A Study Evaluating BPX-501 T Cells and AP1903 for Prevention of Graft Versus Host Disease (GVHD) After Haploidentical, Related, T Cell-Depleted Hematopoietic Cell Transplantation for Non-Malignant Diseases
Phase: PHASE1
Conditions: Primary Immune Deficiency Disorders, Hemophagocytic Lymphohistiocytosis, Inherited Bone Marrow Failure Syndrome, Hemoglobinopathies, Metabolic Disorders
Sponsor: Bellicum Pharmaceuticals

Bellicum Pharmaceuticals 
 
 
Protocol Number BP-003  
 
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A Study Evaluating BPX-501 T cells and AP1903 for Prevention of GVHD after 
HLA-Haploidentical, Related, T Cell-Depleted Hematopoietic Cell 
Transplantation for Non-Malignant Diseases.  
BP-003 
Protocol Number 
BP-003 
Combination Product 
Rivogenlecleucel (BPX-501) – Donor T cells genetically 
modified with BPZ-1001 retroviral vector containing the 
iCasp safety switch gene 
Rimiducid (AP1903) (Dimerizer drug) 
 
Investigators and 
Institution: 
 
Laurie Burroughs , MD, PI 
Fred Hutchinson Cancer Research Center 
 
 
Trial Sponsor: 
Bellicum Pharmaceuticals, Inc. 
3730 Kirby Drive, Suite 1200, Houston, Texas 77098 
Version Number and Date: 
  Version 3.0 
22 February 2021  
ClinicalTrials.gov number 
NCT02231710  
 
 
 
 
 
 

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Investigator’s Agreement 
 
I have read the Investigator’s Brochure and the attached protocol and agree to comply with all 
provisions set forth in protocol number BP-003. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice and applicable FDA regulations/guidelines set forth in 21 CFR Parts 11, 50, 
54, 56, and 312. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• myself (including, if applicable, my spouse [or legal partner] and dependent children) 
• my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
I agree that these statements will be completed before study initiation, during the study if there 
are changes, and after the study is completed. 
This document contains information confidential to Bellicum Pharmaceuticals, Inc. and it must 
not be disclosed to anyone other than recipient study staff and members of the Institutional 
Review Board (IRB).  I agree to ensure that this information will not be used for any purpose 
other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Bellicum Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
Printed Name 
Principal Investigator 
 
 
 
 

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PROTOCOL SYNOPSIS 
A Study Evaluating BPX-501 T cells and AP1903 for Prevention of GVHD after HLA-
Haploidentical, Related, T Cell-Depleted Hematopoietic Cell Transplantation for Non-
Malignant Diseases.  
BP-003 
Study Design 
This is a single arm dose finding study evaluating the safety and efficacy of 
a BPX 501 infusion (T cells genetically modified with the iCasp9 safety 
switch) of 3x106 to 1x107 cells/kg recipient body weight followed by an 
rimiducid (AP1903) infusion on day 7 after a partially mismatched, 
related, T cell-depleted hematopoietic cell transplantation (HCT) in 
patients with non-malignant diseases.  The purpose of this clinical trial is 
to determine the dose of BPX 501 T cell infusion with subsequent planned 
infusion of rimiducid (AP1903) which can facilitate engraftment and 
prevent the occurrence of GVHD.  
Number of 
Patients 
20 Patients 
Number of Sites 
Up to 10 Clinical Sites 
Study Length 
Accrual targeted 24 months; main study conduct 2 years post 
transplantation (and a total of 15 years gene therapy long-term follow-up 
after last BPX-501 treatment) 
 
Investigational 
Products 
1. BPX-501 – Single administration of BPX 501 T cells (3x106 to 1x107 
BPX-501 T cells/Kg), given per intravenous infusion. 
 
2. Rimiducid (AP1903,Dimerizer drug) of 0.4mg/kg administered per 
intravenous infusion 
 
 
 
 

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Patient Eligibility 
Inclusion Criteria 
1. Patient must meet eligibility criteria for allogeneic transplantation 
2. Males or females 
3. Age < 55 years old and > 4 months 
4. Diagnosis of a nonmalignant disorder considered treatable by HCT.  
i.   Primary Immune Deficiency Disorders 
a. Severe Combined Immune Deficiency (SCID) 
b. Combined Immune Deficiency (CID) 
c. Congenital T-cell Defect/Deficiency 
d. Common Variable Immune Deficiency (CVID) 
e. Chronic Granulomatous Disease 
f. IPEX (Immune deficiency, polyendocrinopathy, 
enteropathy, X-linked) or IPEX-like 
g. Wiskott-Aldrich Syndrome 
h. CD40 Ligand Deficiency 
i. Leukocyte Adhesion Deficiency 
j. DOCK 8 Deficiency 
k. IL-10 Deficiency/IL-10 Receptor Deficiency 
l. GATA 2 deficiency 
m. X-linked lymphoproliferative disease (XLP) 
n. Cartilage Hair Hypoplasia 
o. Other primary immune deficiency deemed eligible for HCT 
by the Non-Malignant Board 
ii. Hemophagocytosis Lymphohistiocytosis (HLH) or other 
hemophagocytic disorders 
iii.  Inherited Marrow Failure Disorders 
a. Shwachman Diamond Syndrome 
b. Diamond Blackfan Anemia 
c. Dyskeratosis Congenita  
d. Fanconi Anemia 
e. Congenital Neutropenia 
 
 

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f. Other inherited marrow failure disorder deemed eligible 
for HCT by the Non-Malignant Board 
 
iv. Hemoglobinopathies 
a. Sickle Cell Disease  
b. Thalassemia  
c. Other hemoglobinopathies deemed eligible for HCT by the 
Non-Malignant Board 
v.  Metabolic Disorders 
a. Mucopolysaccharidosis  
b. Sphingolipidoses  
c. Other Metabolic disorder deemed eligible for HCT by the 
Non-Malignant Board 
5. Lack of suitable conventional donor (i.e. 10/10 related or 
unrelated donor) or the presence of advanced disease not 
permitting time to identify an unrelated donor  
6. HLA typing will be performed at high resolution (allele level) for 
the HLA-A, -B, Cw, DRBl, and DQB1 loci.   
a. A minimum match of 5/10 is required.   
b. The donor and recipient must be identical, as determined 
by high resolution typing, in at least one allele of each of 
the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA­ 
DRB1, and DQB1.   
7. If capable of reproduction, patient must agree to use contraception 
or abstinence to prevent pregnancy during the first year of 
enrollment and treatment.  
8. Informed consent signed by patient (if ≥18 years old) or 
parent/guardian (if <18 years old). 
9. Fanconi anemia patients ONLY 
i. Patients must meet one of the following criteria to be eligible for 
this study: 
a. Any patient with Fanconi anemia and bone marrow failure 
involving 2 of the following 3 lineages: granulocyte count 
<0.5 x 109/L, platelet count <20 x 109/L, or hemoglobin <8 
g/dL.  
 
 

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b. Any patient with Fanconi anemia who requires red blood 
cell or platelet transfusions because of marrow failure  
c. Any patient with Fanconi anemia who has a life-threatening 
bone marrow failure involving a single hematopoietic 
lineage.  
 
 
 
 

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Patient Eligibility 
Exclusion Criteria 
Patients are excluded from enrollment if one or more of the following 
criteria are present: 
1. Serious organ dysfunction, defined as: 
a. Cardiac: Left ventricular ejection fraction <35% or left ventricular 
shortening fraction <26%. 
b. Hepatic: Bilirubin >2.5 mg/dL or any AST, ALT, or alkaline 
phosphatase >5 times the upper limit of normal (ULN) for age 
unless discussed and approved by gastroenterology.  
c. Renal: Serum creatinine > 2x ULN or a measured or calculated as 
Glomerular Filtration Rate < 40 ml/min/1.73m2.  
d. Pulmonary: DLCO (diffusion capacity) <50% predicted. If the 
patient is too young to perform pulmonary function tests (PFTs), 
then oxygen saturation <92% on room air. 
2. Pregnant or breast-feeding. 
3. Evidence of HIV infection or known HIV positive serology, antigen or 
PCR. 
4. Bovine product allergy. 
5. Patients with an active infectious disease requiring deferral of 
conditioning; as recommended by an Infectious Disease specialist. 
6. Patients with Fanconi anemia with AML/MDS.   
 
Donor Eligibility 
Inclusion Criteria 
Eligible donors include biological parents, siblings, children, or half-
siblings, etc. Matching will be determined by class I and class II DNA 
typing.  
1. Males or females 
2. Donor age > 18 and < 60 years. 
3. The donor should be sufficiently healthy not to be at increased 
risk from the mobilization procedure.   
4. The donor and patient must be genetically HLA-haploidentical, 
based on high-resolution typing at HLA-A, -B, -C, -DRB1, and –
DQB1. If more than one HLA-haploidentical donor is available and 
of equivalent health, then preference will be given to the least 
HLA-incompatible donor.  
5. Donors must meet the selection criteria as defined by the 
Foundation for the Accreditation of Cell Therapy (FACT) and will 
be screened per the FDA and American Association of Blood 
Banks (AABB) guidelines. 
 
 
 

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6. The donor must have been informed of the investigational nature 
of BPX 501 and have signed an informed consent form that they 
will undergo an additional pheresis procedure. 
7. Capable of undergoing a minimum of two separate leukapheresis 
procedures. The donor must have adequate veins for collection or 
agree to placement of a central venous catheter. If more than one 
HLA-haploidentical donor is available, preference will be given to a 
donor who does not require placement of an apheresis catheter. 
Donor Eligibility 
Exclusion Criteria 
 
1. Presence of a mismatch at an HLA-locus for which the patient is 
homozygous (e.g., patient is homozygous HLA- A01:01, and the 
donor is heterozygous at the same locus, such as HLA-A01:01, -
A02:01. 
2. Presence in the patient plasma of antibody to donor HLA, including 
donor HLA-DP (i.e., patient has a positive anti-donor HLA antibody). 
3. Evidence of active infection. 
4. Evidence of any infection capable of being transmitted by blood 
transfusion, including HIV I/II, HTLV I/II, Hepatitis A, Hepatitis B, 
Hepatitis C, West Nile Virus, or Chagas. Exceptions include EBV, 
CMV, and history of exposure to hepatitis B vaccine (defined by 
positive hepatitis B surface (HBs) antibody and negative HBV DNA). 
5. Medical or psychological factors which increase the risk for 
complications from leukapheresis or G-CSF treatment, including but 
not limited to autoimmune disease, sickle cell trait, coronary artery 
disease, schizophrenia.  
6. Pregnant (positive serum or urine HCG) or breast feeding at the 
time of G-CSF mobilization. 
 
 
 
 
 

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Objectives 
Primary Objectives 
1. To determine the safety (as defined by non-responsive Grade III-IV 
GVHD to rimiducid) of HCT with HLA-haploidentical CD34+ 
selected peripheral blood stem cell (PBSC) grafts and BPX 501 T 
cells followed by scheduled rimiducid infusion on Day 7.  
2. To determine the engraftment rate (defined as >50% donor CD3 
chimerism) on day 28 after HCT with HLA-haploidentical CD34+ 
selected PBSC grafts per dose cohort of BPX 501 T cells followed by 
rimiducid infusion on Day 7.  
Secondary Objectives:  
1. To determine the incidence and severity of acute Grade 2-4 GVHD 
after HCT with HLA-haploidentical CD34+ selected PBSC grafts and 
BPX 501 T cells followed by rimiducidinfusion on Day 7.  
2. To determine the incidence and severity of chronic GVHD after 
HCT with HLA-haploidentical CD34+ selected PBSC grafts and BPX 
501 T cells followed by rimiducid infusion on Day 7. 
3. To measure immune reconstitution after HCT with HLA-
haploidentical CD34+ selected PBSC grafts and BPX 501 T cells 
followed by rimiducid infusion on Day 7 
4. To determine the risk for severe infection during the first 180 days 
after HCT with HLA-haploidentical CD34+ selected PBSC grafts and 
BPX 501 T cells followed by rimiducid infusion on Day 7 
5. Measure disease–specific outcomes  
6. Incidence of graft rejection as measured by CD3 chimerism <5% at 
Day 28 
7. Time to resolution of acute GVHD after administration of rimiducid 
treatment infusion 
8. Time to resolution of chronic GVHD after administration of 
rimiducid treatment infusion 
9. Rates of > grade 3 toxicities according to the modified NIH CTCAE 
criteria version 4.0 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS  
Abbreviation  
 
 
Definition 
AE 
 
 
 
 
Adverse Event 
aGvHD  
 
 
Acute Graft Versus Host Disease 
BMT 
 
 
 
 
Bone Marrow Transplantation 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
cGvHD 
Chronic Graft Versus Host Disease 
CIHSCTR 
Center for International Blood and Marrow Transplant Research 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CRO 
Contract Research Organization 
CSP 
Cyclosporine 
CTL 
Cytotoxic T Lymphocytes 
CTN 
Clinical Trials Network 
CY 
Cyclophosphamide 
DLT 
Dose Limiting Toxicity 
EBV 
Epstein Barr Virus 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GvHD 
Graft Versus Host Disease 
HCT 
Hematopoietic Cell Transplantation 
HIPAA 
(US) Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HSCT 
Haploidentical Stem Cell Transplant 
HSV 
Herpes Simplex Virus 
HVG 
Host versus Graft Disease 
 
 

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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IV 
Intravenous 
LN2 
Liquid Nitrogen 
LPDs 
Lymphoproliferative Diseases 
LTFU 
Long Term Follow-up 
LVEF 
Left Ventricular Ejection  
MACS 
Magnetically Activated Cell Sorting 
MHC 
Major Histocompatibility Complex 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-Gated Acquisition Scan 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse 
Events 
NK 
Natural Killer 
NR 
No Response 
PBMC 
Peripheral Blood Mononuclear Cell 
PBSC 
Peripheral Blood Stem Cell 
PD 
Progressive Disease  
PR 
Partial Response 
RCR 
Replication Competent Retrovirus 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
TBI 
Total Body Irradiation 
TCR 
T-Cell Receptor 
TNC 
Total Nuclear Cell 
TRM 
Transplant-Related Mortality 
 
 
 
 

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TABLE OF CONTENTS 
 
1 
BACKGROUND .............................................................................................................. 17 
1.1            INHERITED HEMATOLOGIC DISORDERS (NON-MALIGNANT DISEASE) .............................. 17 
1.2            HAPLOIDENTICAL TRANSPLANTATION FOR NON MALIGNANT DISEASE .......................... 17 
1.3 
REDUCED INTENSITY CONDITIONING FOR HLA-HAPLOIDENTICAL HCT ............................ 18 
1.4 
BPX 501:  T CELLS MODIFIED WITH THE ICASP SAFETY SWITCH ....................................... 19 
1.4.1 
iCasp9 Safety Switch ..................................................................................................... 19 
1.4.2 
Caspallo TRIAL .............................................................................................................. 20 
1.5 
RATIONALE FOR BPX 501 T CELL ADDBACK TO HLA-HAPLOIDENTICAL CD34+ SELECTED      
PBSC HCT ..................................................................................................................... 20 
1.6 
RATIONALE FOR PLANNED AP1903 INFUSION ON DAY 7 AFTER HLA-HAPLOIDENTICAL              
CD34+ SELECTED PBSC HCT WITH BPX 501 T CELL ADDBACK ........................................... 21 
2.0 
STUDY DESIGN ............................................................................................................. 22 
2.1 
PLANNED ACCRUAL ...................................................................................................... 22 
2.2 
NUMBER OF CENTERS ................................................................................................... 22 
2.3 
ESTIMATED STUDY DURATION ...................................................................................... 22 
2.4 
CLINICAL SCHEMA ........................................................................................................ 22 
2.5 
STUDY OBJECTIVES ....................................................................................................... 23 
2.5.1 
Primary Objectives ....................................................................................................... 23 
2.5.2 
Secondary Objectives ................................................................................................... 23 
2.6 
PATIENT INCLUSION CRITERIA ....................................................................................... 24 
2.7 
PATIENT EXCLUSION CRITERIA ...................................................................................... 26 
2.8 
DONOR SELECTION ....................................................................................................... 26 
2.8.1 
Donor Inclusion Criteria ................................................................................................ 26 
2.8.2 
Donor Exclusion Criteria ............................................................................................... 27 
3 
CLINICAL TRIAL SCHEDULE ............................................................................................ 27 
3.1 
INFORMED CONSENT OF PATIENT AND DONOR ............................................................ 27 
3.2 
GENERATION OF BPX 501 ICASP9 T CELLS ...................................................................... 27 
3.2.1 
Leukapheresis of Donor ................................................................................................ 27 
3.2.2 
BPX 501 Manufacture ................................................................................................... 28 
3.3 
HAPLOIDENTICAL RELATED T DEPLETED HCT PER INSTITUTIONAL STANDARDS ............... 29 
 
 

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3.3.1 
Mobilization of Donor .................................................................................................. 29 
3.3.2 
Stem Cell Apheresis ...................................................................................................... 29 
3.3.3 
T Cell Depletion using the Miltenyi CD34+ CliniMACs ..................................................... 29 
3.3.4 
Conditioning Prior to HCT ............................................................................................. 29 
3.3.5 
Infusion of the HLA-Haploidentical CD34+ Selected PBSC graft ....................................... 32 
3.3.6 
BPX-501 Infusion .......................................................................................................... 32 
3.4 
POST-HCT GVHD PROPHYLAXIS / IMMUNESUPPRESSION .............................................. 33 
3.4.1. 
Cyclosporine (CSP): ....................................................................................................... 33 
3.4.2 
Mycophenolate mofetil (MMF): .................................................................................... 35 
3.4.3 
GVHD prophylaxis contingency plan for patients who receive a CD3 T cell dose >2 x 
105/kg ......................................................................................................................... 36 
3.5 
SUPPORTIVE CARE ........................................................................................................ 36 
3.6 
SCHEDULED RIMIDUCID (AP1903) INFUSION ................................................................. 37 
3.7 
GVHD TREATMENT ....................................................................................................... 37 
3.7.1        Rimiducid (AP1903) Treatment of acute GVHD ............................................................... 38 
3.7.2 
Rimiducid (AP1903) Treatment of chronic GVHD ........................................................... 38 
3.7.3 
OTHER INVESTIGATIONAL AGENTS ................................................................................ 39 
3.7.4 
GENE THERAPY MONITORING PLAN .............................................................................. 39 
4.              PRODUCT PACKAGING, LABELING, STORAGE AND SHIPPING .......................................... 39 
4.1 
BPX-501 PRODUCT PACKAGING, LABELING AND STORAGE ............................................. 39 
4.2 
RIMIDUCID (AP1903) DIMERIZER DRUG PACKAGING, LABELING AND STORAGE ............. 40 
5 
STUDY TREATMENT ...................................................................................................... 40 
5.1 
INFORMED CONSENT .................................................................................................... 41 
5.2 
VISIT WINDOWS ........................................................................................................... 41 
5.3 
SCREENING................................................................................................................... 41 
5.4 
ENROLLMENT ............................................................................................................... 43 
5.5 
DONOR CONSENT AND STEM CELL COLLECTION ............................................................ 43 
5.6 
PATIENT CONDITIONING ............................................................................................... 44 
5.7 
DAY 0 – T DEPLETED HCT AND BPX-501 INFUSION ......................................................... 44 
5.8 
DAYS 0 – DAY 28 ........................................................................................................... 45 
5.8.1 
Day 0 to Day 28 ............................................................................................................ 45 
 
 

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5.8.2 
Day 7 ........................................................................................................................... 46 
5.9 
WEEKS 5 TO 12 ............................................................................................................. 46 
5.10 
MONTHS 6, 9, 12, 18 AND 24 ........................................................................................ 47 
5.11 
MONTHS 30, 36, 42, 48, 54, AND 60 .............................................................................. 49 
5.12 
YEARS 6 THROUGH 15................................................................................................... 49 
5.13 
MONITORING FOR DISEASE SPECIFIC OUTCOMES .......................................................... 49 
5.14 
ADDITIONAL MONITORING FOR RIMIDUCID (AP1903) ................................................... 49 
5.15 
DISCONTINUATION CRITERIA ........................................................................................ 50 
6 
TRIAL DESIGN AND STOPPING RULES ............................................................................ 51 
6.1 
ESCALATION/DE-ESCALATION TRIAL DESIGN ................................................................. 51 
6.2 
STOPPING RULES .......................................................................................................... 53 
6.3 
STATISTICS ................................................................................................................... 54 
6.3.1 
Analysis of Graft Failure ................................................................................................ 54 
6.3.2 
Analysis of Acute and Chronic GvHD ............................................................................. 54 
6.3.3 
Transplant-Related Mortality ........................................................................................ 55 
6.3.4 
Immune Reconstitution ................................................................................................ 55 
6.4 
DATA QUALITY ASSURANCE .......................................................................................... 55 
7 
ASSESSMENT OF SAFETY ............................................................................................... 56 
7.1 
SAFETY PARAMETERS AND DEFINITIONS ....................................................................... 56 
7.2 
ADVERSE EVENT ........................................................................................................... 56 
7.3            SERIOUS ADVERSE EVENT ............................................................................................. 57 
7.3.1 
Protocol-Defined Events of Special Interest/Non-Serious Expedited Adverse Events ...... 58 
7.4 
ADVERSE EVENT REPORTING PERIOD ............................................................................ 58 
7.4.1 
GVHD Adverse Event Reporting .................................................................................... 59 
7.5 
PROCEDURES FOR ELICITING AND RECORDING ADVERSE EVENTS .................................. 60 
7.6 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS ....................... 60 
7.6.1 
Reporting Requirements for Fatal/Life-Threatening SAEs Related to Investigational 
Product ........................................................................................................................ 60 
7.6.2 
Reporting Requirements for All SAEs ............................................................................. 61 
7.6.3 
Type and Duration of Follow-Up of Patients after Adverse Events .................................. 61 
7.6.4 
Post-Study Adverse Events ........................................................................................... 61 
 
 

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8 
REGULATORY AND ETHICAL OBLIGATIONS .................................................................... 62 
8.1. 
INVESTIGATOR REQUIREMENTS AND STUDY INITIATION ............................................... 62 
8.2  
STUDY COMPLETION .................................................................................................... 63 
8.3 
INFORMED CONSENT FORM ......................................................................................... 63 
8.4 
COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE .. 64 
8.5 
STUDY MONITORING REQUIREMENTS .......................................................................... 65 
8.5.1 
Case Report Forms ....................................................................................................... 65 
8.5.2 
Source Data Documentation ......................................................................................... 65 
8.5.3 
Use of Computerized Systems ....................................................................................... 65 
8.5.4 
Study Medication Accountability .................................................................................. 66 
8.6 
DISCLOSURE OF DATA ................................................................................................... 66 
8.7 
RETENTION OF RECORDS .............................................................................................. 66 
9                REFERENCES ................................................................................................................. 67 
10 
APPENDICES ................................................................................................................. 68 
APPENDIX A: SCHEDULE OF ASSESSMENTS ................................................................................... 68 
APPENDIX B: DISEASE OUTCOME MEASURES TABLE ..................................................................... 71 
APPENDIX C: ACUTE GVHD GRADING SCALE ................................................................................. 73 
APPENDIX D: CHRONIC GVHD GRADING SCALE ............................................................................. 74 
APPENDIX E: GVHD RESPONSE CRITERIA ...................................................................................... 76 
APPENDIX F:  SAFETY REPORTING CRITERIA .................................................................................. 77 
APPENDIX G:  CHIMERISM ANALYSIS ............................................................................................ 91 
APPENDIX H: GUIDELINES FOR MONITORING & MANAGEMENT OF NEUROTOXICITY .................... 91 
APPENDIX I: KARNOFSKY/LANSKY PERFORMANCE SCALE ............................................................. 97 
  
 
 
 
 
 
 

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1 
BACKGROUND 
1.1   INHERITED HEMATOLOGIC DISORDERS (NON-MALIGNANT DISEASE) 
There are 5 major “groups” of non-malignant inherited diseases: 1) Primary immune deficiency 
disorders, 2) Inherited marrow failure disorders, 3) Metabolic disorders, 4) Hemoglobinopathies, 
and 5) Hemophagocytic disorders. In general, patients with non-malignant inherited diseases are 
born with an underlying genetic defect that leads to a deficiency in production of normal cells or 
cellular proteins.  Hematopoietic cell transplantation (HCT) is effective in the treatment of a 
variety of non-malignant disorders, by restoring normal cells or cellular proteins to the deficient 
host.  For example, HCT corrects the underlying T cell and platelet defect in patients with Wiskott 
Aldrich syndrome, a primary immune deficiency disorder.  Transplantation has been used to 
provide normal RBCs to patients with hemoglobinopathies such as patients with sickle cell 
disease. Patients with Hurler’s syndrome, also known as mucopolysaccharidosis type I (MPS I), 
lack or have insufficient levels of the enzyme α-L-iduronidase which is corrected by HCT.   
1.2   HAPLOIDENTICAL TRANSPLANTATION FOR NON MALIGNANT DISEASE 
As discussed above, allogeneic HCT is a potentially curative therapy for a variety of life-
threatening nonmalignant diseases. Around half of patients who could benefit from HCT do not 
have an HLA-identical sibling or an HLA-matched unrelated donor.  This proportion is even higher 
among patients belonging to racial or ethnic minorities, since unrelated donor registries contain 
fewer individuals belonging to these minorities.  For these patients, it also may be difficult to find 
umbilical cord blood units of suitable size and HLA-match, and the use of two cord blood units 
together confers a high risk for graft-vs-host disease (GVHD), an undesirable complication for 
patients with nonmalignant diseases. In addition, if graft rejection were to occur, it is not possible 
to go back to the same cord blood donor.  Development of an alternative stem cell source for 
patients lacking an HLA-identical sibling or unrelated donor could expand the availability of this 
procedure.   
One potentially attractive alternative source of stem cells is a HLA-haploidentical relative. There 
are at least two advantages of HLA-haploidentical relatives as compared to unrelated donors.  
First, since all biological parents and children and half of siblings share one HLA haplotype, there 
is a high likelihood of identifying an eligible donor.  Second, donors can be identified promptly, 
whereas the time from initiation of search to identification of an unrelated donor takes a median 
of 49 days.   
The primary barrier to HLA-haploidentical HCT is the occurrence of life-threatening GVHD, which 
is unavoidable unless the graft is depleted of T cells, either through T cell depletion or CD34+ cell 
selection. The Perugia group has pioneered the use of the CliniMACS device to T cell deplete G-
CSF mobilized HLA-haploidentical allografts, resulting in a 4-5 log CD3+ depletion and a median 
CD3+ dose of 2x104/kg.  Their studies show that transplantation of CD34+ selected HLA-
haploidentical peripheral blood stem cell (PBSC) grafts without pharmacological GVHD 
prophylaxis is associated with an incidence of acute GVHD of less than 10%.  Similar results are 
reported by Handgretinger et al in pediatric patients. Immunophenotyping studies find that NK 
 
 

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cells are the first lymphoid subset to emerge, usually within 2 to 3 weeks after HCT, followed by B 
cells (3-6 months) and T cells (3-12 months).  CD8+ T cells typically reconstitute the T cell 
compartment first, and most recipients of CD34+ selected HLA-haploidentical PBSC grafts 
have a deficiency in CD4+ cells, with an inverted CD4+ to CD8+ ratio, for up to 2 years.  The 
delay in reconstitution of CD4+ cells and impairment in TCR diversity likely are the reasons that 
recipients of T cell depleted HCT are at risk for opportunistic infections for months to years 
after HCT.  Specifically, reactivation of viruses such as CMV and adenovirus, and EBV-associated 
lymphoproliferative disorders (EBV-LPD), are observed to a greater degree after T cell depleted 
HCT.  
In addition to delayed T cell reconstitution, T-cell depletion is associated with a heightened risk of 
graft rejection. The Perugia group has overcome this problem by delivery of highly 
immunoablative conditioning including high-dose total body irradiation (TBI), thiotepa, and 
fludarabine and high doses of CD34+ cells and immunosuppressive agents  [Aversa 2011, 2008].  
However, high-dose conditioning is not inconsequential, causing damage to non-hematopoietic 
organs, particularly the liver and lungs, and high risk for infection. These risks may be 
unacceptable for patients with non-malignant diseases, since myeloablative conditioning is not 
required for cure of the disease. In addition, many patients with nonmalignant diseases are not 
eligible for myeloablative conditioning regimens due to significant underlying infections or other 
comorbidities.   
1.3 
REDUCED INTENSITY CONDITIONING FOR HLA-HAPLOIDENTICAL HCT 
A central concept that emerged from canine models of nonmyeloablative conditioning was that 
allogeneic cells induced bidirectional activation and proliferation of host versus graft (HVG) and 
graft versus host (GVH) alloreactive-T cells. Storb and colleagues showed that intensive post-
grafting immune suppression with MMF/CSP controlled both donor and recipient alloreactive T 
cells [Storb 1997]. This fundamental observation allowed the intensity of the conditioning 
regimen to be reduced, resulting in development of a nonmyeloablative regimen consisting of 
fludarabine (FLU; 90 mg/m2) and 2 Gy TBI followed by HLA-matched related or unrelated grafts 
[Niederwieser 2003, Maris 2003]. However, post-HCT MMF/CSP was not sufficient to prevent 
rejection or GVHD after HCT of T-replete HLA-mismatched grafts. The Hopkins group established 
that intensification of post-HCT immune suppression with CY after nonmyeloablative HLA-
haploidentical HCT could overcome graft rejection and prevent severe GVHD, presumably by 
elimination of activated donor and recipient T cells. A key finding was that activated T-cells were 
more susceptible to CY compared to resting T-cells, therefore this approach differed from 
traditional in vivo T cell depletion (e.g., ATG or Campath) and potentially spared non-alloreactive 
T cells that could reconstitute immunity to viral or tumor antigens. Pilot studies conducted jointly 
at the FHCRC and Johns Hopkins demonstrated that this approach could establish stable HLA-
haploidentical grafts in adult patients with hematologic malignancies, with low TRM and low 
incidence of GVHD [Kasamon 2010]. However, the rate of relapse was higher than desired . Since 
relapse is not a factor determining outcome of patients with nonmalignant diseases, researchers 
at the FHCRC studied this approach in 4 patients to date (FHCRC Protocol 2032). Patients were 
conditioned with low-dose CY, fludarabine, and 2 Gy TBI, and post grafting immunosuppression 
 
 

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consisted of CY [50 mg/kg, day +3 (n=3) and +4 (n=1)], MMF and tacrolimus beginning on day +4 
(n=3) or +5 (n=1). All 4 patients engrafted, 3 survive >5.8, 4.9 and 3.3 years after HCT and the 
d]Day 100 TRM is 0% to date. However, among the 3 patients given a single dose of post-HCT CY, 
grade II-IV GVHD and chronic extensive GVHD developed in all, and one died of GVHD-associated 
infections. The first patient given 2 doses of post-HCT CY developed delayed acute grade III and 
chronic extensive GVHD (Burroughs, unpublished). Researchers at the FHCRC have studied a 
similar approach for patients with Fanconi anemia, who have a genetic sensitivity to the 
alkylating agent CY. In this case, no pre-HCT CY was given and post-HCT CY was limited to 25 
mg/kg on days +3 and +4. Of 3 patients treated thus far, engraftment was 100%, however severe 
acute or chronic GVHD developed in 2 (Thakar and Kiem, personal communication to L. 
Burroughs).  
Together these studies show feasibility of establishing donor chimerism in patients given T-
replete HLA-haploidentical marrow grafts using nonmyeloablative conditioning; however the 
incidence of both acute and chronic GVHD appears to be unacceptably high when post-HCT CY is 
used as a strategy to eliminate “alloreactive” donor T cells.  
1.4 
BPX 501:  T CELLS MODIFIED WITH THE ICASP SAFETY SWITCH 
1.4.1 iCasp9 Safety Switch  
Unmodified donor T cell infusion is potentially an effective strategy for conferring anti-viral and 
anti-tumor immunity following allogeneic HCT. However, the administration of greater than 
105/kg unmodified donor T cells to recipients of haploidentical HCT has been associated with an 
increased incidence of GVHD. Brenner et al demonstrated that administration of up to 106/kg of 
CD25+ allodepleted donor T cells after haploidentical HCT 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 group then evaluated the use of higher numbers of 
allodepleted T cells containing an inducible Caspase 9 safety switch in order to treat the potential 
increase in GVHD. 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 - AP1903. Administration of AP1903 dimerizes and activates caspase 9 downstream, leading 
to apoptosis potentially within minutes to hours [Tey 2007, DiStasi 2011]. 
The vector, SFG.iCaspase9.2A.DeltaCD19, consists of inducible caspase 9 (iCasp9) linked, via a 2A-
like sequence, to truncated human CD19 (DeltaCD19). The iCasp 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 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 
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1.4.2 Caspallo TRIAL 
In a recently published clinical report [DiStasi et al 2011], allodepleted haploidentical T cells co-
expressing iCasp9 and a surface-selectable marker gene (Delta CD19) were demonstrated to 
persist and expand in vivo, and repopulate the patients with virus specific T cells. Two patients 
infused with 106 T cells/kg and a third receiving 3x106 T cells/Kg received a single dose (0.4mg/Kg) 
of AP1903 upon developing Grade I/II GVHD. In all three patients, there was a greater than 90% 
reduction in PCR signal 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. Moreover, acute 
GVHD of the skin in all three patients, and of the liver disease in one patient, completely resolved 
after 24 hr. The residual iCasp9 gene modified T cell population then expanded over the next 4-14 
days and continued to help repopulate the patients’ immune system.  The transduced cells were 
further shown to contain virus and fungal-peptide specific precursor cells but which had not 
caused further GVHD. When examined ex vivo, these non-alloreactive iCasp9 T cells remained 
susceptible to apoptosis following exposure to the dimerizer AP1903. 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. Where cells are non-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 dose exposure, allowing subsequent 
re-expansion. This hypothesis was supported by the clinical data showing activation-dependent 
induction of iCasp9 in T lymphocytes and enhanced susceptibility to dimerizer drug in activated 
versus resting T cells. 
1.5 
RATIONALE FOR BPX 501 T CELL ADDBACK TO HLA-HAPLOIDENTICAL CD34+ SELECTED 
PBSC HCT 
As discussed previously, current strategies for establishing T-cell depleted HLA-haploidentical 
grafts rely on high-dose conditioning, which is associated with toxicity and delayed immune 
reconstitution. The major hurdle to developing a successful reduced-intensity regimen for HLA-
haploidentical grafts is overcoming the bidirectional T-cell mediated alloreactions, which form 
primary and opposing barriers of host versus graft (HVG) and GVHD. HVG reactions are 
significantly greater in the setting of HLA-mismatching, therefore a counterbalancing, donor T-cell 
mediated, graft-versus-host (GVH) reaction must be maintained in order to reduce conditioning 
intensity. Recent studies of T-replete HLA-haploidentical HCT using the nonmyeloablative 
conditioning regimen of FLU, low dose CY and 2 GY TBI followed by post-HCT CY as a means to 
deplete T cells post-HCT have shown successful engraftment without significant transplant 
related toxicities and mortality.  In addition, our studies in patients with malignant and 
nonmalignant diseases have shown: 1) alloreactive donor T cells are required for 3-6 days 
following HCT in order to establish engraftment after nonmyeloablative conditioning, and 2) 
purging of alloreactive T cells in vivo reduces the risk for life-threatening GVHD and spares non-
alloreactive T cell immunity.  However, the incidences of acute and chronic GVHD remain 
unacceptably high for patients with nonmalignant diseases who do not require a GVL effect.  
The recent report by Brenner et al [DiStasi 2011] supports the following concepts:  
 
 

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1) Donor T cells can be expanded ex vivo and transduced with a safety switch, iCasp9.  
2) Gene-modified alloreactive T cells express inducible caspase 9, rendering them 
susceptible to the dimerizing agent AP1903.  
3) Infusion of iCasp9 modified T cells does not appear to be associated with severe 
adverse reactions.  
4) Subsequent infusion of AP1903 reverses clinical signs of acute GVHD, suggesting it 
destroys alloreactive donor T cells.  
5) Inactive (i.e, non-alloreactive) donor T cells, are generally sparing from the action of 
AP1903.   
These observations were acquired in a clinical trial using iCasp9 gene-modified donor T cells as 
donor lymphocyte infusion (DLI). These findings suggest the opportunity for using iCasp9 
modified T cells to facilitate engraftment of HLA-haploidentical CD34+ selected grafts, with a 
strategy of pre-emptive “suicide” of alloreactive T cells so as to prevent GVHD, yet allow eventual 
reconstitution of non-alloreactive T cell immunity.  
1.6 
RATIONALE FOR PLANNED AP1903 INFUSION ON DAY 7 AFTER HLA-HAPLOIDENTICAL 
CD34+ SELECTED PBSC HCT WITH BPX 501 T CELL ADDBACK  
The purpose of this clinical study is to determine whether the CaspaCIDe infusion can facilitate 
engraftment and enhance immune reconstitution of HLA-haploidentical CD34+ selected PBSC 
grafts following nonmyeloablative conditioning with Fludarabine (FLU), Cyclophosphamide (CY), 
and 2 Gy TBI. The current study design is based on results of our previous studies of post-HCT CY. 
The backbone conditioning regimen of FLU/CY/TBI is the same as used in studies of post-HCT CY. 
Essentially, instead of using CY to preemptively deplete alloreactive T cells, we will trigger  
apoptosis in the alloreactive T cells by infusion of AP1903. As noted above, the iCasp9 gene is 
preferentially expressed in activated cells compared to resting T cells, therefore apoptosis will be 
triggered in the alloreactive cells, sparing viral specific T cells.  
The dose of BPX 501 (1.0 x 107 CD3+ cells/kg) has been chosen to simulate the “T-replete graft” 
necessary to assure engraftment and similar to that given in studies of post-HCT CY.  Since GVHD 
is not desired, we propose a strategy of pre-emptive elimination of alloreactive T cells. In this 
strategy, the safety switch will be activated on day +7 after HCT so as to eliminate activated, 
presumably alloreactive T cells, but not other T cells important for immune reconstitution. BPX 
501 addback will allow us to test whether graft rejection can be overcome in the 
nonmyeloablative HLA-haploidentical setting through the use of higher T cell doses (genetically 
modified T cells) with the ability to eliminate GVHD through activation of the safety switch with 
the dimerizer, AP1903.  This study is important since it may improve the safety of HLA-
haploidentical HCT through the abrogation of GVHD a major and long-standing complication of 
allogeneic HCT. 
 
 

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2.0 STUDY DESIGN 
This is a single arm study evaluating the safety and efficacy of a BPX 501 infusion (T cells 
genetically modified with the iCasp9 safety switch) followed by rimiducid infusion on Day 7 after 
partially mismatched, related, T cell-depleted HCT in patients with non-malignant diseases.  The 
purpose of this clinical trial is to determine whether the BPX 501 T cell infusion can facilitate 
engraftment and the infusion of rimiducid can prevent the occurrence of GVHD.  
2.1 
PLANNED ACCRUAL 
20 patients 
 
 
 
2.2 
NUMBER OF CENTERS 
 
 
 
Up to 10 centers 
2.3 
ESTIMATED STUDY DURATION            
Accrual targeted 24 months; main study conduct 2 years post HCT (and a total of 15 years 
gene therapy long-term follow-up) 
2.4 
CLINICAL SCHEMA 
Figure 1:  Clinical Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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2.5 
STUDY OBJECTIVES 
2.5.1 Primary Objectives 
 
1. To determine the safety (as defined by non-responsive Grade III-IV GVHD to rimiducid) 
of HCT with HLA-haploidentical CD34+ selected peripheral blood stem cell (PBSC) 
grafts and BPX 501 T cells followed by scheduled rimiducid infusion on Day 7. 
2. To determine the engraftment rate (defined as >50% donor CD3 chimerism) on day 28 
after HCT with HLA-haploidentical CD34+ selected PBSC grafts per dose cohort of BPX 
501 T cells followed by rimiducid infusion on Day 7.  
  
2.5.2 Secondary Objectives 
1. To determine the incidence and severity of acute Grade 2-4 GVHD after HCT with HLA-
haploidentical CD34+ selected PBSC grafts and BPX 501 T cells followed by rimiducid 
infusion on Day 7.  
2. To determine the incidence and severity of chronic GVHD after HCT with HLA-
haploidentical CD34+ selected PBSC grafts and BPX 501 T cells followed by rimiducid 
infusion on Day 7. 
3. To measure immune reconstitution after HCT with HLA-haploidentical CD34+ selected 
PBSC grafts and BPX 501 T cells followed by rimiducid infusion on Day 7 
4. To determine the risk for severe infection during the first 200 days after HCT with HLA-
haploidentical CD34+ selected PBSC grafts and BPX 501 T cells followed by rimiducid 
infusion on Day 7 
5. Measure disease–specific outcomes  
6. Incidence of graft rejection as measured by CD3 donor chimerism <5% at Day 28 
7. Time to resolution of acute GVHD after administration of rimiducid treatment infusion 
8. Time to resolution of chronic GVHD after administration of rimiducid treatment 
infusion 
9. Rates of > grade 3 toxicities according to the modified NIH CTCAE criteria version 4.0  
 
 
 
 

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2.6 
PATIENT INCLUSION CRITERIA  
1. Patient must meet eligibility criteria for allogeneic HCT 
2. Lack of suitable conventional donor (10/10 allele matched related or unrelated 
donor) or presence of rapidly progressive disease not permitting time to identify an 
unrelated donor  
3. Males or females 
4. Age < 55 years old and >4 months. 
5. Diagnosis of a nonmalignant disorder considered treatable by HCT.  
i. Primary Immune Deficiency Disorders 
a) 
Severe Combined Immune Deficiency (SCID) 
b) 
Combined Immune Deficiency (CID) 
c) 
Congenital T-cell Defect/Deficiency 
d) 
Common Variable Immune Deficiency (CVID) 
e) 
Chronic Granulomatous Disease 
f) 
IPEX (Immune deficiency, polyendocrinopathy, enteropathy, X-linked) or 
IPEX-like 
g) 
Wiskott-Aldrich Syndrome 
h) 
CD40 Ligand Deficiency 
i) 
Leukocyte Adhesion Deficiency 
j) 
DOCK 8 Deficiency 
k) 
IL-10 Deficiency/IL-10 Receptor Deficiency 
l) 
GATA 2 deficiency 
m) 
X-linked lymphoproliferative disease (XLP) 
n) 
Cartilage Hair Hypoplasia 
o) 
Other primary immune deficiency deemed eligible for HCT by the Non-
Malignant Board 
ii. Hemophagocytic Lymphohistiocytosis (HLH) or other Hemophagocytic disorders 
iii.  Inherited Marrow Failure Disorders 
a) 
Shwachman Diamond Syndrome 
b) 
Diamond Blackfan Anemia 
c) 
Dyskeratosis Congenita 
d) 
Fanconi Anemia 
 
 

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e) 
Congenital Neutropenia 
f) 
Other inherited marrow failure disorder deemed eligible for HCT by the Non-
Malignant Board  
iv. Hemoglobinopathies 
a) 
Sickle Cell Disease 
b) 
Thalassemia 
c) 
Other hemoglobinopathies deemed eligible for HCT by the Non-Malignant 
Board 
v. Metabolic Disorders 
a) 
Mucopolysaccharidosis 
b) 
Sphingolipidoses 
c) 
Other metabolic diseases deemed eligible for HCT by the Non-Malignant 
Board  
6. Lack of suitable conventional donor (i.e. 10/10 related or unrelated donor) or the 
presence of advanced disease not permitting time to identify an unrelated donor  
7. HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, 
DRBl, and DQB1 loci.   
i. 
A minimum match of 5/10 is required.   
ii. 
The donor and recipient must be identical, as determined by high 
resolution typing, in at least one allele of each of the following genetic 
loci: HLA-A, HLA-B, HLA-Cw, HLA­ DRB1, and DQB1.   
8. If capable of reproduction, patient must agree to use contraception or abstinence to 
prevent pregnancy during the first year of enrollment and treatment.  
9. Informed consent signed by patient (if ≥18 years old) or parent/guardian (if <18 years 
old). 
10. Fanconi anemia patients ONLY 
i) Patients must meet one of the following criteria to be eligible for this study: 
a) 
Any patient with Fanconi anemia and bone marrow failure involving 2 of 
the following 3 lineages: granulocyte count <0.5 x 109/L, platelet count <20 
x 109/L, or hemoglobin <8 g/dL.  
b) 
Any patient with Fanconi anemia who requires red blood cell or platelet 
transfusions because of marrow failure  
c) 
Any patient with Fanconi anemia who has a life-threatening bone marrow 
failure involving a single hematopoietic lineage.  
 
 
 
 

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2.7 
PATIENT EXCLUSION CRITERIA  
Patients are excluded from enrollment if one or more of the following criteria are present: 
1. Serious organ dysfunction, defined as: 
a) 
Cardiac: Left ventricular ejection fraction <35% or left ventricular 
shortening fraction <26%. 
b) 
Hepatic: Bilirubin >2.5 mg/dL or any AST, ALT, or alkaline phosphatase >5 
times the upper limit of normal (ULN) for age unless discussed and 
approved by gastroenterology.  
c) 
Renal: Serum creatinine > 2x ULN or a measured or calculated Glomerular 
Filtration Rate < 40 ml/min/1.73m2.  
d) 
Pulmonary: DLCO (diffusion capacity) <50% predicted. If too young to 
perform pulmonary function tests (PFTs), then oxygen saturation <92% on 
room air. 
2.  Pregnant or breast-feeding. 
3.  Evidence of HIV infection or known HIV positive serology, antigen or PCR. 
4.  Bovine product allergy. 
5.  Patients with an active infectious disease requiring deferral of conditioning; as 
recommended by an Infectious Disease specialist. 
6.  Patients with Fanconi anemia with AML/MDS.   
 
2.8 
DONOR SELECTION 
2.8.1 Donor Inclusion Criteria  
Eligible donors include biological parents, siblings, children, or half-siblings, etc. Matching will 
be determined by class I and class II DNA typing.  
1. 
Males or females 
2. 
Donor age > 18 and < 60 years.  
3. 
The donor should be sufficiently healthy not to be at increased risk from the 
mobilization procedure.   
4. The donor and patient must be at least 5/10 genetically HLA-haploidentical, based on high-
resolution typing at HLA-A, -B, -C, -DRB1, and –DQB1. If more than one HLA-haploidentical 
donor is available and of equivalent health, then preference will be given to the least HLA-
incompatible donor.  
5. 
Donors must meet the selection criteria as defined by the Foundation for the 
Accreditation of Cell Therapy (FACT) and will be screened per the FDA and American 
Association of Blood Banks (AABB) guidelines. 
 
 

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6. 
The donor must have been informed of the investigational nature of BPX 501 and have 
signed an informed consent form that they will undergo an additional pheresis 
procedure. 
7. 
Capable of undergoing a minimum of two separate leukapheresis procedures. The 
donor must have adequate veins for collection or agree to placement of a central 
venous catheter. If more than one HLA-haploidentical donor is available, preference 
will be given to a donor who does not require placement of an apheresis catheter. 
2.8.2 Donor Exclusion Criteria  
1. 
Presence of a mismatch at a HLA-locus for which the patient is homozygous (e.g., 
patient is homozygous HLA- A01:01, and the donor is heterozygous at the same locus, 
such as HLA-A01:01, -A02:01. 
2. 
Presence in the patient plasma of antibody to donor HLA, including donor HLA-DP 
(i.e., patient has a positive anti-donor HLA antibody). 
3. 
Evidence of active infection. 
4. 
Evidence of any infection capable of being transmitted by blood transfusion, including 
HIV I/II, HTLV I/II, Hepatitis A, Hepatitis B, Hepatitis C, West Nile Virus, or Chagas. 
Exceptions include EBV, CMV, and history of exposure to hepatitis B vaccine (defined 
by positive HBs antibody and negative HBV DNA). 
5. 
Medical or psychological factors which increase the risk for complications from 
leukapheresis or G-CSF treatment, including but not limited to autoimmune disease, 
coronary artery disease, schizophrenia.  
6. 
Pregnancy (positive serum or urine HCG) or breast feeding at the time of G-CSF 
mobilization. 
3 
CLINICAL TRIAL SCHEDULE 
3.1 INFORMED CONSENT OF PATIENT AND DONOR 
Patients will be referred for consideration of an HLA-haploidentical PBSC HCT. Both patient and 
donor will be completely evaluated. The protocol will be discussed thoroughly with patient, 
donor and family, and all known risks to the patient and donor will be described. The procedure 
and alternative forms of therapy will be presented as objectively as possible and the risks and 
hazards of the procedure explained to the patient or, in the case of minors, to the patient's 
responsible family members. Consent will be obtained using forms approved by the institution’s 
Institutional Review Board.  
3.2 
GENERATION OF BPX 501 ICASP9 T CELLS 
3.2.1 Leukapheresis of Donor  
A standard stem cell leukapheresis is performed on the donor prior to starting G-CSF mobilization 
for stem cell collection.    The leukapheresis collection will either be shipped overnight in E48 
validated refrigerated shippers with refrigerated gel packs or mononuclear cells will be isolated 
from the PBMC collection per institutional SOPs and cryopreserved in DNase and a standardized 
formulation (BioLife Solutions CryoStor CS10) in 3-4 aliquots, depending on yield.  Aliquots will be 
 
 

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manufacturing, an aliquot is transferred to the manufacturing cleanroom and rapidly 
thawed.  The cells are washed and treated with CD3+/CD28+ antibodies and placed into culture 
media so that the T-cells will proliferate until achieving a target cell number for transduction.  The 
expanded T cells are transduced with BPZ-1001 retroviral construct.  Post-transduction, the cells 
are selected for CD19+ surface marker and the enriched T cell population is allowed to proliferate 
further in order to reach the target dose of CD3+/CD19+ cells.  The cells are formulated with the 
cryopreservation media (CryoStor CS10) and cryopreserved.  The final BPX-501 product is stored 
cryopreserved in the LN2 vapor phase until release testing is complete. The BPX-501 product and 
potentially any remaining PBMC aliquots will be shipped in the LN2 vapor phase in validated 
cryoshippers (Cryoport). 
3.3 
HAPLOIDENTICAL RELATED T DEPLETED HCT PER INSTITUTIONAL STANDARDS 
3.3.1 Mobilization of Donor 
Following screening, and leukapheresis, the donor will receive mobilization therapy with 
subcutaneous G-CSF administration per institutional protocol for mobilization of peripheral blood 
stem cells.  The mobilization phase starts on the first day of administration of G-CSF and 
continues until the final day of the stem cell apheresis collections. 
3.3.2 Stem Cell Apheresis 
Stem cell apheresis will be performed on a continuous flow cell separator according to 
institutional standards.  The stem cell apheresis typically commences on the morning of the fifth 
day of G-CSF treatment and a second collection may follow on the sixth day.  The volume of 
blood processed per stem cell apheresis session should be approximately three to four times 
total blood volume as tolerated by the donor.  A unique identification and labeling system shall 
be used to track the stem cell apheresis product from collection to infusion according to AABB 
and FACT guidelines. 
3.3.3 T Cell Depletion using the Miltenyi CD34+ CliniMACs 
CD34+ cell selection will be performed according to procedures given in the CliniMacs Users 
Operating Manual and institutional Standard Operating Procedures (SOPs) in place at the study 
sites. The total nucleated count, CD34+ count and the CD3+ T cell count will be assessed pre and 
post selection and recorded.  
If there are less than 10 million CD34+ cells/kg recipient weight after the processing of 2 
aphereses, then the investigator should immediately contact the Medical Monitor.   
The selected CD34+ cells will be stored per institutional procedures prior to infusion. 
3.3.4 Conditioning Prior to HCT 
A reduced intensity conditioning regimen will be used.  Patients will be assigned to one of the 
following regimens based on disease and rejection risk.   
 
 

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A. Regimen A: Patients with primary immune deficiency disorders and inherited marrow 
failure disorders (except Fanconi Anemia): Fludarabine, Cyclophosphamide, and 200cGy 
total body irradiation. 
a) Fludarabine (FLU):  Fludarabine will be administered intravenously at a dose of 30 
mg/m2/day IV over 60 minutes for five consecutive days (day -6, -5, -4, -3, and -2) for a 
total dose of 150 mg/m2.  
b) Cyclophosphamide (CY): CY will be given at a dose of 25 mg/kg IV daily on days -6 and -
5 for a total dose of 50 mg/kg. Mesna will be given per institutional standard practice. 
c) Total Body Irradiation (TBI): TBI will be given on day -1 at a dose of 200 cGy, delivered 
according to institutional standard operating procedures.  
B. Regimen B: Patients with Sickle Cell Disease and Inherited Metabolic Disorders:  Due to 
higher risk of graft rejection in patients with sickle cell disease and inherited metabolic 
disorders a slightly more intense regimen will be used. Specifically, patients will receive 
Fludarabine, Cyclophosphamide, and 4 Gy TBI.  
a. Fludarabine (FLU):  Fludarabine will be administered intravenously at a dose of 30 
mg/m2/day IV over 60 minutes for five consecutive days (day -6, -5, -4, -3, and -2) 
for a total dose of 150 mg/m2.  
b. Cyclophosphamide (CY): CY will be given at a dose of 25 mg/kg IV daily on days -6 
and -5 for a total dose of 50 mg/kg. Mesna will be given per institutional standard 
practice. 
c. Total Body Irradiation (TBI): TBI will be given on day -1 at a dose of 400 cGy (200 
cGy twice daily), delivered according to institutional standard operating 
procedures.  
C. Regimen for Fanconi Anemia:  Due to an inherent increased risk of transplant related 
toxicity and mortality a slightly less intense regimen will be used for patients with 
Fanconi anemia.  Specifically, patients will receive fludarabine and 2 Gy TBI (NO 
cyclophosphamide pre HCT),  
a. Fludarabine (FLU):  Fludarabine will be administered intravenously at a dose of 30 
mg/m2/day IV over 60 minutes for five consecutive days (day -6, -5, -4, -3, and -2) 
for a total dose of 150 mg/m2.  
b. Total Body Irradiation (TBI): TBI will be given on day -1 at a dose of 200 cGy, 
delivered according to institutional standard operating procedures.  
The chemotherapeutic agents and TBI administration practices in the conditioning regimens 
will be done according to institutional standards as long as the prescribed doses are the same 
as the recommended regimen above. 
Bladder prophylaxis, supportive care, including fluids and anti-emetics on the day of TBI will be 
administered according to institutional protocols.  
 
PLAN OF TREATMENT/CONDITIONING REGIMENS A, B and C:  
 
 

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Regimen A: Patients with primary immune deficiency disorders and 
inherited marrow failure disorders (except Fanconi Anemia): Fludarabine, 
Cyclophosphamide, and 200cGy total body irradiation. 
 
Day 
Drug(s) 
-6 
Fludarabine 30 mg/m^2/day IV 
Cyclophosphamide 25 mg/kg IV 
-5 
Fludarabine 30 mg/m^2/day IV  
Cyclophosphamide 25 mg/kg IV 
-4 
Fludarabine 30 mg/m^2/day IV 
-3 
Fludarabine 30 mg/m^2/day IV 
Start Cyclosporine 
-2 
Fludarabine 30 mg/m^2/day IV 
-1  
TBI 200 cGy X1 
 0 
PBSC infusion 
+1 
BPX 501 Infusion 
6 hours after end of infusion start MMF 
 
 
 
 
Regimen B: Patients with Sickle Cell Disease and Inherited Metabolic 
Disorders:  Due to higher risk of graft rejection in patients with sickle cell 
disease and inherited metabolic disorders a slightly more intense regimen 
will be used. Specifically, patients will receive Fludarabine, 
Cyclophosphamide, and 4 Gy TBI.  
 
Day 
Drug(s) 
-6 
Fludarabine 30 mg/m^2/day IV 
Cyclophosphamide 25 mg/kg IV 
-5 
Fludarabine 30 mg/m^2/day IV 
Cyclophosphamide 25 mg/kg IV 
-4 
Fludarabine 30 mg/m^2/day IV 
-3 
Fludarabine 30 mg/m^2/day IV 
Start Cyclosporine 
-2 
Fludarabine 30 mg/m^2/day IV 
-1  
TBI 200 cGy X 2 
 0 
PBSC infusion 
+1 
BPX 501 Infusion 
6 hours after end of infusion start MMF 
 
 

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Regimen C for Fanconi Anemia:  Due to an inherent increased risk of 
transplant related toxicity and mortality a slightly less intense regimen 
will be used for patients with Fanconi anemia.  Specifically, patients will 
receive fludarabine and 2 Gy TBI (NO cyclophosphamide pre HCT) 
 
Day 
Drug(s) 
-6 
Fludarabine 30 mg/m^2/day IV 
-5 
Fludarabine 30 mg/m^2/day IV 
-4 
Fludarabine 30 mg/m^2/day IV 
-3 
Fludarabine 30 mg/m^2/day IV 
Start Cyclosporine 
-2 
Fludarabine 30 mg/m^2/day IV 
-1  
TBI 200 cGy X 1 
 0 
PBSC infusion 
+1 
BPX 501 Infusion 
6 hours after end of infusion start MMF 
 
3.3.5 Infusion of the HLA-Haploidentical CD34+ Selected PBSC graft   
Infusion of the HLA-haploidentical CD34+ selected PBSC graft will be performed per institutional 
protocol on Day 0 of the study.  Vital signs blood pressure, heart rate, and respiratory will be 
monitored per institutional standard practice with a recording at least 30 minutes before and 1 
hour after starting infusion. 
 
Maximum dose of CD34+ stem cells/kg is 30X106/kg.   If dose of CD34+ stem cells is less than 
10X106/kg recipient body weight call the Bellicum medical monitor. The medical monitor in 
consultation with the Principle Investigator will determine whether to infuse part or all of the 
CD34-negative fraction along with the CD34+-selected PBSC graft. 
 
3.3.6 BPX-501 Infusion 
BPX-501 infusion of 3X106 to 1X107 cells/kg recipient body weight as per the dosing schedule in 
approximately 15ml will be thawed and infused as outlined in the Procedures Manual. 
The BPX-501 infusion should be administered within 24 hours after the infusion of the HLA-
haploidentical CD34+ selected PBSC graft is complete.  Any delay after 24 hours should be 
discussed with and approved by the Bellicum medical monitor. The BPX-501 infusion will be 
thawed in a 37 °C water bath, diluted with 50ml Plasmalyte, as instructed in the Study Procedures 
Manual and administered over 30 minutes.  The patient will be pretreated with Benadryl and 
 
 

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Tylenol (or equivalent drugs per pharmacy standards) per institutional standards for 
cryopreserved cells. Vital signs blood pressure, heart rate, and respiratory within 1 hour prior to 
starting infusion and at 15, 30, 120 and 240 minutes post-infusion. 
 
Delayed infusion of BPX-501 cells: Patients who receive a CD3+ T cell dose >2 x 105/kg should not 
be given the BPX-501 cells within the first 24 hours after infusion of the CD34+ selected PBSC 
graft. The BPX-501 cells may be reserved for infusion between days +7 to +10, provided post-
transplant cyclophosphamide is given for GVHD prophylaxis on days +3 and +4 (refer to section 
3.4.3). Delayed infusion of BPX-501 cells must be approved by the medical monitor. Patients who 
receive delayed infusion of BPX-501 cells should not receive scheduled rimiducid infusion on day 
+7.  
 
3.4 
POST-HCT GVHD PROPHYLAXIS / IMMUNESUPPRESSION 
Post-HCT immune suppression will consist of Cyclosporine and Mycophenolate Mofetil 
3.4.1. Cyclosporine (CSP): 
Cyclosporine is given IV starting day -3 and administered, monitored and adjusted per 
institutional standards. The initial dose for patient’s ≥6 years old will be 2.0 mg/kg/dose every 12 
hours. The initial dose for patients <6 years old will be 2.0 mg/kg every 8 hours.  Patients > 12 
years old may start CSP orally at 5.0 mg/kg orally every 12 hours.  IV CSP may be transitioned to 
oral CSP after day +7 if clinically tolerated.  CSP should be maintained until day +180.  The CSP 
taper will commence on day 180, providing there is no ongoing GVHD.  The taper should be at a 
rate of roughly 5% per week.  CSP will be dosed based on actual or adjusted body weight per 
institutional standard practice.   
 
CSP Dose adjustments: 
a. CSP, whole blood "trough" levels (i.e., just prior to the next dose) will be evaluated on 
day 0 and twice weekly post-transplant until the initiation of the taper and adjusted if 
necessary to maintain blood levels that target the upper end of the therapeutic range 
during the first 28 days (See Table below).  
b. Further CSP determinations should be performed on a weekly or twice-weekly basis 
until CSP taper is initiated unless high levels are detected (see below table), or toxicity 
is suspected in which case more frequent monitoring will be performed as clinically 
indicated. 
c. After day 28, targeted therapeutic levels of CSP will drop to standard range (see table 
below) until day 180. CSP levels are not required upon initiation of taper unless clinically 
indicated. 
 
 
 

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d. Dose reductions should only be made if CSP toxicity is present or levels exceed the 
upper limits of target by 20%, depending on the method (see below table). Dose 
reductions for high levels without toxicity should be conservative, e.g. 25%, to avoid 
inadequate immunosuppression. 
 
e. If there is nausea and vomiting at any time during CSP treatment the drug should be given 
intraveneously at the dose that was used to obtain a therapeutic level.  ORAL to IV 
conversion:  Oral CSP dose divided by 2.5 = IV dose. 
 
 
 
CSP Level to Target 
Using LC-MS/MS 
Method 
CSP Level to Target Using 
Immunoassay Method 
Day “0” – Day +28 
Whole blood “trough” (just prior to next 
dose) 
400 ng/ml 
 
500 ng/ml 
(upper end therapeutic range 
for this method) 
 
After Day +28 
 
 
120-360 ng/ml 
 
 
150 - 450 ng/ml 
 
Levels exceeding upper limits of target by 
>20% 
• 
With or without CSP toxicity 
• 
Decrease in GFR >50% 
• 
Increase in creatinine 2x baseline 
due to CSP 
 
25% dose reduction 
25% dose reduction 
f.  Drugs that may affect CSP levels are: 
Decrease CSP levels 
Increase CSP levels 
Phenytoin 
Phenobarbital 
Carbamazepine 
Primidone 
Rifampicin 
Nafcillin 
Octreotide 
Sulfonamides 
Trimethoprim 
Metoclopramide 
Erythromycin                       
Ketoconazole                     
Azetazolamide 
Fluconazole*                      
Colchicine 
Itraconazole*                      
Fluoroquinolones 
Voriconazole                      
Imipenem 
 
Caspofungin                      
Azithromycin 
Diltiazem                           
Clarithromycin 
Verapamil                          
Doxycycline 
Nicardipine  
Nifedipine 
Alcohol 
*Discontinuation of fluconazole or itraconazole may lower CSP levels, and if used for antifungal 
prophylaxis, then changes in these drugs should be avoided during the first 2 months posttransplant. 
 
 
 

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3.4.2 Mycophenolate mofetil (MMF): 
MMF will be given at a dose of 15 mg/kg every 8 hours IV or oral (45 mg/kg/day) starting 6 hours 
after the gene modified T cell (BPX 501) infusion is complete.  MMF will continue at a dose of 15 
mg/kg every 8 hours until day 35.  After day 35, MMF will be given at a dose of 15 mg/kg every 12 
hours provided there is no evidence of GVHD or poor donor engraftment (see below for 
definition).  MMF will continue at a dose of 15 mg/kg every 12 hours through day 90 followed by 
a taper of approximately 10% per week if there is no evidence of GVHD.  Patients can be 
transitioned from IV to oral once they are able to take oral medications.  MMF will be dosed 
based on actual or adjusted body weight per institutional standard practice.  
 
Guidelines for mycophenolate mofetil dose adjustment and monitoring: 
a. 
Maintaining MMF: Markedly low (<40%) donor T cell chimerism after HCT may indicate 
impending graft rejection. MMF should be continued at full dose or, if the MMF taper has been 
initiated, reinstitution of full dose MMF should occur. If MMF has been discontinued, MMF should 
be reinitiated at full dose. 
Guidelines for MMF dose adjustment due to drug toxicity:  
a. 
If in the clinical judgment of the attending physician the observed toxicity is related 
to MMF administration, a dose adjustment may occur. The discontinuation of MMF at 
any point should be discussed with the Study PI and should be documented in the 
permanent medical record and all Case Report Forms (CRF). 
b. 
Gastrointestinal toxicity. Severe gastrointestinal toxicities such as gastrointestinal 
hemorrhage have been very rare after nonmyeloablative HCT. In the event of 
gastrointestinal toxicity that requires medical intervention including medication for 
control of persistent vomiting or diarrhea that is considered to be due to MMF after day 
28, a 20% dose reduction will be made or the drug may be given IV. If severe refractory 
diarrhea or overt gastrointestinal bleeding occurs, MMF may be temporarily stopped. The 
MMF should be restarted at 20% reduced dose when the underlying toxicity subsides. 
c. 
Neutropenia. Based on previous experience in patients after nonmyeloablative 
HCT, dose adjustments are likely to occur because of hematopoietic adverse effects, in 
particular neutropenia. A thorough evaluation of neutropenia should occur including 
peripheral blood chimerism studies, marrow aspiration and review of marrow suppressive 
medications. If all other potential causes of marrow toxicity are ruled out, dose 
adjustments will only be made for severe, prolonged neutropenia (ANC <500 for 5 days or 
more) that persists after day +21 post-transplant. Dose reductions should be conservative 
(20%). After day +21, the use of G-CSF will be permitted for severe neutropenia. For severe 
hematologic toxicity related to MMF (neutropenia > 5 days refractory to G-CSF), MMF may 
 
 

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be temporarily stopped. The MMF should be restarted at 20% reduced dose when the 
underlying toxicity subsides.” 
 
3.4.3 GVHD prophylaxis contingency plan for patients who receive a CD3 T cell dose >2 x 
105/kg  
Patients who receive a CD3 T cell dose >2 x 105/kg will be at higher risk for developing 
GVHD from the unmodified donor T cells. Therefore, these patients should receive post-
transplant cyclophosphamide for GVHD prophylaxis. 
At notification of a CD3 T cell dose >2 x 105/kg, the following changes to the treatment 
plan should be made: 
• No BPX-501 cells within 24 hours of the PBSC graft. (Refer to section 3.3.6 for 
information about potential delayed infusion of BPX-501 cells.) 
• Cyclosporine should be discontinued, 
• MMF should either not be started or be discontinued.  
• Rimiducid should not be given on day +7. 
• Contingency GVHD prophylaxis should be given as outlined below 
 
Contingency GVHD prophylaxis for patients who receive CD3 dose >2 x 105/kg 
 
Day + 3 and +4: Cyclophosphamide 50 mg/kg should be given through the central line on 
days +3 and +4 (total cyclophosphamide dose of 100 mg/kg). Dose 
calculation and administration of cyclophosphamide will be according to 
institutional standard practice. Bladder prophylaxis with Mesna should be 
given per institutional standard practice.  
 
Day +5:  
Cyclosporine should be resumed on day +5, as described in section 3.4.1. 
Refer to section 3.4.1 for guidelines for cyclosporine dose adjustment, 
taper, and monitoring.  
 
Day +5:  
MMF 15 mg/kg every 8 hours should be started on day +5, as described 
in section 3.4.2. Refer to section 3.4.2 for guidelines for MMF dose 
adjustment, taper, and monitoring.  
 
3.5 
 SUPPORTIVE CARE 
Patients should receive supportive care (growth factors, anti-emetics, menstrual suppression, 
prophylactic/empiric antibiotics, transfusions of blood products, hyperalimentation, etc.) as 
indicated per institutional standards for allogeneic HCT.   
 
 
 

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3.7.1 Rimiducid (AP1903) Treatment of acute GVHD  
Rimiducid (AP1903) for treatment of GVHD may be infused at any time based on the diagnosis of 
GVHD. If patients develop acute GVHD before or after the scheduled rimiducid infusion, they 
should be evaluated by the clinician at the first signs and symptoms of acute GVHD (see Acute 
GVHD grading scales Appendix C) for grading, possible biopsy and potential initiation of treatment 
with rimiducid.  
Any patient developing acute GVHD Grade 2-4 prior to the Day 7 scheduled rimiducid infusion 
should be treated according to standard institutional protocols, including topical steroids and/or 
systemic steroid treatment and receive an rimiducid infusion at a dose of 0.4 mg/kg IV over 2-4 
hours. Premedication, including Tylenol and Benadryl (or their equivalents based on standard 
institutional pharmacy guidelines) should be given prior to the start of the rimiducid infusion.  The 
Day 7 scheduled infusion will then proceed at the investigator’s discretion based on the patient’s 
clinical status. 
For Grades 2, 3, and 4, corticosteroids (0.5-2 mg/kg/day) should be administered. 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 (children: 0.4 mg/kg to a maximum of 40 mg IV; adults: 
40 mg IV). Acetaminophen and diphenhydramine, or other standard institutional 
pretreatment/prophylaxis, are required prior to the infusion of rimiducid. 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. 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.    
3.7.2 Rimiducid (AP1903) Treatment of chronic GVHD  
Initial treatment with topical or IV steroids, or other systemic treatments (eg, calcineurin 
inhibitors), per institutional standard of care for mild cGVHD should be instituted. Guidelines for 
topical corticosteroid treatment for mild disease include the following. Face, axillae, and groin: 
lower potency steroids (hydrocortisone 1-2.5%, desonide 0.05%) and from the neck down: mid-
strength steroids (e.g., triamcinolone 0.1% cream or ointment). 
Systemic corticosteroids when used should be administered as methylprednisolone 2 mg/kg/day 
IV in a single dose; or a dose equivalent of prednisone or dexamethasone). If no response to 
steroids/systemic therapies occurs within 7 days, or there is a worsening in cGVHD, patients may 
then receive rimiducid:  
Children: 0.4 mg/kg to a maximum of 40 mg IV  
Adults: 40 mg IV  
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  
 
 

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The product label (directly applied to the primary container) includes the patient specific lot 
number, cryopreservation date, T cell dose, storage conditions, sponsor, and product name.  All 
products manufactured under the IND are also labeled with: “Caution: New Drug-Limited by 
Federal Law to Investigational Use” per 21 CFR 312.6. 
 
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 in 
vapor phase of LN2 until time of infusion. At that time, the product will be thawed at 37oC + 2°C 
per Bellicum instructions for infusion to the recipient.   
4.2 
RIMIDUCID (AP1903) DIMERIZER DRUG PACKAGING, LABELING AND STORAGE 
Packaging and Formulation 
The rimiducid for Injection is packaged in 10 mL Type 1 clear glass serum vials. 
 
 
  Each vial is stoppered with a Teflon© coated serum stopper and a yellow flip-
off seal.  
Labeling 
The primary product label (applied directly to the vial) will contain all information for regional 
use, following the requirements of each competent authority and applicable national and 
international regulations as described in the pharmacy manual. 
Storage 
The Rimiducid for Injection vials must be stored at 2-8°C (41oF ± 5oF) in a limited access, qualified 
and monitored refrigerator, preferably without light. 
Preparation for Treatment 
For use, the rimiducid will be diluted prior to administration. The rimiducid is administered via IV 
infusion at the target dose diluted in normal saline with volume as appropriate for weight of patient 
to be administered over 2 hours, using a DEHP-free saline bag and solution set. 
5 STUDY TREATMENT  
The study treatment will only continue after the patient (and/or guardian) and the donor have 
signed the informed consent. 
The Schedule of Assessments is outlined in Appendix A.   
 
 

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5.1 
INFORMED CONSENT 
All potential patients (or guardian) are required to personally sign and date an IRB approved 
Informed Consent Form before beginning any study screening.   
5.2 
VISIT WINDOWS 
Visit windows for Weekly visits are + 3 days.  Visit windows for Monthly visits are + 7 days. 
5.3 
SCREENING 
Screening refers to the period prior to conditioning. Assessments other than donor identification 
should be made within 6 weeks as clinically indicated prior to day of conditioning.   
Assessment 
Description 
1. History and Physical exam 
• 
Vital Signs: Blood pressure, pulse rate, 
respiratory rate and temperature, oxygen 
saturation on room air 
• 
Height & Weight 
• 
Concurrent diseases and therapies,  
• 
Date of initial diagnosis  
• 
Transfusion history 
• 
Females post puberty: pregnancy history, date 
of last sexual intercourse 
2. Karnofsky/Lansky Scale   
• 
See Appendix I  
3. CBC w/differential, platelet count 
• 
Complete blood count (CBC) 
• 
Differential  
• 
Reticulocyte if clinically indicated 
• 
Quantitative platelets. 
4. Serum chemistries 
• 
Electrolytes (Na, K, Chloride, Bicarbonate, 
Calcium, Magnesium, Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
ALT, AST, Alkaline phosphatase, total bilirubin, 
direct bilirubin, LDH 
• 
Albumin.   
5. Quantitative Immunoglobulins 
IgG, IgA, and IgM 
 
 

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6. Fasting cholesterol and triglycerides 
As clinically indicated 
7. Infectious Disease screening 
See Table 3 
8. EKG/LVEF or LVSF 
 
9. Corrected DLCO, FEV1 and FEV2 or 02  
saturation 
 
10. Renal Ultrasound  
If clinically indicated 
 
It is recommended that all patients with Dyskeratosis 
Congenita and Shwachman Diamond Syndrome have a 
renal ultrasound pre HCT.  
 
11. Bone marrow biopsy/aspirate  
If clinically indicated 
 
12. CT scan of the chest abdomen and 
pelvis  
If clinically indicated 
 
13. Chest x-ray 
If clinically indicated 
 
14. Serum Pregnancy (females who have 
gone through puberty only) 
 
15. ABO/Rh typing, direct coombs 
 
16. HLA typing 
 
17. As a pre-transplant reference for 
subsequent determination of donor 
chimerism 10 cc of heparinized peripheral 
blood from the patient (and the donor) 
will be drawn*.  
 
18. Disease staging  
Appendix B 
19. iCasp baseline sample  
Any time after consent through Day 0 
20. Concomitant Medications 
Or on day 0 
21. Baseline Sample for RCR 
Any time after consent through Day 0 
22. Baseline Sample for HAMA 
Any time after consent through Day 0 
 
 

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• 
Donor Inclusion/Exclusion. 
2. Leukapheresis – non mobilized 
peripheral blood 
• 
Leukapheresis product shipped to Bellicum 
3. Mobilization 
• 
Donor treatment with subcutaneous G-CSF 
4. Stem Cell Apheresis  
• 
Graft analysis CD34+ and T cell counts. 
 
5.6 
PATIENT CONDITIONING 
 
 
Assessment 
Description 
1. Conditioning Regimen 
Determine A, B or C. 
5.7 
DAY 0 – T DEPLETED HCT AND BPX-501 INFUSION 
 
 
Assessment 
Description 
1. Vital signs blood pressure, heart rate, 
and respiratory rate, per institutional 
standard - pre, during, and after infusion 
of CD34+ stem cells   
• 
Blood pressure 
• 
Pulse rate 
• 
Respiratory rate 
• 
Temperature 
2. Vital signs blood pressure, heart rate, 
and respiratory rate within 1 hour prior to 
starting infusion and at 15, 30, 120 and 
240 minutes after starting infusion of BPX-
501  
• 
Blood pressure 
• 
Pulse rate 
• 
Respiratory rate 
• 
Temperature 
 
3. CBC w/differential, platelets prior to 
stem cell infusion 
• 
Complete blood count (CBC) 
 
4. Adverse Events 
 
5. Concomitant Medications and 
Transfusions 
 
 
 

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5.8 
DAYS 0 – DAY 28 
 
5.8.1 Day 0 to Day 28 
 
 
Assessment 
Description 
1. Modified H&P/vital signs 
Days 7, 14, 21, 28 
2. GvHD assessment  
Grading Scales (Appendix C & D) 
Daily until Day 28 prior to discharge then 2x/week 
3. CBC w/differential  
Daily until ANC > 500 for 3 days, then 2X per 
week 
4. Quantitative platelet count 
Daily until Platelet count is >20,000 (non-
transfused) then 2X per week 
5. EBV,CMV, and Adeno PCR 
Weekly through day 100 
6. Serum chemistries  
Days 14 and 28 only 
• 
Electrolytes 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
Albumin 
• 
ALT and AST 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
LDHBUN 
• 
Creatinine 
7. iCasp9 Research Sample 
Day 28 only 
8.Chimerism 
CD33, CD3, CD19 and CD56 
Day 28 only 
9. Adverse Events  
Daily until discharge and then 2x/week 
10. Concomitant Medications and 
Transfusions  
Daily until discharge and then 2x/week 
 
 

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11. Neurological Exam 
• Standard neurological exam and 
MMSE/mMMSE 
5.8.2 Day 7 
 
Rimiducid (AP1903) Infusion 
 
Assessment 
Description 
1. Vital signs blood pressure, heart rate, 
and respiratory rate. See Table 1 For Each 
Rimiducid Dose: Vital Sign Monitoring and 
Research Blood Samples.    
• 
Blood pressure 
• 
Pulse rate 
• 
Respiratory rate 
• 
Temperature 
2. iCasp9 Research Sample 
See Table 1 
5.9 
WEEKS 5 TO 12  
 
 
Assessment 
Description 
1. Modified history / Physical exam / GvHD 
assessment, weights 
Grading Scales (Appendix C & D) 
2. CBC w/differential  
Complete blood count (CBC) 
3. platelet count 
quantitative platelets 
4. EBV,CMV, and Adeno PCR 
Weekly through day 100 
5. Serum chemistries  
weeks 8 and 12 only 
• 
Electrolytes 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
albumin 
• 
ALT and AST 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
LDH 
• 
BUN 
 
 

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• 
Creatinine 
6. iCasp9 Research Sample 
Weeks, 8, and 12 
7. RCR sample 
Week 12 only 
8. immunophenotyping (CD3, CD4, CD8, B 
cell, NK cell) 
Week 12 only 
9.Chimerism: CD33, CD3, CD19 and CD56 
Weeks 8, 12 
10. Quantitative Immunoglobulins 
IgG, IgA, and IgM  
(week 12 only) 
11. Adverse Events  
weekly 
12. Concomitant Medications and 
Transfusions  
weekly 
13.Neurological Exam 
• Standard neurological exam and 
MMSE/mMMSE 
 
 
5.10 
MONTHS 6, 9, 12, 18 AND 24  
 
Assessment 
Description 
1. Modified History & Physical exam / 
GvHD assessment, weights 
Grading Scales (Appendix C & D) 
2. CBC w/differential  
Complete blood count (CBC) 
3. platelet count 
Differential quantitative platelets 
4. Serum chemistries  
(months 6, 12, 24) 
• 
Electrolytes 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
 
 

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• 
ALT and AST 
• 
Bilirubin 
• 
Alkaline phosphatase 
• 
LDH 
• 
Glucose 
• 
BUN 
• 
Albumin 
• 
Creatinine 
5. iCasp9 Research Sample 
Months 6, 12, 24 
6. Disease staging 
Month 12;  Appendix B 
7. immunophenotyping (CD3, CD4, CD8, B 
cell, NK cell) 
Months 6, 12, 24 
8. RCR (6 12, 18 and 24 months only) 
 
9. Chimerism 
CD33, CD3, CD19 and CD56 
Months 6, 12, 24 
10. Quantitative Immunoglobulins 
IgG, IgA, and IgM  
(months 12, 24 only) 
11. Adverse Events  
Safety Reporting Criteria (Appendix F) 
All AEs for 30 days starting after BPX-501 infusion 
or rimiducid infusion(s).GVHD will be reported as 
Adverse Events (or SAEs) and followed until 
resolution. 
• All SAEs regardless of attribution for 180 days 
post BPX-501 infusion. 
• After 180 days only SAEs relating to study 
treatment 
12. Concomitant Medications and 
Transfusions  
 
13.Neurological Exam 
• Standard neurological exam and 
MMSE/mMMSE 
 
 
 

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5.11 
MONTHS 30, 36, 42, 48, 54, AND 60 
Assessment 
Description 
1. Modified History and Physical exam 
 
2.Adverse Events 
All AEs for 30 days starting after BPX-501 infusion 
or rimiducid infusion(s).GVHD will be reported as 
Adverse Events (or SAEs) and followed until 
resolution. 
• All SAEs regardless of attribution for 180 days 
post BPX-501 infusion. 
• After 180 days only SAEs relating to study 
treatment 
 
3. Blood Sample for Vector and RCR 
 
4 Neurological Exam 
• Standard neurological exam and 
MMSE/mMMSE 
 
5.12 
YEARS 6 THROUGH 15 
Assessment 
Description 
1. Blood Sample for Vector and RCR 
 
2.Adverse Events 
All AEs for 30 days starting after BPX-501 infusion 
or rimiducid infusion(s).GVHD will be reported as 
Adverse Events (or SAEs) and followed until 
resolution. 
• All SAEs regardless of attribution for 180 days 
post BPX-501 infusion. 
• After 180 days only SAEs relating to study 
treatment 
 
 
5.13 
MONITORING FOR DISEASE SPECIFIC OUTCOMES  
Baseline testing will occur pre-transplant and follow up testing will occur at 12 weeks post-
transplant and yearly as per appendix B. 
 
5.14 
ADDITIONAL MONITORING FOR RIMIDUCID (AP1903) 
In patients who develop GVHD and receive rimiducid, blood samples will be obtained to monitor 
the effects of rimiducid on transgene persistence Vital signs and research blood draws are required. 
See Table 1 For Each rimiducid Dose: Vital Sign Monitoring and Research Blood Samples. 
 
 

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5.15 
DISCONTINUATION 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. 
They may withdraw consent to future treatment with rimiducid, or from continuing participation 
in the study and LTFU. Patients discontinuing from the main study visits (for example due to 
difficulty attending visits) may stay on study, enter LTFU and remain eligible for rimiducid if 
needed.  
Where possible patients who have been treated with BPX-501 will be encouraged to remain on-
study and complete appropriate follow-up assessments. Patients treated with any BPX-501 who 
discontinue, or who are unable to continue to participate in the assessments during the main 24-
month study conduct should still participate in LTFU. Where possible patients should complete 
the 6 month, 12 month and 18 month assessments prior to LTFU. 
If an adverse event (AE) is the reason the patient’s treatment is being discontinued by the 
investigator or the reason that a patient chooses to discontinue treatment, then that adverse 
event must be documented as the reason for treatment discontinuation. 
Patients who withdraw from the study will receive treatment as deemed appropriate by their 
treating physician. 
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 receives other investigational product(s) during the study 
The patient experiences an adverse event (AE) 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. 
If a patient is withdrawn from the study, the investigator should make reasonable effort to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. All 
information should be reported on the appropriate case report forms. Data of patients 
withdrawn from the study will be evaluated, as detailed in the fully executed original consent 
signed by the patient/parent/guardian upon study entry, unless otherwise indicated. Where 
possible, these patients will be monitored in terms of outcome for survival and risk of recurrence. 
The patient/parent/guardian will be informed that follow-up testing or end of study procedures 
may be required to ensure patient safety is properly maintained. 
 
 

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Patients who have disease relapse or progression should continue to be followed on study to 
assess survival status and participate in long-term gene therapy monitoring, as appropriate. 
Patients that cannot be contacted and who do not have a known reason for discontinuation will 
be classified as “lost to follow-up” with respect to the reason for discontinuation. The 
investigator’s study staff should make three documented attempts to contact the patient by 
telephone. If the patient cannot be reached by telephone, the investigator’s staff should attempt 
to contact the patient by certified mail or an alternative similar method, where appropriate. 
6 
TRIAL DESIGN AND STOPPING RULES 
6.1 
ESCALATION/DE-ESCALATION TRIAL DESIGN 
The target enrollment is up to 20 patients. The primary efficacy endpoint is engraftment, defined 
as >50% donor CD3 chimerism. The primary safety endpoint is resistant severe (grade 3-4) acute 
GVHD after treatment with rimiducid.  
The starting dose of 5x106 BPX-501 cells/kg has been chosen based on an estimated one-half log 
lower T cell dose than that found in a bone marrow graft.  The proposed dose should have 
engraftment rates of > 4/5 patients.  Based on the published study (DiStasi) for early GvHD 
treatment intervention with  rimiducid after BPX-501 administration in HLA-haploidentical HCT in 
the DLI setting, 4/4 patients were successfully treated with rimiducid and the predicted incidence 
of severe acute GVHD (grade 3-4) is hypothesized to be 1/5 patients. 
The overall dose finding design could be viewed as the inverse of a traditional MTD study, 
namely, higher dose limiting toxicity of non-engraftment is expected with doses which are too 
low, rather than too high a dose.  The trial design is an escalation/de-escalation trial design with 
planned enrollment of 5 patients /BPX501 dose/Regimen (group) based on the expected 
engraftment rates (> 4/5 engraftment) and based on historical data at the FHCRC (see schema 
diagram below).  
We propose three BPX501 T cell doses to be evaluated in the trial in order to evaluate the safe and 
potentially efficacious dose in enabling engraftment in the non-myeloablative setting in 
transplantation of non-malignant diseases: 
i. 5 X 106/kg BPX 501 T cells (starting dose) 
ii. 1 X 107/kg BPX 501 T cells (escalation) 
iii. 3 X 106/kg BPX 501 T cells (de-escalation) 
The multiple inherited disease indications are essentially stratified over 3 conditioning regimens 
(Conditioning Regimen A, B, or C), and each conditioning regimen will be treated as an 
independent group with respect to dose finding.  Patient treatment will be staggered between 
BPX501 dose cohorts within a group (conditioning regimen), and within a cohort, with a patient 
not being treated until the prior patient in a given cohort/group has completed 30 days post-
 
 

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transplant, thereby allowing analysis of engraftment and chimerism (as outlined in the secondary 
endpoints).   
1 Five patients will be treated at the starting dose.  If 1of 5 experience non-
engraftment then an additional 5 patients will be enrolled at this dose. If no 
further patients fail to engraft, or an additional 1 patient fails to engraft (total 
2 or fewer of 10 patients), then an additional 5 patients will be enrolled at the 
starting dose.   
2 If 2 of the first 5 or 3 of the first10 experience non-engraftment at 5 X 106/kg 
BPX501 T cells then the higher dose level will be triggered, and subsequent 
patients will receive 1 X 107/kg BPX501 T cells.   
3 If 5 of 5 patients engraft at 5 X 106/kg BPX501 T cells, then the following 5 
patients will be enrolled at the lower dose of 3 X 106/kg BPX501 T cells. If 5 of 
5 engraft at 3 X 106/kg BPX501 T cells then an additional 5 patients will be 
enrolled at the 3 X 106/kg BPX501 T cell dose. However, if 1 of the additional 5 
patients fail to engraft at 3 X 106/kg BPX501 T cell dose then the remaining 
cohort will be enrolled at 5 X 106/kg BPX501 T cell dose and will follow the 
rules #1 and #2 above, not to exceed 15 total treated patients.  
4 If 2 of 5 patients do not engraft at 1 X 107/kg BPX501 T cell dose, then the 
study will be halted and plans discussed with the investigators and FDA. If 1 or 
fewer of 5 patients do not engraft at 1 X 107/kg BPX501 T cell dose, then 5 
more patients will be enrolled at the dose of 1 X 107/kg BPX501 T cells.  If 1 of 
these additional patients does not engraft, then the study will be halted and 
discussed with the investigators and FDA. 
The corresponding data on incidence of GVHD will be analyzed in the context of the engraftment 
data in order to determine the ideal dose. We expect that 5 patients per dose change would yield 
at least 10 informative patients for dose finding. 
Patients with a residual CD3+ T cell count of >2 X 105/kg recipient weight in the CD34+ stem 
cell infusion will be considered non-evaluable for purposes of dose adjustment and analysis of 
primary endpoints. Patients who receive delayed infusion of BPX-501 cells will remain on 
study as an exploratory group and monitored for safety. The stopping rule for death in the 
first 30 days will remain in effect for this group; the stopping rules for GVHD before day 7 and 
graft failure cannot be applied.  
 
 
 
 
 
 
 
 
 
 
 

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investigators. 
• Grade III or IV acute GvHD non-responsive to rimiducid infusions  
• Grade 3 or 4 reactions related to infusion;  
• Grade 3 or 4 non-hematologic and noninfectious adverse events, occurring within 30 days 
after infusion  
 
The Sponsor has the right to pause enrollment at any time. 
 
6.3 
STATISTICS 
Descriptive statistics will be utilized to summarize engraftment rates, GvHD incidence, clinical 
and biologic response and other measures of safety and toxicity for the whole population as well 
as analysis stratified by disease and conditioning regimen. 
6.3.1 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 and not 
explained by marrow suppressive medications or infections.   
The cumulative incidence of graft failure estimates will be analyzed by BPX-501 dose, CD34+ cell 
dose in the allograft, and disease.   
6.3.2 Analysis of Acute and Chronic GvHD 
The time and severity of aGvHD are graded according to the Modified Keystone Grading Scale 
(Appendix C).  The time and severity of chronic GvHD are graded according to NIH Consensus 
Criteria (Appendix D). 
6.3.2.1  Analysis of Acute GvHD 
The initial incidence of aGvHD Grades 2-4 by days 100, 180 and 1 year will be determined and 
analyzed by conditioning regimen, BPX-501 dose, rimiducid treatment and degree of HLA match.   
The response rates of aGvHD Grades 1-4 to standard treatment will be determined, as well as the 
number of Grades 1-4 demonstrating non-improvement or progression on standard treatment. 
The rate of Grades 2-4 aGvHD in patients receiving rimiducidtreatment will be determined at 
days 100, 180 and 1 year and analyzed by the number of rimiducid infusions and time to 
resolution of GvHD after last rimiducid infusion. 
The initial incidence of severe aGvHD Grades 3-4 by days 100, 180 and 1 year will be determined 
and analyzed by conditioning regimen, BPX-501 dose, degree of HLA match and age.  The 
response rates of severe aGvHD Grades 3-4 in patients receiving rimiducid treatment will be 
determined at days 100, 180 and 1 year and analyzed by the number of rimiducid infusions and 
time to resolution of GvHD after last rimiducid infusion. 
 
 

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6.3.2.2 Analysis of Chronic GvHD 
The incidence of chronic GvHD according to the new NIH scoring system at 3 months, 6 months 1 
and 2 years will be determined for and analyzed by conditioning regimen, T cell dose, disease 
status, degree of HLA match and age.  The response rates of cGvHD in patients receiving 
rimiducid treatment will be determined at 3 months, 6 months 1 and 2 years and analyzed by the 
number of rimiducid infusions and time to resolution of chronic GvHD after last rimiducid 
infusion. 
6.3.3 Transplant-Related Mortality 
The cumulative incidence of TRM will be determined at 6 months, one year and 2 years for all 
patients transplanted and analyzed by BPX-501 dose, and age.   
6.3.4 Immune Reconstitution 
We will analyze several parameters measuring immune reconstitution resulting from iCasp9-
transduced T cells.  Descriptive summaries of these parameters in the overall patient group 
and by dose group as well as by time of measurement will be presented.  Growth curves 
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.  
6.4  
DATA QUALITY ASSURANCE 
Sponsor will supply eCRFs for this study.  A CRO will be responsible for data management of 
this trial, including quality checking of the data. In the event of discrepant data, the CRO will 
send requests for data clarification to the sites for resolution.     
Sponsor will perform oversight of the data management of this trial, including approval of the 
CRO’s data management and data quality plans.  eCRFs and correction documentation will be 
indexed and imaged.  System backups for data stored at Sponsor and records retention for the 
study data will be consistent with Sponsor’s standard procedures. 
The investigator agrees to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports (ICH E6, section 4.9.1) this 
responsibility may be delegated by the investigator to a member of the investigator's trial staff 
who is authorized to initial CRF changes for the investigator provided such authorization is 
documented. 
 
Data reported on the CRF, which are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained (ICH E6, section 4.9.2). 
Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry (i.e., an audit trail should be maintained); this applies to 
both written and electronic changes and corrections. Any changes required on paper source 
documents or paper CRF should be lined through, example, such that the original entry is clear to 
read and then the change should be initialed and dated by the person making the change.  In the 
 
 

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case of electronic records or other data capture, changes should be made in a way that allows the 
capture of an audit trail with similar intent to the example given for the paper document.  The 
investigator should retain records of the changes and corrections ICH E6, section 4.9.3). 
eCRFS are to be completed using the selected EDC system.  Sites will receive training and a 
manual for appropriate eCRF completion.  All eCRFs should be completed by designated, trained 
examining personnel or the study coordinator as appropriate.  The eCRF should be reviewed and 
electronically signed and dated by the investigator. 
At the end of the study, the investigator will receive patient CRFs for his or her site in a readable 
format on a compact disc that must be kept with the study records. 
7 
ASSESSMENT OF SAFETY 
7.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study drug(s). 
Bellicum or its designee is responsible for reporting relevant SAEs to the FDA 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 
requirements. 
7.2 
ADVERSE EVENT 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an IMP or other protocol imposed intervention, regardless of attribution. 
This includes the following: 
1. AEs not previously observed in the patient 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 
3.  Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms and are considered clinically significant 
 
An event which is part of the natural course of the disease under study (i.e., disease progression, 
death due to disease progression) should still be recorded as an AE or serious AE as applicable 
considering the signs and symptoms of clinical sequelae resulting from disease progression/lack 
of efficacy. 
 
 

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For events not associated with disease progression, the relevant signs and symptoms should be 
reported using a diagnosis whenever possible rather than individual underlying signs and 
symptoms.  When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate AE or SAE as applicable. 
 
 7.3  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 patient 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 patient’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 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
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 
patient or event outcome or action criteria usually associated with events that pose a threat to a 
patient’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 
CRF or eCRF. 
Per ICH E6 Guideline for Good Clinical Practice 4.11 Safety Reporting, all serious adverse events 
(SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or 
other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in Section 7.3 and 
7.4) are recorded on the CRF or eCRF and reported to the Sponsor in accordance with protocol 
instructions.  
 
 

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7.3.1 Protocol-Defined Events of Special Interest/Non-Serious Expedited Adverse Events 
The following events are considered of Special Interest and will need to be reported to the Sponsor 
expeditiously (see Section 7.5 for reporting instructions), irrespective of regulatory seriousness 
criteria.   
•
Grade III-V encephalopathy or neurologic events
7.4 
ADVERSE EVENT REPORTING PERIOD 
The reporting periods for AEs and SAEs are described in Table 4. After informed consent, but 
prior to initiation of BPX-501 infusion, only SAEs caused by a protocol-mandated intervention (i.e. 
outside of institutional standard protocol) will be collected. 
All AEs will be collected for 30-Days following each infusion of BPX-501 or rimiducid. SAEs 
regardless of attribution will be collected until 180 Days post BPX-501 infusion.  After this period, 
investigators should report only SAEs that are felt to be related to the study treatment.   After 
24 months post-transplant patients will be monitored for delayed adverse events for a period of 
15 years (see Section 3.7.4). 
 
 

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Table 4 Adverse Event Reporting Guidelines 
Event Type 
Reporting Period 
Additional Requirements 
SAEs (screening) 
Date of informed consent signature to 
prior to BPX-501 infusion. 
• 
Report new SAE only if 
related to a protocol-
mandated intervention. 
GvHD 
All cases of GvHD should be reported 
regardless of onset date and should not 
be limited to the below AE/SAE reporting 
period 
Not applicable 
AEs (post-IMP) 
• 
From the date of BPX-501 
infusion until 30 days after 
administration regardless of 
causality assessment. 
• 
From the date of rimiducid 
infusion until 30 days after 
administration regardless of 
causality assessment. 
• 
Report new AEs for up 
to 15 years if assessed 
as related to the 
investigational products 
BPX-501 and/or 
rimiducid. 
SAEs 
(post-IMP) 
including 
Adverse 
Events 
of 
Special 
Interest (AESI) 
• 
From the date of BPX-501 
infusion until 180 days after 
administration regardless of 
causality assessment. 
• 
From the date of rimiducid 
infusion until 30 days after 
administration regardless of 
causality assessment. 
• 
Report new SAEs for up 
to 15 years if assessed 
as related to the 
investigational products 
BPX-501 and/or 
rimiducid. 
• 
Report diagnosis of any 
new secondary 
malignancy regardless 
of relationship to 
investigational product 
for up to 15 years. 
Pregnancy of patients 
or partner 
• 
12 months after administration 
of BPX-501 or rimiducid, 
whichever occurs later.  
• 
Report diagnosis of any 
congenital anomaly in 
offspring from a study 
participant or partner 
for up to 15 years.  
7.4.1 GVHD Adverse Event Reporting 
All occurrences of GVHD will be reported as Adverse Events (or SAEs) regardless of their start date 
in relation to study treatment. GVHD events will also be followed until resolution and not limited 
to the standard AE/SAE reporting period. 
 
 
 

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7.6.2 Reporting Requirements for All SAEs 
All SAEs must be reported to Bellicum within 24 hours of learning of the event using the Bellicum 
SAE Report Form. SAE details must also be entered in the eCRF. 
For initial SAE reports, investigators should record all case details that can be gathered within the 
reporting timeframe (24 hours) on the Bellicum SAE Report Form and submit the report to 
SAE information should also be entered into the eCRF as soon 
as possible. Follow-up information should be collected on the eCRF and reported to Bellicum or 
its designee using the Bellicum SAE Report Form as soon as it becomes available and/or upon 
request.  
If local laws require that the site submit all SAEs then the local law will supersede the protocol 
requirements 
7.6.3  Type and Duration of Follow-Up of Patients after Adverse Events 
The investigator should follow all unresolved AEs and SAEs until the events are resolved or 
stabilized, the patient 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 CRF or eCRF and in the patient’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). 
7.6.4 Post-Study Adverse Events 
The investigator should notify the study Sponsor of any death or other SAE occurring at any time 
after a patient 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 
patient that participated in this study.  The investigator should report these events to Bellicum on 
the study CRF or eCRF.  If the study CRF of eCRF system is no longer available, the investigator 
should report the event directly to Bellicum via phone or email. 
Special Reporting Requirements for Neurotoxicity 
BPX-501 cells have been documented to enter the CNS. As the significance of this finding is 
unknown, all CNS events with apparent encephalitis of ≥ Grade 3 severity must be reported to 
Bellicum within the 24 hours (SAE reporting timelines). 
 
Refer to Appendix H for guidelines pertaining to monitoring and management of neurotoxicity. 
  
 
 

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• Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable) , IRB approval letters, and 
pertinent correspondence 
• A Protocol Acceptance Form signed and dated by the Principal Investigator 
• Approval by the NIH Recombinant DNA Review Committee 
8.2  STUDY COMPLETION 
The following data and materials are required by Bellicum before a study can be considered 
complete or terminated: 
• Laboratory findings, clinical data, and all special test results from screening through the 
end of the main study conduct 
• All laboratory certifications for laboratories performing the analysis (if other than 
Bellicum-approved central laboratory), as well as current normal laboratory ranges for all 
laboratory tests 
• CRFs or eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
• Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
• Copies of protocol amendments and IRB approval/notification, if appropriate 
• A summary of the study prepared by the Principal Investigator (IRB summary close letter 
is acceptable) 
• All essential documents (e.g., curriculum vitae for each Principal Investigator and sub-
investigator, U.S. FDA Form 1572 for each site) 
• A signed and dated Protocol Amendment Acceptance Form(s)[if applicable] 
• Updated financial disclosure forms for the Principal Investigator and all sub-investigators 
listed on the U.S. FDA Form 1572 (applicable for 1 year after the last patient has 
completed the study) 
8.3 INFORMED CONSENT FORM 
• Bellicum’s Sample Informed Consent Form will be provided to each site.  Bellicum or its 
designee must review and approve any proposed deviations from the Sample Informed 
Consent Form or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB submission.  Patients must be re-consented to the most 
current version of the Consent Forms during their participation in the study.  The final IRB 
approved Consent Forms must be provided to Bellicum for regulatory purposes. 
 
 

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• The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study.  A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative.  If 
applicable, it will be provided in a certified translation of the local language. 
• All signed and dated Consent Forms must remain in each patient’s study file and must be 
available for verification by study monitors at any time. 
• The Informed Consent Form should be revised whenever there are changes to procedures 
outlined in the informed consent or when new information becomes available that may 
affect the willingness of the patient to participate. 
• For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study.  The final 
revised IRB approved Informed Consent Form must be provided to Bellicum for regulatory 
purposes. 
• If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) regulations, the review, approval, and other processes outlined 
above apply except that IRB review and approval may not be required per study site 
policies. 
8.4 COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient and 
relevant supporting information must be submitted to the IRB by the Principal Investigator for 
review and approval before the study is initiated.  In addition, any patient recruitment materials 
must be approved by the IRB.  
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB annually or more frequently in accordance with the regulatory requirements and 
policies and procedures established by the IRB.  Investigators are also responsible for promptly 
informing the IRB of any protocol changes or amendments and of any unanticipated problems 
involving risk to human patients or others. 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB all unanticipated problems involving risk to 
human patients.  Some IRBs may want prompt notification of all SAEs, whereas others require 
notification only about events that are serious, assessed to be related to study treatment, and 
are unexpected.  Investigators may receive written IND safety reports or other safety-related 
communications from Bellicum.  Investigators are responsible for ensuring that such reports are 
 
 

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reviewed and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB and archived in the site’s Study File.  
8.5 STUDY MONITORING REQUIREMENTS 
Site visits will be conducted by an authorized Bellicum representative to inspect study data, 
patients’ medical records, and CRFs or eCRFs.  The Principal Investigator will permit Bellicum’s 
monitors/representatives or its designees and collaborators, the U.S. FDA, other regulatory 
agencies, Institutional Review Boards, and the respective national or local health authorities to 
inspect facilities and records relevant to this study. 
8.5.1 Case Report Forms 
eCRFs will be completed per the data management system. Sites will receive training and a 
manual for appropriate CRF or eCRF completion. 
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and signed and dated by the 
investigator. 
8.5.2 Source Data Documentation 
Study monitors will perform ongoing source data verification to confirm that critical protocol data 
(i.e., source data) entered onto the CRFs by authorized site personnel are accurate, complete, 
and verifiable from source documents.  
Source documents are where patient data are recorded and documented for the first time.  They 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda, patient diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies of transcriptions that are certified after verification as being 
accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical departments 
involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of data entered into 
the CRFs or eCRFs must never be obliterated or destroyed. 
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsor direct access to 
applicable source documents and reports for trial-related monitoring, Sponsor audits, and IRB 
review.  The investigational site must also allow inspection by applicable regulatory authorities. 
8.5.3 Use of Computerized Systems 
When clinical observations are entered directly into an investigational site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with FDA requirements 
pertaining to computerized systems used in clinical research.  An acceptable computerized data 
collection system (for clinical research purposes) would be one that (1) allows data entry only by 
 
 

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authorized individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the database 
from tampering; and (4) ensures data preservation. 
8.5.4 Study Medication Accountability 
All study drug required for completion of this study will be provided by Bellicum.  The recipient 
will acknowledge receipt of the drug by returning the appropriate documentation form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug received at, dispensed from, returned to and disposed of by 
the study site should be recorded by using the Drug Inventory Log. 
Study drug will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to Bellicum with the appropriate documentation, as 
determined by the study site.  If the study site chooses to destroy study drug, the method of 
destruction must be documented. 
Bellicum must evaluate and approve the study site’s drug destruction standard operating 
procedure prior to the initiation of drug destruction by the study site. 
8.6 DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the Informed Consent Form (or separate authorization to use and 
disclose personal health information) signed by the patient or unless permitted or required by 
law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA and other regulatory agencies, national and local health authorities, Bellicum 
monitors/representatives and collaborators, and the IRB for each study site, if appropriate. 
8.7 RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of this study and the 
distribution of investigational drug, including CRFs, or printouts of the eCRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after the last marketing application approval in an ICH region or after at 
least 2 years have elapsed since formal discontinuation of clinical development of the 
investigational product.  All state and local laws for retention of records also apply.  
No records should be disposed of without the written approval of Bellicum.  Written notification 
should be provided to Bellicum for transfer of any records to another party or moving them to 
another location. 
 
 

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9       REFERENCES 
Amrolia PJ, Muccioli-Casadei G, Huls H et al. Adoptive immunotherapy with allodepleted 
donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. 
Blood 2006;108:1797-1808. 
Aversa F, T cell depleted haploidentical transplantation: positive selection. Pediatric Reports 
2011; volume 3:(s2)14 
Aversa F, Haploidentical haematopoietic stem cell transplantation for acute leukaemia in 
adults: experience in Europe and the United States. Bone Marrow Transplantation (2008) 41, 
473–481 
Di Stasi A, Tey S-K, Dotti, G et al; Inducible Apoptosis as a Safety Switch for Adoptive Cell 
Therapy N Engl J Med 2011;365:1673-83 
Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolaños-Meade J, Morris LE, Crilley PA, 
O'Donnell PV, Rossiter N, Huff CA, Brodsky RA, Matsui WH, Swinnen LJ, Borrello I, Powell JD, 
Ambinder RF, Jones RJ, Fuchs EJ. Biol Blood Marrow Transplant. 2010 Apr;16(4):482-9 
Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, Maloney DG, 
Storer B, Lange T, Chauncey T, Deininger M, Pönisch W, Anasetti C, Woolfrey A, Little MT, 
Blume KG, McSweeney PA, Storb RF. Blood. 2003 Feb 15;101(4):1620-9.  
Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, 
McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, 
Hegenbart U, Anasetti C, Blume K, Storb R. Blood. 2003 Sep 15;102(6):2021-30.  
Tey SK, Dotti G, Rooney CM, Heslop HE, Brenner MK. Inducible caspase 9 suicide gene to 
improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol 
Blood Marrow Transplant 2007; 13: 913-24. 
Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP, Leisenring W, Shulman H. Blood. 1997 
Apr 15;89(8):3048-54. 
 
 
 
 
 
 

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10 
APPENDICES 
APPENDIX A: SCHEDULE OF ASSESSMENTS 
A1: Screening Assessments 
Activity 
Screening1 
History, Physical exam, height and weight2 
X 
Vital Signs3 
X 
CBC w/differential, platelet count (reticulocyte, if 
indicated) 
X 
Disease staging  (Appendix B) 
X 
Serum chemistries4 
X 
Quantitative Immunoglobulins (IgG, IgA, and IgM) 
X 
Infectious Disease titers5 
X 
EKG/LVEF or LVSF6 
X 
DLCO, FEV1 and FEV2 or 02 saturation 
X 
Renal Ultrasound, if clinically indicated 
X 
Bone marrow biopsy7/aspirate, if clinically indicated 
X 
CT scan of the chest, abdomen and pelvis, if clinically 
indicated 
X 
Chest x-ray, if clinically indicated 
X 
Serum Pregnancy (females past puberty only) 
X 
ABO/Rh typing direct coombs 
X 
HLA typing 
X 
10 cc of heparinized peripheral blood to determine 
subsequent chimerism (patient and donor) 
X 
Blood sample for iCasp tracking -  research 
X 
Concomitant Medications 
X 
Blood Sample for RCR  
Any time after consent through Day 0 
Blood Sample for HAMA 
Any time after consent through Day 0 
Immune Reconstitution Research Studies 
Any time after consent through Day 0 
1Screening refers to the period prior to conditioning.  Assessments, other than donor identification, should be made within 6 weeks prior to day of conditioning. 
2History and height are required only at Screening. 
3Vital signs: blood pressure, pulse rate, respiratory rate, temperature and oxygen saturation on room air. 
4Serum chemistries panel: electrolytes, glucose, BUN, ALT, AST, creatinine, bilirubin (total and direct), alkaline phosphatase, LDH, albumin.  Include fasting cholesterol 
and triglycerides if clinically indicated. Electrolytes to include; sodium, potassium, chloride, bicarbonate, calcium, magnesium and phosphorus.. 
5Infectious disease titers: Cytomegalovirus (CMV), antibody test, hepatitis panel (Hepatitis B including HBsAg, HBcAb (IgM and IgG); Hepatitis C Ab), HIV including HIV 
Ag, HIV 1+2 Ab, HTLV I/II Ab, herpes simples virus (HSV), varicella zoster virus VZV) and Toxoplasma serology. For patients with an underlying B cell deficiency or defect 
or those that have received IVIG within 3 months of HCT the following PCR studies are required: Hepatitis B PCR, Hepatitis C PCR, HIV PCR, CMV PCR, EBV PCR; 
Adenovirus PCR, VZV, and HSV PCR, as clinically indicated. 
6To be determined by MUGA or echocardiogram. 
7For pathology and cytogenetics, flow cytometry, and molecular studies. Sample to be provided to Bellicum. 
 
 

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11  All AEs will be collected for 30 days following each infusion of BPX-501 or rimiducid (AP1903).  GvHD will be reported as Adverse Events (or SAEs) and followed until 
resolution. SAEs regardless of attribution will be collected until 180 days post BPX-501 infusion. After this period, investigators should report only SAEs related to the study 
treatment. 
 
 

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APPENDIX B: DISEASE OUTCOME MEASURES TABLE 
 
Disease-Specific Studies – as feasible 
Timing of studies: Studies should be obtained pre-transplant and on specified post-HCT timelines  
 
1. Sickle Cell Disease: All patients with Sickle Cell Disease will require a % hemoglobin S pre 
HCT and around day +84 and then at 1 year following HCT.  In addition, % hemoglobin S 
should be checked if there is falling donor chimerism and concern of inadequate disease 
response. 
2. Bone Marrow Failure Syndromes:  All bone marrow failure syndromes should have 
appropriate genetic testing pre HCT.   
3. Dyskeratosis Congenita - Telomere length analysis and appropriate genetic studies  
4. Shwachman Diamond Syndrome - Appropriate genetic studies 
5. Diamond Blackfan Anemia - Appropriate genetic studies 
6. Fanconi Anemia – Appropriate genetic studies 
7. Immunodeficiency Diseases:   Lymphocyte phenotype (subsets), Lymphocyte function as 
clinically indicated, Quantitative Immunoglobulins and Immunology Consult.  In addition, 
the following immunodeficiency disease specific studies should be considered. 
a) Chronic granulomatous disease -Genetic analysis of cytosolic components of 
NADPH oxidase system (pre-transplant only if not already completed).  
Neutrophil oxidative burst should be evaluated pre-transplant if not already 
completed and around day 80 and 1 year following transplantation or as 
clinically indicated. 
b) Leukocyte adhesion defect -Flow cytometry analysis of CD18 expression pre-
transplant if not already completed and around day 80 and 1 year following 
transplantation or as clinically indicated. 
c) Wiskott-Aldrich syndrome - Gene sequence (pre-transplant only if not 
already completed); Flow cytometry for determination of WASP expression 
pre-transplant if not already completed and around day 80 and 1 year 
following transplantation or as clinically indicated.and  
d) IPEX: - Flow cytometry for expression of FOXP3 pre-transplant if note already 
completed and around day 80 and 1 year following transplantation or as 
clinically indicated.   
e) CD40 Ligand Deficiency - Flow cytometry for expression of CD40 Ligand pre-
transplant if not already completed and around day 80 and 1 year following 
transplantation or as clinically indicated.  
  
 
 

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f) Hemophagocytosis Lymphohistiocytosis (HLH) – Appropriate genetic studies 
(pre-transplant only if not completed).  NK function analysis pre transplant if 
not already completed and around day 80 and 1 year following 
transplantation or as clinically indicated.   
8. Mucopolysaccharidosis - Disease specific enzyme level. 
a) Marrow, skin, liver, and/or gut biopsy as indicated according to disease for 
determination of storage material  
b) Lumbar puncture for storage material determination, as indicated  
c) MRI of head, as indicated. 
9. Sphingolipidoses 
a) Nerve conduction studies. 
b) MRI of head. 
9 Osteopetrosis 
a) Send bone biopsy to pathology for assessment of disease.  
b) Head MRI 
 
 
 
 

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APPENDIX D: CHRONIC GVHD GRADING SCALE 
NIH Consensus Grading Chronic GvHD 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 

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Appendix D 
 
NIH Consensus Grading Chronic GvHD (cont) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  

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APPENDIX E: GVHD RESPONSE CRITERIA 
 
Complete response (CR) is defined as a CIHSCTR score of 0 for the GvHD grading in all evaluable 
organs.   For a response to be scored as CR at Day 56 or later, the participant must still be in CR 
on that day and have had no intervening additional therapy for an earlier progression, PR or NR. 
Partial response (PR) is defined as improvement in one or more organs involved with GvHD 
symptoms without progression in others.  For a response to be scored as PR at Day 28 or later, 
the participant must still be in PR on that day and have had no intervening additional therapy 
for an earlier progression, PR or no response (NR). 
Mixed response (MR) is defined as improvement in one or more organs with deterioration in 
another organ manifesting symptoms of GvHD or development of symptoms of GvHD in a new 
organ. 
Progression of GvHD (PD) is defined as deterioration in at least one organ without any 
improvement in others. 
No response (NR) is defined as absence of any improvement or progression as defined.  
Patients receiving secondary therapy (including need to re-escalate steroid dose to > 2.5 
mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) will be classified 
as non-responders. 
 
 
 
 

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APPENDIX F:  SAFETY REPORTING CRITERIA 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient evaluation 
time points should be adopted.  Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact.  All AEs and SAEs, 
whether reported by the patient or noted by authorized study personnel, will be recorded in 
the patient’s medical record and on the Adverse Event CRF or eCRF or Serious Event CRF. 
For each AE and SAE recorded on the applicable CRF or eCRF, the investigator will make an 
assessment of seriousness (see Section 7.3 for seriousness criteria), severity and causality.  
The adapted AE grading (severity) scale found in the NCI CTCAE v4.03 will be used for AE 
reporting. 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  Refer to 
definitions of an SAE. 
 
 

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Adapted from 
COMMON TOXICITY CRITERIA (CTC)  
Version 4.0 
 
 
Grade 
Adverse Event 
3 
4 
5 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Disseminated intravascular 
coagulation 
Laboratory findings and 
bleeding 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Febrile neutropenia 
ANC <1000/mm3 with a 
single temperature of 
>38.3 degrees C (101 
degrees F) or a sustained 
temperature of >=38 
degrees C (100.4 degrees 
F) for more than one hour 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hemolysis 
Transfusion or medical 
intervention indicated 
(e.g., steroids) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hemolytic 
uremic 
syndrome 
Laboratory findings with 
clinical consequences 
(e.g., renal insufficiency, 
petechiae) 
Life-threatening 
consequences, (e.g., CNS 
hemorrhage or 
thrombosis/embolism or 
renal failure) 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
CARDIAC DISORDERS 
 
Atrial fibrillation 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker), or ablation 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Atrial flutter 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker), or ablation 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Atrioventricular 
block 
complete 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
 

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Constrictive pericarditis 
Symptomatic heart failure 
or other cardiac 
symptoms, responsive to 
intervention 
Refractory heart failure or 
other poorly controlled 
cardiac symptoms 
Death 
Heart failure 
Severe with symptoms at 
rest or with minimal 
activity or exertion; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
Death 
Left 
ventricular 
systolic 
dysfunction 
Symptomatic due to drop 
in ejection fraction 
responsive to intervention 
Refractory or poorly 
controlled heart failure due 
to drop in ejection fraction; 
intervention such as 
ventricular assist device, 
intravenous vasopressor 
support, or heart transplant 
indicated 
Death 
Myocardial infarction 
Severe symptoms; cardiac 
enzymes abnormal; 
hemodynamically stable; 
ECG changes consistent 
with infarction 
Life-threatening 
consequences; 
hemodynamically unstable 
Death 
Myocarditis 
Severe with symptoms at 
rest or with minimal 
activity or exertion; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support) 
Death 
Pericardial effusion 
Effusion with physiologic 
consequences 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Pericardial tamponade 
 - 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Ventricular arrhythmia 
Medical intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic compromise; 
urgent intervention 
indicated 
Death 
 
 

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Grade 
Adverse Event 
3 
4 
5 
 
GASTROINTESTICAL DISORDERS 
 
Ascites 
Severe symptoms; 
invasive intervention 
indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Diarrhea 
Increase of >=7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Duodenal ulcer 
Severely altered GI 
function; TPN indicated; 
elective operative or 
endoscopic intervention 
indicated; limiting self 
care ADL; disabling 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Gastric ulcer 
Severely altered GI 
function; TPN indicated; 
elective operative or 
endoscopic intervention 
indicated; limiting self 
care ADL; disabling 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Gastritis 
Severely altered eating or 
gastric function; TPN or 
hospitalization indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Lower gastrointestinal 
hemorrhage 
Transfusion, radiologic, 
endoscopic, or elective 
operative intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Mucositis oral 
Severe pain; interfering 
with oral intake 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Oral hemorrhage 
Transfusion, radiologic, 
endoscopic, or elective 
operative intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Pancreatitis 
Severe pain; vomiting; 
medical intervention 
indicated (e.g., analgesia, 
nutritional support) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
 

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Typhlitis 
Symptomatic (e.g., 
abdominal pain, fever, 
change in bowel habits 
with ileus); peritoneal 
signs 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
GENERAL DISORDERS AND ADMINISTARTION SITE CONDITIONS 
 
Multi-organ failure 
Shock with azotemia and 
acid-base disturbances; 
significant coagulation 
abnormalities 
Life-threatening 
consequences (e.g., 
vasopressor dependent 
and oliguric or anuric or 
ischemic colitis or lactic 
acidosis) 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
HEPATOBILIARY DISORDERS 
 
Cholecystitis 
Severe symptoms; 
radiologic, endoscopic or 
elective operative 
intervention indicated 
Life-threatening 
consequences; urgent 
operative intervention 
indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Immune system disorders - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
 

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Grade 
Adverse Event 
3 
4 
5 
 
INFECTIONS AND INFESTATIONS 
 
Enterocolitis infectious 
IV antibiotic, antifungal, 
or antiviral intervention 
indicated; radiologic, 
endoscopic, or operative 
intervention indicated; 
profuse watery diarrhea 
with signs of 
hypovolemia;  bloody 
diarrhea; fever; severe 
abdominal pain; 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Infections and infestations - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 
Aspartate aminotransferase 
increased 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
 - 
Blood bilirubin increased 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
 - 
Carbon monoxide diffusing 
capacity decreased 
Asymptomatic decrease  
of >8 units drop;  >5 units 
drop along with the 
presence of pulmonary 
symptoms (e.g. , >Grade 2  
hypoxia or >Grade 2 or 
higher dyspnea) 
 - 
 - 
Cardiac troponin I increased 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
 - 
 - 
Cardiac troponin T 
increased 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
 - 
 - 
 
 

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Creatinine increased 
>3.0 baseline; >3.0 - 6.0 x 
ULN 
>6.0 x ULN 
 - 
Weight gain 
>=20% from baseline 
 - 
 - 
Grade 
Adverse Event 
3 
4 
5 
 
METABOLISM AND NUTRITIONAL DISORDERS 
 
Hypercalcemia 
Corrected serum calcium 
of >12.5 - 13.5 mg/dL;>3.1 
- 3.4 mmol/L;  Ionized 
calcium  >1.6 - 1.8 
mmol/L; hospitalization 
indicated 
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L;  
Ionized calcium  >1.8 
mmol/L; life-threatening 
consequences 
Death 
Hypertriglyceridemia 
>500 mg/dL - 1000 mg/dL;  
>5.7 mmol/L - 11.4 
mmol/L 
>1000 mg/dL; >11.4 
mmol/L;  life-threatening 
consequences 
Death 
Hyperuricemia 
>ULN - 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
>10 mg/dL; >0.59 mmol/L; 
life-threatening 
consequences 
Death 
Tumor lysis syndrome 
Present 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INC CYSTS AND POLYPS) 
 
Treatment 
related 
secondary malignancy 
Non life-threatening 
secondary malignancy 
Acute life-threatening 
secondary malignancy; 
blast crisis in leukemia 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
NERVOUS SYSTEM DISORDERS 
 
Dysarthria 
Severe impairment of 
articulation or slurred 
speech 
 - 
 - 
Intracranial hemorrhage 
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or 
operative intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Ischemia cerebrovascular 
 - 
 - 
 - 
 
 

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Leukoencephalopathy 
Severe symptoms; 
extensive T2/FLAIR 
hyperintensities, involving 
periventricular white 
matter involving 2/3 or 
more of susceptible areas 
of cerebrum +/- moderate 
to severe increase in SAS 
and/or moderate to 
severe ventriculomegaly 
Life-threatening 
consequences; extensive 
T2/FLAIR hyperintensities, 
involving periventricular 
white matter involving 
most of susceptible areas 
of cerebrum +/- moderate 
to severe increase in SAS 
and/or moderate to severe 
ventriculomegaly 
Death 
Seizure 
Multiple seizures despite 
medical intervention 
Life-threatening; prolonged 
repetitive seizures 
Death 
Syncope 
Fainting; orthostatic 
collapse 
 - 
 - 
Nervous system disorders - 
Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
RENAL AND URINARY DISORDERS 
 
Chronic kidney disease 
eGFR or CrCl 29 - 15 
ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2; dialysis or 
renal transplant indicated 
Death 
Renal and urinary disorders 
- Other, specify 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling;  limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
 
 

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Grade 
Adverse Event 
3 
4 
5 
 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
 
Adult respiratory distress 
syndrome 
Present with radiologic 
findings; intubation not 
indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Apnea 
Present; medical 
intervention indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Bronchopulmonary 
hemorrhage 
Transfusion, radiologic, 
endoscopic, or operative 
intervention indicated 
(e.g., hemostasis of 
bleeding site) 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Hypoxia 
Decreased oxygen 
saturation at rest (e.g., 
pulse oximeter <88% or 
PaO2 <=55 mm Hg) 
Life-threatening airway 
compromise; urgent 
intervention indicated 
(e.g., tracheotomy or 
intubation) 
Death 
Pleural effusion 
Symptomatic with 
respiratory distress and 
hypoxia; surgical 
intervention including 
chest tube or pleurodesis 
indicated 
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Pneumonitis 
Severe symptoms; 
limiting self care ADL; 
oxygen indicated 
Life-threatening respiratory 
compromise; urgent 
intervention indicated 
(e.g., tracheotomy or 
intubation) 
Death 
Pulmonary edema 
Severe dyspnea or 
dyspnea at rest; oxygen 
indicated; limiting self 
care ADL 
Life-threatening respiratory 
compromise; urgent 
intervention or intubation 
with ventilatory support 
indicated 
Death 
Respiratory failure 
 - 
Life-threatening 
consequences; urgent 
intervention, intubation, or 
ventilatory support 
indicated 
Death 
 
 

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Grade 
Adverse Event 
3 
4 
5 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Erythema multiforme 
Target lesions covering 
>30% BSA and associated 
with oral or genital 
erosions 
Target lesions covering 
>30% BSA; associated with 
fluid or electrolyte 
abnormalities; ICU care or 
burn unit indicated 
Death 
Grade 
Adverse Event 
3 
4 
5 
 
VASCULAR DISORDERS 
 
Capillary leak syndrome 
Severe symptoms; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Hypotension 
Medical intervention or 
hospitalization indicated 
Life-threatening and urgent 
intervention indicated 
Death 
Thromboembolic event 
Thrombosis (e.g., 
uncomplicated pulmonary 
embolism [venous], non-
embolic cardiac mural 
[arterial] thrombus), 
medical intervention 
indicated 
Life-threatening (e.g., 
pulmonary embolism, 
cerebrovascular event, 
arterial insufficiency); 
hemodynamic or 
neurologic instability; 
urgent intervention 
indicated 
Death 
Vasculitis 
Severe symptoms, 
medical intervention 
indicated (e.g., steroids) 
Life-threatening; evidence 
of peripheral or visceral 
ischemia; urgent 
intervention indicated 
Death 
 
 
 
 
 
 

B ellic u m P h ar m ac e utic als  
 
 
Pr ot oc ol N u m b er B P -0 0 3  
 
V ersi o n 3. 0 
 
 P a g e 8 7  of 9 7  
 
 
T a bl e F . 1    A d v ers e E v e nt Gr a di n g ( S e v erit y) Sc al e  
Gr a d e  
S e v erit y  
Alt er n at e D escri pti o n  a 
1 
 
 
 
Mil d ( a p pl y e v e nt -s p ecific 
N CI  C T C A E gr a di n g crit eri a)  
 
 
Tr a nsi e nt or mil d disc o mf ort 
( 4 8  h o urs); n o i nt erf er e nc e wit h 
t h e p ati e nt ’s d ail y activiti es; n o 
m e dic al i nt erv e nti o n/t h er a py 
r e q uir e d 
2 
 
 
 
M o d er at e ( a p pl y e v e nt -s p ecific  
N CI C T C A E gr a di n g crit eri a)  
 
 
Mil d t o m o d er at e i nt erf er e nc e 
wit h t h e p ati e nt ’s d ail y activiti es; 
n o or mi ni m al m e dic al 
i nt er v e nti o n/t h er a py r e q uir e d 
3 
 
 
 
S e v er e ( a p pl y ev e nt -s p ecific  
N CI C T C A E gr a di n g crit eri a)  
 
 
C o nsi d er a bl e i nt erf er e nc e wit h t h e 
p ati e nt ’s d aily activiti es; m e dic al 
i nt er v e nti o n/t h er a py r e q uir e d; 
h os pit aliz ati o n p ossi bl e  
4 
V er y s e v er e, lif e t hr e at e ni n g,  
or dis a bli n g ( a p pl y e v e nt -s p ecific 
N CI C T C A E gr a di n g crit eri a)  
Extr e m e li mit ati o n i n activit y; 
si g nific a nt m e dic al 
i nt er v e nti o n/t h er a py r e q uir e d, 
h os pit aliz ati o n pr o b a bl e  
5  
D e at h r el at e d t o A E  
 
aUs e t h es e alt er n ativ e d efi niti o ns f or Gr a d e 1, 2, 3, a n d 4 ev e nts w h e n t h e o bs erv e d or r e p ort e d A E is 
n ot i n t h e N CI C T C A E listi n g.  
 
T h e i n v esti g at or’s ass ess m e nt of c a us alit y f or i n divi d u al A E r e p orts is p art of t h e st u d y 
d oc u m e nt ati o n pr oc ess.  R e g ar dl ess of t h e “ Y es” or “ N o” c a us alit y ass ess m e nt f or i n di vi d u al A E 
r e p orts, t h e S p o ns or will pr o m ptl y e v al u at e all r e p ort e d S A Es a g ai nst c u m ul ati v e pr o d uct 
ex p eri e nc e t o i d e ntif y a n d ex p e diti o usl y c o m m u nic at e p ossi bl e n e w s af et y fi n di n gs t o 
i n v esti g at ors a n d a p plic a bl e r e g ul at or y a ut h oriti es.   
T o e ns ur e c o nsist e ncy of c a us alit y ass ess m e nts, i n v esti g at ors s h o ul d a p ply t h e f oll o wi n g 
g e n er al g ui d eli n es f or t h e ass ess m e nt of c a us ality:  
 
 
 
 

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Table F.2   Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship possible AND other drugs, 
therapeutic interventions or underlying conditions do not provide 
sufficient explanation for the AE/SAE.   
NO 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship unlikely, OR other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the AE/SAE.    
Recording Adverse Events on the CRF or eCRF 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF or eCRF.  Avoid colloquialisms and abbreviations. 
Only one medical concept should be recorded in the event field on the Adverse Event CRF or 
eCRF. 
a. 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF or eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded as an AE or SAE on the CRF or eCRF.  
If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
b. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF or eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF or eCRF.  For 
example, if a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be recorded separately on the CRF or eCRF. 
c. 
Persistent or Recurrent Adverse Events 
 
 

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A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the CRF or eCRF 
unless their severity increases.  If a persistent AE becomes more severe, it should be 
recorded again on the Adverse Event CRF or eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points 
and subsequently recurs.  All recurrent AEs should be recorded on Adverse Event CRF 
or eCRF. 
d. 
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will 
be recorded as AEs or SAEs on the CRF or eCRF (e.g., abnormalities that require study 
drug dose modification, discontinuation of study treatment, more frequent follow-up 
assessments, further diagnostic investigation, etc.) 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the 
Adverse Event CRF or eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF or eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF or eCRF, unless their 
severity, seriousness, or etiology changes.  
e. 
Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 
7.4), regardless of attribution, will be recorded on a CRF or eCRF and expeditiously 
reported to the Sponsor.   
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the CRF or eCRF.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, record 
“Unexplained Death” on the CRF or eCRF. 
If the death is attributed to the original diagnosis, record “Disease Progression” (listing 
specific disease) as the SAE term on the CRF or eCRF.   
f. 
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the Medical and Surgical History CRF. 
 
 

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A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on an Adverse Event CRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
g. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this 
protocol.   
There are some hospitalization scenarios that do not require reporting as an SAE when 
there is no occurrence of an AE.  These scenarios include a planned hospitalization or 
prolonged hospitalization to: 
• Perform an efficacy measurement for the study 
• Undergo a diagnostic or elective surgical procedure for a preexisting medical 
condition that has not changed 
• Receive scheduled therapy for the target disease of the study 
Abortion, whether therapeutic or spontaneous, should always be classified as serious 
recorded on a CRF, and expeditiously reported to the Sponsor.   
Any congenital anomaly/birth defect in a child born to a female patient or female 
partner of a male patient exposed to the investigational product should be recorded and 
reported as an SAE. 
If a female patient becomes pregnant while receiving investigational therapy or within 
120 days after the last dose of investigational product, Bellicum should be notified 
within 24 hours of learning of the pregnancy, but this is not reported as an AE or SAE 
 
 
 
 

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APPENDIX G:  CHIMERISM ANALYSIS 
 
Samples from FHCRC should be sent to Clinical Immunogenetics Lab (206-667-7700; SCCA G7-
200) for a DNA-based assay that compares the profile of amplified fragment length 
polymorphisms (ampFLP) of the patient and donor.  
 
Sample should consist of 20cc (or 2cc/kg for patients <10kg) peripheral blood in heparinized 
green top and 3cc red top tube (no additive) 
 
Other institutions may use VNTR analysis (sex- matched transplants) or sex chromosome 
analysis 
 
 
APPENDIX H: GUIDELINES FOR MONITORING & MANAGEMENT OF NEUROTOXICITY 
Neurologic complications occur in approximately 6.4-19.2% (Dowling 2017, Syed 2016, Uckan 
2005) of patients after allogeneic hematopoietic stem cell transplantation. They are the cause of 
death in 10-15% of children undergoing allogeneic HSCT (Uckan 2005). Children who develop 
encephalopathy have a poor prognosis, with a minority experiencing partial or complete 
neurologic recovery. The etiologies of these complications are diverse and include infection, 
posterior reversible encephalopathy syndrome (PRES), metabolic encephalopathy, medications, 
GVHD, hemorrhage, multi-organ dysfunction, and inflammatory conditions. Risk factors for these 
complications include acute GVHD, thrombocytopenia, delayed platelet engraftment, primary 
underlying disease, and age (Dowling 2017, Syed 2016, Uckan 2005). CNS toxicity may occur at 
different rates among different donor sources (matched unrelated or haploidentical donors have 
a higher rate than matched related donors) (de Brabander 2000). 
 
Particular attention should be paid to the onset of Grade 2 or higher level of depressed 
consciousness, encephalopathy, hypersomnia, lethargy, leukoencephalopathy, meningismus, 
myelitis, reversible posterior leukoencephalopathy syndrome (PRES), seizure, or somnolence. 
 
Diagnostic evaluation should include assessment of focal versus generalized type of symptoms. 
Generalized findings may include seizures, metabolic encephalopathy, or infection, while focal 
findings raise suspicion for mass lesions, hemorrhage, stroke, or spinal cord abnormalities (Syed 
2016, Uckan 2005). 
 
Guidelines monitoring of neurotoxicity are provided in Table F.1. Patients should undergo a daily 
neurologic examination and mini-mental status examination (MMSE) (Folstein 1975) or modified 
mini mental status examination (pediatric population) while inpatient during the hematopoietic 
stem cell transplant, both before and after infusion of BPX-501. Daily neurologic examinations 
should also be performed during any readmissions after allogeneic HSCT. A neurologic 
examination should be performed as part of all routine clinical follow-up examinations during 
each outpatient visit while patients are being treated on BPX-501 clinical trials.   
 
 

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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 (e.g., Busulfan) or prophylactic GVHD medications (e.g., 
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)
•
Start management of stroke/ischemia per institutional guidelines if 
suspected
•
Administration of 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 (e.g. 
methylprednisolone 500 mg IV every 12 hours x 2 days for adults or 30 
mg/kg/day IV 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 repeated every 48 hours for up to 3 doses. Please 
notify the medical monitor at Bellicum prior to the administration of 
rimiducid for neurotoxicity (see Table H.3).
•
Peripheral blood should be sent to the Sponsor for research use to 
evaluate for 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
Within 4 hrs prior to rimiducid dose(s), 30 minutes after 
initiation of infusion; and at 2, 4, 6, 8, and 24 hours post-
rimiducid doses, and at 7, 14, 21, and 28 days after the final 
dose of rimiducid (if more than one dose is administered)
•
If cerebrospinal fluid (CSF) can be safely obtained, CSF should be sent to 
the Sponsor for research use to evaluate for BPX-501 cells (CD3+CD19+) 
prior to initiation of high-dose corticosteroids or rimiducid.  If a sample 
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rimiducid for the treatment of neurotoxicity, CSF should be sent to the 
Sponsor for research use to evaluate for BXP-501 cells (CD3+CD19
+) (see Table H.3) 
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. (see Table H.3)
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 
(e.g.
methylprednisolone 500 mg IV every 12 hours x 2 days for adults or 30
mg/kg/day IV x 2 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 (e.g.
methylprednisolone 500 mg IV every 12 hours x 2 days for adults or 30
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d.
recent seizures
e.
impaired consciousness
f.
papilledema
2.
Check platelet and coagulation status (platelet >
40 X 109/L; INR <1.5)
3.
Check medications before LP
Coagulopathy 
Uncorrected bleeding diathesisAnti-
coagulant medication 
Patient-related risk factors: 
1.
Determine risk profile and inform patient before
and during LP procedure
Procedures to Minimize Risk 
1.
25G atraumatic needle; small needle/atraumatic
needle
2.
<4 LP attempts
3.
Passive withdrawal
4.
Lateral recumbent position
1.
Collections up to 30 mL
Post-LP Headache, back pain, post-LP 
complaints, 
*Table H.3. modified from Engelborghs 2017
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. 
Engelborghs S, et al. Consensus guidelines for lumbar puncture in patients with neurological diseases. Elsevier. 
2017;8:111-126.  
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. 
Grauer O, et al.  Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic 
stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host 
disease.  Brain 2010;133:2852-2965. 
Kamble RT, et al.  Central nervous system graft-versus-host disease: report of two cases and literature review.  Bone 
Marrow Transplant. 2007;39:49-52. 
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. 
Uckan D, et al.  Life-threatening neurological complications after bone marrow transplantation. Bone Marrow 
Transplant 2005;35:71-76. 
 
 

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APPENDIX I: KARNOFSKY/LANSKY PERFORMANCE SCALE 
 
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