorded prior to rimiducid infusion, at 15, 30, 60, 120 and 240 minutes after start of 
infusion. When possible, considering patient weight, blood samples will be drawn within 4 hours 
prior to the initiation of rimiducid infusion; 30 mins after initiation of the infusion; at 2 hours (< 5 
min prior to end of the rimiducid infusion), 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after 
the initiation of the infusion. Each sample collected out to 24 hours should be split for separate 


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processing. Approximately 0.5 to 1 mL of blood should be processed to plasma and stored at -80 C 
for later PK analysis of rimiducid. The remaining samples, at least 0.3 mL of blood, should be used 
for prompt CD3+CD19+ T cell analysis. Additional samples (at least 0.3 mL) will be drawn at 48 
hours, and 7 days after the start of each rimiducid infusion and 14 days, 21 days, and 28 days after 
the final dose of rimiducid (in the event multiple doses are administered) and evaluated for T cell 
responses only. 
5.11.1.2 Chronic GvHD Treatment 
Chronic GVHD (cGVHD) typically occurs 100 days or later after HSCT.  cGvHD can often present 
with a sicca-like syndrome with thickened skin, lichen planus, papules, cholestatic jaundice, 
scleroderma-like skin, eye and GI lesions. cGVHD patients can also develop obstructive pulmonary 
disease symptoms. 
cGVHD is typically classified into mild (i.e., localized skin involvement, with/or without liver 
dysfunction) or moderate to severe (i.e., generalized skin involvement or localized skin and/or 
hepatic dysfunction, plus liver histology showing hepatitis/necrosis/cirrhosis, eye involvement, 
salivary gland involvement, or effects on other organs).  Moderate to severe cGVHD usually involves 
more than one organ with an organ severity score of moderate or greater (or mild or greater for 
lungs). Management guidelines for cGVHD are shown in Appendix C. 
Response should be assessed per Appendix C.  Three general categories of overall response are used 
in clinical trials: complete response (CR), partial response (PR), and lack of response (unchanged, 
mixed response, progression). Complete response is defined as resolution of all manifestations in 
each organ or site, and PR is defined as improvement in at least 1 organ or site without progression 
in any other organ or site. The 2014 NIH Consensus Working Group recommends that skin, mouth, 
liver, upper and lower GI, esophagus, lung, eye, and joint/fascia be considered in evaluating overall 
response. Genital tract and other manifestations are not included due to lack of validated response 
measures. 
Partial response in a specific organ requires an improvement of 1 or more points on a 4 to 7-point 
scale or an improvement of 2 or more points on a 10 to 12-point scale. The overall category of PR 
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5.14 Concomitant Therapies 
The protocol will be conducted during the routine clinical care of the patients. All treatments such 
as transfusions and critical medications, defined as below shall be collected in the EDC database: 
• Drugs and radiation treatment in conditioning regimens, including most recent 
chemotherapy regimen and G-CSF  
• Treatment for GvHD 
• Prophylaxis and/or treatment for infectious complications  
• Treatments in association with SAEs or AEs of special interest such as febrile neutropenia 
and anaphylaxis 
Standard supportive care treatments, non-prescription medications/OTCs, NSAIDs, laxatives/stool 
softeners, vitamins, and herbal supplements will not be collected if they are not protocol-mandated. 
Anti-viral prophylaxis will be administered per standard site procedures (for representative 
treatment see Appendix G).     
Any post-transplantation pharmacological treatment (including steroids, calcineurin inhibitors, 
Mycophenolate Mofetil (MMF), Methotrexate (MTX), serotherapy) aimed at preventing GvHD will 
not be allowed unless approved by Medical Monitor/Sponsor. 
5.15 Transfusion Requirements 
The use of platelet transfusions will be carried out according to standard practice and will be recorded 
as the number and type of units given. 
Red cell transfusion will be given according to standard practice and the number and type of units 
will be recorded. 
All platelets and red cells will be leukocyte depleted and irradiated in accordance with transfusion 
policy for patients undergoing HSCT. 
6 
EVALUATION CRITERIA 
6.1 
Clinical Assessment 
2-3 weeks prior to the start of the study a clinical assessment of the patients will be performed with 
documentation of performance status, height, weight and surface area calculated. Constitutional 
symptoms will also be documented at this time.  


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6.2 
Laboratory Investigations 
Lab tests will be performed according to Appendix G and H. Additional tests will be undertaken as 
is the standard institutional practice post-transplant (for representative protocols see Appendix G).   
6.3 
Radiological Investigations 
Radiological investigations will be undertaken as is the standard practice prior to transplant.  
6.4 
Microbiological Investigations 
Microbiological investigations and treatment will be undertaken as is the standard institutional 
practice post-transplant (for representative protocols see Appendix G)  
6.5 
Definition of Engraftment 
For the purpose of evaluation hematopoietic recovery is defined as neutrophils > 0.5 x 109/L for 3 
consecutive days together with platelet count > 20 x 109/L and without platelet support for 7 
consecutive days. 
Donor/recipient chimerism will be evaluated post-transplant through the analysis of Variable Number 
of Tandem Repeats (VNTR) polymorphism or other types of chimerism analysis per institutional 
standard. The same method shall be used for the same subject throughout the post- transplant period. 
7 SAFETY REPORTING 
7.1 Parameters of safety, assessment of AE and SAE 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry variables vital signs and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study drug(s). The AE 
grading (severity) scale found in the NCI CTCAE v4.03 will be used for AE reporting. The NCI 
CTCAE v4.03 can be found: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 
Bellicum or its designee is responsible for reporting relevant SAEs to the FDA, EU and other, 
applicable regulatory authorities, and participating investigators, in accordance with ICH guidelines, 
FDA regulations, European Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory 
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Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless 
of attribution. 
This includes the following: 
1. AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period  
2. Pre-existing medical conditions judged by the investigator to have worsened in severity or 
frequency or changed in character during the protocol-specified AE reporting period 
Serious Adverse Event 
An SAE is any AE that is any of the following: 
1. Fatal (i.e., the AE actually causes or leads to death) 
2. Life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate 
risk of death) 
3. Requires or prolongs inpatient hospitalization 
4. Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
5. A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product(s) 
6. Considered a significant medical event by the investigator (e.g., may jeopardize the subject 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
7. Suspected transmission of infectious agent via a medicinal product 
Readmission to the hospital after stem cell transplantation is expected as a result of a number of 
transplant-associated adverse effects such as:  
• Recurrence of the leukemia or cancer  
• Febrile episode, including febrile neutropenia  
• Bleeding from thrombocytopenia (low platelets)  
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These re-hospitalizations should be reported in the electronic case report form (eCRF) as AEs, not 
SAEs, for this study as they are expected after the stem cell transplant. However, if local laws require 
that the site submit all SAEs then the local law will supersede the protocol requirements. Should any 
of the above expected conditions worsen or develop into serious, life-threatening events which are 
unexpected or considered study-related, then they must be reported to the sponsor as per SAE 
reporting guidelines. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs 
or symptoms and are considered clinically significant. Grades 1-4 hematologic toxicity is expected 
during the first 100 days after the stem cell transplantation and so will not be considered as an AE or 
reported as a SAE.  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (as 
in mild, moderate, or severe pain); the event itself may be of relatively minor medical significance 
(such as severe headache). “Serious” is a regulatory definition and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or vital 
functions. Seriousness (not severity) serves as the guide for defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
eCRF. 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in Section 7.1) are 
recorded on the eCRF and reported to the Sponsor in accordance with protocol instructions.  
Adverse Event Reporting Period 
After informed consent, but prior to initiation of BPX-501 infusion, only SAEs will be collected. All 
AEs (except GvHD) will be collected following infusion of BPX-501 or rimiducid until 180-days 
post-transplant. SAEs regardless of attribution will be collected during the same timeframe until 
180-days post-transplant. From 180 days, AEs and SAEs will be collected on the follow-on protocol 
BP-404.  
GvHD Adverse Event Reporting 
All occurrences of GvHD will be reported as Adverse Events (or SAEs) regardless of their start date 
in relation to BPX-501 infusions. GvHD events will also be followed until resolution and not limited 
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Reporting Requirements for All SAEs 
Investigators will submit reports of life-threatening or fatal SAEs, to Bellicum within 24 hours of 
learning of the events. All other SAEs will be reported to Bellicum on the SAE Report form within 1 
business day of learning of the event.  For initial SAE reports, investigators should record all case 
details that can be gathered within 24 hours on the Bellicum SAE Report form and submit the report 
electronically. Relevant follow-up information should be submitted to Bellicum or its designee as 
soon as it becomes available and/or upon request.  
Type and Duration of Follow-Up of Subjects after Adverse Events 
The investigator should follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the subject is lost to follow up, or it has been determined that the study treatment or 
participation is not the cause of the AE/SAE. Resolution of AEs and SAEs (with dates) should be 
documented on the Adverse Event eCRF and in the subject’s medical record to facilitate source data 
verification (SDV). 
For some SAEs, the Sponsor or its designee may follow up with the site by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report). 
Post-Study Adverse Events 
The investigator should notify the study Sponsor of any death or other SAE occurring at any time 
after a subject has discontinued or terminated study participation if felt to be related to prior study 
treatment. The Sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of a subject 
that participated in this study. The investigator should report these events to Bellicum on the study 
eCRF. If the study eCRF system is no longer available, the investigator should report the event 
directly to Bellicum on the SAE Report form. 
7.2 
End of Study 
The study will evaluate event-free survival for all evaluable patients enrolled at 180 days (6 months) 
after transplantation (active period).  Patients will then be followed for long term safety and outcome 
study for 2-years post-transplant in BP-404, and then for a total of 15 years for gene therapy safety 
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DATA COLLECTION, QUALITY ASSURANCE AND MANAGEMENT 
7.3 
Recording of Data 
Data will be recorded on electronic database and will be entered after validation into a computer 
system for subsequent tabulation and analyses. The investigator must ensure that each subject’s 
anonymity is maintained. Subjects will be identified by a unique Subject Identification Number. 
Study related documents should be kept in strict confidence by the investigator in compliance with 
applicable regulations and ICH GCP Guidelines. 
7.4 
Data quality Assurance 
The Investigators undertake to perform the study in accordance with this Protocol, Good Clinical 
Practice and the applicable regulatory requirements. 
The Investigators are required to ensure compliance with the investigational product schedule, visits 
schedule and procedures required by the protocol. 
The Investigators agree to provide all information requested in the Case Report Form in an accurate 
and legible manner. 
7.5 
Data Management 
The investigator will fill in eCRF for documentation. All relevant data collected during the study for 
all of the patients enrolled into the study have to be entered into the database by the responsible 
investigator or someone authorized by him in a timely manner. The principal investigator (PI) will 
review all the eCRF’s of each patient and confirm the completeness, medical correctness and 
plausibility of the documented data by his signature on all eCRF pages.  
Additions and corrections in the eCRF will be dated and signed by the responsible physician or an 
authorized person. Reasons must be given for corrections that are not self-explanatory  
Bellicum or CRO will ensure that the clinical trial is conducted, recorded, and reported in accordance 
with the protocol, ICH-GCP, and the applicable regulatory requirement(s).  
Representatives of Bellicum or the CRO must be allowed to visit all study site locations periodically 
to assess the data, quality and study integrity. On-site they will review study records and directly 
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verify that the facilities remain acceptable. Source documents are defined as: patient files, letters, and 
laboratory/histology records.  
7.6 
Statistical Methods 
The material of this section is the basis for the Statistical Analysis Plan of this study. This plan may 
be revised during the study to accommodate Clinical Trial Protocol Amendments.  
7.6.1 Sample Size  
175 evaluable patients treated with BPX-501 T cells in the Phase II extension phase will be recruited 
over a total over a period of 60 months.  
7.6.2 Analysis Populations 
The analysis population will be stratified by malignant and non-malignant indications. The safety 
population is proposed to comprise the entire pediatric population. 
7.6.3 General Statistical Approach 
Descriptive statistics will be utilized to summarize GvHD rates, clinical and biologic response and 
other measures of safety and toxicity in those subjects who received rimiducid administration as 
well as for the whole population.  
Data per cohort will be presented, stratified according to the type of disorder, e.g. malignant or non-
malignant. 
All summary tables for quantitative parameters will display mean, standard deviation, median, range 
(minimum and maximum), and two-sided 95% confidence intervals, as well as number of missing 
data, where relevant. All summary tables for qualitative parameters will display counts, percentages, 
two-sided 95% confidence intervals, and, number of missing data, where relevant. Time to event 
parameters, such as time to immune reconstitution, will be summarized using the Kaplan-Meier (KM) 
analysis method, including the 25th, 50th (median) and 75th-percentile statistics, and number of 
censored observations. 
7.6.4 Study Patient Description 
• Disposition of Patients 


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• The number of enrolled patients will be summarized by country, center, and dose using counts 
and percentages. 
• The number of patients either completing 180 days follow-up as well as those eligible to be 
enrolled in the follow-up protocol will be summarized using counts and percentages. 
7.6.5 Demographic and Baseline Characteristics 
Baseline characteristics will be described using the patient populations and their accompanying 
donors. Demographics, medical history, qualifying disorder, and other baseline variables will be 
summarized as appropriate to the type of data. Data analysis will include evaluation of demographic 
and baseline characteristic data, including at least age, sex, race, ethnicity, type of disease and 
duration, prior HSCT, conditioning and HLA typing. Donor characteristics including age, ethnicity 
and relationship will also be summarized. 
7.6.6 Infectious complications 
Cumulative incidence of infectious complications at 180 days will be analyzed, as defined by 
cumulative incidence of clinically significant viral reactivations, patients requiring antiviral 
treatment, rehospitalizations due to viral infection, bacterial and fungal infections and use of non-
prophylactic antibiotic and antifungal use at 180 days 
7.6.7 Engraftment and GVHD Analysis 
Duration of hospitalization for the transplant procedure will be reported 
7.6.7.1 Analysis of Time to Neutrophil Engraftment 
The time to neutrophil engraftment will be measured by determining the first of three consecutive 
measurements of an ANC > 500/µL following the conditioning regimen induced nadir, starting from 
Day 0.  
The cumulative incidence of neutrophil engraftment estimates will be analyzed by BPX-501 dose, 
CD34+ cell dose in the allograft, γδT cell dose in the allograft, αβT cell dose in the allograft, ATG 
dosing, conditioning regimen and disease status.  


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7.6.7.2 Analysis of Platelet Engraftment 
Time to platelet engraftment will be measured by determining the first of three consecutive 
measurements of platelet count >20,000/µL without platelet transfusion support for seven days, 
starting from Day 0. The cumulative incidence of platelet engraftment estimates will be analyzed by 
BPX-501 dose, CD34+ cell dose in the allograft, γδT cell dose, αβT cell dose in the allograft, ATG 
dosing, conditioning regimen and disease status.  
7.6.7.3 Analysis of Graft Failure 
Primary graft failure is defined as failure to achieve an absolute ANC > 500 cells/µL by Day +30. 
Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in 
neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy.  
The cumulative incidence of graft failure estimates will be analyzed by BPX-501 dose, CD34+ cell 
dose in the allograft, γδT cell dose, αβT cell dose in the allograft, ATG dosing, conditioning regimen 
and disease status.  
7.6.7.4 Analysis of Acute and Chronic GvHD 
The time and severity of aGvHD are graded according to the Modified Keystone Grading Staging 
Schema (Appendix B). The time and severity of cGvHD are graded according to NIH Consensus 
Criteria (Appendix C).  
7.6.8 Grade I-IV Acute GvHD: 
The initial incidence of aGvHD Grades I-IV by Days 100 and 180 will be determined and will be 
analyzed by indication (malignant, non-malignant), conditioning regimen, BPX-501 dose, αβ T cell 
dose in the allograft, ATG dosing and degree of HLA match.  
The response rates of aGvHD to standard treatment will be determined, as well the number of patients 
with aGVHD demonstrating non-improvement or progression on standard treatment. Time to 
resolution of GvHD will be analyzed in patients receiving rimiducid. 
The initial incidence of severe aGvHD Grades III-IV by Days 100 and 180 will be determined and 
will be analyzed by conditioning regimen, BPX-501 dose, and degree of HLA match. The response 
rates of severe aGvHD Grades III and IV in patients receiving rimiducid treatment will be determined 
at Days 100 and 180 and time to resolution of GvHD after rimiducid infusion. 
 


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7.6.9 Chronic GvHD: 
The initial incidence of severe cGvHD at 6 months will be determined and will be analyzed by 
conditioning regimen, αβT cell dose, disease status, and degree of HLA match. The response rates of 
cGvHD in patients receiving rimiducid treatment will be determined at 6 months and analyzed by the 
number rimiducid infusion and time to resolution of cGvHD after rimiducid infusion. 
7.6.10 Analysis of Time to Disease Relapse 
To assess the incidence of acute leukemia relapse from the day of transplant, a cumulative incidence 
curve will be computed along with a 95% confidence interval. Death prior to relapse will be 
considered a competing risk. The risk of relapse estimates at six-months post-transplant will be 
analyzed by regimen, disease status, GvHD status, and BPX-501 dose.  
7.6.11 Transplant-Related Mortality 
TRM will be assessed within the first 6 months following transplant.  In malignant patients TRM 
(NRM) is defined as death occurring in a patient who was in complete remission. Relapse will be 
considered a competing risk. The cumulative incidence of TRM at will be determined at 6 months. 
The follow-on protocol will determine disease free survival at 1 year and 2 years, followed by safety 
evaluations for gene therapy for 15 years.  
7.6.12 Immune Reconstitution 
• CD3+ cell count, CD4+ cell count and CD8+ cell count at day 180, as well as B cells and 
Immunoglobulin levels at Day 180, additional analysis will include CD45 RA/RO, CD62L 
and CCR7. 
• Descriptive summaries of these parameters in the overall patient group and by dose group as 
well as by time of measurement will be presented.  
• Kinetics representing measurements over time within a patient will be generated to visualize 
general patterns of immune reconstitution.  
• The proportion of iCasp9 positive cells will also be summarized at each time point.  
7.6.13 Disease-free/cGvHD free survival at 180 days 
Chronic GvHD/Disease free survival will be assessed at 180 days. 


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7.6.14 Disease status at time of discharge, 100 and 180 days 
7.6.14.1 Non-malignant disease patients: 
Disease status of each specific disease indication at 180 days: 
a. Primary immune disorders as determined by CD3 T cell count >500 cells/ul and 
lower normal levels of IgA and IgM at 180 days 
b. Haemoglobinopathies as determined by incidence of RBC transfusion dependence 
and haemoglobin of >8.5 g/dL at 180 days 
c. Fanconi Anemia as determined by RBC >3,000,000 cells/ul, neutrophil count 
determined by 1500 cells/ul and >150,000 platelet counts at 180 days 
7.6.14.2 Malignant disease patients 
Leukemia as determined by PFS at 180 days 
7.7 
Safety Analysis 
Safety analysis will investigate the analysis populations over the time period defined as from the 
infusion date of the respective treatment to study end date.  
7.8 
Adverse Events (AEs) 
All adverse events recorded during the study will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and be graded according to the NCI CTCAE v4.03 scale (see    
Appendix C).    
AEs will be summarized for the following 
Number (%) of patients with any AE, 
Number (%) of patients with any SAE, 
Number (%) of patients permanently withdrawn from study due to an AE. 
All summaries will be presented by treatment group and stratified by type of disorder (e.g. malignant 
or non-malignant). They will include overall frequency of patients with events as well as frequency 
of patients with events by primary system organ class and preferred term. A patient will only be 
counted once within each system organ class and preferred term. For summaries regarding severe or 
study-drug related AEs, the highest severity or relationship will be considered for each patient per 
preferred term. 


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7.9 
Deaths and Serious Adverse Events (SAE), AEs Leading to Treatment Discontinuation 
SAEs, events leading to death, and AEs leading to treatment discontinuation will be summarized 
overall as well as by primary system organ class and preferred term. 
7.10 Reporting of Deviations to the Protocol 
All the deviations to the protocol will be described and justified in a separate form.  
8 
ETHICAL ISSUES/CONSIDERATIONS 
8.1 
Institutional and Ethical Review 
The study will be conducted according to the ethical principles of the declaration of Helsinki, the 
ICH-GCP Guidelines, the EU Clinical Trial Directive (2001/120/EG), Italian Ministry of Health 
decree of July 15, 1997, FDA and other international regulatory agencies.  
8.2 
Investigator's Responsibilities 
Any investigator or co-investigator who signed this protocol agrees to carry out this research in 
accordance with the protocol approved by the ethical committee, GCP and regulatory requirements. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). The PI has the right to prematurely discontinue the 
study for significant efficacy or safety problems and will notify the co-investigators in writing, as 
well as the ethics committees and the competent authorities according to law and regulations. 
8.2.1 Patient Informed Consent 
The patient or parents/legal guardians are to be informed both in writing and verbally by the 
investigating physician. The patient and his/her parents/guardians must be given ample opportunity 
to decide whether or not to participate in this study and to ask questions concerning this. It must also 
be made clear to the patient that he/she can withdraw from the study at any time without giving 
reasons and that he/she will not be in any way disadvantaged by this. Assent will be documented as 
required by the IRB or the EC. The informing physician, the patient or guardian must each personally 
date and sign an informed consent form with a declaration on data privacy. Any informed consent 
will be part of the investigator’s file and retained with it. The patient will retain a copy of the patient 
information. 


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Each patient enrolled in this experimental protocol will not be included in any other trial, including 
those addressing issues related to supportive care. Other investigational agents may not be 
administered from the time of HSCT through Day 180 (6 months) except as clinically indicated for 
any experimental therapy for GvHD non-responsive to rimiducid, infections not responding to 
standard treatments or disease relapse. 
8.2.2 Data Management and Storage 
The investigator will organize the storage of the identification codes of the patients for at least 15 
years after the end of the study. The files of the patients (medical records) and other original data will 
be kept for a minimum period of 15 years. Relevant parts of those records specific to support the 
traceability of BPX-501 from donor to recipient will be retained as applicable by the investigator, 
manufacturer and Sponsor per local requirement. 


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Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted haploidentical "three-
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Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell 
transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 
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Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T-depleted bone marrow 
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Bendelac A, Bonneville M, Kearney, J F. Autoreactivity by design: innate B and T lymphocytes. 
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T cells in a nonhuman primate model Blood. 2004; 103:1261-1269. 
Bernardo ME, Zecca M, Giorgiani G, et al. Donor NK alloreactivity improves the outcome of children 
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αβ+ T and B-cells in children with non-malignant disorders. Blood. 2014;124(5):822-6. 
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Dieli F, et al. Granulysin-dependent killing of intracellular and extracellular Mycobacterium 
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Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L. What is a Natural Killer cell? Nature 
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Appendix A:  Performance Status Criteria 
KARNOFSKY (≥16 years of age) 
LANSKY (<16 years of age) 
100 
normal, no complaints, no signs of disease 
100 
Fully active 
90 
capable of normal activity, few symptoms or 
signs of disease 
90 
Minor restriction in physically strenuous play 
80 
normal activity with some difficulty, some 
symptoms or signs 
80 
Restricted in strenuous play, tires more easily, otherwise 
active 
Unable to work, able to live at home, cares for 
most personal needs, a varying amount of 
assistance is needed 
Mild to moderate restriction 
 
70 
caring for self, not capable of normal 
activity or work 
70 
Both greater restriction of and less time spent in active 
play 
60 
requiring some help, can take care of most 
personal requirements 
60 
Ambulatory up to 50% of the time, limited active play 
with assistance/supervision 
50 
requires help often, requires frequent 
medical care 
50 
Considerable assistance required for any active play, fully 
able to engage in quiet play 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly 
Moderate to severe restriction 
 
40 
disabled, requires special care and help 
40 
Able to initiate quiet activities 
30 
severely disabled, hospital admission 
indicated but no risk of death 
30 
Needs considerable assistance for quiet activity 
20 
very ill, urgently requiring admission, 
requires supportive measures or treatment 
20 
Limited to very passive activity initiated by others (e.g. 
TV) 
10 
moribund, rapidly progressive fatal disease 
processes 
10 
Completely disabled, not even passive play 
 
 
 








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• 
Consideration by the investigator for other medications per 
institutional guidelines (eg, calcineurin inhibitors, sirolimus, 
mycophenolate) 
• 
If no response to steroids and/or other aGvHD medications after 48 
hours, patients may then receive rimiducid: 
 
o Children: 0.4 mg/kg to a maximum of 40 mg IV 
o Adults: 40 mg IV 
o If there is evidence of clinical improvement (e.g. partial 
response) but not complete resolution after the first dose of 
rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours  
o Daily examination on day 1 and day 2 should be performed after 
initiating treatment with rimiducid, then weekly for 1 month, 
every 2 weeks for 100 days, and monthly after 100 days post-
rimiducid administration 
o For new or recurrent Grade 2 through 4 aGvHD episodes, 
rimiducid may be considered for repeat administration with the 
above guidelines if the investigator considered rimiducid to offer 
clinical benefit with prior episodes 
• 
Peripheral blood should be collected for evaluation of BPX-501 cells 
(CD3+CD19+) at the following times:  
o Prior to administration of systemic corticosteroid doses (e.g, 
methylprednisolone), at 4 and 24 hours post-systemic 
corticosteroid doses, and at 7, 14, 21 and 28 days post-systemic 
corticosteroid doses 
o When possible, considering patient weight, blood samples will 
be drawn within 4 hours prior to the initiation of rimiducid 
infusion; 30 mins after initiation of the infusion; at 2 hours (< 5 
min prior to end of the rimiducid infusion), 4 hours, 6 hours, 8 
hours, 12 hours, and 24 hours after the initiation of the infusion. 
Each sample collected out to 24 hours should be split for separate 
processing. Approximately 0.5 to 1 mL of blood should be 
processed to plasma and stored at -80 C for later PK analysis of 
rimiducid. The remaining samples, at least 0.3 mL of blood, 
should be used for prompt CD3+CD19+ T cell analysis. 
Additional samples (at least 0.3 mL) will be drawn at 48 hours, 
and 7 days after the start of  each rimiducid infusion and 14 days, 
21 days, and 28 days after the final dose of rimiducid (in the 
event multiple doses are administered) and evaluated for T cell 
responses only. 
 
 
 
 


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Appendix C:  Chronic GvHD Grading Scale 
NIH Consensus Grading Chronic GvHD 
 


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Appendix C NIH Consensus Grading Chronic GvHD (cont.) 
 
Table C.1: 
Global scoring of cGvHD 
Number of Organs 
Mild cGvHD 
Moderate cGvHD 
Severe cGvHD 
1 
Score 1 
Score 2 
Score 3 
2 
Score 1 
Score 2 
Score 3 
3 
Score 1 
Score 3 
Lung involvement 
Score 1 
Score 2 
Mild cGvHD = 1 or 2 organs involved (except for lung) with maximum score of 1 
Moderate cGvHD = lung score of 1 or 3 organs with score of 1 or at least 1 organ with score of 2 
Severe cGvHD = lung score of 2 or score of 3 in any organ. 
 
Reference:   
Filipovitch AH et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-
host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. 




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o Children: 0.4 mg/kg to a maximum of 40 mg IV 
o Adults: 40 mg IV 
o If there is evidence of clinical improvement (e.g. partial 
response) but not complete resolution after the first dose of 
rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours 
o Daily examination on day 1 and day 2 should be performed after 
initiating treatment with rimiducid, then weekly for 1 month, 
every 2 weeks for 100 days, and monthly after 100 days post-
rimiducid administration 
o For new or recurrent cGvHD episodes, rimiducid may be 
considered for repeat administration with the above guidelines if 
the investigator considered rimiducid to offer clinical benefit 
with prior episodes 
• 
Peripheral blood should be collected for evaluation of BPX-501 cells 
(CD3+CD19+) at the following times:  
o Prior to administration of systemic corticosteroid doses (e.g, 
methylprednisolone), at 4 and 24 hours post-systemic 
corticosteroid doses, and at 7, 14, 21 and 28 days post-systemic 
corticosteroid doses 
o When possible, considering patient weight, blood samples will 
be drawn within 4 hours prior to the initiation of rimiducid 
infusion; 30 mins after initiation of the infusion; at 2 hours (< 5 
min prior to end of the rimiducid infusion), 4 hours, 6 hours, 8 
hours, 12 hours, and 24 hours after the initiation of the infusion. 
Each sample collected out to 24 hours should be split for separate 
processing. Approximately 0.5 to 1 mL of blood should be 
processed to plasma and stored at -80 C for later PK analysis of 
rimiducid. The remaining samples, at least 0.3 mL of blood, 
should be used for prompt CD3+CD19+ T cell analysis. 
Additional samples (at least 0.3 mL) will be drawn at 48 hours, 
and 7 days after the start of  each rimiducid infusion and 14 days, 
21 days, and 28 days after the final dose of rimiducid (in the 
event multiple doses are administered) and evaluated for T cell 
responses only. 


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Table C.3 
Response Determination for Chronic GvHD 
 
Reference: Lee SJ et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health 
Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response 
Criteria Working Group Report. Biol Blood Marrow Transplant 2015;21: 984-999. 
 
 




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Appendix E:  Eligibility for Allotransplantation 
1. High-risk ALL in 1st CR 
2. ALL in 2nd CR 
3. High-risk AML in 1st CR 
4. AML in 2nd CR 
5. Myelodysplastic syndromes 
 
 


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Appendix F:  ATG Pharmacokinetics and Dosing 
Anti-thymocyte globulin will be administrated from Day -4 to Day -2 (3 consecutive days).  
Fresenius rabbit ATG is recommended to be administered at a dose of 4-5 mg/kg/day whereas 
the approximate equivalent dose of Thymoglobulin to be administered will be 1-1.25 mg/kg/day.  
Table F1 below, shows the pharmacokinetics of a dose twice that which is intended in to be used in 
the study of the rabbit ATG, and demonstrates that by Day 14 the concentration of ATG falls below 
100ug/ml. 
Similarly, Figure F2 demonstrates that a dose of 10 mg/kg/day over 4 days (twice that suggested for 
the current protocol) has an active ATG (the fraction binding T cells) half-life of about 7 days. 
The proposed administration period for the BPX-501 T cells of Day14 ± 4 days is consistent with 
approximately 2 half-life reductions in ATG levels regardless of the source of ATG. 
Table F1: Median serum levels of ATG in 14 children after receiving dose of 10mg/kg ATG on Days -
5, -4 and -3 (Rabbit ATG, Fresenius) (Locatelli, personal communication)  
Sampling Time 
ATG-Fresenius Serum Concentration 
(All Patients n=14) 
 
Median (µg /mL) 
IQR (µg /mL) 
Follow up 
 
 
Day -2 
181.7 
111.75-261.8 
Day -1 
168.6 
119.65-325.8 
Day 0 
153.1 
104.6-195.8 
Day +3 
154.6 
91.71-187.3 
Day +5 
103.7 
84.6-177.9 
Day +7 
112.5 
96.0-148.8 
Day +14 
99.1 
71.9-136.4 
Day +21 
93 
63.8-134.1 
Day +28 
75.6 
49.7-104.1 
Day +42 
57.6 
30.8-77.2 
Day +56 
44.5 
18.1-46.8 
 
 




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Appendix G:  Standard Institutional Donor Mobilization, Clinical Concomitant 
Care, Lab and Microbiological Monitoring 
Suggested recommendations based on the Pediatric Hospital (OPBG), Rome standards 
The selected donor will receive recombinant G-CSF at a dose of 12-16 µg/kg/d by daily subcutaneous 
injection beginning from Day –5 from the leukapheresis procedure with twice daily injection to Day 
–3 and three daily injection being administered from Day –2. On Day –2, CD34+ cells counts will be 
taken, if the number of CD34+ cells is ≥ 0.04 x109/L, the leukapheresis will be performed on Day –
1; if not, the donor will receive plerixafor (240 µg/kg) on Day –1 and the leukapheresis will be 
performed on Day 0. 
 
All patients will receive anti-viral prophylaxis with acyclovir (10 mg/kg/day from Day -2 to Day 
+180), anti-bacterial prophylaxis and anti-fungal prophylaxis with i.v. liposomal amphotericin-B or 
mold-active azoles (i.e. voriconazole, posaconazole). Pneumocistis Jirovecii pneumonia prophylaxis 
will be administered with cotrimoxazole (or aerosol pentamidine in case of allergy/intolerance to 
cotrimoxazole) from engraftment to 1 year after the allograft. 
According to standard practice in the hospital, blood counts and differentials will be performed at 
least 3 times per week after transplant until the neutrophil count reaches 0.5 x 109/L. Thereafter, at 
least 2 times per week until the neutrophil count is > 1.0 x 109/L and platelets > 100 x 109/L. 
Subsequently, blood counts and differentials will be performed approximately every 2 weeks until + 
100 days. Samples for biochemistry, related to the routine monitoring of hepatic and renal function, 
will be taken pre-transplant and thereafter at least 3 times weekly until engraftment and subsequently 
checked twice a week until + 100 days. Further results from routine outpatient follow-up controls 
after this time will be documented up to one-year post transplant. 
Microbiological investigations will be according to standard procedures for the determination of an 
infectious organism in a child undergoing HSCT. These will include regular surveillance cultures 
(inclusive of oral flora), blood cultures and viral screening. All infections, either presumed or proven 
and treated, will be documented. Anti-microbial therapy and its duration will be documented. 
Reactivation of human cytomegalovirus (HCMV) infection will be tested at least twice a week till 
Day +60, using assessment of quantitative DNA in blood. Between Day +60 and 100 patients will be 
tested at least once a week. Thereafter, children will be tested during scheduled controls in the 
outpatient unit until 1 year after the allograft. Patients experiencing HCMV reactivation will be pre-
emptively treated in the presence of more than 5,000 HCMV DNA copies/mL. Pre-emptive therapy 
will be based on administration of intravenous ganciclovir (5 mg/kg twice a day), replaced by 
foscarnet (90 mg/kg twice a day) in case of ganciclovir-induced neutropenia (less than 0.5x109 
neutrophils/l) or sustained increase of HCMV DNA levels in blood during therapy with ganciclovir. 
Anti-viral treatment will be stopped in the presence of virus clearance from blood, i.e. after two 
consecutive negative results. Relapse episodes will be treated similarly. 
Determination of quantitative EBV DNA and adenovirus DNA in blood will be performed at least 
once a week for the first 100 days after the allograft. Children with an Adenovirus viral load in blood 
greater 100,000 copies/mL confirmed on 2 consecutive samples will be treated with cidofovir (1 
mg/kg/dose thrice a week) till viral clearance.  


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Patients with more than 10,000 copies/mL of EBV DNA in blood will be allowed to receive further 
doses of rituximab, which will be administered according to the schedule usually employed to 
prevent/treat EBV-related PTLD.  
Galactomannan will be determined twice a week for the first 2 months after transplantation. Children 
with galactomannan levels greater than the normal values, associated with clinical or radiological 
signs suspected for an invasive aspergillosis will receive appropriate anti-fungal therapy. 


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Appendix H:  Laboratory Tests 
Activity 
Timing 
BM & Disease Evaluation 1 
Pre-transplant, Days 30±7, 100±10, and 180±10 post-transplant, and 
thereafter as needed 
Chimerism 2 
Days 30±7 and 100±10 post-transplant, and thereafter as needed 
Hematology3 
 
Pre-transplant, post-transplant according to standard practice in the 
hospital until engraftment; then, 30±7, 44±7, 60±7, 74±7, 88±7, 100±10, 
and 100±10 post-transplant.  
Serum Chemistry4 
Pre-transplant, Days 30±7, 60±7, 44±7, 88±7, 100±10, 180±10 
post-transplant.   
Blood Sample for Immune 
Reconstitution/iCasp5   
 
Pre-transplant, Day 30±7, 60±7, 100±10, and Day 180±10 post-transplant.  
IgG 
IgG, IgM and IgA levels: Pre-transplant, Day 30±7, Day 60±7, 
Day 100±10, and Day 180±10 post-transplant.  
Bellicum Research Samples6   
BPX-501 T cell Post-Dose Levels  
Baseline (-10 days to -1 day), immediately prior to BPX-501 infusion, 7 
days post-BPX-501 infusion, weekly for one month after BPX-501 
infusion (± 4 days), every 2 weeks ± 4 days to 100-days post BPX-501 
infusion, monthly ± 14 days for until 1 year post BPX-501 infusion, every 
6 months ± 1 month for 24 months post BPX-501 infusion.   
Post-systemic corticosteroid administration:  
Prior to administration of systemic corticosteroids doses (e.g. 
methylprednisolone), at 4 and 24 hours post-systemic corticosteroid 
initiation, and at 7, 14, 21, and 28 days post-systemic corticosteroid 
initiation.  
Blood Sample for HAMA  
Pre-transplant and Day 100±10 post-transplant   
Blood Sample for RCR  
 
Pre-transplant, Day 100±10d post-transplant, Day 180±10d. Follow-up 
protocol to monitor for 1 year, then every 6 months for 5 years then yearly 
for 10 years (15 years total)  
Rimiducid Infusion Blood 
Samples7 
When possible, considering patient weight, blood samples will be drawn 
within 4 hours prior to the initiation of rimiducid infusion; 30 mins after 
initiation of the infusion; at 2 hours (< 5 min prior to end of the rimiducid 
infusion), 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after the 
initiation of the infusion. Each sample collected out to 24 hours should be 
split for separate processing. Approximately 0.5 to 1 mL of blood should 
be processed to plasma and stored at -80 C for later PK analysis of 
rimiducid. The remaining samples, at least 0.3 mL of blood, should be 
used for prompt CD3+CD19+ T cell analysis. Additional samples (at least 
0.3 mL) will be drawn at 48 hours and 7 days after the start of each 
rimiducid infusion and 14 days, 21 days, and 28 days after the final dose 
of rimiducid (in the event multiple doses are administered) and evaluated 
for T cell responses only. 
 
1Bone marrow evaluation is for subjects with hematological malignancies or non-malignant disorders such as 
congenital/hereditary cytopenia, including Fanconi Anemia and severe aplastic anemia. Disease evaluations for 
hematological malignancies such as acute leukemia include a bone marrow aspirate and biopsy. Cytogenetics, molecular, 
or other institutional assessment to determine Minimal Residual Disease (MRD) can be recorded at Baseline. Bone 
marrow aspirate for pathology and cytogenetics will be performed at Day 30, Day 100 and 180 Days. Additional 
assessment can be performed if clinically indicated.  


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2Donor/host chimerism analysis shall be performed according to standard practice in the hospital. The same method shall 
be used for the same subject.  
3According to standard practice in the hospital, blood counts and differentials will be performed at least 3 times per week 
after transplant until the neutrophil count reaches 0.5 x 109/L. Thereafter, at least 2 times per week until the neutrophil 
count is > 1.0 x 109/L and platelets > 100 x 109/L.  
4Serum chemistry panel: electrolytes, glucose, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, LDH, 
albumin. Electrolytes include sodium, potassium, chloride, carbon dioxide, calcium, and magnesium.  
5The immune reconstitution flow panel includes CD3+ cells, alpha/beta CD3+ cells, gamma/delta CD3+ cells, CD4+ 
cells, CD8+ cells, NK cells and B cells, CD45RA, CD45RO, D62L and CCR7. After BPX-501 infusion, the flow panel 
will expand to include CD3+/CD19+ cells, CD3+/CD19+/CD4+ cells and CD3+/CD19+/CD8+ cells. Data from flow 
panel will be used to assess immune reconstitution. 
6 BPX-501 T cell post-dose levels samples should be sent to Bellicum and the post systemic corticosteroids administration 
should be analyzed locally, similar to rimiducid sample. 
7At least 20 ml (or as weight permits) will be taken and sent to the Sponsor to analyze the effects of the rimiducid 
dimerizer drug on circulating gene modified T cells. Refer to Appendix J for the processing of samples for pPK testing. 
 
 












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Grade ≥ 2 
(Generalized)2 
• 
Perform routine institutional care for patients with altered mental 
status/obtundation (eg, continuous vital sign monitoring, oxygen, suction, 
airway protection measurements and consideration of need for mechanical 
ventilation, ICU admission) 
• 
Neurology consult and EEG evaluation 
• 
CBC analysis and peripheral blood smear evaluation to evaluate for 
thrombotic microangiopathy (TTP/HUS) 
• 
Evaluation for electrolyte and acid-base etiologies 
• 
Evaluation for liver dysfunction and evidence of hyperammonemia/veno-
occlusive disease (VOD) 
• 
Perform daily neurological and mini-mental status examinations during 
hospitalizations to evaluate for resolution/worsening of symptoms 
• 
Perform CNS imaging (MRI and/or contrast enhanced CT) 
• 
Perform CSF evaluation for presence of cell counts (and differential), 
glucose, protein and gram stain for bacteria. 
o CSF evaluations for other infectious etiologies (eg, herpes viruses, 
JC virus, fungal, West Nile virus and toxoplasma) 
o CSF samples should be sent to the Sponsor for research use to 
evaluate for the presence of BPX-501 cells 
• 
Consider empiric use of anticonvulsants if seizure is expected  
o Special consideration should be considered for conditioning agents 
(eg, Busulfan) or prophylactic GvHD medications (eg, calcineurin 
inhibitors) as an etiology and institutional guidelines should be 
instituted for possible treatments (eg, prophylactic GvHD 
medication changes and/or treatment with seizure medications) 
• 
Consideration of high-dose corticosteroid treatment (1000 mg/day x 3-5 days 
for adults or 30 mg/kg/day x 2-5 days in children) if no evidence of 
CNS/systemic infection 
• 
Consideration of empiric antiviral and/or anti-fungal therapy as per 
institutional standard of care should be considered if infectious etiology is 
suspected (tailored for lab data results) 
• 
A brain biopsy should be considered if other diagnostic tests are unrevealing 
as to an etiology. 
• 
Rimiducid may be administered if CNS infection ruled out and no 
improvement after 48 hours of high-dose corticosteroids (1000 mg/day x 
2 days for adults or 30 mg/kg/day x 2 days in children) rimiducid may be 
administered in conjunction with corticosteroids and anti-infective agents. 
Samples for PK analysis of rimiducid for research use, should be collected 
before and after rimiducid, including samples of the CNS for PK analysis if 
the patient’s condition allows. If there is evidence improvement (e.g. partial 
response) but not complete resolution after the first dose of rimiducid, then 
rimiducid can be given every 48 hours for 3 doses. Please notify the medical 
monitor at Bellicum prior to the administration of rimiducid for 
neurotoxicity. 
• 
Peripheral blood should be collected for evaluation of BPX-501 cells 
(CD3+CD19+) at the following times:  
o Prior to administration of systemic corticosteroid doses (e.g, 
methylprednisolone), 
at 
4 
and 
24 
hours 
post-systemic 
corticosteroid doses, and at 7, 14, 21 and 28 days post-systemic 
corticosteroid doses 
o When possible, considering patient weight, blood samples will be 
drawn within 4 hours prior to the initiation of rimiducid infusion; 30 
mins after initiation of the infusion; at 2 hours (< 5 min prior to end 
of the rimiducid infusion), 4 hours, 6 hours, 8 hours, 12 hours, and 
24 hours after the initiation of the infusion. Each sample collected 


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out to 24 hours should be split for separate processing. 
Approximately 0.5 to 1 mL of blood should be processed to plasma 
and stored at -80 C for later PK analysis of rimiducid. The remaining 
samples, at least 0.3 mL of blood, should be used for prompt 
CD3+CD19+ T cell analysis. Additional samples (at least 0.3 mL) 
will be drawn at 48 hours and 7 days after the start of each rimiducid 
infusion and 14 days, 21 days, and 28 days after the final dose of 
rimiducid (in the event multiple doses are administered) and 
evaluated for T cell responses only. 
* All grading corresponding to NCI CTCAE v4.03: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm#ctc 40 
1. 
Includes but not limited to cranial nerve abnormalities, brachial plexopathy, ischemia, nystagmus, pyramidal tract 
syndrome, radiculitis, focal seizure, stroke, transient ischemic attack 
2. 
Includes but not limited to aphonia, ataxia, cognitive disturbance, depressed level of consciousness, dysarthria, dysphasia, 
encephalopathy, headache, hypersomnia, lethargy, memory impairment, meningismus, seizures, somnolence, tremor, 
visual disturbances 
 
References: 
de Brabander C, et al. Increased incidence of neurological complications in patients receiving an allogeneic bone marrow transplantation 
from alternative donors. J Neurol Neurosurg Psychiatry. 2000:68:36-40. 
Dowling MR, et al.  Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact.  Bone 
Marrow Transplantation 2017;1-8. 
Folstein MF, et al.  “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 
1975:12:189-198. 
Mental Status Examination in Primary Care: A Review. American Family Physician. 2009:80: No.8. pp809-814.  
Syed FI, et al.  Central nervous system complications of hematopoietic stem cell transplant.  Hematol Oncol Clin N Am 
2016:30:887-898. 
Teng EL, Chui HC. The modified mini-mental status (3MS) examination. J Clin Psychiatry. 1987; 48(8): 314-8 
Uckan D, et al.  Life-threatening neurological complications after bone marrow transplantation. Bone Marrow Transplant 2005:35:71-
76. 
 
 

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