Conditions: Acute Myeloid Leukemia Myelodysplastic Syndromes
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study compares the safety and effectiveness of giving rivogenlecleucel (BPX-501 T cells) to patients with AML or MDS post haploidentical hematopoietic stem cell transplant compared to post-transplant cyclophosphamide.

Detailed description:
In the Phase 2 portion, participants will undergo αβ T cell and CD19+ B cell depleted haploidentical HSCT followed by an infusion of a fixed dose of rivogenlecleucel (BPX-501 T cells) per kg. These participants will be evaluated for prespecified dose limiting toxicities (DLTs) for a 100-day dose limiting toxicity window.

Following completion of the Phase 2 portion, participants will be enrolled and randomized to one of two treatment arms in the Phase 3 portion.

* Arm A:αβ T-cell and CD19+ B-cell-depleted haplo-HSCT plus treatment with rivogenlecleucel
* Arm B: haplo-HSCT plus post transplant cyclophosphamide

Pediatric patients ages 12-17 will also be included in US only.

Arms:
arm 1: Determining the safety of maximum allowable Dose for BPX-501 starting at 3 x 10E6 cells/kg

Rimiducid will be administered to inactivate rivogenlecleucel in the event of GVHD not responsive to standard of care treatment arm 2: αβ T cell and CD19+ B cell-depleted, related haploidentical hematopoietic stem cell transplantation (haplo-HSCT) plus rivogenlecleucel arm 3: haplo-HSCT followed by post-transplant cyclophosphamide (PTCy) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Interventions: intervention 1: rivogenlecleucel intervention 2: rimiducid intervention 3: Cyclophosphamide intervention 4: haplo-HSCT
Intervention descriptions: intervention 1: Biological: T cells transduced with caspase 9 safety switch intervention 2: administered to inactivate rivogenlecleucel in the event of GVHD intervention 3: GVHD prophylaxis intervention 4: treatment for disease

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
Version 3.0 
Page 1 of 109 
 
A Randomized Phase II/III Study of αβ T Cell-Depleted, Related, Haploidentical 
Hematopoietic Stem Cell Transplant (Haplo-HSCT) Plus Rivogenlecleucel vs. Haplo-HSCT 
Plus Post-Transplant Cyclophosphamide (PTCy) in Patients with Acute Myeloid Leukemia 
(AML) or Myelodysplastic Syndrome (MDS) 
 
Protocol Number: 
BPX501-301A 
Trial Sponsor: 
Bellicum Pharmaceuticals, Inc. 
2130 W. Holcombe Blvd, Suite 800 
Houston, TX 77030 
ClinicalTrials.Gov/ 
NCT03699475 
Version Number: 
3.0 
Date: 
05 Mar 2019 
 
Confidentiality Statement 
This document contains information confidential to Bellicum Pharmaceuticals, Inc. and it may not be disclosed to 
anyone other than recipient study staff and members of the Institutional Review Board (IRB)/Institutional Biosafety 
Committee (IBC) and Ethical Committees (ECs). This information cannot be used for any purpose other than either 
evaluation or conduct of the clinical study described here without prior written consent from Bellicum 
Pharmaceuticals, Inc. 
 
 
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Investigator’s Agreement 
I have read this protocol and agree to comply with all provisions set forth in this protocol, including 
all statements regarding confidentiality, and to complete the study within the time designated. 
I assume responsibility for the conduct of this study at my study site. I will ensure that I have 
sufficient resources allocated to this project such that the safety of my patients is protected at all 
times and that I complete my obligations to the sponsor according to the agreed timelines. I will 
delegate responsibilities only to those who are qualified by education, training, and experience. I 
will ensure the integrity of the data generated by my team and that all team members are familiar 
with the study protocol and the study medication. 
I agree that I will grant access to the applicable records, my staff allocated to the conduct of this 
protocol and my facilities for the purposes of monitoring, auditing and any required inspections 
associated with the conduct of this clinical trial. 
I agree to comply with the ICH Guideline on Good Clinical Practice, applicable EMA regulations 
and applicable FDA guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
Confidential information contained in the protocol document will not be used for any other purpose 
other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
Printed Name 
Principal Investigator 
 
 
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PROTOCOL SYNOPSIS  
Title: 
A Randomized Phase II/III Study of αβ T Cell-Depleted, Related, 
Haploidentical Hematopoietic Stem Cell Transplant (Haplo-HSCT) 
Plus Rivogenlecleucel vs. Haplo-HSCT Plus Post-Transplant 
Cyclophosphamide (PTCy) in Patients with Acute Myeloid 
Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
Protocol Number: 
BPX501-301A 
Version Number: 
3.0 
Investigational Product(s):   
Rivogenlecleucel ( BPX-501) 
Rimiducid (AP1903) 
Phase: 
II/III 
Indication(s): 
Acute Myeloid Leukemia 
Myelodysplastic Syndromes 
Sponsor: 
Bellicum Pharmaceuticals, Inc. 
Objectives: 
Phase II 
The primary objectives for the phase II portion of the study are as follows: 
• 
To determine the maximum allowable dose/schedule of rivogenlecleucel and the recommended 
Phase III dose of rivogenlecleucel 
• 
To assess the activity of rimiducid in subjects who develop GVHD post rivogenlecleucel 
administration 
Phase III 
Efficacy Objectives: 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of haplo-HSCT and rivogenlecleucel compared with haplo-HSCT and 
PTCy in subjects with AML and MDS as measured by overall survival (OS)  
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate relapse-free survival (RFS) 
• 
To evaluate graft-versus-host disease-free, relapse-free survival (GRFS)  
• 
To evaluate non-relapse mortality (NRM) 
• 
To evaluate time to resolution of GVHD after administration of rimiducid 
Safety Objectives: 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of haplo-HSCT and rivogenlecleucel compared with haplo-HSCT and 
PTCy in subjects with AML and MDS, focusing on serious adverse events, National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0), 
Grade > 3 adverse events 
Patient Reported Outcome Objectives: 
The patient reported outcome (PRO) objectives for this study are as follows: 
• 
To compare quality of life following haplo-HSCT and rivogenlecleucel compared with haplo-
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HSCT and PTCy in subjects with AML and MDS, as measured by MD Anderson Symptom 
Inventory (MDASI), Functional Assessment of Cancer Therapy – Bone Marrow Transplant 
(FACT-BMT), and 36-Item Short Form Health Survey (SF-36) 
Study Design: 
This is a two-part study, consisting of a single-arm Phase II and a randomized Phase III portion. Phase II 
is an open-label, multicenter study to assess safety and determine the MAD of rivogenlecleucel in 
subjects with AML or MDS. A total of approximately 10 subjects will be enrolled and dosed in Cohort 1 
to confirm the MAD of 3 x 106 BPX-501 cells/kg, based on evaluation of dose-limiting toxicities. Based 
on prespecified DLT criteria and dose modification rules, a second cohort (Cohort 2) may be opened at a 
lower dose level to enroll an additional 10 subjects, if needed.  
Following completion of Phase II and the Safety Cohort meeting, in the Phase III portion, 168 subjects 
will be enrolled and randomized 1:1 to receive either αβ T cell and CD19+ B cell-depleted haploidentical 
stem cell transplantation plus rivogenlecleucel (Arm A) or haploidentical stem cell transplantation plus 
post-transplant cyclophosphamide (Arm B). Randomization will be stratified according to the following 
factors:  
• 
Age (< 60 and >60) 
• 
Disease (AML vs. MDS) 
• 
Conditioning regimen 
Overall Study Design 
 
Number of Subjects: 
Approximately 10 subjects (but up to 20 subjects) will be dosed in Phase II. Approximately 168 subjects 
will be randomized from approximately 40 centers and randomly assigned in 1:1 ratio to receive either 
haplo-HSCT and rivogenlecleucel (Arm A) or haplo-HSCT and PTCy (Arm B). 
Study Duration: 
The enrollment period for Phase II is anticipated to be 3-4 months.  
The enrollment period for Phase III is anticipated to be 21 months. Patients will be followed until the time 
of death, study discontinuation, or the time of the primary analysis for OS, whichever occurs first. The 
primary analysis for OS is expected to occur approximately 42 months after the first patient is 
randomized, or, given 18 months of accrual, approximately 24 months after the last patient is randomized. 
 
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Study Population: 
The target study population consists of subjects with AML or MDS who meet all of the following 
inclusion criteria and none of the exclusion criteria: 
Subject Inclusion Criteria: 
1. Signed informed consent 
2. Meets institutional criteria to undergo allogeneic HSCT 
3. Age 12-70 y/o 
4. Diagnosis of AML or MDS as defined below: 
a. AML with intermediate to adverse risk as defined by ELN genetic risk stratification 
(Dohner 2017) 
i. AML in first complete remission (CR1) with high-risk features defined as > 1 
cycle of induction therapy required to achieve remission, OR preceding MDS or 
myeloproliferative disease 
1. Adverse cytogenetics as defined below:  
a. t(6;9)(p23;q34.1); DEK-NUP214  
b. t(v;11q23.3); KMT2A rearranged 
c. t(9;22)(q34.1;q11.2); BCR-ABL1  
d. inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); 
GATA2,MECOM(EVI1)  
e. -5 or del(5q); -7; -17/abn(17p)  
f. Complex karyotype, monosomal karyotype 
g. Wild-type NPM1 and FLT3-ITDhigh 
h. Mutated RUNX1 
i. 
Mutated ASXL 
j. 
Mutated TP53 
ii. AML in CR1 with > 1 of the following intermediate-risk features: 
1. mutated NPM1 and FLT3-ITD high 
2. wild-type NPM1 without FLT3-ITD or with FLT3-ITD low (without 
adverse-risk genetic lesions)  
3. t(9;11)(p21.3;q23.3) MLLT3-KMT2A 
4. Cytogenetic abnormalities not classified as favorable or adverse  
b. AML in second or subsequent complete remission  
c. AML with myelodysplasia-related changes (AML-MRC) in first or subsequent complete 
remission. 
d. Therapy-related AML in first or subsequent complete remission 
e. De novo AML in first complete remission with intermediate or adverse genetic 
abnormalities 
f. De novo AML in second or subsequent complete remission 
g. MDS  
i. High or very high-risk by IPSS-R classification 
ii. Intermediate risk or higher having failed a hypomethylating agent  
5. Lack of suitable conventional donor (i.e., HLA 10/10 related or unrelated donor) 
6. At least a 5/10 genotypic identical haplotype match measured by HLA typing at high resolution 
(allele level) for the HLA-A, -B, -C, -DRBl, and -DQB1 loci 
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7. The donor and recipient must be identical for at least one allele of each of the following genetic 
loci: HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 
8. Patients with adequate organ function as measured by: 
a. Cardiac: Left ventricular ejection fraction > 40% 
b. Pulmonary: DLCO (corrected for hemoglobin) > 40% and FEV1 > 50% 
c. Hepatic: total bilirubin < 2x the upper limit of normal and ALT and AST < 3x the upper 
limit of normal.  
d. Renal: estimated creatinine clearance > 50 mL/min/based on the Cockcroft-Gault formula  
9. 
Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 
Subject Exclusion Criteria: 
1. HLA 10/10 allele matched (HLA-A, -B, -C, -DRBl, and -DQB1) related donor or unrelated donor   
a. An HLA 10/10 allele-matched unrelated donor may be considered eligible for the study if 
the Study PI determines a haploidentical donor is the best available donor option for the 
patient due to other considerations (e.g., graft acquisition time) 
2. Autologous hematopoietic stem cell transplant ≤ 3 months before enrollment 
3. Prior allogeneic transplantation 
4. Active CNS involvement by malignant cells (less than 2 months from conditioning) 
5. Current uncontrolled clinically active bacterial, viral or fungal infection 
6. Positive HIV serology or viral RNA 
7. Pregnancy (positive serum or urine βHCG) or breastfeeding 
8. Fertile men or women unwilling to use effective forms of birth control or abstinence for a year 
after transplantation 
9. Radiographic or histologic evidence of, or known history of cirrhosis 
10. Overlapping MDS and myeloproliferative neoplasms (MPN) disease  
11. Patients with acute promyelocytic leukemia (APL) 
12. Known hypersensitivity to dimethyl sulfoxide (DMSO) 
Donor Inclusion Criteria: 
1. Related donors include biological parents, siblings, or children, half-siblings or grandchildren 
2. Age 18-75 y/o 
3. Sufficiently healthy to undergo mobilization for peripheral blood stem cell harvest by institutional 
guidelines  
4. Should be at least a full haplotype matched donor (e.g., at least a 5/10 match at HLA-A, -B, -C, -
DRB1, and -DQB1); other selection criteria may include gender, age, CMV status and body 
weight of donor and presence of anti-donor HLA antibodies 
5. Donor must be examined and have specific tests performed according to existing institutional 
guidelines and meet institutional guidelines for candidacy as a donor 
6. Donor must have been informed of the investigational nature of rivogenlecleucel and the 
manufacturing process and have signed an informed consent form to undergo apheresis 
7. Donor must have adequate peripheral venous catheter access for leukapheresis or must agree to 
placement of a central catheter 
Donor Exclusion Criteria: 
1. Evidence of active infection (including urinary tract infection, upper respiratory tract infection, 
etc.) or viral hepatitis exposure (on screening), unless only HBs Ab+ and HBV DNA negative 
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2. Positive HIV serology or viral RNA 
3. Medical or physical reason why makes the donor unlikely to tolerate or cooperate with growth 
factor therapy and apheresis 
4. Factors that place the donor at increased risk for complications from apheresis or G-CSF therapy 
(e.g., autoimmune disease, sickle cell trait, symptomatic coronary artery disease requiring 
therapy, previous thrombotic events) 
5. Pregnancy (positive serum or urine βHCG) or breastfeeding 
Investigational Products: 
Rivogenlecleucel (formerly BPX-501) is a T cell product consisting of human T cells obtained from 
donor leukapheresis and gene modified to include the iCasp9 safety gene. The product is provided as a 
combined CD3+ and CD19+ frozen T cell suspension in a formulation containing DMSO for IV 
administration. 
Rivogenlecleucel will be administered as a single IV infusion on Day +14 after haplo-HSCT (window ± 4 
days). The dose for Phase II will be 3 x 106 BPX-501 cells/kg, and if this is determined to be the MAD, 
this will also be the dose pursued in Phase III. 
All subjects should receive premedications per institutional standards (e.g., acetaminophen plus an 
antihistamine) for cellular therapy products, for prevention of infusion-related/ hypersensitivity reactions.  
In subjects who receive rivogenlecleucel and develop GVHD and/or neurotoxicity, rimiducid is available 
to activate the iCasp9 safety gene and induce apoptosis of the gene modified cells. Rimiducid is a lipid-
permeable compound available for IV infusion and requires dilution prior to administration. Subjects who 
receive rimiducid and achieve clinical benefit may receive up to a total of 3 doses. Due to the risk of 
infusion-related reactions, subjects should receive premedication with acetaminophen, diphenhydramine, 
ranitidine, and other supportive care therapy per institutional standards for potential anaphylaxis. 
Study Assessments: 
Efficacy Assessments: 
Disease response will be assessed according to CIBMTR criteria for AML and MDS. An independent 
Data Monitoring Committee (iDMC) will be put in place to support independent analyses of trial efficacy 
and safety data. 
Safety Assessments: 
Adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities (type, frequency, and 
severity) will be collected. Adverse events of special interest (AESIs) will include Grade III-IV 
encephalopathy or neurologic events, Grade III-IV infections, Grade III-IV graft-versus-host disease, and 
graft failure; the list of AESIs may be updated during the course of the study based on observed safety 
signals. 
Replication-competent retrovirus (RCR) and viral copy number (VCN) will be performed at specified 
timepoints during the study. 
Other Assessments:  
The following assessments will be performed at specified timepoints. 
Pharmacokinetic Assessments: Limited PK parameters (for rimiducid) will be estimated using non-
compartmental analysis 
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Pharmacodynamics/Biomarkers: Biomarker assessments will include, but are not limited to, flow 
cytometry analysis of naïve and memory T cell populations, thymic function, T cell repertoire and T cell 
function.  
Statistical Methods: 
Phase II: 
The incidence, type, and severity of DLTs and the incidence and severity of AEs will be summarized. 
The incidence of acute GVHD (Grade II-IV and Grade III-IV) and chronic GVHD will be summarized, 
including the time of onset for each.  
The incidence of aGVHD and the outcome of treatment with rimiducid will be summarized.  
Phase III: 
The primary efficacy endpoint is OS, defined as the time from randomization to death due to any cause. 
Subjects will be followed until the time of death, study discontinuation, whichever occurs first. Subjects 
still on study at the time of primary analysis will be censored at the date they were last known to be alive. 
The primary analysis for OS is expected to occur approximately 42 months after the first patient is 
randomized, or, given 18 months of accrual, approximately 24 months after the last patient is randomized. 
 
 
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LIST OF ABBREVIATIONS AND TERMS 
AE 
Adverse Event 
Allo-HSCT 
Allogeneic Hematopoietic Stem Cell Transplant 
AML 
Acute Myeloid Leukemia 
aGVHD 
Acute Graft Versus Host Disease 
BMT 
Bone Marrow Transplant 
cGVHD 
Chronic Graft Versus Host Disease 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CTL 
Cytotoxic T Lymphocytes 
EC 
Ethics Committee  
eCRF 
Electronic Case Report Form 
DLT 
Dose Limiting Toxicity 
EBV 
Epstein-Barr Virus 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FKBP 
Human FK-506-Binding Protein 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GRFS 
Graft-Versus-Host Disease & Relapse-Free Survival 
GVHD 
Graft-Versus-Host Disease 
GVL 
Graft-Versus-Leukemia 
HSCT 
Hematopoietic Stem Cell Transplant 
HSV 
Herpes Simplex Virus 
IB 
Investigator’s Brochure 
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IBC 
Institutional Biosafety Committee  
iCasp9/iC9 
Inducible Caspase 9 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
iDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
INR 
Internationalized Normalized Ratio 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
ITT 
Intent to Treat 
IV 
Intravenous 
LP 
Lumbar Puncture 
LPLV 
Last Patient Last Visit 
MAD 
Maximum Allowable Dose 
MDS 
Myelodysplastic Syndrome 
MMSE 
Mini Mental Status Exam 
MNC 
Mononuclear Cell 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse Events 
NRM 
Non-Relapse Mortality 
PBMC 
Peripheral Blood Mononuclear Cell 
PBSC 
Peripheral Blood Stem Cells 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PRO 
Patient Reported Outcome 
PTCy 
Post-Transplant Cyclophosphamide 
PTLD 
Post-Transplant Lymphoproliferative Disorder 
RBC 
Red Blood Cell  
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RCR 
Replication Competent Retrovirus 
RFS 
Relapse-Free Survival 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
OS 
Overall Survival 
TBI 
Total Body Irradiation 
TCR 
T Cell Receptor 
VCN 
Vector Copy Number 
 
 
 
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Table of Contents 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL .................................................. 3 
PROTOCOL SYNOPSIS ............................................................................................................... 4 
LIST OF ABBREVIATIONS AND TERMS ............................................................................... 10 
List of Figures ............................................................................................................................... 18 
List of Tables ................................................................................................................................ 18 
1. INTRODUCTION .................................................................................................................... 20 
1.1 Allogeneic Stem Cell Transplant for AML and MDS ........................................................ 20 
1.2 Modified Donor T Cells After Allo-HSCT ......................................................................... 20 
1.3 Rivogenlecleucel Investigational Drug Product .................................................................. 20 
1.3.1 iCasp9 Safety Switch .................................................................................................... 21 
1.3.2 Rivogenlecleucel and GVHD Treatment Rationale ..................................................... 21 
1.4 Clinical Activity of Rivogenlecleucel +/- Rimiducid ......................................................... 22 
1.4.1 CASPALLO Trial ......................................................................................................... 22 
1.4.2 Rimiducid ..................................................................................................................... 22 
1.4.3 DOTTI Trial ................................................................................................................. 23 
1.5 Ongoing Sponsored Clinical Studies................................................................................... 23 
2. STUDY PURPOSE AND RATIONALE ................................................................................. 23 
2.1 Rationale for Patient Population ......................................................................................... 23 
2.2 Rationale for Study Treatment ............................................................................................ 23 
2.2.1 Rationale for Post-Transplant Cyclophosphamide Dose .............................................. 23 
2.2.2 Rationale for Starting Dose of Rivogenlecleucel ......................................................... 24 
2.2.3 Rationale for Starting Dose of Rimiducid .................................................................... 24 
2.3 Rationale for PK Evaluation ............................................................................................... 25 
2.4 Rationale for Biomarker Evaluation ................................................................................... 25 
2.5 Justification of Endpoints .................................................................................................... 25 
3. OBJECTIVES/ENDPOINTS .................................................................................................... 26 
4. STUDY DESIGN AND INVESTIGATIONAL PLAN ........................................................... 26 
4.1 Overall Study Design .......................................................................................................... 27 
4.2 Phase II Study Design ......................................................................................................... 27 
4.2.1 Dose-Limiting Toxicities .............................................................................................. 28 
4.3 Phase III Study Design ........................................................................................................ 29 
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4.4 OUTCOME MEASURES ................................................................................................... 30 
4.4.1 Safety Outcome Measures ............................................................................................ 30 
4.4.2 Efficacy Outcome Measures ......................................................................................... 30 
4.4.3 Pharmacokinetic Outcome Measures ........................................................................... 33 
4.4.4 Exploratory Biomarker Assessments ............................................................................ 34 
4.5 Study Oversight ................................................................................................................... 34 
4.5.1 Cohort Review Committee ........................................................................................... 34 
4.5.2 Independent Data Monitoring Committee .................................................................... 34 
4.6 End of Study ........................................................................................................................ 35 
5. STUDY POPULATION ........................................................................................................... 35 
5.1 Patient Eligibility: Inclusion Criteria .................................................................................. 35 
5.2 Patient Eligibility: Exclusion Criteria ................................................................................. 36 
5.3 Donor Eligibility: Inclusion Criteria ................................................................................... 37 
5.4 Donor Eligibility: Exclusion Criteria .................................................................................. 37 
5.5 Method of Treatment Assignment....................................................................................... 37 
5.5.1 Phase II ......................................................................................................................... 38 
5.5.2 Phase III ........................................................................................................................ 38 
6. STUDY TREATMENT ............................................................................................................ 38 
6.1 Phase II and Phase III Arm A: αβ T Cell/CD19+ B Cell Depleted Haplo-HSCT Plus 
Rivogenlecleucel ....................................................................................................................... 38 
6.1.1 Donor Leukapheresis and Rivogenlecleucel Manufacturing ........................................ 38 
6.1.2 Stem Cell Mobilization of Donor ................................................................................. 39 
6.1.3 Myeloablative Preparative (Conditioning) Regimen .................................................... 40 
6.1.4 HSCT Infusion .............................................................................................................. 41 
6.1.5 Rivogenlecleucel .......................................................................................................... 41 
6.1.6 Rimiducid ..................................................................................................................... 42 
6.1.7 Investigational Medicinal Product Accountability ....................................................... 42 
6.2 Phase III Arm B: Haplo-HSCT Plus Post-Transplant Cyclophosphamide (PTCy) ............ 43 
6.2.1 Stem Cell Mobilization of Donor ................................................................................. 43 
6.2.2 Myeloablative Preparative (Conditioning) Regimen (Arm B) ..................................... 43 
6.2.3 HSCT Infusion .............................................................................................................. 44 
6.2.4 Post-Transplant Cyclophosphamide (PTCy) Administration ....................................... 44 
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6.2.5 GVHD Prophylaxis....................................................................................................... 44 
6.3 Supportive Care ................................................................................................................... 45 
6.4 Concomitant Medications ................................................................................................... 45 
6.4.1 Permitted Therapies ...................................................................................................... 46 
6.4.2 Prohibited Therapies ..................................................................................................... 46 
7. STUDY ASSESSMENTS & PROCEDURES ......................................................................... 46 
7.1 Informed Consent ................................................................................................................ 46 
7.2 Screening ............................................................................................................................. 46 
7.2.1 Infectious Diseases Screening ...................................................................................... 47 
7.3 Study Assessments .............................................................................................................. 48 
7.3.1 Laboratory Monitoring ................................................................................................. 48 
7.3.2 Surveillance Cultures and Microbiological Monitoring ............................................... 48 
7.3.3 Disease Evaluations ...................................................................................................... 49 
7.3.4 Minimal Residual Disease Evaluations ........................................................................ 49 
7.3.5 Exploratory Biomarker Sample Collection .................................................................. 49 
7.3.6 Gene Therapy Monitoring Plan .................................................................................... 49 
7.4 Assessments to be Performed upon Disease Progression or Relapse ................................. 50 
7.5 Survival Follow-up and Subsequent Anticancer Therapy ................................................... 50 
7.6 Subject Discontinuation ...................................................................................................... 50 
7.7 Study Discontinuation ......................................................................................................... 51 
7.8 Long-term Follow-up (LTFU) Study (Phase II and Phase III Arm A) ............................... 51 
8. POTENTIAL RISKS AND MANAGEMENT OF TREATMENT TOXICITIES .................. 51 
8.1 Risks Associated with Rivogenlecleucel............................................................................. 51 
8.2 Acute GVHD ....................................................................................................................... 52 
8.3 Chronic GVHD ................................................................................................................... 54 
8.4 Neurotoxicity ....................................................................................................................... 55 
8.5 Risks Associated with Rimiducid ....................................................................................... 59 
8.5.1 Management of Patients Who Experience Rimiducid-Specific Adverse Events ......... 60 
8.6 Risks Associated with Cyclophosphamide ......................................................................... 60 
9. SAFETY REPORTING AND EVALUATION ....................................................................... 60 
9.1 Safety Plan........................................................................................................................... 60 
9.2 Safety Parameters & Definitions ......................................................................................... 60 
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9.2.1 Adverse Event............................................................................................................... 61 
9.2.2 Serious Adverse Event .................................................................................................. 61 
9.2.3 Protocol-Defined Events of Special Interest/Non-Serious Expedited Adverse Events 62 
9.3 Eliciting Adverse Events ..................................................................................................... 62 
9.4 Assessment of Severity and Causality of Adverse Events .................................................. 62 
9.5 Recording Adverse Events on the CRF............................................................................... 63 
9.5.1 Diagnosis versus Signs and Symptoms ........................................................................ 64 
9.5.2 Adverse Events Occurring Secondary to Other Events ................................................ 64 
9.5.3 Persistent or Recurrent Adverse Events ....................................................................... 64 
9.5.4 Abnormal Laboratory Values ....................................................................................... 64 
9.5.5 Deaths ........................................................................................................................... 65 
9.5.6 Preexisting Medical Conditions.................................................................................... 65 
9.5.7 Hospitalization, Prolonged Hospitalization or Surgery ................................................ 65 
9.5.8 Pregnancy ..................................................................................................................... 65 
9.6 Guidance for Capturing and Reporting Adverse Events ..................................................... 66 
9.6.1 Adverse Event Reporting Period .................................................................................. 66 
9.6.2 Procedures for Eliciting and Recording Adverse Events ............................................. 67 
9.6.3 Expedited Reporting Requirements for Serious Adverse Events or Protocol Defined 
Events of Special Interest ...................................................................................................... 67 
9.6.4 Reporting Requirements for All SAEs and Pregnancy Reports ................................... 67 
9.6.5 Reporting SAEs to the IRB or Ethics Committee ........................................................ 67 
9.6.6 Type and Duration of Follow-Up of Patients after Adverse Events ............................. 68 
9.6.7 Post-Study Adverse Events .......................................................................................... 68 
10. STATISTICAL AND ANALYSIS PLAN ............................................................................. 68 
10.1 General Statistical Approach ............................................................................................. 68 
10.2 Study Design and Randomization ..................................................................................... 69 
10.3 Sample Size Determination ............................................................................................... 69 
10.3.1 Phase II ....................................................................................................................... 69 
10.3.2 Phase III ...................................................................................................................... 70 
10.4. Populations for Analyses .................................................................................................. 70 
10.4.1 Phase II ....................................................................................................................... 70 
10.4.2 Phase III ...................................................................................................................... 70 
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10.5 Statistical Analyses ........................................................................................................... 71 
10.5.1 Phase II Analysis ........................................................................................................ 71 
10.5.2 Phase III Analysis ....................................................................................................... 71 
10.5.3. Safety Analyses (Toxicities) ...................................................................................... 73 
10.5.4 Other Analyses ........................................................................................................... 73 
10.6 Interim Analyses ............................................................................................................... 73 
11. DATA QUALITY AND MONITORING REQUIREMENTS .............................................. 74 
11.1 Case Report Forms ............................................................................................................ 74 
11.2 Study Monitoring .............................................................................................................. 74 
11.3 Use of Computerized Systems .......................................................................................... 75 
12. ETHICAL CONSIDERATIONS ............................................................................................ 75 
12.1 Compliance with Laws and Regulations ........................................................................... 75 
12.2 Informed Consent .............................................................................................................. 75 
12.3 Institutional Review Board or Ethics Committee ............................................................. 76 
12.4 Confidentiality ................................................................................................................... 76 
12.5 Future Use of Stored Specimens ....................................................................................... 77 
13. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ..................... 77 
13.1 Investigator Responsibilities ............................................................................................. 77 
13.2 Study Documentation ........................................................................................................ 77 
13.3 Retention of Records ......................................................................................................... 78 
13.4 Site Audits and Regulatory Inspections ............................................................................ 78 
13.5 Protocol Deviations ........................................................................................................... 78 
13.6 Financial Disclosure .......................................................................................................... 78 
13.7 Quality Control and Quality Assurance ............................................................................ 78 
13.8 Publication Policy ............................................................................................................. 79 
14. REFERENCES ....................................................................................................................... 80 
Appendix A: Arm A – Schedule of Assessments ...................................................................... 84 
Table A-14: Pre-treatment Period ............................................................................................. 84 
Table A-15: Treatment Period (Day 0 up to Day +100) ........................................................... 86 
Table A-16: Treatment Period (> Day 100 to End of Study) .................................................... 89 
Appendix B: Arm B – Schedule of Assessments.......................................................................... 92 
Table B-17: Pre-treatment Period ............................................................................................. 92 
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Table B-18: Treatment Period (Day 0 up to Day +100) ........................................................... 94 
Table B-19: Treatment Period (> Day 100 to End of Study) .................................................... 97 
Appendix C: Donor – Schedule of Assessments .......................................................................... 99 
Table C-20: Donor Assessments ............................................................................................... 99 
Appendix D: Research Laboratory Tests for Subjects Receiving Rivogenlecleucel .................. 100 
Appendix E: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale and 
Conversion from Karnofsky Scale .............................................................................................. 102 
Appendix F: Acute GVHD Grading Scale.................................................................................. 103 
Appendix G: Chronic GVHD Activity Assessment – Clinician ................................................. 104 
Appendix H: GVHD Response Criteria ...................................................................................... 107 
Appendix I: Chronic GVHD Activity Assessment – Patient Self Report .................................. 108 
Appendix J: Response Determination for Chronic GVHD Based on Clinician Assessment ..... 109 
 
List of Figures 
Figure 1: Overall Study Design .................................................................................................... 27 
Figure 2: Phase II Design .............................................................................................................. 27 
Figure 3: Phase III Study Schema ................................................................................................. 29 
Figure 4: Study Schema for Subjects Receiving Rivogenlecleucel .............................................. 38 
 
List of Tables 
Table 1: Study Objectives and Endpoints ..................................................................................... 26 
Table 2: Alternative Dose Exploration if MAD is Exceeded in Cohort 1 .................................... 29 
Table 3: Pretransplant Infectious Diseases Screening .................................................................. 47 
Table 4: Guidelines for Management of Acute GVHD ................................................................ 52 
Table 5: Guidelines for Management of Chronic GVHD ............................................................. 54 
Table 6:  Monitoring for Neurologic Complications .................................................................... 56 
Table 7: Guidelines for Management of Neurotoxicity ................................................................ 56 
Table 8: Recommended Procedures to Rule-out Contraindications for LP and Procedures to 
Minimize Risks ............................................................................................................................. 59 
Table 9: Adverse Event Grading (Severity) Scale ........................................................................ 62 
Table 10: Causal Attribution Guidance ........................................................................................ 63 
Table 11: Adverse Event Reporting Guidelines ........................................................................... 66 
Table A-12: Pre-treatment Period ................................................................................................. 84 
Table A-13: Treatment Period (Day 0 up to Day +100) ............................................................... 86 
Table A-14: Treatment Period (> Day 100 to End of Study) ....................................................... 89 
Table B-15: Pre-treatment Period ................................................................................................. 92 
Table B-16: Treatment Period (Day 0 up to Day +100) ............................................................... 94 
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Table B-17: Treatment Period (> Day 100 to End of Study) ........................................................ 97 
Table C-18: Donor Assessments ................................................................................................... 99 
 
 
 
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1. INTRODUCTION 
1.1 Allogeneic Stem Cell Transplant for AML and MDS 
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder resulting from accumulation 
of abnormal immature cells in the bone marrow, which interfere with normal hematopoiesis and 
subsequently leads to fatal infection, bleeding, or organ infiltration (Estey 2006). The 
myelodysplastic syndromes (MDS) encompass a series of hematologic conditions characterized 
by chronic cytopenias and abnormal cellular maturation, which may in turn predisposes the 
patient towards progression to AML, often refractory to treatment (Scott 2010). Together, AML 
and MDS are the most common myeloid malignancies in adults, affecting predominantly an 
older population.  
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option 
for patients with refractory/relapsed AML or high-risk MDS. The combination of high-dose 
conditioning chemotherapy/radiation, followed by donor peripheral blood or marrow stem cell 
products, including mature and immature immune cells, can induce an immune response that 
helps to destroy any remaining leukemia cells, known as the "graft-versus-leukemia" (GVL) 
effect. Available clinical data have established that the T cells contained within the donor graft 
exert this GVL effect. Also, targeted αβ T cell depletion may limit graft-versus-host disease 
(GVHD) (Locatelli 2017, Bertaina 2014) while maintaining the GVL effect and potentially 
decreasing opportunistic infections. The combined benefit of targeted αβ T cell depletion and T 
cells to induce GVL is hypothesized to be instrumental in long term efficacy of patients treated 
with allo-HSCT. 
1.2 Modified Donor T Cells After Allo-HSCT 
Despite this potential therapeutic benefit of GVL and decrease in opportunistic infections, the 
utilization of a “T cell add back” standard approach is limited in clinical practice due to the 
potential for GVHD. Graft-versus-host disease can result in devastating effects on the patient and 
is challenging to treat. T cell depletion strategies have reduced GVHD rates (Bertaina 2014); 
however, such approaches may be associated with reduced GVL and potential for increased 
opportunistic infections due to delayed immune reconstitution. A treatment approach of selective 
depletion of αβ T cells and CD19+ B cells, coupled with an infusion of polyclonal T cells with a 
broad T cell repertoire (BPX-501 T cells) with an inducible Caspase-9 safety switch may lead to 
low rates of GVHD and more rapid immune reconstitution. 
1.3 Rivogenlecleucel Investigational Drug Product 
Rivogenlecleucel (formerly BPX-501) is an investigational product in clinical development to 
allow for improved immune reconstitution, possible protection from infections, and a reduction 
in malignancy relapse. 
Rivogenlecleucel consists of human T cells which are obtained from normal donor 
leukapheresis, ex vivo culture-expanded to high purity, gene-modified with BPZ-1001 
(SFG.iCasp9.2A.ΔCD19 retroviral vector containing the iCasp9 safety gene, as well as truncated 
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CD19 selectable marker), and then selected to ensure a high percentage of T cells carrying the 
safety gene. The final product is formulated, cryopreserved, shipped to the clinical site, thawed 
and infused into the patient. Rivogenlecleucel is intended to aid in engraftment, promote immune 
reconstitution, potentially aid in graft versus leukemia (GVL) effect and can be removed from 
the body upon infusion of the dimerizing agent, rimiducid.  
1.3.1 iCasp9 Safety Switch 
Unmodified donor T cell infusion is potentially an effective strategy for conferring anti-viral and 
anti-tumor immunity following allogeneic stem cell transplantation (Di Stasi 2011). However, 
the administration of greater than 105 cells/kg unmodified donor T cells to recipients of 
haploidentical stem cell transplantation has been associated with increased incidence of GVHD. 
It has been previously demonstrated that administration of up to 107 cells/kg of CD25+ 
allodepleted donor T cells after haploidentical transplantation for hematological malignancies 
could be administered safely and that the addition of these T cells was effective in controlling 
viral disease (Amrolia 2006). However, mortality due to disease relapse remained high, 
presumably due to the estimated frequency of tumor-reactive precursors being 1 to 2 logs lower 
than the frequency of virus-reactive precursors. The use of higher numbers of allodepleted T 
cells containing an inducible caspase 9 safety gene to treat the potential increase in GVHD was 
then evaluated. The caspase-recruiting domain of the human caspase 9 was modified with a drug 
binding domain, permitting T cell elimination after administration of a chemical dimerization 
drug, rimiducid. Administration of rimiducid dimerizes and activates caspase 9 which activates 
downstream caspases, leading to apoptosis potentially within minutes to hours (Di Stasi 2011; 
Tey 2007).  
The gammaretrovirus, SFG.iCaspase9.2ADeltaCD19 (BPZ-1001), consists of inducible caspase 
9 (iCasp9) linked, via a 2A-like sequence, to truncated human CD19 (DeltaCD19). The iCasp9 
genetic modification, unlike the HSV-TK based safety gene, is human-derived and therefore 
likely to be less immunogenic. Moreover, pre-clinical and clinical studies show that killing 
occurs with much greater rapidity (within 3 hours) than with HSV-TK. Further advantages of the 
iCasp9 system are that killing induced by the dimerizer drug is primarily restricted to 
activated/proliferating cells, thus targeting alloreactive T cells active in GVHD but sparing anti-
viral donor T cells and potentially anti-tumor specific T cells. Additionally, administration of the 
commonly used drug, ganciclovir, is not precluded which is a limitation of the HSV thymidine 
kinase depletion strategies. 
1.3.2 Rivogenlecleucel and GVHD Treatment Rationale 
The goal of graft engineering is to enable alternative transplants such as haploidentical-related 
HSCT to be performed as safely as matched unrelated donor transplants. Anasetti and colleagues 
published data from the BMT CTN 0201 randomized study of matched unrelated donor bone 
marrow (BM) vs. peripheral blood (PB) in hematopoietic cell transplantation for hematologic 
malignancies. Results from the primary analysis after 2 years of follow up showed similar 
survival, disease-free survival and treatment-related mortality between the graft types. There 
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were higher rates of graft failure with BM (9% v. 3%; p=0.002) and a higher rate of chronic 
GVHD with PB (53% v 41%; p=0.01) (Anasetti 2012).  
Lee and colleagues later published 5-year results from this study, specifically looking at GVHD 
quality of life measures. Their results showed that at 5 years, patient reported outcomes (PROs) 
were all significantly better for BM patients (as measured by Functional Assessment of Cancer 
Therapies – Bone Marrow Transplant (FACT-BMT) Trial Outcome Index (TOI), Mental Health 
Inventory (MHI) psychological well-being, and cGVHD symptoms scale scores) (Lee 2015). 
1.4 Clinical Activity of Rivogenlecleucel +/- Rimiducid 
1.4.1 CASPALLO TRIAL 
In a Phase I study, ten subjects between the ages of 3 and 17 years who had undergone stem cell 
transplantation for relapsed acute leukemia were treated with the genetically modified T cells. 
The cells were detected in peripheral blood from all ten subjects and increased in number over 
time, despite their constitutive transgene expression. A single dose of the dimerizing drug, 
rimiducid, given to the subjects in whom GVHD developed, eliminated more than 90% of the 
modified T cells within 30 minutes after administration and a further log reduction within 24 
hours. Moreover, acute GVHD of the skin in all three subjects treated with rimiducid, and of the 
liver disease in one, completely resolved after 24 hours (Di Stasi 2011).  
The residual iCasp9 gene-modified T cell population expanded over the next 4-14 days and 
continued to help repopulate the subjects’ immune systems. The transduced cells were further 
shown to contain the virus and fungal-peptide specific precursor cells which had not caused 
further GVHD. When examined ex vivo, these non-alloreactive iCasp9 T cells remained 
susceptible to apoptosis following exposure to the dimerizer rimiducid. The authors concluded 
that a single dose of dimerizer drug could eliminate the subpopulation of T cells causing GVHD 
but could spare viral-specific CTLs. 
The iCasp9 gene is most highly expressed in activated and proliferating T cells, such as those 
causing GVHD. If cells are not activated, due to lack of viral stimulation, for example, 
expression of the transgene is lower and in a minority of these cells, iCasp9 levels are 
insufficient to induce apoptosis after single rimiducid dose exposure, allowing subsequent re-
expansion (Berger 2004). This hypothesis was supported by the CASPALLO clinical data 
showing activation-dependent induction of iCasp9 in gene-modified T lymphocytes and 
enhanced susceptibility to dimerizer drug in activated versus resting T cells. 
1.4.2 Rimiducid 
Rimiducid is a member of a new class of lipid-permeable compounds termed activating, or 
dimerizer, drugs that act by inducing clustering of engineered proteins inside cells. Rimiducid-
inducible activation of the iCasp9 protein is achieved by expressing a chimeric protein (iCasp9), 
fused to a drug-binding domain derived from human FK506-binding protein (FKBP). This 
chimeric protein is quiescent inside cells until the administration of rimiducid, which cross-links 
the FKBP domains of two of these iCasp9 proteins, initiating iCasp9 signaling. This signaling 
induces apoptosis of the gene-modified cells. 
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1.4.3 DOTTI Trial 
In a follow-up to the CASPALLO trial, an investigator-sponsored Phase I study (DOTTI) was 
performed to assess the safety and efficacy of iCasp9 T cells not depleted of an alloreactive 
component. Twelve subjects who underwent haplo-HSCT (median age, 10 years; range, 2-50 
years) were infused with non-allodepleted iCasp9 T cells. Four subjects developed Grade I & II 
acute GVHD and received a single dose of rimiducid eliminating 85-95% of circulating iCasp9 T 
cells within 30 minutes of rimiducid infusion, with no recurrence of GVHD within 90 days. 
There were no immediate or delayed adverse events reported associated with the rimiducid 
infusion. 
Following activation and expansion in vivo, adoptively transferred T cells can produce 
proinflammatory cytokines and induce other cells, including monocytes, to release additional 
proinflammatory mediators causing life-threatening cytokine release syndrome (CRS). Although 
severe CRS is an uncommon manifestation of T cell engraftment after HSCT, one subject in this 
trial developed signs and symptoms compatible with GVHD and CRS. Administration of 
rimiducid improved clinical symptoms and decreased proinflammatory cytokines including IL-6. 
(Zhou 2015). 
1.5 Ongoing Sponsored Clinical Studies 
Currently, there are multiple ongoing clinical trials sponsored by Bellicum investigating 
rivogenlecleucel and rimiducid in different populations, including adult and pediatric subjects. 
For additional information on these trials, please refer to the rivogenlecleucel and rimiducid 
Investigator’s Brochures.  
2. STUDY PURPOSE AND RATIONALE  
2.1 Rationale for Patient Population 
Approximately 50% of patients who could potentially benefit from HSCT do not have an 
HLA-identical sibling or an HLA-identical unrelated donor. This percentage is even higher 
among patients belonging to non-Caucasian populations, as unrelated donor registries contain 
relatively fewer donors from these populations (~20%) vs. Caucasian populations (~80%) 
(CIBMTR Transplant Summary Report, 2012-2016). Development of an alternative stem cell 
source for patients facing these challenges could expand opportunities for stem cell transplant 
and is hypothesized to improve patient outcomes.   
2.2 Rationale for Study Treatment 
2.2.1 Rationale for Post-Transplant Cyclophosphamide Dose  
Cyclophosphamide is an alkylating agent used for the treatment of multiple malignant diseases. 
The administration of high-dose post-transplantation cyclophosphamide (PTCy) has shown 
positive results in the reduction of GVHD.  
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Recent studies have shown that high-dose cyclophosphamide given early after HSCT does not 
compromise engraftment and can decrease the risk of chronic GVHD. In studies of HLA 
haploidentical BMT with reduced-intensity conditioning, PTCy was given at 50 mg/kg on days 3 
and 4 or only on day 3 followed by tacrolimus and mycophenolate mofetil (MMF) (O’Donnell 
2002; Luznik 2008; Luznik 2012). The cumulative incidences of grades II-IV GVHD and grades 
III-IV aGVHD were 34% and 6%, respectively; the incidence of extensive chronic GVHD was 
25% after a single dose of cyclophosphamide and only 5% after 2 doses of PTCy (Luznik 2008). 
In a prospective phase 2 study, high-dose cyclophosphamide was given as single agent 
prophylaxis on days 3 and 4 after HLA-matched related or unrelated BMT with 
busulfan/cyclophosphamide conditioning. The day 100 cumulative incidences of grades II-IV 
aGVHD and grades III-IV aGVHD were 43% and 10%, respectively (Luznik 2010). In a follow-
up study, PTCy was given on days 3 and 4 after HLA-matched related or unrelated BMT with 
busulfan/fludarabine conditioning. The cumulative incidences of grades II-IV aGVHD, grades 
III-IV aGVHD, and chronic GVHD were 51%, 15%, and 14%, respectively. Taken together, 
these results show that the cumulative incidences of GVHD is consistent when PTCy is given as 
the sole GVHD prophylaxis after HLA-matched related or unrelated BMT (Kanakry 2014). 
2.2.2 Rationale for Starting Dose of Rivogenlecleucel 
The first dose level explored in this trial will be rivogenlecleucel 3 x 106 cells/kg. This dose level 
was initially explored in the CASPALLO study in pediatric subjects (n= 2) and further evaluated 
in adults in BP-001, a Phase I/II dose escalation trial study evaluating safety and feasibility of 
rivogenlecleucel after partially mismatched, related, T cell depleted HSCT. In this trial, four dose 
levels were explored in the dose escalation stage (1 x 105, 2 x 105, 5 x 105, and 3 x 106 BPX-501 
T cells/kg), and 3 x 106 BPX-501 cells/kg was determined to be the MAD. Preliminary analysis 
of the 19 subjects treated at this dose level suggests that the toxicity is relatively mild with one 
case of Grade III acute GVHD. 
In BP-001, subjects received GVHD prophylaxis with an abbreviated course of tacrolimus (60 
days post-HSCT). In this study, the Phase II portion will help to establish the MAD of BPX-501 
in subjects who do not receive GVHD prophylaxis other than T cell depletion.  
2.2.3 Rationale for Starting Dose of Rimiducid 
The utility of employing rimiducid in the elimination of transduced lymphocytes under the 
control of iCasp9 has been evaluated in many models including a murine model implanted with 
Raji tumor cells [Bellicum Study #BEL-R&D-RP-0069]. Here, eight-week-old female, immune-
deficient mice (NOD.CgPrkdcscid Il2rgtm1Wjl/SzJ; NSG) were engrafted with 5x105 Raji tumor 
cells re-suspended in 100 µL of PBS. After 2 days, mice were injected IV with 1x107 firefly 
luciferase-enhanced green fluorescent protein (ffLuc-eGFP) labeled CD19-CIDeCAR-T cells. To 
evaluate the functionality of the safety gene, mice bearing Raji tumor cells, and receiving CAR-T 
cells (transduced with the F36V-FKBP receptor) labeled with the eGFP-FFluc gene, were treated 
with rimiducid (intraperitoneal dosing) over a wide range of doses (5, 0.5, 0.05, 0.005, 0.0005, or 
0.00005 mg/kg). Rimiducid treatment was initiated when the T cell bioluminescent signal was 
exponentially increasing and/or after mice lost 15% of body weight, indicating active expansion 
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of the transgenic cells. Circulating transfected CAR-T cells were rapidly eliminated, as 
evidenced by diminished luminescence (BLI), following a single administration of rimiducid 
with maximal effects noted at doses of 0.5 and 5 mg/kg.  An evaluation of the disposition of 
rimiducid in the NSG mouse has established similar exposures, regarding both Cmax and AUC, 
following the parenteral administration of equivalent doses in humans (Iuliucci 2001).  
Therefore, maximal responses to rimiducid are likely to occur in the range of 0.5 to 5.0 mg/kg.  
Furthermore, in previous clinical studies conducted in both adult and pediatric subjects, an 
intravenous dose of 0.4 mg/kg efficiently eliminated alloreactive BPX-501 cells (Di Stasi 2011; 
Zhou 2015). 
2.3 Rationale for PK Evaluation 
The pharmacokinetics of rimiducid have been evaluated in 28 normal healthy volunteers in a 
Phase 1 single ascending dose study. Rimiducid exhibited linear pharmacokinetics across all 
doses from 0.01 to 1.0 mg/kg. Dose-adjusted Cmax was approximately 1200 ng/mL, while 
clearance remained constant across all doses at 5.5 to 7.5 ng/ml/kg. To date, a comprehensive 
evaluation of the disposition of rimiducid in patients has not been conducted. Therefore, this 
study will serve as an important source for the initial evaluation of rimiducid PK in adult subjects 
with AML. 
2.4 Rationale for Biomarker Evaluation 
The effect of rivogenlecleucel on immune reconstitution, thymic function, and T cell repertoire 
has not been formally assessed in this patient population particularly in direct comparison to 
patients receiving PTCy for GVHD prophylaxis. Assessment of the relative contribution of 
rivogenlecleucel to the T cell repertoire in the post-transplant period and the role of 
rivogenlecleucel in response to a tumor or opportunistic infection will inform a more thorough 
understanding of the mechanism of action of rivogenlecleucel. 
2.5 Justification of Endpoints 
The primary objective of the Phase II portion of the study will be to establish the safety and 
maximum tolerated dose (MTD) of rivogenlecleucel in patients with AML/MDS undergoing αβ 
T cell and CD19+ B cell depleted haplo-HSCT. This will be determined by the incidence and 
severity of all adverse events (AEs), including dose-limiting toxicities (DLTs). 
The primary objective of the Phase portion of the study will be to confirm the safety and efficacy 
of rivogenlecleucel in the sample population of patients. This will be determined by overall 
survival (OS) as assessed by an independent Data Monitoring Committee (iDMC). Key 
secondary endpoints of the Phase III portion of this study are the rate of graft-versus-host disease 
(GVHD), relapse-free survival (RFS), and non-relapse mortality (NRM). Treatment response 
will be assessed according to the Center for International Blood & Marrow Transplant Research 
(CIBMTR) response criteria for AML and MDS.  
 
 
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3. OBJECTIVES/ENDPOINTS 
The objectives and corresponding endpoints for the study are presented in Table 1. 
Table 1: Study Objectives and Endpoints 
Objective 
Endpoints 
Phase II 
Primary 
• 
Determine the maximum allowable 
dose/schedule of rivogenlecleucel  
• 
Assess the activity of rimiducid in 
subjects developing GVHD post 
rivogenlecleucel administration 
• 
Determine the recommended Phase 
III dose of rivogenlecleucel 
• 
Incidence of DLTs 
• 
Incidence and severity of adverse events (AEs) 
• 
Assess the rate of GVHD in subjects at the established 
rivogenlecleucel maximum allowable dose (MAD) 
 
Phase III 
Primary 
• 
Evaluate overall survival (OS) 
• 
OS, as defined as the time from randomization until 
death from any cause 
Secondary 
• 
Evaluate supportive measures of 
activity of rivogenlecleucel on 
relapse-free survival (RFS), graft-
versus-host disease-free, relapse-
free survival (GRFS), and non-
relapse mortality (NRM) 
• 
RFS, defined as the time from randomization to 
relapse or death from any cause, whichever comes 
first, in subjects in remission 
• 
GRFS, defined as the time from randomization to the 
occurrence of Grade III-IV acute GVHD; chronic 
GVHD requiring systemic immunosuppression; disease 
relapse or death; whichever comes first  
• 
NRM, defined as time from randomization to death 
without relapse/disease progression  
• 
Evaluate efficacy of rimiducid in 
resolving GVHD after 
rivogenlecleucel 
• 
Time to resolution of GVHD after administration of 
rimiducid 
• 
Assess patient-reported outcomes 
(PROs) and quality of life 
measures 
• 
FACT-BMT total score (change from baseline) 
• 
SF-36 total score (change from baseline) 
• 
MDASI total score (change from baseline) 
 
4. STUDY DESIGN AND INVESTIGATIONAL PLAN 
This is an open-label, multicenter, randomized Phase II/III study to evaluate the efficacy of αβ T 
cell and CD19+ B cell-depleted, related haploidentical hematopoietic stem cell transplantation 
(haplo-HSCT) plus rivogenlecleucel vs. haplo-HSCT followed by post-transplant 
cyclophosphamide (PTCy) in subjects with AML or MDS. 
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4.1 Overall Study Design 
This study will consist of two parts – a single-arm Phase II portion (to establish MAD, safety and 
preliminary activity) and a randomized Phase III portion (to assess safety and efficacy). The 
overall study design is described schematically in Figure 1. 
Figure 1: Overall Study Design  
 
4.2 Phase II Study Design 
This is an open-label, multicenter, Phase II study to assess safety and to determine the MAD of 
rivogenlecleucel in subjects with AML or MDS. A total of approximately 10 subjects will be 
enrolled and dosed in Cohort 1 to confirm the MAD of 3 x 106 BPX-501 cells/kg (Figure 2). 
Figure 2: Phase II Design 
 
Following a conditioning regimen (Section 6.1.3), subjects will undergo αβ T cell and CD19+ B 
cell-depleted HSCT on Day 0 followed by an infusion of rivogenlecleucel 3 x 106 cells/kg on 
Day +14 (with a window of ± 4 days). These subjects will be evaluated for prespecified dose 
limiting toxicities (DLTs) within a 100-day DLT window (Section 4.2.1).  
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Safety will be monitored by assessing adverse events including but not limited to rate of 
infection, and changes in physical exam and laboratory studies. 
Subjects participating in the Phase II portion of the study will continue on study and followed 
for safety leading up to roll-over in the Long-term Follow-up Study (Section 7.8). 
4.2.1 Dose-Limiting Toxicities 
The dose limiting toxicities detailed in this section will apply only to subjects enrolled in Phase 
II of the trial. Subjects enrolled outside of Phase II (i.e., Phase III) will undergo comprehensive 
safety assessments.  
All subjects who experience a DLT during the DLT assessment window of 100 days (HSCT to 
Study Day 100) will be considered evaluable for safety evaluation decisions.  
Subjects who withdraw from study treatment (rivogenlecleucel; rimiducid) for any reason other 
than a DLT during this assessment window will not be considered evaluable for DLTs and will be 
replaced.  
4.2.1.1 DLT Criteria  
A DLT is defined as one of the following toxicities occurring during the DLT assessment window 
that is considered by the investigator to be related to study treatment. If an adverse event is clearly 
due to progressive disease and unrelated to study treatment, these adverse events will not be 
considered DLTs. Investigators are encouraged to perform additional testing to determine the 
underlying etiology and most appropriate attribution.  
Any of the following adverse events that occur within the DLT window will be considered a DLT: 
• Grade III or IV acute GVHD attributable to rivogenlecleucel and non-responsive to > 1 
dose of rimiducid treatment (plus standard doses (at least 1 mg/kg) of methylprednisone 
or dose equivalent of other corticosteroids, and/or calcineurin inhibitor) within 14 days 
• Grade 3-4 neurologic events attributable to rivogenlecleucel 
• Death due to any cause other than underlying disease 
• Any CTCAE Grade 3-5 adverse events related to rivogenlecleucel (including allergic 
reactions, infusion reactions, and any other related adverse reactions whether expected or 
unexpected). 
4.2.1.1 Dose Modification Rules & Changes in Dose Following Dose-Limiting Toxicity 
Dose modification in Phase II will occur in accordance with the following rules: 
• Up to 10 subjects will be initially enrolled and dosed in Phase II (Cohort 1) 
• If > 3 of the 10 subjects enrolled experience a DLT attributable to rivogenlecleucel, an 
alternative dose/schedule will be evaluated and a second cohort will be opened (i.e., 
Cohort 2, Dose Level -1) 
• If < 3 of the 10 subjects enrolled experience a DLT attributable to rivogenlecleucel, this 
dose level will be assessed as the MAD and the recommended dose level for Phase III. 
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In the event of unacceptable toxicity, the Sponsor, in consultation with the Study Investigators, 
may decide to explore alternative dose/schedules. The regimen for additional dose levels will be 
adjusted and will depend on the safety and tolerability observed in Dose Level 1. Table 2 
describes adjustments that could possibly be made. 
Table 2: Alternative Dose Exploration if MAD is Exceeded in Cohort 1 
Cohort 1 Tolerability 
Safety Outcome 
Further Steps 
< 3 DLTs  
Determined safe and tolerable by DLT 
criteria 
None; MAD established 
 3 or more DLTs 
DLTs observed or Sponsor/Primary 
Investigator determined safety 
concerns 
Open Cohort 2: Enroll/dose 
approximately 10 subjects at 
Dose Level -1 of rivogenlecleucel 
1 x 106 cells/kg 
4.3 Phase III Study Design 
Following completion of Phase II and the Safety Cohort meeting, 168 subjects will be enrolled 
and randomized to one of two treatment arms (see Figure 3).  
• Arm A: αβ T cell and CD19+ B cell-depleted haploidentical stem cell transplantation 
plus rivogenlecleucel   
• Arm B: haploidentical stem cell transplantation plus post-transplant cyclophosphamide 
Figure 3: Phase III Study Schema 
 
Enrollment will follow a randomized 1:1 design including stratification factors (Section 5.5.2).  
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Subjects will undergo conditioning chemotherapy and infusion of stem cells (either T/B cell 
depleted or not).  Subjects in Arm A will receive an αβTCR/CD19+ depleted haploidentical 
stem cell transplant and rivogenlecleucel on Day +14 (±4 days) post-transplant (see Section 
6.1).  Subjects in Arm B will receive a T cell replete haploidentical HSCT followed by 
cyclophosphamide 50 mg/kg on Days +3 and +4 post-transplant (see Section 6.2). Subjects who 
develop GVHD will receive standard GVHD therapy with corticosteroids and/or additional 
agents per institutional standard of care, and rimiducid (Arm A) to inactivate rivogenlecleucel.  
Safety will be monitored by assessing adverse events, including but not limited to the rate of 
Grade 3/4 infection and changes in physical exam and laboratory studies.  
4.4 OUTCOME MEASURES 
4.4.1 Safety Outcome Measures 
The safety and tolerability of rivogenlecleucel +/- rimiducid will be assessed in the following 
ways: 
• Incidence, type, and severity of DLTs (Phase II only) 
• Incidence, type, nature, and severity of adverse events (graded according to NCI CTCAE 
5.0 criteria) 
• Changes in vital signs, physical findings, and clinical laboratory test results, as 
appropriate  
• Incidence of adverse events of special interest (Section 9.2.3). 
4.4.2 Efficacy Outcome Measures 
The efficacy outcomes measures will be assessed as indicated in the following sections. 
Malignant efficacy response criteria (i.e., disease progression) will be determined by the 
investigator with use of the following response criteria. An independent Data Monitoring 
Committee (iDMC) will be put in place to support independent analyses of trial efficacy and 
safety data (Section 4.5.2). 
4.4.2.1 Definitions of Response for AML 
The Center for International Blood and Marrow Transplant Research criteria for AML will be 
used to categorize responses (https://www.cibmtr.org/manuals/fim/1/en/topic/aml-response-
criteria).  
Complete Remission (CR) 
Hematologic complete remission is defined as meeting all the following response criteria for 
at least four weeks.  
• 
< 5% blasts in the bone marrow 
• 
No blasts with Auer rods 
• 
Normal maturation of all cellular components in the bone marrow 
• 
No extramedullary disease (e.g., CNS, soft tissue disease) 
• 
Neutrophils ≥ 1,000/µL 
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• 
Platelets ≥ 100,000/µL 
• 
Transfusion independent 
In some cases, there may not be a four-week interval between completion of therapy and the pre-
transplant disease assessment. In this case, CR should still be reported as the patient disease 
status at transplant since it represents the "best assessment" before HSCT. This is an exception to 
the criteria that CR be durable beyond four weeks; the pre-transplant disease status should not be 
changed based on early relapse or disease assessment post-transplant. 
Recipients with persistent cytogenetic or molecular abnormalities who meet the above CR 
criteria will be included for evaluation of hematologic CR. 
Recipients meeting the above CR criteria regardless of how many courses of therapy were 
required to achieve CR will be included for evaluation of hematologic CR. 
The number of this complete remission can be determined by using the following guidelines:  
• 
1st CR: no prior relapse 
• 
2nd CR: one prior relapse 
• 
3rd or higher: two or more prior relapses 
Complete Remission with Incomplete Hematologic Recovery (CRi) 
Hematologic complete remission with incomplete hematologic recovery is defined as 
meeting all of the following response criteria for at least four weeks:  
• 
< 5% blasts in the bone marrow 
• 
No blasts with Auer rods 
• 
Normal maturation of all cellular components in the bone marrow 
• 
No extramedullary disease (e.g., CNS, soft tissue disease) 
• 
Transfusion independent (Please note, if the physician documents transfusion 
dependence related to treatment and not the patient’s underlying AML, CRi can be 
reported) 
Primary Induction Failure (PIF) 
PIF will be defined in patients who received treatment for AML but never achieved CR or CRi 
at any time. PIF is not limited by the number of unsuccessful treatments; this disease status only 
applies to recipients who have never been in CR or CRi. 
Relapse (REL) 
Relapse is defined as the recurrence of disease after CR, meeting one or more of the 
following criteria:  
• 
≥ 5% blasts in the marrow or peripheral blood 
• 
Extramedullary disease 
• 
Disease presence determined by a physician upon clinical assessment 
The number assigned to this relapse can be determined by using the following guidelines:  
• 
1st relapse: one prior CR 
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• 
2nd relapse: two prior CRs 
• 
3rd or higher: three or more CRs 
Partial response (PR) will not be included when determining the number of relapses. Recipients 
who achieve a PR to treatment should be classified as either PIF or relapse; PR in AML is 
generally of short duration and is unlikely to predict clinical benefit. 
4.4.2.2 Definitions of Response for MDS 
The Center for International Blood and Marrow Transplant Research criteria for MDS will be 
used to categorize responses (https://www.cibmtr.org/manuals/fim/1/en/topic/mds-mpn-
response-criteria; Savona 2015). 
Complete Remission (CR) 
Requires all of the following to be maintained for a minimum of four weeks: 
Bone marrow evaluation: 
• 
< 5% myeloblasts with normal maturation of all cell lines 
Peripheral blood evaluation: 
• 
Hemoglobin ≥ 11 g/dL untransfused without erythropoietic support 
• 
ANC ≥ 1000/mm3 without myeloid growth factor support 
• 
Platelets ≥ 100,000/mm3 without thrombopoietic support 
• 
0% blasts in blood 
In some cases, there may not be a four-week interval between completion of therapy and the pre-
transplant disease assessment. In this case, CR should still be reported as the status at transplant 
since it represents the "best assessment” prior to HSCT. This is an exception to the criteria that 
CR be durable beyond four weeks; the pre-transplant disease status should not be changed based 
on early relapse or disease assessment post-transplant. 
Hematologic Improvement (HI) 
Requires one measurement of the following maintained for at least eight weeks without 
ongoing cytotoxic therapy: 
Hematologic improvement – erythropoietic (HI-E): 
• 
Hemoglobin increase of ≥ 1.5 g/dL untransfused, or 
• 
For RBC transfusions performed for hemoglobin ≤ 9.0: reduction in RBC units 
transfused in 8 weeks by ≥ 4 units compared to the number of units transfused in the 
8 weeks prior to treatment 
Hematologic improvement – platelets (HI-P): 
• 
For pre-treatment platelet count of > 20×109, platelet absolute increase of ≥ 30×109 
• 
For pre-treatment platelet count of < 20×109, absolute platelet increase of ≥ 
20×109 and ≥ 100% increase from pre-treatment level 
Hematologic improvement – neutrophils (HI-N): 
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• 
Neutrophil count increase of ≥ 100% from pre-treatment level and an absolute 
increase of ≥ 500/mm3 
No Response (NR)/Stable Disease (SD) 
Does not meet the criteria for at least HI, but no evidence of disease progression to AML. 
Progression from Hematologic Improvement (Prog from HI) 
Requires at least one of the following in the absence of another explanation (e.g., infection, 
bleeding, ongoing chemotherapy, etc.): 
• 
≥ 50% reduction from maximum response levels in granulocytes or platelets 
• 
Reduction in hemoglobin by ≥ 1.5 g/dL 
• 
Transfusion dependence 
Note: declining donor chimerism does not meet the criteria for progression. If the above 
criteria for progression have been met, but a hematologic improvement was not previously 
achieved, report “No Response (NR) / Stable Disease (SD)”. 
Relapse from Complete Remission (Rel from CR) 
Requires at least one of the following: 
• 
Return to pre-treatment bone marrow blast percentage 
• 
Decrease of ≥ 50% from maximum response levels in granulocytes or platelets 
• 
Transfusion dependence or hemoglobin level ≥ 1.5 g/dL lower than prior to therapy 
Note: declining donor chimerism does not meet the criteria for relapse. 
Progression to AML 
≥ 20% blasts in the blood or bone marrow 
4.4.3 Pharmacokinetic Outcome Measures 
Plasma concentrations of rimiducid will be determined in each subject administered rimiducid, 
and limited pharmacokinetic parameters will be estimated using non-compartmental analysis.  
Tmax and the exposure parameters Cmax and AUCtlast will be estimated for each subject where:  
• Cmax is the maximum observed concentration  
• Tmax is the time to maximum observed concentration  
• AUCtlast is the area under the concentration-time curve from hour 0 to the last measurable 
concentration, calculated using the linear trapezoidal rule for increasing concentrations 
and the logarithmic rule for decreasing concentrations  
Due to the limited number of plasma samples collected, the terminal half-life will not be 
calculated. Systemic clearance (CLs) will be calculated as: CLs = Doseiv / AUCtlast. Estimated 
pharmacokinetic parameters will be obtained using commercial software such as Phoenix 
WinNonlin (Certara USA, Inc., Version 6.2 or higher) or another suitable 21 CFR Part 11 
compliant software. 
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Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the Statistical Analysis Plan (SAP) or alternative document. Pharmacokinetic analysis will use 
actual times as recorded on the CRF. Other data handling procedures will be detailed in the SAP. 
4.4.4 Exploratory Biomarker Assessments 
Recovery of naïve and memory T cell populations, measured by flow cytometry, may be 
assessed to evaluate immune reconstitution.  The thymic function may be assessed by the 
measurement of T cell receptor excision circles.  T cell repertoire may be assessed by flow 
cytometry or T cell receptor sequencing.  Additional in vitro T cell function assays may be 
conducted to assess the response to a tumor or viral antigens as appropriate and contingent upon 
the availability of sufficient samples.  
4.5 Study Oversight  
4.5.1 Cohort Review Committee 
Following treatment completion of the ten subjects in Cohort 1 of the Phase II portion of this 
study, safety and tolerability will be assessed by evaluation of DLTs within the prespecified 100-
day DLT window, counting 100 days from the time that the last subject is enrolled and receives 
haplo-HSCT. If data suggest that a second cohort should be opened at a lower dose level based 
on evaluation of DLTs (Section 4.2.1), then another cohort review meeting will be scheduled 
after subjects in Cohort 2 complete the 100-day DLT assessment window. 
Subject safety will be evaluated by a Cohort Review Committee, which will include 
representatives from various functional areas from the Sponsor, as well as principal investigators 
from sites participating in Phase II. Roles, responsibilities, and further details regarding the 
Cohort Review Committee are detailed in a separate Charter.  
4.5.2 Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will be put in place to support periodic 
review of efficacy and safety data for the Phase III portion of this study. Reviews by the iDMC 
will be conducted according to a charter written and approved prior to initiation of the Phase III 
portion of the study. Members of the iDMC will be external to the Sponsor and the study team 
and will follow a charter that outlines their roles and responsibilities.  
The iDMC will meet approximately every 6 months and subsequently at a frequency determined 
by the iDMC and the Sponsor according to the emerging safety profile. In addition, either the 
Sponsor or the iDMC can request ad hoc iDMC meetings at any time that potential safety 
concerns arise. 
An interim analysis of efficacy data will be conducted and further reviewed by the iDMC when 
approximately 55 (50%) of the OS events required for the primary efficacy analysis have 
occurred (Section 10.6).  
Further details about the definition, role, and responsibility of the iDMC are reflected in the 
iDMC Charter and remain separate from this protocol.  
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4.6 End of Study 
The end of study will occur after the last patient, last visit (LPLV) occurs and enough events 
have been observed in order to meet the primary endpoint (Section 10.5.2.1). LPLV is expected 
to occur approximately 36 months after the last subject is enrolled. After enough events have 
occurred and it is determined that the study may be closed, subjects will enter a long-term 
follow-up study for gene monitoring (Section 7.8). 
5. STUDY POPULATION 
5.1 Patient Eligibility: Inclusion Criteria 
Subjects must meet all the following criteria to be enrolled into this study: 
1. Signed informed consent 
2. Meets institutional criteria to undergo allogeneic HSCT 
3. Age 12-70 y/o 
4. Diagnosis of AML or MDS as defined below: 
a. AML with intermediate to adverse risk as defined by ELN genetic risk 
stratification (Dohner 2017) 
i. AML in first complete remission (CR1) with high-risk features defined as 
> 1 cycle of induction therapy required to achieve remission, OR 
preceding MDS or myeloproliferative disease 
1. Adverse cytogenetics as defined below:  
a. t(6;9)(p23;q34.1); DEK-NUP214  
b. t(v;11q23.3); KMT2A rearranged 
c. t(9;22)(q34.1;q11.2); BCR-ABL1  
d. inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); 
GATA2,MECOM(EVI1)  
e. -5 or del(5q); -7; -17/abn(17p)  
f. Complex karyotype, monosomal karyotype 
g. Wild-type NPM1 and FLT3-ITDhigh 
h. Mutated RUNX1 
i. Mutated ASXL 
j. Mutated TP53 
ii. AML in CR1 with > 1 of the following intermediate-risk features: 
1. Mutated NPM1 and FLT3-ITD high 
2. Wild-type NPM1 without FLT3-ITD or with FLT3-ITD low 
(without adverse-risk genetic lesions)  
3. t(9;11)(p21.3;q23.3) MLLT3-KMT2A 
4. Cytogenetic abnormalities not classified as favorable or adverse  
b. AML in second or subsequent complete remission  
c. AML with myelodysplasia-related changes (AML-MRC) in first or subsequent 
complete remission. 
d. Therapy-related AML in first or subsequent complete remission 
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e. De novo AML in first complete remission with intermediate or adverse genetic 
abnormalities 
f. De novo AML in second or subsequent complete remission 
g. MDS  
i. High or very high-risk by IPSS-R classification 
ii. Intermediate risk or higher having failed a hypomethylating agent  
5. Lack of suitable conventional donor (i.e., HLA 10/10 related or unrelated donor) 
6. At least a 5/10 genotypic identical haplotype match measured by HLA typing at high 
resolution (allele level) for the HLA-A, -B, -C, -DRBl, and -DQB1 loci 
7. The donor and recipient must be identical for at least one allele of each of the following 
genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 
8. Patients with adequate organ function as measured by: 
a. Cardiac: Left ventricular ejection fraction > 40% 
b. Pulmonary: DLCO (corrected for hemoglobin) > 40% and FEV1 > 50% 
c. Hepatic: total bilirubin < 2x the upper limit of normal and ALT and AST < 3x the 
upper limit of normal.  
d. Renal: estimated creatinine clearance > 50 mL/min/based on the Cockcroft-Gault 
formula  
9. Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 
5.2 Patient Eligibility: Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in this study: 
1. HLA 10/10 allele matched (HLA-A, -B, -C, -DRBl, and -DQB1) related donor or 
unrelated donor   
a. An HLA 10/10 allele-matched unrelated donor may be considered eligible for the 
study if the Study PI determines a haploidentical donor is the best available donor 
option for the patient due to other considerations (e.g., graft acquisition time) 
2. Autologous hematopoietic stem cell transplant ≤ 3 months before enrollment 
3. Prior allogeneic transplantation 
4. Active CNS involvement by malignant cells (less than 2 months from conditioning) 
5. Current uncontrolled clinically active bacterial, viral or fungal infection 
6. Positive HIV serology or viral RNA 
7. Pregnancy (positive serum or urine βHCG) or breastfeeding 
8. Fertile men or women unwilling to use effective forms of birth control or abstinence for a 
year after transplantation 
9. Radiographic or histologic evidence of, or known history of cirrhosis 
10. Overlapping MDS and myeloproliferative neoplasms (MPN) disease  
11. Patients with acute promyelocytic leukemia (APL) 
12. Known hypersensitivity to dimethyl sulfoxide (DMSO) 
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5.3 Donor Eligibility: Inclusion Criteria 
A donor must meet all the following criteria to be considered eligible and assessments must be 
completed before leukapheresis. 
1. Related donors include biological parents, siblings, or children, half-siblings or 
grandchildren 
2. Age 18-75 y/o 
3. Sufficiently healthy to undergo mobilization for peripheral blood stem cell harvest by 
institutional guidelines  
4. Should be at least a full haplotype matched donor (e.g., at least a 5/10 match at HLA-A, 
-B, -C, -DRB1, and -DQB1); other selection criteria may include gender, age, 
cytomegalovirus (CMV) status, body weight of donor, and presence of anti-donor HLA 
antibodies 
5. Donor must be examined and have specific tests performed according to existing 
institutional guidelines and meet institutional guidelines for candidacy as a donor 
6. Donor must have been informed of the investigational nature of rivogenlecleucel and the 
manufacturing process and have signed an informed consent form to undergo apheresis 
7. Donor must have adequate peripheral venous catheter access for leukapheresis or must 
agree to placement of a central catheter 
5.4 Donor Eligibility: Exclusion Criteria 
If the donor meets any of the following criteria, they will not be considered eligible. All 
assessments must be completed before leukapheresis. 
1. Evidence of active infection (including urinary tract infection, upper respiratory tract 
infection, etc.) or viral hepatitis exposure (on screening), unless only HBs Ab+ and HBV 
DNA negative 
2. Positive HIV serology or viral RNA 
3. Medical or physical reason why makes the donor unlikely to tolerate or cooperate with 
growth factor therapy and apheresis 
4. Factors that place the donor at increased risk for complications from apheresis or G-CSF 
therapy (e.g., autoimmune disease, sickle cell trait, symptomatic coronary artery disease 
requiring therapy, previous thrombotic events) 
5. Pregnancy (positive serum or urine βHCG) or breastfeeding 
5.5 Method of Treatment Assignment 
This is a two-part (Phase II and Phase III) clinical trial. The Phase III part of this study will be 
unblinded and enrolled in a randomized fashion. 
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5.5.1 Phase II 
Before initiating screening, the study site should confirm with the Sponsor or designee that slots 
remain in the planned cohort for enrollment. The Sponsor or designee will communicate to the 
sites impending closure of screening for a cohort. 
Upon completion of all screening evaluations, the site eligibility packet will be forwarded to the 
Sponsor for approval.  
5.5.2 Phase III 
This is an open-label, randomized phase of the trial. 
Randomization will be handled in a 1:1 fashion and stratified on the following factors: 
• Age (< 60 and >60) 
• Disease (AML vs. MDS) 
• Conditioning regimen 
6. STUDY TREATMENT  
6.1 Phase II and Phase III Arm A: αβ T Cell/CD19+ B Cell Depleted Haplo-HSCT Plus 
Rivogenlecleucel 
Subjects in Phase II and in Phase III Arm A will receive an αβTCR and CD19+ B cell depleted 
haploidentical stem cell transplant on Day 0 with administration of rivogenlecleucel on Day +14 
(± 4 days) (Figure 4).   
Figure 4: Study Schema for Subjects Receiving Rivogenlecleucel 
 
6.1.1 Donor Leukapheresis and Rivogenlecleucel Manufacturing 
For subjects receiving rivogenlecleucel, a standard stem cell leukapheresis for obtaining T cells 
is performed on the donor prior to starting G-CSF mobilization for stem cell collection; two 
separate apheresis sessions must occur. Detailed information can be found in the Apheresis & 
Cell Therapy Manual.  
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Non-mobilized leukapheresis should occur as soon as possible after donor consent to allow for 
sufficient time for manufacturing of rivogenlecleucel; at latest, leukapheresis should occur at 
least 15 days prior to stem cell transplant (Day 0). Time from leukapheresis to arrival of 
rivogenlecleucel at the site takes approximately 28 days.  
The leukapheresed T cells will be shipped overnight in validated shipping units with refrigerated 
gel packs to the Sponsor’s centralized GMP manufacturing facility for processing and gene 
modification as outlined in the Apheresis & Cell Therapy Manual. If < 2 x 109 MNC are 
collected, then the apheresis results must be discussed with the Medical Monitor and an 
additional apheresis may be required. Inadequate number of T cells for manufacturing of 
rivogenlecleucel will result in subjects not receiving rivogenlecleucel treatment; however, the 
subject will be followed up for 2 years to collect safety data.  
6.1.2 Stem Cell Mobilization of Donor  
Following screening, and non-mobilized leukapheresis for obtaining T cells, the donor will 
receive mobilization therapy with G-CSF (or equivalent) 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 collection. 
6.1.2.1 Donor Apheresis  
Donor 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; a second collection may follow on the sixth day if the target CD34+ 
cell count is not met. 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.  
Depletion of TCRαβ cells and CD19+ B cells from the donor hematopoietic stem cell apheresis 
product will be performed according to procedures given in the Miltenyi CliniMACS ® platform 
instrument Users Operating Manual and institutional Standard Operating Procedures (SOPs) in 
place at the study sites. The total nucleated count, CD34+ count, αβ CD3+ T cell count, and CD19+ 
B cell count, as well as other graft characteristics, will be assessed pre- and post-selection and 
recorded.  
If the target CD34+ cell count from the TCRαβ T cells and CD19+ B depleted product is not met, 
then a CD34+ cell selection on additional apheresis can be performed according to procedures 
given in the CliniMACS® Users Operating Manual and institutional Standard Operating 
Procedures (SOPs) in place at the study sites.   
A maximum of three successive daily apheresis sessions may be performed. The target in the 
combined allografts shall be ≥ 5 million CD34+ cells/kg recipient total body weight. If there are 
less than a total of 5 million CD34+ cells/kg recipient weight in the combined allografts, the 
investigator should immediately contact the Medical Monitor. If there are fewer than 2.5 
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million CD34+cells/kg recipient weight in the combined allografts, the subject shall be 
discontinued from the study and will receive another type of stem cell transplant.  
A residual CD3+ TCRαβ+ cell count of > 2 x 105 cells/kg recipient total body weight will result 
in an exclusion criterion and the subject will not receive rivogenlecleucel after infusion of the 
selected allograft. However, the subject will be followed up to 2 years after transplant.  
The selected apheresis product(s) will be stored per institutional procedures prior to infusion. 
6.1.3 Preparative (Conditioning) Regimen  
The transplant preparative (conditioning) regimen will utilize one of the recommended regimens 
below and should be administered per institutional standards, including dose adjustments.  
It is recommended that dosing of conditioning chemotherapy for obese individuals should follow 
the recommendations provided in Bubalo 2014. 
Selection of the conditioning regimen will be based on the discretion of the investigator. 
Option #1: Flu/Bu/Cy (fludarabine, busulfan, and cyclophosphamide) (Solomon 2012) 
For fludarabine, busulfan and cyclophosphamide dosing and monitoring guidelines, please refer 
to the local prescribing information. Seizure prophylaxis should be administered per institutional 
guidelines while on busulfan. 
 
Day 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
rATG 
X 
X 
X 
 
 
 
 
 
 
 
Bu 
 
 
 
X 
X 
X 
X 
 
 
 
Flu 
 
 
 
 
X 
X 
X 
X 
X 
 
Cy 
 
 
 
 
 
 
 
X 
X 
 
• Fludarabine:  25 mg/m2/daily IV on Days -6 to -2 
• Busulfan:  110 mg/m2/daily IV on days -7 to -4  
• Cyclophosphamide: 14.5 mg/kg/daily IV on Day -3 and -2  
Option #2: Flu/Mel/TBI (fludarabine, melphalan, and total body irradiation) (Karduss-
Urueta 2016; Mino 2018) 
For fludarabine and melphalan dosing and monitoring guidelines, please refer to the local 
prescribing information.  
 
Day 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
rATG 
X 
X 
X 
 
 
 
 
 
 
 
Mel 
 
 
 
X 
 
 
 
 
 
 
Flu 
 
 
 
 
X 
X 
X 
X 
 
 
TBI 
 
 
 
 
 
 
 
 
(X) 
(X) 
• Melphalan:  140 mg/m2/day IV on Day -7 
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• Fludarabine: 40 mg/m2/day on Days -6 to -3 (total dose of 160 mg/m2) 
• 
TBI: 200 cGy on Day -2 or -1 (total dose of 200 cGy) 
 
As determined by the treating physician, subject age > 50 years or those with significant 
comorbidities may receive a lower dose of melphalan at 100 mg/m2. 
6.1.3.1 Rabbit Anti-thymocyte Globulin (Thymoglobulin) 
Subjects receiving rivogenlecleucel should receive rabbit anti-thymocyte globulin (rATG) for 
prevention of graft failure (Locatelli 2017; Lang 2018). Administration of rATG should be 
completed by Day -7. Dosing should be as follows, with premedications and supportive care per 
standard institutional guidelines: 
• Thymoglobulin®: 1-1.125 mg/kg/d starting Day -10 for 3 days 
6.1.4 HSCT Infusion 
The infusion of the TCR αβ T cell / CD19+ B cell depleted product will be administered on Day 
0 for subjects in the rivogenlecleucel treatment arm.  
6.1.5 Rivogenlecleucel        
Rivogenlecleucel is a T cell product composed of donor T cells that have been ex vivo culture-
expanded to high purity, gene-modified with BPZ-1001 (SFG.iCasp9.2A.ΔCD19 retroviral 
vector containing the iCasp9 safety gene and truncated CD19 selectable marker), and then 
selected to ensure a high percentage of T cells carrying the safety gene. The drug product is 
provided as a combined CD3+ and CD19+ frozen T cell suspension in a formulation containing 
DMSO for IV administration. Additional details of product formulation, packaging, labeling, 
tracking, accountability, preparation, administration, disposal, and destruction are provided in the 
Apheresis & Cell Therapy Manual.  
6.1.5.1 Dose and Schedule 
Rivogenlecleucel will be administered as an IV infusion at the target dose level of 3 x 106 
cells/kg for all subjects enrolled in Cohort 1 of the Phase II portion of this study. Weight at 
Screening will be used to determine the total rivogenlecleucel cell dose. Rivogenlecleucel should 
be administered on Day 14 after HSCT (± 4 days). 
Depending on results of the Cohort Review Meeting and evaluation of safety (i.e., DLTs) in 
Phase II, subjects will either receive rivogenlecleucel 3 x 106 cells/kg during Phase III, or a 
second cohort with treatment at a lower dose level will be opened in Phase II and this MAD will 
be pursued in Phase III. 
6.1.5.2 Premedications 
All subjects should receive premedications per institutional standards (e.g., acetaminophen plus 
an antihistamine) for cellular therapy products, for prevention of infusion-related/ 
hypersensitivity reactions.  
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6.1.5.3 Preparation and Administration 
Refer to the Apheresis and Cell Therapy Manual for detailed instructions on rivogenlecleucel 
administration.  Briefly, rivogenlecleucel should be thawed, diluted immediately, and infused 
within 90 minutes using either central or peripheral venous access devices.  The start and stop 
time of the infusion will be recorded. 
Record vital signs prior to rivogenlecleucel infusion, at 15 (± 5), 30 (± 5), and 120 (± 15) 
minutes after start of the infusion.  
6.1.6 Rimiducid 
Rimiducid may be given to subjects who receive rivogenlecleucel and develop GVHD (acute 
and/or chronic) and/or neurotoxicity, based on guidelines detailed in Sections 8.2, 8.3, and 8.4. 
Subjects who experience disease progression/relapse and move on to receive subsequent 
anticancer therapy are not eligible to receive rimiducid. 
Rimiducid drug substance is dissolved in Solutol® HS15 (also known as Kolliphor® HS15) and 
therefore has the potential to induce an infusion or hypersensitivity reaction.  To minimize or 
mitigate infusion-related toxicity, subjects should receive premedication with acetaminophen, 
diphenhydramine, ranitidine, and other supportive care therapy per institutional standards for 
potential anaphylaxis. 
Rimiducid is administered at a dose of 0.4 mg/kg, with a maximum dose of 40 mg. Prior to 
administration, rimiducid should be diluted in normal saline to a volume that supports infusion 
over 2 hours, as described in the Pharmacy Manual. 
Rimiducid may be administered using either central or peripheral venous access devices.  The start 
and stop time for the infusion will be recorded. 
Record vital signs prior to rimiducid infusion, at 15 and 30 (± 5), 60 (± 10), 120 and 240 (± 15) 
minutes after start of the infusion.  
For reach rimiducid administration, blood/tissue samples should be collected. Refer to Appendix 
D for details of sample collection. 
6.1.7 Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for this study will be provided by the 
Sponsor. This includes rivogenlecleucel and rimiducid.  
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 the Sponsor with the appropriate documentation, as 
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determined by the study site. If the study site chooses to destroy study drug, the method of 
destruction must be documented.  
The Sponsor must evaluate and approve the study site’s drug destruction standard operating 
procedure prior to the initiation of drug destruction by the study site. 
6.2 Phase III Arm B: Haplo-HSCT Plus Post-Transplant Cyclophosphamide (PTCy) 
Subjects in Arm B (Phase III) will receive a T and B cell replete, standard haploidentical stem 
cell transplant with administration of post-transplant cyclophosphamide and standard GVHD 
prophylaxis with tacrolimus and mycophenolate mofetil, as described in Sections 6.2.4 and 6.2.5 
below. 
6.2.1 Stem Cell Mobilization of Donor 
The donor will receive mobilization therapy with G-CSF (or equivalent) 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 collection. 
6.2.1.1 Donor Apheresis 
Donor 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; a second collection may follow on the sixth day if the target CD34+ 
cell count is not met. 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. 
A maximum of three successive daily apheresis sessions may be performed. The target in the 
combined allografts shall be ≥ 5 million CD34+ cells/kg recipient total body weight. If there are 
less than a total of 5 million CD34+ cells/kg recipient weight in the combined allografts, the 
investigator should immediately contact the Medical Monitor. If there are fewer than 2.5 
million CD34+cells/kg recipient weight in the combined allografts, the subject shall be 
discontinued from the study and will receive another type of stem cell transplant.  
The selected apheresis product(s) will be stored per institutional procedures prior to infusion. 
6.2.2 Preparative (Conditioning) Regimen (Arm B) 
The transplant preparative (conditioning) regimen will utilize one of the recommended regimens 
below and should be administered per institutional standards, including dose adjustments.  
It is recommended that dosing of conditioning chemotherapy for obese individuals should follow 
the recommendations provided in Bubalo 2014. 
Selection of the conditioning regimen will be based on the discretion of the investigator. 
 
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Option #1: Flu/Bu/Cy (fludarabine, busulfan, and cyclophosphamide) (Solomon 2012) 
For fludarabine, busulfan and cyclophosphamide dosing and monitoring guidelines, please refer 
to the local prescribing information. Seizure prophylaxis should be administered per institutional 
guidelines while on busulfan. 
 
Day 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Bu 
 
 
 
X 
X 
X 
X 
 
 
 
Flu 
 
 
 
 
X 
X 
X 
X 
X 
 
Cy 
 
 
 
 
 
 
 
X 
X 
 
• Fludarabine:  25 mg/m2/daily IV on Days -6 to -2 
• Busulfan:  110 mg/m2/daily IV on days -7 to -4  
• Cyclophosphamide: 14.5 mg/kg/daily IV on Day -3 and -2  
Option #2: Flu/Mel/TBI (fludarabine, melphalan, and total body irradiation) (Karduss-
Urueta 2016; Mino 2018) 
For fludarabine and melphalan dosing and monitoring guidelines, please refer to the local 
prescribing information.  
 
Day 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Mel 
 
 
 
X 
 
 
 
 
 
 
Flu 
 
 
 
 
X 
X 
X 
X 
 
 
TBI 
 
 
 
 
 
 
 
 
(X) 
(X) 
• Melphalan:  140 mg/m2/day IV on Day -7 
• Fludarabine: 40 mg/m2/day on Days -6 to -3 (total dose of 160 mg/m2) 
• TBI: 200 cGy on Day -2 or -1 (total dose of 200 cGy) 
 
As determined by the treating physician, subject age > 50 years or those with significant 
comorbidities may receive a lower dose of melphalan at 100 mg/m2. 
6.2.3 HSCT Infusion 
Subjects in Arm B will receive a standard haploidentical HSCT (T/B cell replete) on Day 0. 
Infusion of the PBSC product should follow institutional standards. 
6.2.4 Post-Transplant Cyclophosphamide (PTCy) Administration 
Cyclophosphamide will be administered at a dose of 50 mg/kg per day intravenously on days 3 
and 4 after transplant for subjects in Arm B. Dosing & administration and supportive measures 
(e.g., IV fluids, mesna) should be per institutional standard of care. 
6.2.5 GVHD Prophylaxis 
GVHD prophylaxis will only be administered to subjects enrolled in Phase III, Arm B.  
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PTCy should be administered as detailed in Section 6.2.4. Tacrolimus and mycophenolate 
mofetil (MMF) will be administered to subjects for GVHD prophylaxis, as detailed below: 
• Tacrolimus will be administered from day +5 through day +180. Dosing should follow 
local prescribing information and institutional guidelines (e.g., 1 mg intravenously daily, 
adjusted to achieve a therapeutic level of 5-15 ng/mL and then converted to oral form 
until discontinuation) 
• MMF will be administered from day +5 through day +35. Dosing should follow local 
prescribing information and institutional guidelines (e.g., 15 mg/kg by mouth three times 
daily) 
6.3 Supportive Care 
All subjects should receive the following:  
• Transfusion support per standard institutional practice  
• Anti-infective prophylaxis against herpes viruses, cytomegalovirus, Pneumocystis 
jirovecii, bacterial, and fungal infections according to standard institutional practices  
• Routine CMV antigenemia/viral load testing by hybrid capture or PCR based methods 
per institutional guidelines (with preemptive ganciclovir or valganciclovir therapy in 
subjects who develop a positive assay, as per institutional guidelines); CMV testing is 
recommended weekly through Day 100 post-transplant. Additional timelines are reflected 
in the Schedule of Assessments (Appendices A, B, and C).   
• Monitoring and prevention of EBV reactivation and EBV lymphoproliferative disease 
(PTLD), with consideration for using rituximab preemptively  
• Supportive care (growth factors (e.g., G-CSF), antiemetics, allopurinol, menstrual 
suppression, prophylactic antibiotics, empiric antibiotics, transfusions of blood products, 
hyperalimentation, etc.) as indicated. 
It is recommended that rituximab will be administrated at a dosage of 200 mg/m2 or per 
institutional guidelines on Day -1 to prevent the occurrence of EBV-related post-transplant 
lymphoproliferative disease (PTLD).  
It is recommended that filgrastim (or equivalent) be administered to reduce the time to neutrophil 
recovery after HSCT. Dosing & administration of filgrastim should be per institutional 
guidelines. 
6.4 Concomitant Medications  
Concomitant medications include any prescription medication or over-the-counter preparations 
used by a subject between the screening evaluation and the End of Study visit.  
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF.  
All treatments such as transfusions and critical medications, defined as below, shall be collected 
in the EDC database: 
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• Drugs given in conditioning regimens 
• Most recent chemotherapy regimen and use of granulocyte-colony stimulating factor (G-
CSF or equivalent) 
• Prophylaxis and/or treatment for GVHD 
• Prophylaxis and/or treatment for infectious complications 
• Treatment in association with SAEs or AEs of special interest, such as febrile neutropenia 
and anaphylaxis 
6.4.1 Permitted Therapies 
Permitted therapies include all therapy not listed under prohibited therapy. 
In the event of infusion related reactions (IRR), the subject should be treated per institutional 
guidelines. Treatment may include diphenhydramine, acetaminophen, ranitidine or other H2 
blockers, and systemic corticosteroid. 
6.4.2 Prohibited Therapies 
Other investigational agents may not be administered while on study except as clinically 
indicated for GVHD non-responsive to frontline standard of care and rimiducid (for subjects 
receiving rivogenlecleucel), or infections not responding to standard treatment. In the event 
treatment is administered for any of these events, it should be appropriately documented in the 
clinical database. 
Subjects should remain on study despite receiving another investigational agent for refractory 
GVHD/infections. 
7. STUDY ASSESSMENTS & PROCEDURES 
The schedule of assessments is provided in the Appendices: Appendix A, Appendix B, and 
Appendix C. Subjects will be closely monitored for safety and tolerability throughout the 
duration of the study. All assessments must be performed and documented for each subject. 
Subjects should be assessed for toxicity prior to each dose and during all study assessment visits.  
If the timing of the protocol-mandates study visit coincides with a holiday and/or weekend that 
precludes the visit, the study visit should be scheduled on the nearest following feasible date with 
subsequent visits rescheduled accordingly.  
7.1 Informed Consent 
The informed consent will be obtained per institutional practices before study screening is 
initiated for both subject and donor. 
7.2 Screening 
The standard screening process begins when the subject signs the IRB/IEC-approved informed 
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consent form for participation in the study, and continues through the protocol-specified visit 
window. 
Standard pretransplant work-up for the donor and subject performed prior to formally entering 
the Screening period is acceptable for fulfilling Screening assessments, as long as these are done 
within a reasonable time frame (as deemed by the Investigator). If there are questions with the 
timing of assessments, then discussion with the Medical Monitor is warranted. 
Refer to the Schedule of Assessments (Appendices A, B and C) for the required Screening 
evaluations. 
7.2.1 Infectious Diseases Screening 
Refer to Table 3 for a list of required pretransplant pathogen-specific testing in the donor and 
recipient (subject).  
Table 3: Pretransplant Infectious Diseases Screening  
 
Donor 
Recipient 
CMV IgG 
 
 
Hepatitis B (HBsAg, anti-HBsAg, anti-HBc) +/- viral load 
 
 
Hepatitis C (IgM, IgG) 
 
 
Hepatitis C viral load* 
 
 
VZV IgG 
 
 
HSV IgG 
 
 
EBV (VCA IgG) 
 
 
HIV-1, -2 antibodies 
 
 
HIV-1 viral load 
 
 
HTLV-1, -2 antibodies 
 
 
RPR or VDRL or a Treponema pallidum antibody test 
 
 
West Nile virus antibodies 
 
 
Toxoplasma gondii IgG 
 
 
Screening for TB 
 
 
* In addition to serologic testing for hepatitis C, all HSCT candidates should undergo a careful history and physical 
examination for risk factors, signs, and symptoms of hepatitis C, as well as serum alanine aminotransferase (ALT) 
testing. Hepatitis C viral load testing should be performed in all HSCT donors as well as in HCT candidates at 
increased risk for hepatitis C infection, including those who have received a transfusion with blood not tested for 
hepatitis C (e.g., before 1992 in developed countries), history of IV or inhaled drug use, tattoos, or unexplained 
elevation of serum ALT. Viral load testing should also be performed in HSCT candidates with positive hepatitis C 
serologic testing. 
Adapted from:  
Wingard JR. Evaluation for infection before hematopoietic cell transplantation. Thorner AR, ed. UpToDate. Waltham, MA: 
UpToDate Inc. https://www.uptodate.com (Accessed on February 5, 2019.)  
US Food and Drug Administration. Testing HCT/P donors: Specific requirements. 
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm151757.htm (Accessed on February 5, 2019). 
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7.3 Study Assessments   
Visit windows for weekly visits are +/- 3 days until Day 100, unless otherwise specified. Visit 
windows after Day 100 will be +/-14 days, through the first year. Visit windows between Month 
12 to Month 24 will be +/- 21 days. After Month 24, visit windows are +/- 28 days. 
Refer to Appendices A, B and C for the Schedule of Assessments for the donor and recipient. 
The study schedule is divided into three portions: Pre-treatment Phase, Treatment Phase (Day 0 
to Day +100), and Treatment Phase (> Day +100 to End of Study).  
The Pre-treatment Phase refers to the time of screening/subject enrollment (and randomization 
for Phase III), from Days -42 to -1.  
The first Treatment Phase encompasses haplo-HSCT on Day 0 through Day +100, including 
rivogenlecleucel administration for Phase II and Phase III Arm A subjects. For Phase II, the 
Treatment period coincides with the DLT evaluation window. 
The second Treatment Phase continues from > Day +100 through the End of Study, or at the 
time that subject experiences an event (i.e., death), whichever occurs later. This Treatment Phase 
includes follow-up visits for evaluation of safety and disease status at indicated times. The End 
of Study (EOS) visit will take place after death or withdrawal of consent, and subsequently 
subjects still alive will be encouraged to participate in the LTFU study (Section 7.8). For subjects 
who withdraw from the study early, the EOS visit should be completed at the time of study 
withdrawal. 
Beyond Month 24, subjects should continue to be followed every 6 months (or more frequently 
as clinically indicated, at the discretion of the investigator). Evaluations should be performed as 
per institutional standard of care, including laboratory assessments.  
7.3.1 Laboratory Monitoring 
Laboratory monitoring should be performed according to standard institutional practice for 
HSCT patients. In general, blood counts with differentials should be performed at least 3 times 
per week after transplant until the neutrophil count reaches 0.5 x 109/L. Thereafter, at least 2 
times per week until the neutrophil count is > 1.0 x 109/L and platelets > 100 x 109/L. 
Subsequently, blood counts and differentials should be performed approximately every 2 weeks 
until + 100 days. Samples for biochemistry, related to the routine monitoring of hepatic and renal 
function, will be taken pre-transplant and thereafter at least 3 times weekly until engraftment and 
subsequently checked twice a week until + 100 days.  
7.3.2 Surveillance Cultures and Microbiological Monitoring 
Microbiological investigations will be according to standard institutional practice for the 
determination of an infectious organism in a subject undergoing HSCT. These will include regular 
surveillance cultures (inclusive of oral flora), blood cultures and viral screening. All infections, 
either presumed or proven and treated, should be documented, and treated according to standard 
of care. 
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7.3.3 Disease Evaluations 
Disease evaluations will be conducted at timepoints listed in the Schedule of Assessments 
(Appendix A, B and C) using the response criteria detailed in Section 4.4.2. Response will be 
assessed by the investigator and by the iDMC based on physical examinations, laboratory results, 
bone marrow (BM) examinations, and other findings as clinically relevant, using CIBMTR 
response criteria for AML and MDS. 
All subjects should be evaluated according to institutional standard of care until relapse. If 
disease recurs, a bone marrow aspirate and biopsy should be performed. For disease evaluation, a 
BM aspirate is required and BM biopsy in addition is preferred. If aspirate is unattainable (i.e., 
dry tap), a BM biopsy is required. BM aspirate and biopsy should be sent to the Central 
Laboratory for confirmation. 
7.3.4 Minimal Residual Disease Evaluations 
Minimal residual disease (MRD) status should be assessed at various timepoints during the study 
(including at baseline) to evaluate for depth of response, as performed by the site per institutional 
standard practice on peripheral blood and/or BM samples.  
7.3.5 Exploratory Biomarker Sample Collection 
Immune Reconstitution samples will be collected from all subjects, throughout the study period.   
For subjects in Phase II and Phase III Arm A, the iCasp T cell tracking samples will be collected 
at routine timepoints throughout the study from subjects receiving rivogenlecleucel. Assessment 
of immune reconstitution, thymic function, T cell repertoire and T cell function will be carried 
out as appropriate and depending on recovery of sufficient cell number after sample processing.  
Refer to the Schedule of Assessments and Appendix D for timepoints of sample collection. 
Further details and instructions for sample collection are in the Laboratory Manual. 
7.3.6 Gene Therapy Monitoring Plan 
Per FDA guidelines, before HSCT and for 5-years post-stem cell transplant, subjects will be 
evaluated with a physical exam and blood testing for vector copy number (VCN) and replication 
competent retrovirus (RCR). VCN will be tested every six months. After 5 years, blood samples 
will be drawn annually for another 10 years (total of 15-year follow-up), if vector is detected.  
Blood drawn for RCR testing will be analyzed pre-HSCT and at 3, 6, and 12 months after 
treatment, and annually for up to fifteen years. If all post-treatment PCR assays are negative for 
RCR during the first year, yearly samples are archived. If the testing is positive at one of those 
time points, additional samples will be drawn and analyzed throughout the 15-year follow-up 
period. 
Refer to the Schedule of Assessments for details of sample collection. 
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7.4 Assessments to be Performed upon Disease Progression or Relapse 
The evaluations listed in the Schedule of Assessments for progressive disease or relapse 
(Appendix A, Table A-16; Appendix B, Table B-19) should be performed as soon as possible 
after disease progression/relapse is suspected. These subjects should continue to be followed for 
survival status and subsequent anticancer therapy (Section 7.5). 
7.5 Survival Follow-up and Subsequent Anticancer Therapy 
After disease progression or relapse, subjects will be contacted to assess survival status 
approximately every 12 weeks until death, withdrawal of consent, loss to follow-up, or study 
termination by Sponsor, whichever comes first. Along with survival, subsequent anticancer 
therapy information will also be collected. Prior to the primary analysis or study closure, subjects 
whose survival status is unknown may be assessed again for survival follow-up. 
If a subject withdraws from the study and does not consent to continued follow-up of associated 
clinical outcome information, the investigator may consult public records, such as those 
establishing survival status.  
7.6 Subject Discontinuation  
The subject has the right to withdraw from the study at any time under the current version of the 
Declaration of Helsinki and other regulations that may be applicable. Such withdrawal will be 
without prejudice to his or her future medical treatment at the institution and by the physician. 
Other reasons that result in any subject discontinuing from the study may include the following:  
• Unable/ineligible to undergo planned HSCT 
• Withdrawal of consent by the subject or non-compliance of the subject with the protocol, 
defined as refusal or inability to adhere to the study schedule  
• At the request of the Investigator or Sponsor for administrative or other reasons  
• Loss to follow-up  
• Death 
If a subject withdraws 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.  
Subjects that cannot be contacted and who do not have a known reason for discontinuation will 
be classified as "lost to follow-up" concerning the reason for discontinuation. The Investigator’s 
study staff should make three documented attempts to contact the subject by telephone. If the 
subject cannot be reached by telephone, the Investigator’s staff should attempt to contact the 
subject by certified mail or a similar alternative method, where appropriate. 
Even after a subject withdraws from study, they may still be asked to participate in the Long-
term Follow-up Study and undergo gene therapy monitoring as per FDA guidelines.  
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7.7 Study Discontinuation  
The Sponsor has the right to terminate this study at any time for various reasons.  
The Sponsor has the right to close a study site at any time. Reasons for closing a site may 
include, but are not limited to the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Noncompliance with the ICH guidelines for GCP 
• No study activity (i.e., all subjects have completed treatment and all obligations have 
been fulfilled) 
7.8 Long-term Follow-up (LTFU) Study (Phase II and Phase III Arm A)  
Patients will be followed until the time of death, study discontinuation, or the time of the primary 
analysis for OS, whichever occurs first. The primary analysis for OS is expected to occur 
approximately 42 months after the first patient is randomized, or, given 18 months of accrual, 
approximately 24 months after the last patient is randomized. Patients still on study at the time of 
primary analysis will be consented to agree to a LTFU study as part of a commitment to 
assessing long-term safety and efficacy of rivogenlecleucel. 
The LTFU study may include subjects from all active and future clinical trials exploring 
rivogenlecleucel. All subjects treated with rivogenlecleucel who either complete the primary 
follow-up period specified in this protocol or who prematurely withdraw after at least one dose 
of rivogenlecleucel will be asked to enroll in the LTFU protocol at the end-of-study visit or at the 
time of withdrawal, respectively. A separate informed consent form will be provided for the 
LTFU protocol. Subjects who do not consent to participate in the LTFU protocol or who are lost 
to follow-up will be followed for survival through public record. 
8. POTENTIAL RISKS AND MANAGEMENT OF TREATMENT TOXICITIES 
A summary of management of potential treatment toxicity is provided below. A complete 
discussion of potential risks associated with rivogenlecleucel and rimiducid are available in the 
current version of the Investigator’s Brochures.  
8.1 Risks Associated with Rivogenlecleucel 
Rivogenlecleucel consists of human T cells which are obtained from normal donor 
leukapheresis, ex-vivo culture-expanded to high purity, gene-modified with BPZ-1001 
(SFG.iCasp9.2A.ΔCD19 retroviral vector containing the iCasp9 safety gene, as well as truncated 
CD19 selectable marker), and then selected to ensure a high percentage of T cells carrying the 
safety gene. 
Rivogenlecleucel is intended to aid in engraftment, promote immune reconstitution, potentially 
aid in graft versus leukemia (GVL) effect and is largely removed from the body upon infusion of 
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the dimerizing agent, rimiducid. Considering this mechanism of action, it is hypothesized that 
administration of rivogenlecleucel can increase the risk of GVHD (acute or chronic). Preliminary 
results from 100 pediatric subjects with high-risk acute leukemias (acute lymphoblastic leukemia 
and acute myeloid leukemia) with follow up > 180 days demonstrate that 21.9% of subjects 
experienced acute GVHD (11.5% Grade II-IV; 3.1% Grade III-IV). Of the 37 subjects who 
developed GVHD, rimiducid was used in 11 of these subjects. A best overall response of CR or 
PR was seen in 73% of these subjects (Locatelli 2018). Despite the associated risk of GVHD, 
these data suggest that BPX-501 does not show an increased risk over standard of care and in 
subjects who develop GVHD and receive rimiducid, the majority achieved responses of CR or 
PR.  
Toxicities associated or possibly associated with rivogenlecleucel should be managed according 
to standard medical practice. Additional tests should be used to determine a possible etiology. 
8.2 Acute GVHD  
For guidance on the treatment of aGVHD please refer to Table 4.  
For patients in Arm A, if aGVHD develops before rivogenlecleucel administration, the infusion 
should be held and the event followed until resolution. If the event completely resolves and the 
subject is on less than or equal to 0.5 mg/kg methylprednisone (or equivalent) within 28 days 
from onset of an event, rivogenlecleucel can be administered.  
Refer to Appendix F for the grading scale for aGVHD, and Appendix H for GVHD response 
criteria.  
Table 4: Guidelines for Management of Acute GVHD  
Event 
Management 
aGVHD, Grade 1  
• 
Consider skin biopsy to establish the diagnosis 
• 
Initial treatment with topical corticosteroids per institutional standard of 
care for Grade 1 skin aGVHD. Guidelines for topical corticosteroid 
treatment include the following or per institutional guidelines. The use 
of fractionated corticosteroid administration is also allowed:  
o Face, axillae, and groin: lower potency steroids (hydrocortisone 
1-2.5%, desonide 0.05%)  
o From the neck down: mid-strength steroids (e.g., triamcinolone 
0.1% cream or ointment) 
• 
If no response to topical steroids or worsening in stage or grade of skin 
aGVHD after 48 hours, subjects may receive systemic corticosteroids 
per institutional guidelines  
 
For patients in Arm A: 
• 
If no response to systemic steroids or worsening in stage or grade of 
skin aGVHD after 48 hours, subjects may then receive rimiducid: 
o Rimiducid Dose: 0.4 mg/kg (max dose 40 mg) IV 
o If there is evidence of clinical improvement (e.g., partial 
response) but not complete resolution after the first dose of 
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rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours 
o Daily examination on day 1 and day 2 should be performed 
after initiating treatment with rimiducid, then weekly for 1 
month, every 2 weeks for 100 days, and monthly after 100 days 
post-rimiducid administration 
o For new or recurrent Grade 1 aGVHD episodes, rimiducid may 
be considered for repeat administration with the above 
guidelines if the investigator considered rimiducid to offer a 
clinical benefit with prior episodes 
• 
If no response to systemic steroids or rimiducid, the investigator 
should consider other medications per institutional guidelines (e.g., 
calcineurin inhibitors, sirolimus, mycophenolate) 
• 
Peripheral blood and/or tissue and plasma (PK) samples should be 
collected in the event of administration of systemic corticosteroids or 
rimiducid for aGVHD as detailed in Appendix D.   
aGVHD,  
Grades 2, 3 and 4 
• 
Consider tissue (e.g., skin, gut, liver) biopsy to establish the diagnosis 
• 
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 (Martin 1990); fractionated 
dosing of steroids is also permitted 
• 
Consideration by the investigator for other medications per 
institutional guidelines (e.g., calcineurin inhibitors, sirolimus, 
mycophenolate) 
 
For patients in Arm A: 
• 
If no response to steroids or other aGVHD medications after 48 hours, 
subjects may then receive rimiducid: 
o Rimiducid Dose: 0.4 mg/kg (max dose 40 mg) IV 
o If there is evidence of clinical improvement (e.g., partial 
response) but not complete resolution after the first dose of 
rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours 
o Daily examination on day 1 and day 2 should be performed 
after initiating treatment with rimiducid, then weekly for 1 
month, every 2 weeks for 100 days, and monthly after 100 days 
post-rimiducid administration 
o For new or recurrent Grade 2 through 4 aGVHD episodes, 
Rimiducid may be considered for repeat administration with 
the above guidelines if the investigator considered rimiducid to 
offer a clinical benefit with prior episodes 
• 
Peripheral blood and/or tissue and plasma (PK) samples should be 
collected in the event of administration of systemic corticosteroids or 
rimiducid for GvHD as detailed in Appendix D.  
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8.3 Chronic GVHD  
For guidance on the treatment of cGVHD please refer to Table 5.  
At each evaluation, complete the Chronic GVHD Activity Assessment-Clinician and Chronic 
GVHD Activity Assessment-Patient Self Report (Appendix G and Appendix I). Refer to 
Appendix H for GVHD response criteria. 
Table 5: Guidelines for Management of Chronic GVHD 
Event 
Management 
cGVHD - Mild 
• 
Consider tissue biopsy to establish the diagnosis 
• 
Treatment for mild cGVHD should be per institutional guidelines  
 
For patients in Arm A: 
• 
If no response to steroids/systemic therapies occurs within 7 days, or 
there is a worsening in cGVHD, subjects may then receive rimiducid: 
o Rimiducid Dose: 0.4 mg/kg (max dose 40 mg) IV 
o If there is evidence of clinical improvement (e.g., partial 
response) but not complete resolution after the first dose of 
rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours 
o Daily examination on day 1 and day 2 should be performed 
after initiating treatment with rimiducid, then weekly for 1 
month, every 2 weeks for 100 days, and monthly after 100 days 
post-rimiducid administration 
o For new or recurrent cGVHD episodes, rimiducid may be 
considered for repeat administration with the above guidelines 
if the investigator considered rimiducid to offer a clinical 
benefit with prior episodes 
• 
Peripheral blood and/or tissue and plasma (PK) samples should be 
collected in the event of administration of systemic corticosteroids or 
rimiducid for GvHD as detailed in Appendix D. 
cGVHD – Moderate 
to Severe 
• 
Consider tissue biopsy to establish the diagnosis 
• 
Initial treatment with IV steroids or other systemic treatments (e.g., 
calcineurin inhibitors) per institutional standard of care for extensive 
cGVHD should be instituted 
• 
Management of steroid-refractory cGVHD should follow institutional 
guidelines (Arm B subjects) 
• 
Patients with chronic GVHD receiving a prolonged course of systemic 
steroids should receive adequate infections prophylaxis for 
encapsulated bacterial infections, PCP, and VZV, per institutional 
standard of care 
 
For patients in Arm A: 
• 
If no response steroids/systemic therapies occur within 7 days, or there 
is a worsening in cGVHD, subjects may then receive rimiducid 
o Rimiducid Dose: 0.4 mg/kg (max dose 40 mg) IV 
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o If there is evidence of clinical improvement (e.g., partial 
response) but not complete resolution after the first dose of 
rimiducid, then rimiducid may be repeated up to a total of 3 
doses beginning 48 hours after the first dose, with each dose 
separated by 48 hours 
o Daily examination on day 1 and day 2 should be performed 
after initiating treatment with rimiducid, then weekly for 1 
month, every 2 weeks for 100 days, and monthly after 100 days 
post-rimiducid administration 
o For new or recurrent cGVHD episodes, Rimiducid may be 
considered for repeat administration with the above guidelines 
if the investigator considered Rimiducid to offer a clinical 
benefit with prior episodes 
• 
Peripheral blood and/or tissue and plasma (PK) samples should be 
collected in the event of administration of systemic corticosteroids or 
rimiducid for GvHD as detailed in Appendix D.  
8.4 Neurotoxicity  
There is a potential risk of neurotoxicity in patients undergoing HSCT, and in those receiving 
rivogenlecleucel. BPX-501 cells have been documented to enter the central nervous system. This 
finding is of unknown significance. 
Neurologic complications occur in approximately 6.4-19.2% of patients after allogeneic 
hematopoietic stem cell transplantation (Dowling 2017; Syed 2016; Uckan 2005). 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; Grauer 2010). 
CNS toxicity may occur at different rates among different donor sources, with a higher incidence 
in matched unrelated or haploidentical donors compared with matched related donors (de 
Brabander 2000). 
Careful 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 the 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. 
Guidelines monitoring of neurotoxicity are provided in Table 6. Subjects should undergo a daily 
neurologic examination and mini-mental status examination (MMSE) (Folstein 1975) or 
modified mini mental status examination (pediatric population; Ouvrier 1993) while inpatient 
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during the hematopoietic stem cell transplant. Daily neurologic examinations should be 
performed during any readmissions after allogeneic HSCT.   
In subjects receiving rivogenlecleucel, neurologic evaluation should be performed as stated 
above, and should occur both before and after the infusion of rivogenlecleucel. A neurologic 
examination should be performed as part of all routine clinical follow-up examinations during 
each outpatient visit while subjects are being treated on rivogenlecleucel clinical trials. 
In the event of the development of Grade 2 or higher nervous system disorders or mental status 
changes, refer to Table 7 below for evaluation and management guidelines. 
In cases where a lumbar puncture (LP) is potentially warranted to evaluate the cerebrospinal 
fluid (CSF) to aid in the differential diagnosis of clinical neurological changes, procedures and 
precautions should be taken to rule out contraindications for performing an LP, consistent with 
consensus guidelines for performing LPs in subjects with neurological diseases (Table 8; 
Engelborghs 2017).  
If a diagnostic LP is performed, attempts should be made to minimize side effects such as 
infections, pain, and post-LP headaches, including, but not limited to: a) use of 25G atraumatic 
type needles, b) performing 4 or fewer attempts, c) passive CSF collection instead of active CSF 
withdrawal using a syringe, d) collection of less than 30 mL of CSF, and e) lateral recumbent 
position (Table 8; Engelborghs 2017). 
Table 6:  Monitoring for Neurologic Complications 
Timing 
Neurologic examination 
Mini-mental status 
examination 
In all subjects 
Baseline (before conditioning and HSCT) 
 
 
Daily while inpatient  
 
 
Change in mental status or presence of CNS 
dysfunction (e.g., reduced consciousness, 
delirium) 
 
 
In subjects who receive rivogenlecleucel (in addition to evaluations above) 
Before rivogenlecleucel infusion 
 
 
Routine outpatient clinic visits or 
emergency room visits 
 
 
 
Table 7: Guidelines for Management of Neurotoxicity 
Event 
Management* 
Grade ≥ 2 (Focal)1 
• 
Consider neurology consultation and performing EEG 
• 
Perform daily neurological and mini-mental status examinations during 
hospitalizations to evaluate for resolution/worsening of symptoms 
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• 
Perform CNS imaging (MRI or contrast-enhanced CT) 
• 
Consider CSF evaluation for the presence of cell counts (and 
differential), glucose, protein, and gram-stain for bacteria.  
o CSF evaluations for other infectious etiologies (e.g., 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 a 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 (e.g., 
prophylactic GVHD medication changes or treatment with 
seizure medications) 
• 
Start management of stroke/ischemia per institutional guidelines if 
suspected 
• 
Administration of antiviral 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 
 
For patients in Arm A: 
• 
Rimiducid 0.4 mg/kg (max dose 40 mg) may be administered if CNS 
infection is ruled out and there is no improvement after 48 hours of 
high-dose corticosteroids (e.g., methylprednisone 500 mg IV every 12 
hours x 2 days for adults)  
• 
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 CSF for 
PK analysis if the subject’s condition allows (see Appendix D for 
sample collection details) 
• 
If there is evidence of 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 before the administration 
of rimiducid for neurotoxicity  
Grade ≥ 2 
(Generalized)2 
• 
Perform routine institutional care for subjects with altered mental 
status/obtundation (e.g., continuous vital sign monitoring, oxygen, 
suction, airway protection measurements and consideration of the 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 of liver dysfunction and evidence of 
hyperammonemia/veno-occlusive disease (VOD) 
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• 
Perform daily neurological and mini-mental status examinations during 
hospitalizations to evaluate for resolution/worsening of symptoms 
• 
Perform CNS imaging (MRI or contrast-enhanced CT) 
• 
Perform CSF evaluation for the presence of cell counts (and 
differential), glucose, protein and gram stain for bacteria.  
o CSF evaluations for other infectious etiologies (e.g., herpes 
viruses, JC virus, fungal, West Nile virus and toxoplasma) 
• 
Consider empiric use of anticonvulsants if a 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 (e.g., 
prophylactic GVHD medication changes or treatment with 
seizure medications) 
• 
Consideration of high-dose corticosteroid treatment (e.g., 
methylprednisone 500 mg IV every 12 hours x 2 days for adults) if no 
evidence of CNS/systemic infection 
• 
Consideration of empiric antiviral 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 
 
For patients in Arm A: 
• 
Rimiducid 0.4 mg/kg (max dose 40 mg) may be administered if CNS 
infection is ruled out and there is no improvement after 48 hours of 
high-dose corticosteroids (e.g., methylprednisone 500 mg IV every 12 
hours x 2 days for adults)  
• 
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 CSF for PK analysis if the subject’s condition allows (see Appendix 
D for sample collection details).  
• 
If there is evidence of improvement (e.g., partial response) but not 
complete resolution after the first dose of rimiducid, then rimiducid can 
be given every 48 hours for 3 doses 
• 
Please notify the medical monitor at Bellicum before the administration 
of rimiducid for neurotoxicity  
* All grading corresponding to NCI CTCAE v5.0: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
1. Includes but not limited to cranial nerve abnormalities, brachial plexopathy, ischemia, nystagmus, 
pyramidal tract syndrome, radiculitis, focal seizure, stroke, transient ischemic attack 
2. Includes but not limited to aphonia, ataxia, cognitive disturbance, depressed level of consciousness, 
dysarthria, dysphasia, encephalopathy, headache, hypersomnia, lethargy, memory impairment, 
meningismus, seizures, somnolence, tremor, visual disturbances 
 
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Table 8: Recommended Procedures to Rule-out Contraindications for LP and Procedures 
to Minimize Risks 
Recommended Procedures* 
Risk Factors 
Rule out LP contraindication 
1. Brain imaging before LP in case of: 
a. an intracranial lesion with mass effect 
b. abnormal intracranial pressure 
c. tonsillar herniation is suspected 
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 diathesis 
Anti-coagulant medication 
Patient-related risk factors: 
1. Determine risk profile and inform subject 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 
5. Collections up to 30 mL 
Post-LP Headache, back pain, post-LP 
complaints 
 
*Table modified from Engelborghs 2017. 
8.5 Risks Associated with Rimiducid 
Rimiducid is a member of a new class of lipid-permeable divalent compounds, termed activating 
(or dimerizer) drugs that act by inducing clustering of engineered proteins inside cells. 
Rimiducid is an investigational new drug to be administered to subjects after the administration 
of cells carrying engineered proteins that activate signaling in cells. Rimiducid activity is based 
on the principle of intracellular signaling mechanisms that can be regulated by specific protein-
protein interactions. By selecting protein interactions that produce a desired cellular response and 
engineering those proteins to interact only in the presence of a small molecule drug such as 
rimiducid, it is possible to bring complex biological processes under direct pharmacologic 
control. 
Rimiducid was tested in normal, healthy people at doses 2.5-fold greater than those used in the 
clinical trials using gene modified cells. The only side effect noted was facial flushing 
(redness) in one person. Although not observed in subjects to date, rimiducid was associated 
with non-clinically significant modest elevations of hepatic transaminases, bilirubin and alkaline 
phosphatase in the acute and/or subacute non-human primate studies (Covance 6843-121; 
Charles River WIL-372501). It is possible that other side effects may occur (Iuliucci 2001). 
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Rimiducid is formulated in 25% Kolliphor HS 15, a non-ionic surfactant. Prior to administration, 
rimiducid is diluted in normal saline, which may lead to the formation of micro-micelles. 
Micelles of polyethoxylated pharmaceutical surfactants, such as Kolliphor, are known to activate 
complement, leading to anaphylactoid-like reactions or pseudoallergy. Such responses may be 
the result of the activation of mast cell and subsequent degranulation (Szebeni 2001).  
Therefore, Bellicum recommends that subjects are pre-medicated using standard procedures for 
the prevention of infusion reactions prior to administration of rimiducid. Such pre-treatment 
regimens would typically be administered thirty minutes to one hour prior to the infusion of 
rimiducid. 
Considering rimiducid’s mechanism of action, it is hypothesized to have relatively mild toxicity 
profile. As of 18 October 2018, results from completed and ongoing studies with 
rivogenlecleucel show that there have been 32 subjects treated with rimiducid. Currently, no 
SUSARs related to rimiducid have been reported under this program.  
For further details regarding clinical safety and a more comprehensive list of observed adverse 
events, please refer to the rimiducid IB. 
8.5.1 Management of Patients Who Experience Rimiducid-Specific Adverse Events 
Toxicities associated or possibly associated with rimiducid should be managed according to 
standard medical practice. Additional tests should be used to determine a possible etiology. 
Due to the minimal number of AEs reported, no formalized AE treatment guidelines exist for 
rimiducid. In the event of IRR, it is recommended to treat the subject per institutional guidelines. 
For all adverse events thought to be causally related to rimiducid, it is recommended to contact 
the study Medical Monitor. 
8.6 Risks Associated with Cyclophosphamide  
Please refer to the local prescribing information for the complete toxicity profile of 
cyclophosphamide.  
9. SAFETY REPORTING AND EVALUATION 
9.1 Safety Plan 
The safety plan for subjects in this study is based on the available clinical experience with 
rivogenlecleucel and rimiducid. The anticipated important safety risks for the study treatment is 
detailed within Section 8. This section is considered a highlight and does not include exhaustive 
safety and toxicity information on the study treatment(s). Please refer to the individual study 
treatment IB for a complete summary of safety information. 
9.2 Safety Parameters & Definitions 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and other variables; 
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measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug(s).  
Sponsor 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. 
9.2.1 Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution.  
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE 
reporting period  
• 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  
• Abnormal laboratory values or tests that induce clinical signs or symptoms that are 
considered clinically significant 
9.2.2 Serious Adverse Event 
The definition of an SAE is any AE that is any of the following:  
• Fatal (i.e., the AE causes or leads to death)  
• Life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death)  
• Requires or prolongs inpatient hospitalization  
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions)  
• A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product(s)  
• Considered a significant medical event by the investigator (e.g., may jeopardize the 
subject or may require medical/surgical intervention to prevent one of the outcomes listed 
above)  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs.  
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. 
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Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
CRF.  
The investigator is responsible for ensuring that AEs and SAEs are recorded on the CRF and 
reported to the Sponsor in accordance with protocol instructions. 
9.2.3 Protocol-Defined Events of Special Interest/Non-Serious Expedited Adverse Events  
The following events are considered Adverse Events of Special Interest (AESI) and will need to 
be reported to the Sponsor expeditiously on the CRF and SAE form, irrespective of regulatory 
seriousness criteria.  
• Grade III-IV encephalopathy or neurologic events 
• Grade III-IV acute graft-versus-host disease 
• Severe chronic graft-versus-host disease 
9.3 Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject 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?”  
9.4 Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each subject contact.  All AEs and 
SAEs, whether reported by the subject or noted by authorized study personnel, will be recorded 
in the subject’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 SAE Form, the investigator will make 
an assessment of seriousness, severity and causality.   
The AE grading (severity) scale (Table 9) found in the NCI CTCAE v5.0 will be used for AE 
reporting: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  Refer to 
definitions of an SAE.  
Table 9: Adverse Event Grading (Severity) Scale  
Grade 
Severity 
Alternate Descriptiona 
1 
Mild (apply event-specific NCI 
CTCAE grading criteria) 
Transient or mild discomfort (< 48 hours); no 
interference with the patient’s daily activities; no 
medical intervention/therapy required 
2 
Moderate (apply event-specific NCI 
CTCAE grading criteria) 
Mild to moderate interference with the patient’s 
daily activities; no or minimal medical 
intervention/therapy required 
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3 
Severe (apply event-specific NCI 
CTCAE grading criteria) 
Considerable interference with the patient’s daily 
activities; medical intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening, or 
disabling (apply event-specific NCI 
CTCAE grading criteria) 
Extreme limitation in activity; significant medical 
intervention/therapy required, hospitalization 
probable 
5 
Death related to AE 
 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not in the NCI 
CTCAE listing. 
The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process and is based on the Investigator’s clinical judgment.  In addition to the 
“Related” or “Not Related” Investigator causality assessment (Table 10) for individual AE 
reports, the Sponsor will  promptly evaluate all reported SAEs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators and applicable regulatory authorities.   
To ensure consistency of causality assessments, investigators should apply the following general 
guidelines for the assessment of causality: 
Table 10: Causal Attribution Guidance 
9.5 Recording Adverse Events on the CRF   
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the CRF.  Avoid colloquialisms and abbreviations. Only one medical concept should be recorded 
in the event field on the Adverse Event CRF.  
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms and are considered clinically significant. Grades 1-4 hematologic toxicity is 
anticipated during the first 100 days after stem cell transplantation and so will not be considered 
as an adverse event or reported as a SAE.  
Readmission to the hospital after stem cell transplantation is anticipated as a result of a number 
of transplant-associated side effects such as, but not limited to, the following:  
• Recurrence of the leukemia or cancer  
• Febrile neutropenia  
• Bleeding from thrombocytopenia  
• Acute or chronic GVHD  
Is the AE/SAE suspected to be caused by the investigational product based on facts, evidence, 
science-based rationales, and clinical judgment? 
Related  
There is a reasonable possibility that the investigational product caused the event.  
Not Related 
There is no reasonable possibility the event was attributed to the investigational 
product.   
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If in the opinion of the investigator, these re-hospitalizations are transplant-associated side 
effects, these events should be reported in the eCRF as AEs (not SAEs) for this study as they are 
not unexpected after the stem cell transplant. 
9.5.1 Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF or SAE Form 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.  If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
9.5.2 Adverse Events Occurring Secondary to Other Events 
In general, AEs/SAEs 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 SAE Form. 
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 SAE Form.  For example, if a 
severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately on the CRF or SAE Form. 
9.5.3 Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points.  Such events should only be recorded once in the CRF unless their severity 
increases.  If a persistent AE becomes more severe, it should be recorded again on the Adverse 
Event CRF.   
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on Adverse Event CRF or eCRF. 
9.5.4 Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF and SAE Form (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 5× the upper limit of normal associated with cholecystitis), 
only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF. 
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 
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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.  
9.5.5 Deaths 
All deaths that occur during the protocol-specified AE reporting period (Section 9.6), regardless 
of attribution, will be recorded on a CRF 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 “XXX (i.e., AML or MDS) 
Progression” as the SAE term on the CRF or eCRF. 
9.5.6 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 History CRF. 
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 or SAE Form, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent headaches”). 
9.5.7 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 
9.5.8 Pregnancy 
The investigator should report to the sponsor or designee all instances in female subjects or 
partners of male subjects within 24 hours of their knowledge of the pregnancy using the 
Pregnancy Form. In addition, abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs and must be 
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reported using the SAE Report Form. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required.  
• If a female subject becomes pregnant while receiving investigational therapy or within 
120 days after the last dose of investigational product, a Pregnancy Report CRF should 
be completed, printed, and faxed to the Sponsor or its designee within 24 hours of 
learning of the pregnancy 
• 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 subject or female partner 
of a male subject exposed to the investigational product should be recorded and reported 
as an SAE 
• The Pregnancy Form should be completed and sent to the Sponsor as described in Section 
9.6.4 
9.6 Guidance for Capturing and Reporting Adverse Events  
9.6.1 Adverse Event Reporting Period 
After informed consent, but prior to haplo-HSCT on Day 0, only SAEs caused by a protocol-
mandated intervention (i.e., outside of institutional standard protocol) will be collected. 
Table 11 details the guidance for Adverse Event Reporting after the Treatment Phase has 
initiated. 
Table 11: Adverse Event Reporting Guidelines 
AE type 
Timepoint 
Rivogenlecleucel 
Rimiducid 
Adverse Events 
< 30 days post dose 
√ 
√ 
Serious Adverse Events 
< 180 days post dose 
√ 
√ 
Serious Adverse Events 
Related to Study 
Treatment 
181 days – 24 months 
post dose 
√ 
√ 
Pregnancy of Subject or 
Partner 
No less than 12 months 
following the last dose of 
myeloablative therapy 
√ 
√ 
All AEs (except GVHD) will be collected for 30 days following each infusion of 
rivogenlecleucel or rimiducid. SAEs regardless of attribution will be collected until 180-days 
post rivogenlecleucel infusion and/or rimiducid. After this period, investigators should report 
only SAEs that are felt to be related to the study treatment (rivogenlecleucel and/or rimiducid).  
9.6.1.1 GVHD Adverse Event Reporting 
All occurrences of GVHD will be reported as Adverse Events (or SAEs), regardless of their start 
date in relation to rivogenlecleucel (if applicable). GVHD events will also be followed until 
resolution and not limited to the standard AE/SAE reporting period.  
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9.6.2 Procedures for Eliciting and Recording Adverse Events  
Instructions and clarifications for the eliciting and recording of Adverse Events are in 
Section 9.6.2 of this protocol. 
9.6.3 Expedited Reporting Requirements for Serious Adverse Events or Protocol Defined 
Events of Special Interest  
Any life-threatening or fatal SAE that is attributed by the investigators to the investigational 
product will be telephoned to the Medical Monitor immediately, followed by submission of 
written case details on a SAE Report Form within 24 hours.  
Medical Monitor Contact Information: 
Primary Medical Monitor 
Medical Monitor 
Tara L. Chen 
Email 
tchen@bellicum.com  
Telephone No. 
+1-628-400-2536  
Contact for SAE Reporting 
FAX No.: 617-315-4825 (US) / +34-976 20 44 02 (EU)  
E-Mail: BellicumSafety@pharmalex.com  
 
Back-up Medical Monitor 
Medical Monitor 
Paul Woodard  
Email 
pwoodard@bellicum.com  
Telephone No. 
+1-415-254-1109 
Contact for SAE Reporting 
FAX No.: 617-315-4825 (US) / +34-976 20 44 02 (EU)  
E-Mail: BellicumSafety@pharmalex.com  
 
9.6.4 Reporting Requirements for All SAEs and Pregnancy Reports 
Investigators will submit reports of SAEs and pregnancy, to the Sponsor within 24 hours of 
learning of the events. For initial SAE reports, investigators should record all case details that 
can be gathered within 24 hours on an SAE Report Form or Pregnancy Report Form and submit 
electronically. Relevant follow-up information should be submitted to Sponsor or its designee as 
soon as it becomes available and/or upon request.  
Contact information for SAE Report Forms and Pregnancy Forms:  
 
Email: BellicumSafety@pharmalex.com 
 
Fax (back-up): +1-617-315-4825 (US) / +34 976 20 44 02 (EU) 
9.6.5 Reporting SAEs to the IRB or Ethics Committee 
The investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the required Ethics Committees or IRBs.  
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9.6.6 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 subject is lost to follow up, or it has been determined that the study treatment or 
participation is not the cause of the AE/SAE. Resolution of AEs and SAEs (with dates) should be 
documented on the Adverse Event CRF or eCRF and in the subject’s medical record to facilitate 
source data verification (SDV).  
For some SAEs, the Sponsor or its designee may follow up with the site by telephone, fax, 
electronic mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report). Within 24 hours of receipt of new follow-up information, the Investigator must 
update the SAE report and submit any supporting documentation to the sponsor or designee.  
9.6.7 Post-Study Adverse Events 
The investigator should notify the study Sponsor of any death or other SAE occurring at any time 
after a subject has discontinued or terminated study participation if the event is deemed to be 
related to prior study treatment. The Sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that participated in this study. The investigator should report 
these events to Sponsor via the study CRF or eCRF. If the study CRF of eCRF system is no 
longer available, the investigator should report the event directly to Sponsor via phone or email. 
10. STATISTICAL AND ANALYSIS PLAN 
10.1 General Statistical Approach 
Analyses will be conducted on databases which are locked or frozen for data extract.  
Unless otherwise indicated, data from all investigative sites will be combined in the statistical 
analysis. Data will be summarized for each of the performance outcomes assessed. Continuous 
endpoints will be summarized using the number of observations, mean, median, minimum and 
maximum values. Categorical endpoints will be summarized using the number of observations 
and percentages. Time-to-event assessments will be summarized using Kaplan-Meier and 
Nelson-Aalen estimation procedures, as appropriate. Statistical tests will be two-sided with a 
type-1 error rate of 5% or one-sided with a type-1 error rate of 2.5%.  All confidence intervals 
will be presented at a 95% confidence level. 
Baseline demographics, clinical characteristics, and relevant medical history will be summarized 
for each treatment group.  
All outcome analyses will be based on the time from randomization to the first occurrence of the 
outcome. For each time-to-event endpoint, a Kaplan-Meier plot with the number of subjects at 
risk at specific time points for each treatment group will be presented. 
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The significance level for all statistical tests is 5%. The inferential statistics and tests of 
hypotheses comparing the two treatment arms will be presented in more details in a separate 
formal statistical analysis plan (SAP) document. 
The primary analysis for the Phase III portion is planned to be conducted 24 months after the last 
subject has been randomized. Adverse events will be coded using the most recent MedDRA 
version available at the time of analysis.  Concomitant medications will be coded using the most 
recent version of the World Health Organization (WHO) Drug. 
10.2 Study Design and Randomization 
This study consists of 2 parts: 
Phase II (safety and preliminary activity assessment of rivogenlecleucel treatment); and  
Phase III (randomized safety and efficacy assessment).  The Phase III is a 1:1 ratio 
randomization to two arms to evaluate the efficacy of αβ T cell and CD19+ B cell depleted, 
related haploidentical hematopoietic stem cell transplantation (haplo-HSCT) plus 
rivogenlecleucel (Arm A) vs. haplo-HSCT followed by post-transplant cyclophosphamide 
(PTCy) (Arm B) in subjects with acute myeloid leukemia (AML) or myelodysplastic syndrome 
(MDS). Randomization will be stratified as detailed in Section 5.5.2. Each eligible subject will 
be randomized to one of the treatment arms by the Randomization and Trial Supply Management 
(RTSM) system and will be assigned a unique subject identification number.   
10.3 Sample Size Determination 
Total Subject Enrollment:   Phase II Sample + Phase III Sample = 10 + 168 = 178 subjects. 
The phase III sample size of subjects for the study is based on the primary endpoint of overall 
survival (OS) from the time of randomization.    
10.3.1 Phase II  
The sample size for Phase II (10 subjects) was not based on formal statistical power calculations 
but rather estimation considerations. It is assumed from clinical experience that 10 subjects 
enrolled would be sufficient to provide clinical precision to detect minimum Grade 3-4 acute 
GVHD of at least 30% associated with the selected rivogenlecleucel dose to allow adjustment of 
the dosing of rivogenlecleucel if necessary for the subsequent Phase III of the study. 
 
  Sample 
 
 
 
 
 
 
Confidence 
Size 
Actual       Proportion 
Lower 
Upper 
Width if 
Level 
(N) 
Width 
(P) 
Limit 
Limit 
P = 0.5 
0.950 
10 
0.423 
0.150 
0.035 
0.459 
0.527 
0.950 
20 
0.308 
0.150 
0.052 
0.360 
0.401 
0.950 
30 
0.253 
0.150 
0.063 
0.316 
0.337 
 
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10.3.2 Phase III  
A total sample size of 168 (split equally between the two groups), or 110 deaths, achieves 90% 
power to detect a hazard rate of 0.537 when the proportions surviving in the rivogenlecleucel 
treatment group is 0.458 and in the Comparator group is 0.234 at 42 months (or 0.80 and 0.66 at 
12 months, respectively), at a significance level (alpha) of 0.025 using a one-sided log-rank test.  
These results assume that two sequential looks are made using the O'Brien-Fleming spending 
function to determine the test boundaries and that the survival times are exponential with respect 
to OS (Chow et al. 2003, Lan and DeMets 1983, O'Brien and Fleming 1979). The nominal 
significance level at Look 1 is 0.001525 (upper boundary = 2.9626) and at Look 2 (final) is 
0.024501 (upper boundary = 1.9686). 
A potential sample size adjustment is planned to occur at approximately 50% (55 deaths) of the 
statistical information, with respect to OS (Look 1). At this occasion, the conditional power (the 
probability of rejecting a false null hypothesis at the end of the study given the data that have 
emerged so far) will be calculated, from which an increase in sample size might be made 
(Pocock 1977; Reboussin 1992; Jennison and Turnbull 2000; Proschan 2006). These calculations 
will be made by the iDMC at the interim review. The only information that will be conveyed is 
what the increase in sample size will be or if the sample size will remain the same. There will be 
no attempt of conducting any hypotheses testing at the time of this interim analysis.  
10.4. Populations for Analyses 
10.4.1 Phase II 
For purposes of analysis, the following populations are defined for the Phase II portion of the 
study: 
• Safety Evaluable Population (SEP) – The safety evaluable population will include all 
subjects enrolled into Phase II who receive rivogenlecleucel.  
• DLT-Evaluable Population – The DLT-evaluable population will include all subjects 
enrolled into Phase II who receive rivogenlecleucel and complete the DLT observation 
window. 
10.4.2 Phase III 
For purposes of analysis, the following populations are defined for the study: 
• Intent-to-treat Population (ITT) – The ITT population will include all subjects 
randomized to receive either treatment. The primary and secondary efficacy outcomes 
analyses will be based on the ITT population for the study. 
• Safety Evaluable Population (SEP) – The safety evaluable population will include all 
subjects who were randomized and who underwent hematopoietic stem cell 
transplantation. Comparative safety analyses may also be conducted restricting to 
subjects who were randomized and went on to successfully receive rivogenlecleucel. 
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• Rimiducid-evaluable Population (RP) – The rimiducid population will include all 
subjects who received rimiducid while on study.  
Additional analysis populations may be defined on the availability of data, e.g., samples used for 
pharmacokinetic or biomarker testing. These populations will be specified in the statistical 
analysis plan.  
10.5 Statistical Analyses 
A separate, formal statistical analysis plan (SAP) will be developed and finalized before database 
lock and will provide details on planned statistical analyses including any inferential statistics 
and hypothesis testing. Sensitivity analyses intended to characterize the robustness of the safety 
and efficacy results will also be specified in the SAP. This section provides only a summary of 
the endpoints and the general planned statistical analyses. 
10.5.1 Phase II Analysis  
10.5.1.1 Maximum Allowable Dose Determination 
The maximum allowable dose is defined as the highest dose of rivogenlecleucel that did not 
cause dose-limiting toxicities (as specified in Section 4.2.1) in three or more subjects. The rate of 
DLT-qualified events at the dose(s) explored in the cohort(s) will be summarized. 
The MAD established in Phase II will be the recommended dose in Phase III. 
10.5.1.2 Assessment of the Rate of GVHD  
The incidence of acute GVHD (Grade II-IV and Grade III-IV) and chronic GVHD will be 
summarized, including the time of onset for each.  
10.5.1.3 Outcome Assessment of Rimiducid Treatment for Patients Receiving 
Rivogenlecleucel 
The incidence of aGVHD and the outcome of treatment with rimiducid (Recovered: Yes/No) 
will be summarized. A resolution will be defined as complete response or improvement of at 
least one grade of acute GVHD in subjects receiving 1-3 doses of rimiducid. The results will be 
reviewed to inform the recommendation to begin the Phase III portion of the study. 
10.5.2 Phase III Analysis 
10.5.2.1 Primary Efficacy Analysis 
The primary endpoint is overall survival (OS), defined as the time from randomization to death 
due to any cause. Subjects will be followed until the time of death, study discontinuation, 
whichever occurs first. Subjects still on study at the time of primary analysis will be censored at 
the date they were last known to be alive. The primary analysis for OS is expected to occur 
approximately 42 months after the first patient is randomized, or, given 18 months of accrual, 
approximately 24 months after the last patient is randomized. Patients still on study at the time of 
primary analysis will be consented to agree to a LTFU study as part of a commitment to 
assessing long-term safety and efficacy of BPX-501. 
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The primary analysis will be performed using the Cox proportional hazards model (Cox 1972). 
The Cox regression model will be used to estimate the hazard ratio and 2-sided 95% confidence 
interval (CI), with the p-value estimated using the log-rank test statistic. Kaplan-Meier plots with 
numbers of subjects at risk at specific time points will be presented for each treatment group. 
10.5.2.2 Secondary Efficacy Analyses 
The following secondary endpoints will be evaluated in the study. A Type I error control plan for 
testing secondary and exploratory endpoints of interest will be provided in a separate SAP. 
Unless otherwise stated, the Cox regression model will be used to estimate the hazard ratio and 
the 2-sided 95% CI. Kaplan-Meier or Nelson-Aalen plots with numbers of subjects at risk at 
specific time points will be presented for each treatment group, as appropriate. 
10.5.2.2.1 Relapse-Free Survival (RFS) 
Relapse-free survival is defined as the time from randomization to relapse or death from any 
cause, whichever occurs first.  
10.5.2.2.2 GVHD-Free, Relapse-Free Survival (GRFS) 
GRFS is defined as the time from randomization to the occurrence of Grade 3-4 acute GVHD, 
chronic GVHD requiring systemic treatment, disease relapse, or death due to any cause, 
whichever occurs first.  
For AML, relapse is defined as the recurrence of disease after having achieved a CR, following 
CIBMTR criteria.  
For MDS, relapse is defined as a worsening in response after HSCT compared with the disease 
status prior to the preparative regimen, following CIBMTR criteria. For example, a subject 
transplanted in HI who has Progression from HI post-HSCT would have this event considered a 
relapse.  
10.5.2.2.3 Non-Relapse Mortality (NRM) 
Non-relapse mortality is defined as time from randomization to death without relapse/recurrence. 
Only deaths without prior evidence of relapse or recurrence will be considered events, and all 
other deaths will be censored.  
10.5.2.2.4 Time to Resolution of GVHD After Administration of Rimiducid 
Resolution of GVHD after administration of rimiducid is defined as the time from administration 
of the first dose of rimiducid to complete response in subjects receiving 1-3 doses of rimiducid.  
10.5.2.3 Other Secondary Endpoints 
10.5.2.3.1 Patient Reported Outcome (PRO) 
The quality of life will be assessed according to self-assessed Functional Assessment of Cancer 
Therapy – Bone Marrow Transplant (FACT-BMT), 36-Item Short Form Health Survey (SF-36), 
and the MD Anderson Symptom Inventory (MDASI). The percent change from baseline will be 
summarized by each treatment arm.   
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10.5.3. Safety Analyses (Toxicities) 
10.5.3.1. Adverse Events (AEs) 
The primary safety for this study is mortality. Adverse events (AE) occurring during the study 
will be collected and graded according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE).  The incidence, severity, and relationship to study intervention for each treatment arm 
by MedDRA System Organ Class (SOC) and the preferred term will be summarized. Adverse 
events leading to premature discontinuation from the study and serious adverse events grades ≥ 
grade 3 will be summarized separately by treatment arm. 
10.5.3.2 Other Safety Analyses (Toxicities) 
Other safety summaries will include: (i) Clinical Safety Laboratory Assessments that will be 
collected and graded according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE); (ii) Physical Examinations assessed at different visit time points; and (iii) Vital Signs. 
Statistical analysis methods and summaries will be described in greater details in the statistical 
analysis plan to be finalized before the database lock.  
10.5.4 Other Analyses 
Any PK and biomarker exploratory analyses considered to be necessary for this study will be 
described in the statistical analysis plan finalized before database lock. 
10.6 Interim Analyses 
A total sample size of 168 (split equally between the two groups), or 110 deaths, achieves 90% 
power to detect a hazard rate of 0.537 when the proportions surviving in the BPX-501 treatment 
group is 0.458 and in the Comparator group is 0.234 at 42 months (or 0.80 and 0.66 at 12 
months, respectively), at a significance level (alpha) of 0.025 using a one-sided log-rank test. 
This analysis is expected to occur approximately 42 months after the first patient is randomized, 
or, given 18 months of accrual, approximately 24 months after the last patient is randomized. 
These results assume that 2 sequential looks are made using the O'Brien-Fleming spending 
function to determine the test boundaries and that the survival times are exponential OS (Chow 
2003; Lan and DeMets 1983; O'Brien and Fleming 1979). The nominal significance level at 
Look 1 is 0.001525 (upper boundary = 2.9626) and at Look 2 (final) is 0.024501 (upper 
boundary = 1.9686). 
A potential sample size adjustment is planned to occur at approximately 50% (55 deaths) of the 
statistical information, concerning OS (Look 1). At this occasion, the conditional power (the 
probability of rejecting a false null hypothesis at the end of the study given the data that have 
emerged so far) will be calculated, from which an increase in sample size might be made 
(Pocock 1977; Reboussin 1992; Jennison and Turnbull 2000; Proschan 2006). These calculations 
will be made by the iDMC at the interim review. The only information that will be conveyed is 
what the increase in sample size will be or if the sample size will remain the same. There will be 
no attempt of making any hypotheses testing of any kind at this occasion. 
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The Sponsor reserves the right to potentially conduct up to one additional interim analysis over 
the duration of the trial. The decision to conduct this previously unplanned interim analysis may 
be based off of accumulating information reflective of strong deviations from study planning 
assumptions, emerging safety signals or other sources of independent information. In this case, a 
protocol amendment will be submitted, and the iDMC charter and the Type I error control plan 
set forth in the SAP will both be updated.  
11. DATA QUALITY AND MONITORING REQUIREMENTS  
11.1 Case Report Forms 
Electronic data capture (EDC) will be used. Therefore, patient data from source documents will 
be entered directly into the clinical database at the Investigator Sites using electronic Case 
Report Forms (eCRFs). The PI is responsible for assuring that source documentation is 
appropriately maintained, and that data entered into the eCRF are complete and accurate, and 
that entries and updates are performed promptly. 
Bellicum personnel (or designees) will review the data entered by investigational staff for 
completeness and accuracy.  If potential discrepancies are discovered, electronic data queries 
stating the nature of the potential discrepancy and requesting clarification will be sent to the 
investigational site via the EDC system.  Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.  
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. 
11.2 Study Monitoring 
Qualified individuals designated by Bellicum will monitor all aspects of the study according to 
the protocol/amendment(s), ICH/GCP and standard operating procedures for compliance with 
applicable government regulations. In accordance with regulations and guidelines, the PI agrees 
to allow these monitors direct access to the clinical supplies, dispensing, and storage areas and to 
all of the Investigator’s source documentation, including but not limited to original medical 
records of the study subjects, test and procedure results, Investigator and study staff notes, etc. in 
order to verify the accuracy of the data recorded in the CRF, and, if requested, agrees to assist 
the monitors. The PI and staff are responsible for being present or available for consultation 
during routinely scheduled site visits conducted by Bellicum or its designees. The review of the 
subjects’ medical records will be performed in a manner to ensure that confidentiality is 
adequately maintained.  
Members of the Bellicum Quality Assurance Department or designees may conduct an audit of a 
clinical site at any time during or after completion of the study. The PI will be informed if an 
audit is to take place and advised as to the scope of the audit. Representatives of the FDA or 
other regulatory agencies may also conduct an audit of the study. If informed of such an 
inspection, the PI should notify Bellicum immediately. The PI will ensure that the auditors have 
access to the clinical supplies, study site facilities, source documentation, and all study files. All 
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inspections and audits will be carried out considering data protection as well as patient 
confidentiality to the extent that local, state, and federal laws apply. 
11.3 Use of Computerized Systems 
When clinical observations are entered directly into an investigational site's computerized 
medical record system (i.e., in place of original hardcopy records), the electronic record can 
serve as the source document if the system has been validated under FDA requirements on 
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 
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. 
12. ETHICAL CONSIDERATIONS 
12.1 Compliance with Laws and Regulations 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting). Studies 
conducted in the United States or under a U.S. Investigational New Drug (IND) application will 
comply with U.S. FDA regulations and applicable local, state, and federal laws. Studies 
conducted in the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC) (as 
amended). 
12.2 Informed Consent 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent Forms 
such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided 
to each site. If applicable, it will be provided in a certified translation of the local language. The 
Sponsor or their designee must review and approve any proposed deviations from the Sponsor’s 
sample Informed Consent Forms or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before submission to the Institutional Review Board (IRB) 
or Ethics Committee (EC). The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Forms must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history or clinical 
records for each subject shall document the informed consent process and that written informed 
consent was obtained prior to participation in the study. 
The Informed Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the subject to 
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participate. The final revised IRB/EC-approved Consent Forms must be provided to the Sponsor 
for health authority submission purposes. Subjects must be re-consented to the most current 
version of the Informed Consent Forms (or to a significant new information/findings addendum 
in accordance with applicable laws and IRB/EC policy) during their participation in the study. 
For any updated or revised Informed Consent Forms, the case history or clinical records for each 
subject shall document the informed consent process and that written informed consent was 
obtained using the updated/revised Informed Consent Forms for continued participation in the 
study. 
A copy of each signed Informed Consent Form must be provided to the subject or the subject’s 
legally authorized representative. All signed and dated Informed Consent Forms must remain in 
each subject’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Informed Consent Form may also include subject 
authorization to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for subject authorization for use and disclosure of personal health 
information under the 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. 
12.3 Institutional Review Board or Ethics Committee 
It is the responsibility of the Investigator to ensure that the appropriate IRB or IEC has reviewed 
and approved this protocol prior to initiating the study. The IRB/IEC must also review and 
approve the investigative site’s informed consent form (ICF), other written information provided 
to the subject, and all subject materials that may be used. 
If the protocol, Investigator’s Brochure, or ICF are amended during the study, per local 
regulations the Investigator is responsible for ensuring that the IRB/IEC has reviewed and 
approved these amended documents. In addition, IRB/IEC approval of the amended documents 
must be obtained before implementation and before new subjects are consented to participate in 
the study using the amended version of the ICF. 
12.4 Confidentiality 
The Sponsor maintains confidentiality standards by coding each subject enrolled in the study 
through assignment of a unique subject identification number. Subject names are not included in 
data sets that are transmitted to any Sponsor location. 
Subject 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 subject or unless permitted or required by 
law. 
Medical information may be given to a subject’s personal physician or other appropriate medical 
personnel responsible for the subject’s welfare for treatment purposes.  
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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, Sponsor’s 
monitors/representatives and collaborators, and the IRB for each study site, if appropriate. 
12.5 Future Use of Stored Specimens 
Samples of blood and/or tissue collected during this study may be stored for future research at 
Bellicum Pharmaceuticals, Inc. in subjects who provide consent. 
13. STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
13.1 Investigator Responsibilities 
The Investigator is responsible for ensuring that all study site personnel, including sub-
investigators and other responsible study staff members, conduct the study in compliance with 
the Declaration of Helsinki and the ICH E6 Guideline for GCP, including the archiving of 
essential documents. 
The Investigator will ensure adherence to the basic principles of GCP, as outlined in 21 CFR 
312, Subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, Part 50 and 21 CFR, 
Part 56. 
The Investigator, sub-investigators, and key study staff as listed on FDA Form 1572 will comply 
with 21 CFR, Part 54, providing documentation of any financial conflict of interest. This 
documentation must be provided prior to the Investigator’s (and any sub-investigators’) 
participation in the study. The Investigator and sub-investigator(s) agree to notify the Sponsor of 
any change in reportable interests during the study and for 1 year following study close-out at the 
Investigator’s site. 
If necessary to amend either the protocol or the study ICF, the Investigator will be responsible 
for ensuring that the IRB/EC reviews and approves the amended documents, and that subjects 
are informed of applicable changes, and updates in a timely manner 
The Investigator will sign and return to the Sponsor the “Protocol Signature Page” of the original 
protocol and any protocol amendment, provide current medical licenses, curriculum vitae, and 
FDA Form 1572 “Statement of Investigator.” All forms must be updated as applicable 
throughout the study. 
13.2 Study Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including but not limited to the protocol, protocol amendments, 
Informed Consent Forms, and documentation of IRB/EC and governmental approval. In 
addition, at the end of the study, the Investigator will receive the subject data, which includes an 
audit trail containing a complete record of all changes to data. 
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13.3 Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP of the guideline 
require that records and documents pertaining to the conduct of this study and the distribution of 
investigational drug, including CRFs, or data on 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 the Sponsor. Written 
notification should be provided to the Sponsor for transfer of any records to another party or 
moving them to another location. 
13.4 Site Audits and Regulatory Inspections 
Representatives of regulatory authorities, the Sponsor, or IRB/IEC may conduct inspections or 
audits of the clinical study. If the Investigator is notified of an inspection by a regulatory 
authority, the Investigator will notify the Sponsor immediately. The Investigator will provide to 
representatives of a regulatory agency or the Sponsor access to records, facilities, and personnel 
for the effective conduct of any inspection or audit. 
13.5 Protocol Deviations 
The Investigator should document and explain any protocol deviations. The Investigator should 
promptly report any deviations that might have an impact on subject safety and data integrity to 
the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and procedures. 
13.6 Financial Disclosure 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. The Investigator shall 
promptly update this information if any relevant changes occur during the study or for 1 year 
following completion of the study. 
13.7 Quality Control and Quality Assurance 
The Sponsor or its designee will perform quality control and quality assurance checks of all 
clinical studies that it sponsors. Before the enrollment of any subject in this study, Sponsor 
personnel will review and provide training as needed to the Investigator, sub-investigators, and 
study site personnel regarding the following: protocol, IB, CRFs and procedures for their 
completion, informed consent process, and procedures for reporting SAEs. Site visits will be 
performed by the Sponsor or its designee periodically throughout the study. During these visits, 
information recorded on the CRFs will be verified against source documents, and requests for 
clarification or correction may be made. The CRFs will be reviewed for safety information, 
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completeness, accuracy, and logical consistency. Computer programs that identify data 
inconsistencies may be used to help monitor the clinical study. Requests for clarification or 
correction will be sent to Investigators via data queries. 
13.8 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor prior to submission. 
This allows the Sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsors will generally support publication of 
multicenter trials only in their entirety and not as individual center data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. Any formal publication of the study in which 
contribution of Sponsor personnel exceeded that of conventional monitoring will be considered 
as a joint publication by the Investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of data from this study will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise. 
 
 
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of αβ+ T and B-cells in children with non-malignant disorders. Blood 2014;124(5):822-826. 
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Chow S-C, Shao J, Wang H. 2003. Sample Size Calculations in Clinical Research. New York, 
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de Brabander C, Cornelissen J, Smitt P, et al. Increased incidence of neurological complications 
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Di Stasi A, Tey SK, Dotti G, et al. Inducible apoptosis as a safety switch for adoptive cell 
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Grauer O, Wolff D, Bertz H, et al.  Neurological manifestations of chronic graft-versus-host 
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Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. Boca 
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Kanakry CG, O'Donnell PV, Furlong T, et al. Multi-institutional study of post-transplantation 
cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone 
marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 
2014;32(31):3497-3505. 
Karduss-Urueta AJ, Perez R, Suarez G, et al. Haploidentical stem cell transplantation with post-
transplant cyclophosphamide using as conditioning fludarabine melphalan plus 200-400cGy of 
total body irradiation. Very good balance between tolerance and anti leukemic activity. Blood 
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Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
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cells following αβ-T and B-cell-depleted HLA haploidentical HSCT (haplo-HSCT) in children 
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Appendix A: Arm A – Schedule of Assessments 
Table A-12: Pre-treatment Period 
 
Study Period 
 
Screening 
Conditioning 
Notes 
Day 
-42 to -1 -10 to -1 
Visit window (Days) 
 
 
Procedure 
Informed Consent 
X 
 
 
Eligibility Criteria Assessment 
X 
 
 
Demography 
X 
 
 
Medical History 
X 
 
 
ECOG Performance Status 
X 
X 
Assess within 7 days of conditioning. 
Concomitant Medications 
X 
X 
Only concomitant medications of interest may be recorded. 
Adverse Events 
X 
X 
Record AEs/SAEs related to protocol-mandated procedures during Pre-treatment. 
Height & weight 
X 
 
Weight at screening will be used to determine total BPX-501/CD34+ cell dose. 
Physical Examination 
X 
X 
Should include a routine neurological exam with evaluation of the cranial nerves, motor 
and sensory skills, coordination, and balance. 
Vital Signs 
X 
X 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. 
ECG 
X 
 
May be performed up to 8 weeks before Screening. 
Echocardiogram/ MUGA 
X 
 
Left Ventricular Ejection Fraction (LVEF) to be determined by MUGA or 
echocardiogram; may be performed up to 8 weeks before Screening. 
Pulmonary Function Test 
(PFT) 
X 
 
Pulmonary function testing should include diffusing capacity of the lungs for carbon 
monoxide (DLCO) and FEV1; may be performed up to 8 weeks before Screening. 
Chest X-Ray 
X 
 
 
Pregnancy Test 
X 
 
Serum or urine β-HCG required for females of child bearing potential only. 
HLA typing 
X 
 
HLA-A, -B, -C, -DRBI performed at high resolution. Screening for anti-HLA donor-
specific antibodies should be included. 
Hematology 
X 
X 
WBC with differential, RBC, Hgb, HCT, platelet count (quantitative), and ALC.  
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Study Period 
 
Screening 
Conditioning 
Notes 
Day 
-42 to -1 -10 to -1 
Visit window (Days) 
 
 
Procedure 
Serum Chemistries 
X 
X 
Glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, chloride, calcium, 
total protein, albumin, total and direct bilirubin, alkaline phosphatase, ALT, AST, 
magnesium, phosphate, bicarbonate, lactate dehydrogenase (LDH), uric acid, 
triglycerides. 
Coagulation 
X 
 
Prothrombin time /activated partial thromboplastin time (aPTT), international 
normalized ratio (INR), fibrinogen, and D-dimer; should be performed prior to any 
biopsy procedures. 
Infectious Diseases Screening 
X 
 
Refer to Section 7.2.1, Table 4, for details of tests to be performed. 
Quantitative Immunoglobulins 
X 
 
 
iCasp T Cell Tracking 
X 
 
 
RCR 
X 
 
Must be collected prior to start of conditioning. 
Bone Marrow & Disease 
Evaluation 
X 
 
Disease evaluation, including bone marrow aspirate/biopsy, MRD status, and 
cytogenetics and analysis of peripheral blood must be performed in all subjects; 
assessments must occur within 30 days from initiation of conditioning. 
Patient Reported Outcomes 
(FACT-BMT, SF-36, MDASI) 
X 
 
Required in Phase III only. 
ALC = absolute lymphocyte count; CMV = cytomegalovirus; Hct = hematocrit; Hgb = hemoglobin; HSV = herpes simplex virus; RBC = red blood cell; VZV = varicella 
zoster virus; WBC = white blood cell. 
*Hepatitis C viral load testing should be performed in all subjects at increased risk for hepatitis C infection, including those who have received a transfusion with blood 
not tested for hepatitis C (e.g., before 1992 in developed countries), history of IV or inhaled drug use, tattoos, or unexplained elevation of serum ALT. If subject has 
positive HCV serologic test, viral load testing should be performed. 
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Table A-13: Treatment Period (Day 0 up to Day +100) 
 
Study Period 
Notes 
Haplo-HSCT 
 
BPX-501  
 
 
 
 
 
 
Day 
0 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
 
± 4 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exams are required as listed in the schedule of 
assessment. Additional physical examinations should be 
conducted based on the discretion of the investigator. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For rivogenlecleucel infusion, vitals should be obtained within 1 
hour prior to start of infusion and at 15 (+/- 5), 30 (+/- 5), and 
120 (+/- 15) minutes after start of infusion. 
Neurotoxicity Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical neurological exam + MMSE (or modified MMSE) 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood counts with differentials should be performed at least 3 
times per week after transplant until ANC > 0.5 x 109/L for 3 
days after nadir reached. Thereafter, CBC at least 2 times per 
week until the neutrophil count is > 1.0 x 109/L and platelets > 
100 x 109/L. 
Serum Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to start of conditioning, serum creatinine is used to calculate 
the creatinine clearance using the Cockcroft-Gault method. 
Coagulation 
X 
X 
X 
X 
 
 
 
 
 
Prothrombin time /activated partial thromboplastin time (aPTT), 
international normalized ratio (INR), fibrinogen, and D-dimer; 
Coagulation tests should be performed prior to any biopsy 
procedures. 
Viral Monitoring 
 
Weekly until Day +100 
Weekly blood monitoring for EBV, HHV6, adenovirus, and 
CMV is recommended for at least 6 months after last dose of 
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Study Period 
Notes 
Haplo-HSCT 
 
BPX-501  
 
 
 
 
 
 
Day 
0 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
 
± 4 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
rATG or when ALC > 300 cells/mm3, whichever is later. 
Additional viral monitoring may be performed at the discretion of 
the treating physician. 
Haplo-HSCT 
X 
 
 
 
 
 
 
 
 
Patients who receive rivogenlecleucel will receive a TCR αβ/B 
cell-depleted haplo-HSCT.  
Bone Marrow & Disease 
Evaluation 
 
 
 
 
 
X 
 
 
X 
Disease assessment including bone marrow evaluation should 
occur on Day +30 and every 3 months for the first year (e.g., Day 
+100, Month 6, Month 9, and Month 12), then every six months 
for the 2nd year, and annually thereafter. Additional evaluations 
may be performed at the discretion of the investigator.  
MRD Evaluation 
See Notes 
MRD evaluation should be assessed based on institutional 
standard practice as part of disease evaluation post-HSCT. 
Immune Reconstitution 
 
 
 
 
X 
X 
X 
X 
X 
The basic clinical flow panel includes CD3+ cells, α/β CD3+ 
cells, γ/δ CD3+ cells, CD4+ cells, CD8+ cells, NK cells, and B 
cells.  
After BPX-501 infusion, the flow panel will include 
CD3+/CD19+ cells, CD3+/CD19+/CD4+ cells, and 
CD3+/CD19+/CD8+ cells.  
Any sample remaining after flow cytometry analysis will be 
processed to PBMCs and frozen for further analysis of T cell 
phenotype and function. 
Chimerism 
 
 
 
 
 
X 
 
 
X 
Donor/host chimerism analyses shall be performed according to 
standard institutional practice. The same method shall be used for 
the same patient. Additional tests may be performed as needed. 
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Study Period 
Notes 
Haplo-HSCT 
 
BPX-501  
 
 
 
 
 
 
Day 
0 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
 
± 4 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
Quantitative 
Immunoglobulins 
 
 
 
 
 
 
 
X 
X 
 
GVHD Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD assessment will occur at all study visits and should be 
performed according to standard institutional guidelines.  
Subjects should receive daily GVHD assessments for 7 days after 
the initiation of the first rimiducid infusion and then resume the 
GVHD assessments per the schedule in the protocol. 
Patient Reported 
Outcomes (FACT-BMT, 
SF-36, MDASI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Required in Phase III only. 
BPX-501 infusion 
 
 
X 
 
 
 
 
 
 
Rivogenlecleucel will be administered on Day 14 (window ±4 
days). 
iCasp T Cell Tracking 
 
 
See Notes 
Immediately prior to BPX-501 infusion, weekly for 1 month, then 
biweekly through Day 100. 
If corticosteroids are administered for treatment of GVHD and/or 
neurotoxicity, additional samples should be collected. Refer to 
Appendix D for specific timepoints of sample collection. 
RCR 
 
 
 
 
 
 
 
 
X 
 
Rimiducid PK/PD samples 
 
 
See Appendix D 
If rimiducid is administered, refer to Appendix D for specific 
timepoints of sample collection. 
 
 
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Table A-14: Treatment Period (> Day 100 to End of Study) 
 
Study Period 
Relapse 
EOS 
Notes 
Day 
120 
150 
180 
270 
365 
 
 
 
 
 
Month 
4 
5 
6 
9 
12 
15 
18 
21 
24 
>24* 
Visit window (Days) 
±14 
±14 
±14 
±14 
±14 
±21 
±21 
±21 
±21 
±28 
 
±14 
Procedure 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exams are required as listed in the schedule 
of assessments. Additional physical examinations 
should be conducted based on the discretion of the 
investigator. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Bone Marrow & Disease 
Evaluation 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Disease assessment including bone marrow 
evaluation should occur every 3 months for the first 
year (e.g., Month 6, Month 9, and Month 12), then 
every six months for the 2nd year, and annually 
thereafter. Additional evaluations may be performed 
at the discretion of the investigator.  
MRD Evaluation 
See Notes 
See 
Notes 
X 
 
MRD evaluation should be assessed based on 
institutional standard practice as part of disease 
evaluation post-HSCT. 
Immune Reconstitution 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
The basic clinical flow panel includes CD3+ cells, 
α/β CD3+ cells, γ/δ CD3+ cells, CD4+ cells, CD8+ 
cells, NK cells, and B cells.  
After BPX-501 infusion, the flow panel will include 
CD3+/CD19+ cells, CD3+/CD19+/CD4+ cells, and 
CD3+/CD19+/CD8+ cells.  
Any sample remaining after flow cytometry analysis 
will be processed to PBMCs and frozen for further 
analysis of T cell phenotype and function. 
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Study Period 
Relapse 
EOS 
Notes 
Day 
120 
150 
180 
270 
365 
 
 
 
 
 
Month 
4 
5 
6 
9 
12 
15 
18 
21 
24 
>24* 
Visit window (Days) 
±14 
±14 
±14 
±14 
±14 
±21 
±21 
±21 
±21 
±28 
 
±14 
Procedure 
Chimerism 
 
 
 
 
X 
 
 
 
 
 
X 
 
Donor/host chimerism analyses shall be performed 
according to standard institutional practice. The same 
method shall be used for the same patient. Additional 
tests may be performed as needed. 
Quantitative 
Immunoglobulins 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
GVHD Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD assessment will occur at all study visits and 
should be performed according to standard 
institutional guidelines.  
Subjects should receive daily GVHD assessments for 
7 days after the initiation of the first rimiducid 
infusion and then resume the GVHD assessments per 
the schedule in the protocol. 
Patient Reported 
Outcomes (FACT-BMT, 
SF-36, MDASI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Required in Phase III only. 
Survival and Subsequent 
Anticancer Therapy 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
iCasp T Cell Tracking 
Monthly through 1 year 
 
X 
 
X 
 
 
 
Monthly through 1 year, then at Month 18 and Month 
24.  
If corticosteroids are administered for treatment of 
GVHD and/or neurotoxicity, additional samples 
should be collected. Refer to Appendix D for specific 
timepoints of sample collection. 
RCR/VCN 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
RCR and VCN are tested on the same sample. VCN 
is tested every 6 months through year 5 then every 
year through year 10, if vector is detected.  RCR is 
tested at Screening, month 3, 6, 12, then annually 
through year 15.   
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Study Period 
Relapse 
EOS 
Notes 
Day 
120 
150 
180 
270 
365 
 
 
 
 
 
Month 
4 
5 
6 
9 
12 
15 
18 
21 
24 
>24* 
Visit window (Days) 
±14 
±14 
±14 
±14 
±14 
±21 
±21 
±21 
±21 
±28 
 
±14 
Procedure 
Rimiducid PK/PD samples 
See Appendix D 
 
 
 
If rimiducid is administered, refer to Appendix D: 
Research Laboratory Tests for Subjects Receiving 
BPX-501 for specific timepoints of sample 
collection. 
* After Month 24, evaluations should be performed every 6 months, or more frequently, at the discretion of the treating physician.  
 
 
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Appendix B: Arm B – Schedule of Assessments 
Table B-15: Pre-treatment Period 
 
Study Period 
 
Screening 
Conditioning 
Notes 
Day 
-42 to -1 -10 to -1 
Visit window (Days) 
 
 
Procedure 
Informed Consent 
X 
 
 
Eligibility Criteria Assessment 
X 
 
 
Demography 
X 
 
 
Medical History 
X 
 
 
ECOG Performance Status 
X 
X 
Assess within 7 days of conditioning. 
Concomitant Medications 
X 
X 
 
Adverse Events 
X 
X 
Record AEs/SAEs related to protocol-mandated procedures during Pre-treatment. 
Height & weight 
X 
 
Weight at screening will be used to determine total CD34+ cell dose. 
Physical Examination 
X 
X 
Should include a routine neurological exam with evaluation of the cranial nerves, motor 
and sensory skills, coordination, and balance. 
Vital Signs 
X 
X 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. 
ECG 
X 
 
May be performed up to 8 weeks before Screening. 
Echocardiogram/ MUGA 
X 
 
Left Ventricular Ejection Fraction (LVEF) to be determined by MUGA or 
echocardiogram; may be performed up to 8 weeks before Screening. 
Pulmonary Function Test 
(PFT) 
X 
 
Pulmonary function testing should include diffusing capacity of the lungs for carbon 
monoxide (DLCO) and FEV1; may be performed up to 8 weeks before Screening. 
Chest X-Ray 
X 
 
 
Pregnancy Test 
X 
 
Serum or urine β-HCG required for females of child bearing potential only. 
HLA typing 
X 
 
HLA-A, -B, -C, -DRBI performed at high resolution. Screening for anti-HLA donor-
specific antibodies should be included. 
Hematology 
X 
X 
WBC with differential, RBC, Hgb, HCT, platelet count (quantitative), and ALC. 
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Study Period 
 
Screening 
Conditioning 
Notes 
Day 
-42 to -1 -10 to -1 
Visit window (Days) 
 
 
Procedure 
Serum Chemistries 
X 
X 
Glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, chloride, calcium, 
total protein, albumin, total and direct bilirubin, alkaline phosphatase, ALT, AST, 
magnesium, phosphate, bicarbonate, lactate dehydrogenase (LDH), uric acid, 
triglycerides. 
Coagulation 
X 
 
Prothrombin time /activated partial thromboplastin time (aPTT), international 
normalized ratio (INR), fibrinogen, and D-dimer; should be performed prior to any 
biopsy procedures. 
Infectious Diseases Screening 
X 
 
Refer to Section 7.2.1, Table 4, for details of tests to be performed. 
Quantitative Immunoglobulins 
X 
 
 
Bone Marrow & Disease 
Evaluation 
X 
 
Disease evaluation, including bone marrow aspirate/biopsy, MRD status, and 
cytogenetics and analysis of peripheral blood must be performed in all subjects; 
assessments must occur within 30 days from initiation of conditioning. 
Patient Reported Outcomes 
(FACT-BMT, SF-36, MDASI) 
X 
 
Required in Phase III only. 
ALC = absolute lymphocyte count; CMV = cytomegalovirus; Hct = hematocrit; Hgb = hemoglobin; HSV = herpes simplex virus; RBC = red blood cell; 
VZV = varicella zoster virus; WBC = white blood cell. 
*Hepatitis C viral load testing should be performed in all subjects at increased risk for hepatitis C infection, including those who have received a 
transfusion with blood not tested for hepatitis C (e.g., before 1992 in developed countries), history of IV or inhaled drug use, tattoos, or unexplained 
elevation of serum ALT. If subject has positive HCV serologic test, viral load testing should be performed. 
 
 
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Table B-16: Treatment Period (Day 0 up to Day +100) 
 
Study Period 
Notes 
Haplo-HSCT 
PTCy 
 
 
 
 
 
 
 
 
Day 
0 
3-4 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
± 1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exams are required as listed in the schedule of 
assessment. Additional physical examinations should be 
conducted based on the discretion of the investigator. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurotoxicity Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical neurological exam + MMSE (or modified MMSE). 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood counts with differentials should be performed at least 3 
times per week after transplant until ANC > 0.5 x 109/L for 3 
days after nadir reached. Thereafter, CBC at least 2 times per 
week until the neutrophil count is > 1.0 x 109/L and platelets > 
100 x 109/L. 
Serum Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to start of conditioning, serum creatinine is used to calculate 
the creatinine clearance using the Cockcroft-Gault method. 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time /activated partial thromboplastin time (aPTT), 
international normalized ratio (INR), fibrinogen, and D-dimer; 
coagulation tests should be performed prior to any biopsy 
procedures. 
Viral Monitoring 
 
 
Weekly until Day +100 
Weekly blood monitoring for EBV, HHV6, adenovirus, and 
CMV is recommended until ALC > 300 cells/mm3. Additional 
viral monitoring may be performed at the discretion of the 
treating physician. 
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Study Period 
Notes 
Haplo-HSCT 
PTCy 
 
 
 
 
 
 
 
 
Day 
0 
3-4 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
± 1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
Haplo-HSCT 
X 
 
 
 
 
 
 
 
 
 
 
Post-transplant 
Cyclophosphamide 
 
X 
 
 
 
 
 
 
 
 
Cyclophosphamide will be administered to patients on Days 3 
and 4. 
Bone Marrow & Disease 
Evaluation 
 
 
 
 
 
 
X 
 
 
X 
Disease assessment including bone marrow evaluation should 
occur on Day +30 and every 3 months for the first year (e.g., Day 
+100, Month 6, Month 9, and Month 12), then every six months 
for the 2nd year, and annually thereafter. Additional evaluations 
may be performed at the discretion of the investigator.  
MRD Evaluation 
See Notes 
MRD evaluation should be assessed based on institutional 
standard practice as part of disease evaluation post-HSCT. 
Immune Reconstitution 
 
 
 
 
 
X 
X 
X 
X 
X 
The basic clinical flow panel includes CD3+ cells, α/β CD3+ 
cells, γ/δ CD3+ cells, CD4+ cells, CD8+ cells, NK cells, and B 
cells.  
Any sample remaining after flow cytometry analysis will be 
processed to PBMCs and frozen for further analysis of T cell 
phenotype and function. 
Chimerism 
 
 
 
 
 
 
X 
 
 
X 
Donor/host chimerism analyses shall be performed according to 
standard institutional practice. The same method shall be used for 
the same patient. Additional tests may be performed as needed. 
Quantitative 
Immunoglobulins 
 
 
 
 
 
 
 
 
X 
X 
 
GVHD Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD assessment will occur at all study visits and should be 
performed according to standard institutional guidelines. 
 
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Study Period 
Notes 
Haplo-HSCT 
PTCy 
 
 
 
 
 
 
 
 
Day 
0 
3-4 
7 
14 
19 
26 
33 
40 
68 
100 
Month 
 
 
 
 
 
 
1 
 
2 
3 
Visit window (Days) 
 
± 1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Procedure 
Patient Reported 
Outcomes (FACT-BMT, 
SF-36, MDASI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Required in Phase III only. 
 
 
 
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Table B-17: Treatment Period (> Day 100 to End of Study) 
 
Study Period 
Relapse 
EOS 
Notes 
Day 
120 
150 
180 
270 
365 
 
 
 
 
 
Month 
4 
5 
6 
9 
12 
15 
18 
21 
24 
>24* 
Visit window (Days) 
±14 
±14 
±14 
±14 
±14 
±21 
±21 
±21 
±21 
±28 
 
±14 
Procedure 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exams are required as listed in the schedule 
of assessments. Additional physical examinations 
should be conducted based on the discretion of the 
investigator. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Bone Marrow & Disease 
Evaluation 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Disease assessment including bone marrow 
evaluation should occur every 3 months for the first 
year (e.g., Month 6, Month 9, and Month 12), then 
every six months for the 2nd year, and annually 
thereafter. Additional evaluations may be performed 
at the discretion of the investigator.  
MRD Evaluation 
See Notes 
See 
Notes 
X 
 
MRD evaluation should be assessed based on 
institutional standard practice as part of disease 
evaluation post-HSCT. 
Immune Reconstitution 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
The basic clinical flow panel includes CD3+ cells, α/β 
CD3+ cells, γ/δ CD3+ cells, CD4+ cells, CD8+ cells, 
NK cells, and B cells.  
Any sample remaining after flow cytometry analysis 
will be processed to PBMCs and frozen for further 
analysis of T cell phenotype and function. 
Chimerism 
 
 
 
 
X 
 
 
 
 
 
X 
 
Donor/host chimerism analyses shall be performed 
according to standard institutional practice. The same 
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Study Period 
Relapse 
EOS 
Notes 
Day 
120 
150 
180 
270 
365 
 
 
 
 
 
Month 
4 
5 
6 
9 
12 
15 
18 
21 
24 
>24* 
Visit window (Days) 
±14 
±14 
±14 
±14 
±14 
±21 
±21 
±21 
±21 
±28 
 
±14 
Procedure 
method shall be used for the same patient. Additional 
tests may be performed as needed. 
Quantitative 
Immunoglobulins 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
GVHD Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GVHD assessment will occur at all study visits and 
should be performed according to standard 
institutional guidelines.  
Patient Reported 
Outcomes (FACT-BMT, 
SF-36, MDASI) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Required in Phase III only. 
Survival and Subsequent 
Anticancer Therapy 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
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Appendix C: Donor – Schedule of Assessments 
Table C-18: Donor Assessments 
 
Study Period 
 
Screening 
Leukapheresis 
(Arm A Only) 
Mobilization 
Apheresis 
Notes 
Day 
-42 to -1 
Prior to -15 
 
 
Visit window (Days) 
 
 
 
 
Procedure 
Informed Consent 
X 
 
 
 
 
Eligibility Criteria Assessment 
X 
 
 
 
 
HLA typing 
X 
 
 
 
HLA-A, -B, -C, -DRBI performed at high resolution.  
Demography 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Pregnancy Test 
X 
 
 
 
Serum or urine β-HCG required for females of child bearing potential only. 
Infectious Diseases Screening 
X 
 
 
 
Refer to Section 7.2.1, Table 4, for details of tests to be performed. 
Vital Signs 
 
X 
X 
 
 
T cell collection 
 
X 
 
 
For subjects receiving rivogenlecleucel, donor will undergo two separate apheresis 
sessions. Non-mobilized leukapheresis for collection of donor T cells should occur by 
Day -21, but no later than Day -15 to allow enough time for manufacturing. The T cells 
are shipped to Sponsor’s centralized GMP manufacturing facility (see Section 6.1.1). 
Mobilization 
 
 
X 
 
The donor will receive mobilization therapy with G-CSF administration per institutional 
protocol for mobilization of peripheral blood stem cells. 
For subjects receiving rivogenlecleucel, donor mobilization should start after successful 
leukapheresis (T cell collection).  
Allograft collection 
 
 
 
X 
For subjects receiving rivogenlecleucel, donor stem cells will be TCRαβ/CD19+ B cell 
depleted.  
Subjects not receiving rivogenlecleucel (Phase III, Arm B) will receive a standard T/B 
cell replete haploidentical transplant. 
* Hepatitis C viral load testing should be performed in all donors at increased risk for hepatitis C infection, including those who have received a transfusion with blood 
not tested for hepatitis C (e.g., before 1992 in developed countries), history of IV or inhaled drug use, tattoos, or unexplained elevation of serum ALT. 
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109 
 
Appendix D: Research Laboratory Tests for Subjects Receiving Rivogenlecleucel 
Sample Collection 
Timing 
HAMA 
Screening, Day 100 
RCR/VCN  
RCR and VCN are tested on the same sample.  
VCN is tested every 6 months (i.e., Month 6, 12, 18, etc.) through year 5 
then every year through year 10, if vector is detected.   
RCR is tested at Screening, Month 3 (Day 100), 6, 12, then annually 
through year 15.   
Immune reconstitution 
(clinical flow) 
The basic clinical flow panel includes CD3+ cells, α/β CD3+ cells, γ/δ 
CD3+ cells, CD4+ cells, CD8+ cells, NK cells, and B cells. After BPX-
501 infusion, the flow panel will include CD3+/CD19+ cells, 
CD3+/CD19+/CD4+ cells, and CD3+/CD19+/CD8+ cells. Any sample 
remaining after flow cytometry analysis will be processed to PBMCs 
and frozen for further analysis of T cell phenotype and function. 
Timepoints of collection: 
Screening, Day 26, 33, 40, 68, 100 
iCasp T cell tracking 
Peripheral blood and/or tissue should be sent to the Sponsor or designee 
for research purposes to evaluate for BPX-501 cells (CD3+CD19+) at 
the following times: 
• 
Immediately prior to BPX-501 infusion, weekly for 1 month, 
biweekly through day 100, monthly through 1 year, then at 
month 18 & month 24. 
If corticosteroids are administered for treatment of GVHD and/or 
neurotoxicity, additional samples should be collected at the following 
times:  
• 
Prior to administration of systemic corticosteroids doses (e.g., 
methylprednisone), at 4 and 24-hours post-systemic 
corticosteroid initiation, and at 7, 14, 21, and 28 days post 
systemic corticosteroid initiation. 
If cerebrospinal fluid (CSF) can be safely obtained prior to the initiation 
of high-dose corticosteroids, CSF should be sent to the Sponsor for 
research use to evaluate for BPX-501 cells (CD3+CD19+).   
Clinical staff are to adhere, as closely as practical, to the indicated 
sample collection timepoints; however, actual collection date and times 
are to be recorded, and samples collected outside of the specified times 
are not considered protocol deviations. 
Rimiducid PD  
For each rimiducid administration blood samples should be collected to 
characterize the pharmacodynamic response of BPX-501 cells:  
• 
Within 4 hours prior to rimiducid dose(s),  
• 
30 minutes after initiation of infusion; and  
• 
At 2 (≤ 5 minutes prior to infusion termination), 4, 6, 8, 12, 24 
and 48 hours after initiation of infusion.  
Additionally: 
• 
Samples should be collected for analysis at 7, 14, 21, and 28 
days after the final dose of rimiducid.  
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• 
If additional doses of rimiducid are given beyond 28 days after 
the end of rimiducid administration(s) then this time course 
restarts and sample collections should be made following the 
schedule above. 
Clinical staff are to adhere, as closely as practical, to the indicated 
sample collection timepoints; however, actual collection date and times 
are to be recorded, and samples collected outside of the specified times 
are not considered protocol deviations. Except samples collected at 2 
hours (≤ 5 minutes prior to rimiducid infusion termination) which must 
be collected within the specified time frame due to the rapid distribution 
of rimiducid. 
NOTE: All samples are to be collected contralateral to the site of 
rimiducid or corticosteroid administration. 
Rimiducid Plasma (PK) 
samples 
Plasma should be sent to the Sponsor designee for research purposes to 
evaluate rimiducid concentrations for each dose of rimiducid at the 
following times: 
• 
For each rimiducid administration plasma samples should be 
collected within 4 hours prior to rimiducid dose(s), 30 minutes 
after initiation of infusion; and at 2 (≤ 5 minutes prior to 
infusion termination), 4, 6, 8, 12, 24 hours after initiation of 
infusion. 
Clinical staff are to adhere, as closely as practical, to the indicated 
sample collection timepoints; however, actual collection date and times 
are to be recorded, and samples collected outside of the specified times 
are not considered protocol deviations. Except samples collected at 2 
hours (≤ 5 minutes prior to rimiducid infusion termination) which must 
be collected within the specified time frame due to the rapid distribution 
of rimiducid. 
NOTE: All samples are to be collected contralateral to the site of 
rimiducid or corticosteroid administration. 
Rimiducid CSF samples 
• 
If a sample of CSF can be safely obtained after initiation of 
corticosteroids and/or rimiducid for the treatment of 
neurotoxicity, CSF should be sent to the Sponsor designee for 
research use such as evaluation of BXP-501 cells 
(CD3+CD19+), rimiducid, or other analyses . The actual date 
and time of CSF sample collections should be recorded. 
 
 
 
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BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Appendix E: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale and 
Conversion from Karnofsky Scale 
ECOG Status 
ECOG 
Grade 
Karnofsky 
Grade 
Karnosfky Status 
Fully active, able to carry on all pre-
disease performance without restriction 
0 
100 
Normal, no complaints 
Restricted in physically strenuous activity 
but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light 
house work, office work 
1 
90 
Able to carry on normal 
activities. Minor signs or 
symptoms of disease 
Restricted in physically strenuous activity 
but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light 
house work, office work 
1 
80 
Normal activity with effort 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities; up 
and about more than 50% of waking hours 
2 
70 
Care for self. Unable to carry on 
normal activity or to do active 
work 
Ambulatory and capable of all selfcare but 
unable to carry out any work activities; up 
and about more than 50% of waking hours 
2 
60 
Requires occasional assistance, 
but able to care for most of his 
needs 
Capable of only limited selfcare; confined 
to bed or chair more than 50% of waking 
hours 
3 
50 
Requires considerable assistance 
and frequent medical care 
Capable of only limited selfcare; confined 
to bed or chair more than 50% of waking 
hours 
3 
40 
Disabled. Requires special care 
and assistance 
Completely disabled; cannot carry on any 
selfcare; totally confined to bed or chair 
4 
30 
Severely disabled. 
Hospitalization indicated though 
death not imminent 
Completely disabled; cannot carry on any 
selfcare; totally confined to bed or chair 
4 
20 
Very sick. Hospitalization 
necessary. Active supportive 
treatment necessary 
Completely disabled; cannot carry on any 
selfcare; totally confined to bed or chair 
4 
10 
Moribund 
Dead 
5 
0 
Dead 
Adapted from Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5,649-655. 
 
 
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Appendix F: Acute GVHD Grading Scale 
 
Reference:  
Harris AC, et al. BBMT 2016; 22:4 
 
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BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Appendix G: Chronic GVHD Activity Assessment – Clinician 
 
 
 
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Bellicum Pharmaceuticals, Inc., Rivogenlecleucel
IND 015243, SN 0094


BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Bellicum Pharmaceuticals, Inc., Rivogenlecleucel
IND 015243, SN 0094


BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Appendix H: GVHD Response Criteria 
Adapted from:  
Lee SJ, et al. Biol Blood Marrow Transplant 2015;21(6):984-999. 
Martin PJ, et al. Biol Blood Marrow Transplant 2009;15:777-784. 
Complete response (CR) is defined as complete resolution of GVHD manifestation in all organs, 
without need for secondary GVHD therapy. 
Partial response (PR) is defined as improvement in GVHD stage in all initially affected organs, 
without resolution in all organs, worsening in any other GVHD target organ or need for secondary 
GVHD therapy.  
 
Progression of GVHD (PD) is defined as worsening GVHD in at least 1 organ with or without 
improvement in any other organ.  
 
No response (NR) is defined as the same severity of GVHD in any organ or death, or the 
addition of secondary GVHD and required therapy with increased steroids or additional GVHD 
therapy were also considered to have no response.  
 
For acute GVHD, very good partial response (VGPR) is defined as: 
• Skin 
o No rash, or residual erythematous rash involving <25% of the body surface, 
without bullae (residual faint erythema and hyperpigmentation do not count) 
• Liver 
o Total serum bilirubin concentration <2 mg/dL or <25% of baseline at enrollment 
• Gut 
o Tolerating food or enteral feeding 
o Predominantly formed stools 
o No overt gastrointestinal bleeding or abdominal cramping 
o No more than occasional nausea or vomiting 
 
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BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Appendix I: Chronic GVHD Activity Assessment – Patient Self Report 
 
 
 
 
 
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BPX501-301A                                                                               Bellicum Pharmaceuticals, Inc 
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Appendix J: Response Determination for Chronic GVHD Based on Clinician Assessment 
 
 
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