Conditions: Acute Myeloid Leukemia Myelodysplastic Syndromes Myeloproliferative Disorder Chronic Lymphocytic Leukemia B-cell Lymphoma T-cell Lymphoma Non Hodgkin Lymphoma Hodgkin Lymphoma Chronic Myelomonocytic Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate whether addition of a low dose of total body irradiation (TBI) to a standard preparation for transplant \[total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG)\] conditioning will help to augment donor chimerism without reducing tolerability of this regimen or increasing the risk of graft-vs-host disease (GVHD)

Detailed description:
Primary Objective:

• Determine the proportion of patients with full donor T-cell chimerism at Day 28 following hematopoietic cell transplantation.

Secondary Objectives:

* Determine the risk of disease progression, overall and event free survival, and non-relapse mortality, following treatment with TLI; ATG; and TBI.
* Determine the incidence of acute and chronic GVHD following treatment with TLI; ATG; and TBI.

Exploratory Objectives:

• Determine the changes in frequency of hematopoietic stem, progenitor, and mature cell subsets and the changes in cytokine milieu and cellular architecture in the bone marrow of patients receiving TLI compared to TLI+TBI.

Arms:
arm 1: TBI, single exposure on Day -1, 80 centigray (cGy) in addition to total lymphoid irradiation (TLI, 120 cGy/day for 9 days, weekends excluded) and anti-thymocyte globulin (ATG) 1.5 mg/kg (conditioning regimen)

Interventions: intervention 1: Total body irradiation (TBI) intervention 2: Anti-thymocyte globulin (ATG) intervention 3: Tacrolimus intervention 4: Mycophenolate mofetil (MMF) intervention 5: Total lymphoid irradiation (TLI)
Intervention descriptions: intervention 1: Administer Total body irradiation (TBI) 80 cGy on Day 1 of standard TLI ATG conditioning intervention 2: Given intravenous (IV), Dose 1.5 mg/kg x 5 days intervention 3: Oral, Dose 0.05 mg/kg twice daily, can be given intravenous (IV) intervention 4: Given Oral, 15 mg/k every 2 hours for peripheral blood stem cells (PBSC) from matched related donors; 15 mg/kg every 8 hours for PBSC from unrelated donors (URDs) or mismatched related donors. intervention 5: 9 x 120 cGy over 11 days

Protocol document:
Prot_SAP_001.pdf: 
IRB-47407  
Page 1 of 30 
v5.  10August  2020 
Very Low-dose Total Body Irradiation in Combination with Total Lymphoid Irradiation 
and anti-Thymocyte Globulin to Improve Donor Engraftment in Patients Undergoing 
Non-Myeloablative Hematopoietic Cell Transplantation  
IRB-47407  
BMT330 
NCT03734601 
Coordinating Center 
Stanford Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA 94305 
Protocol Director 
Robert Lowsky, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305  Ph:  650-723-0822 Fax:  650-725-8950 
rlowsky@stanford.edu  
Co-Investigators 
Wen-Kai-Weng, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Robert Negrin, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Sally Arai, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Laura Johnston, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
David Miklos, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Judith Shizuru, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305 
 
Everett Meyer, MD 
Division of Blood and Marrow Transplantation 
and Cellular Therapeutics Facility Laboratory 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Andrew Rezvani, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Lori S Muffly, MD, MS 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr Stanford, CA  94305 
 
Parveen Shiraz, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr MC5623, Stanford, CA  94305 
 
Matthew Frank, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 
Samuel Strober, MD 
Divisions of Immunology & Rheumatology 
CCSR Building,  
Stanford, California 94305 
 


IRB-47407  
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v5.  10August  2020 
Richard Hoppe, MD 
Radiation Therapy,  
875 Blake Wilbur Drive 
Stanford,  California  94305 
 
Michael Spinner, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Drive, Stanford, CA 94305 
 
Study Coordinator 
Khanh Nguyen, CRCA 
Division of blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr., Stanford, CA 94305 
 
Study Coordinator 
Troy Zeno, CRCA 
Division of blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr., Stanford, CA 94305 
 
Biostatistician 
Philip Lavori, PhD  
Department of Health Research and Policy 
Biostatistics Shared Resource, 
Redwood Building, Stanford, CA 94305 
 
 
 


IRB-47407  
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v5.  10August  2020 
TABLE OF CONTENTS 
Protocol Synopsis 
4 
List of Abbreviations and Definition of Terms 
5 
Schema 
6 
1. 
Objectives 
7 
1.1 
Primary Objective 
7 
1.2 
Secondary Objectives 
7 
2. 
Background and Rationale 
7 
3. 
Participant Selection and Pre-Enrollment Requirements 
10 
3.1 
Patient Inclusion Criteria (on Participant Eligibility Checklist) 
11 
3.2 
Patient Exclusion Criteria (on Participant Eligibility Checklist) 
12 
3.3  
Informed Consent Process 
14 
3.4 
Study Timeline 
14 
4. 
Treatment Plan 
15 
4.1 
Treatment Schedule 
15 
4.2 
Criteria for Removal 
15 
4.3 
Alternatives 
16 
4.4 
Compensation 
16 
5. 
Adverse Events and Reporting Procedures 
16 
5.1 
Adverse Events 
16 
5.2 
Adverse Event Reporting 
17 
6. 
Data Capture 
17 
7. 
Study Calendar 
19 
8. 
Measurements and Statistical Methods 
21 
9. 
Regulatory Considerations 
21 
10. 
Statistical Considerations 
22 
10.1 
Statistical Analysis 
22 
10.2 
Stopping Rule 
22 
10.3 
Sample Size 
23 
10.4 
Accrual Estimate 
23 
References 
24 
Appendix A 
Glucksberg clinical stage and grade of acute GVHD 
26 
Appendix B 
Response Criteria by Disease Histology 
27 
 
Protocol Synopsis 
TITLE  
Very Low-dose Total Body Irradiation in Combination with Total Lymphoid 
Irradiation and anti-Thymocyte Globulin to Improve Donor Engraftment in 
Patients Undergoing Non-Myeloablative Hematopoietic Cell Transplantation for 
Leukemia and Lymphoma 
STUDY PHASE 
Phase 2  


IRB-47407  
Page 4 of 30 
v5.  10August  2020 
STUDY SITE 
Stanford University Medical Center, CA 94305 
INDICATION 
Patients with leukemia and lymphoma who are not eligible for myeloablative 
transplantation 
STUDY AGENT  
The addition of low-dose total body irradiation to total lymphoid irradiation and 
anti-thymocyte globulin as transplant conditioning therapy  
PRIMARY ENDPOINT 
and OBJECTIVE(S) 
To determine the proportion of patients with full donor T-cell chimerism at 
Day 28 following hematopoietic cell transplantation   
SECONDARY 
ENDPOINTS AND 
OBJECTIVE(S) 
1. To determine the risk of disease progression, overall and event-free 
survival, and non-relapse mortality, following treatment with TLI/ATG/TBI 
2. To determine the incidence of acute and chronic GVHD following treatment 
with TLI/ATG/TBI 
STUDY 
OBSERVATION 
PERIOD 
Patients will be followed for 1 year from the time of transplant 
TREATMENT 
SUMMARY 
The efficacy of non-myeloablative allogeneic transplantation is mediated in part 
by the establishment of an alloreactive donor T-cell compartment following 
transplant with minimal toxicity.  The objective of this study is to evaluate 
whether a single administration of low-dose TBI to standard TLI/ATG 
non-myeloablative transplant conditioning will help to augment donor chimerism 
without reducing tolerability of this regimen or increasing the risk of GVHD.  
This is a single institution, open-label, single treatment study evaluating the 
efficacy of low-dose TBI added to TLI/ATG in adults with leukemia and 
lymphoma undergoing allogeneic HCT from sibling or unrelated donors.  
SAMPLE SIZE  
20 patients  
SUMMARY OF 
SUBJECT ELIGIBILTY 
Patients with the following histologically-confirmed disease: 
1. Acute myeloid leukemia (AML) 
2. Chronic lymphocytic leukemia (CLL) 
3. Myelodysplastic syndrome (MDS) /  
Myeloproliferative disease syndrome  (MPD) 
4. Non-Hodgkin lymphoma (NHL) 
5. Hodgkin lymphoma (HL) 
Patients not undergoing ablative transplant conditioning 
Patients with HLA-matched or single antigen/allele mismatched related or 
unrelated donors. 
CONTROL GROUP 
Not applicable.  Single-arm study. 


IRB-47407  
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v5.  10August  2020 
LIST OF ABBREVIATIONS and DEFINITION OF TERMS 
AE 
Adverse event 
Kg 
Kilograms 
AML 
Acute myeloid leukemia 
KPS 
Karnofsky performance status 
ALT 
Aspartate aminotransferase 
LVEF 
Left ventricular ejection fraction 
AST 
Alanine aminotransferase 
MC 
Mixed chimerism 
ATG 
Anti-thymocyte globulin 
MDS 
Myelodysplastic syndrome 
BID 
bis in die (twice-a-day) 
MEP 
Megakaryocyte erythroid progenitors 
CFR 
Code of Federal Regulations 
MG 
Milligrams 
cGY 
Centigray 
MkP 
Megakaryocyte progenitors 
CLL 
Chronic lymphocytic leukemia 
MMF 
Mycophenolate mofitel  
CLP 
Common lymphoid progenitors 
MPD 
Myeloproliferative disease syndrome 
CML 
Chronic myelogenous leukemia 
MPPS 
Multipotent progenitors 
CMML 
Chronic myelomonocytic leukemia 
NCI 
National Cancer Institute 
CMP 
Common myeloid progenitors 
NHL 
Non-Hodgkin lymphoma 
CNS 
Central nervous system 
NK 
Natural killer cells 
CR 
Complete remission / response  
NRM 
Non-relapse mortality 
CRF 
Case report / record form 
OnCore OnCore enterprise research system 
CRi 
CR + incomplete blood count recovery 
OS 
Overall survival  
CTCAE Common Terminology Criteria for Adverse Events 
PAMPS pathogen-associated molecular pattern 
DAMP 
Damage-associated molecular pattern 
PBSC 
Peripheral blood stem cells 
DLCO 
Diffusing capacity – lung for carbon monoxide 
PB 
Peripheral blood 
DLI 
Donor leukocyte infusion 
PCR 
polymerase chain reaction 
DSMC 
Data Safety Monitoring Committee 
PD 
Progressive disease, tumor progression 
EFS 
Event-free survival  
PR 
Partial response 
EP 
Electrophysiology  
RIC 
Reduced intensity conditioning  
FACS 
Fluorescence activated cell sorting 
SAE 
Serious adverse event 
FDA 
Food and Drug Administration 
SCI 
Stanford Cancer Institute  
FDC 
Full donor chimerism  
SD 
Stable Disease 
FISH 
Fluorescence in situ hybridization  
SGOT 
Serum glutamic oxaloacetic transaminase 
GCP 
Good Clinical Practice 
SIN 
Subject identification number 
G-CSF 
Filgrastim, granulocyte-colony stimulating factor 
SRC 
Scientific Review Committee  
GVHD 
graft-versus-host disease  
STRs 
Short tandem repeats 
GVT 
graft-versus-tumor  
TAC 
Tacrolimus 
GMP 
granulocyte macrophage progenitors 
TBI  
Total body irradiation 
HCT 
Hematopoietic cell transplant 
TBili 
Total bilirubin 
HL 
Hodgkin lymphoma 
TCD 
T-cell depleted  
HLA 
Human leukocyte antigen 
TLI 
Total lymphoid irradiation  
HSC 
Hematopoietic stem cell 
ULN 
Upper limit of normal 
ICH 
Int’l Conference on Harmonization 
URD 
Unrelated donor 
IRB 
Institutional Review Board 
 
 


IRB-47407  
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v5.  10August  2020 
SCHEMA 
 
 
 
1 
TLI:  Total lymphoid irradiation 
2 
TBI:  Total body irradiation 
3 
ATG:  Anti-thymocyte globulin  
4 
Tac:  Tacrolimus (can be IV) 
See also Section 8 Study Calendar 
5 
PBSC:  Peripheral blood stem cells.  The PBSC infusion procedure is called 
a hematopoietic cell transplant (HCT) 
6 
MMF:  Mycophenolate mofitel.  15 mg/k PO BID for PBSC from 
matched-related donors;  15 mg/kg PO q8 hours for PBSC from 
unrelated donors (URDs) or mismatched related donors. 
7 
STRs:  Short tandem repeats for engraftment analysis 
Study Day 
Radiation 
ATG 
Marrow, PBSC, & other 
Day -11 
TLI 1 120 cGy ATG 3 1.5 mg/kg 
 
Day -10 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -9 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -8 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -7 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -4 
TLI 120 cGy 
 
 
Day -3 
TLI 120 cGy 
 
Start oral Tac 4 
Day -2 
TLI 120 cGy 
 
 
Day -1 
TLI 120 cGy 
TBI 2 80 cGy 
 
 
Day 0 
 
 
Infusion of mobilized PBSC 5 
Days +28: 
+ 56; +90; 
+180; +360 
 
 
STRs 7 
AML 
MDS 
MPD 
CLL 
NHL 
HL 
CMML 
Patient Screening / Eligibility 
• 
Age ≤ 80 
• 
Not eligible for a 
myeloablative preparative 
regimen 
• 
Available HLA-matched or 
single allele/antigen 
mismatched related or 
unrelated donor 
• 
Estimated creatinine 
clearance ≥ 50 mL/min 
• 
LVEF ≥ 30%  
• 
DLCO ≥ 40% predicted  
(adjusted for Hgb) 
• 
TBili < 3 mg/dL 
• 
AST/ALT < 3 x ULN 
• 
KPS ≥ 60 
HLA-matched or  
single antigen/allele mismatched related or unrelated donor 
Donor:  G-CSF 16 µg/kg x 5 days 
Collection of hematopoietic cells by apheresis,  
desired goal of ≥ 5 x 106 CD34+ cells/kg  
recipient weight for infusion on Day 0 


IRB-47407  
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v5.  10August  2020 
1. 
OBJECTIVES 
1.1 Primary Objective 
1. To determine the proportion of patients with full donor T-cell chimerism at Day 28 following 
hematopoietic cell transplantation 
1.2 Secondary Objectives 
2. To determine the risk of disease progression, overall and event free survival, and 
non-relapse mortality, following treatment with TLI/ATG/TBI 
3. To determine the incidence of acute and chronic GVHD following treatment with    
TLI/ATG/TBI 
2. 
BACKGROUND 
2.1 Allogeneic Hematopoietic Cell Transplantation 
Allogeneic hematopoietic cell transplantation (HCT) is proven effective therapy for patients with a 
variety of hematolymphoid malignancies.  Following allogeneic HCT, a significant percentage of 
patients who were otherwise considered to have incurable cancers using best of care 
non-transplantation therapies have long-term disease free control and appear cured.  These 
patients are characterized by developing donor type hematopoiesis and have complete resolution 
of all disease-related signs, symptoms and markers.  Generally, patients who undergo allogeneic 
HCT are doing so as a “last ditch” effort for long-term disease control and possibly cure after 
exhausting all chemotherapy, and radiation therapy based treatment strategies.  Often many of 
the patients who undergo allogeneic HCT for treatment of their lymphoma have had disease 
relapse even after high dose chemotherapy and autologous stem cell rescue (autologous HCT).  
2.2 Relapse of Disease following Allogeneic HCT 
The main cause for treatment failure following allogeneic HCT is disease relapse.  Depending, in 
part, on the disease, disease status at the time of transplantation, and the intensity of the 
transplantation regimen, disease relapse occurs in roughly 25 to 80% of patients.  For example, 
following a full dose transplant in younger patients with acute leukemia in 1st or 2nd complete 
remission (CR) and using a graft from a HLA-matched sibling, the 2-year risk of disease relapse 
was < 30% [1-8].  In contrast, the 2-year risk of disease relapse for younger patients with 
refractory acute leukemia who received a full-dose transplant was > 70% [9-11].  Older 
(> 55 years of age) patients or younger patients with medical co-morbidities that preclude full 
dose conditioning undergo reduced intensity conditioning (RIC) allogeneic HCT.  The 2-year risk 
of disease relapse in patients with acute leukemia in CR who received RIC allogeneic HCT was 
> 50% [12, 13].  Similarly, disease relapse remains the major cause of treatment failure for 
patients with T-cell, large B-cell and Hodgkin lymphomas and chronic lymphocytic leukemia (CLL) 
and occurs in > 40% who undergo RIC allogeneic HCT with chemotherapy, sub-lethal total body 
irradiation (TBI), or total lymphoid irradiation combined with anti-thymocyte globulin 
(TLI/ATG) [13-18].   
2.3 Treatment for Disease Relapse Following Allogeneic HCT 
Disease relapse following allogeneic HCT remains an ominous clinical event, which usually 
results in progressive disease and death.  Treatment strategies of patients with relapse following 


IRB-47407  
Page 8 of 30 
v5.  10August  2020 
allogeneic HCT can often be further complicated by the overall general poor clinical status of the 
patient.  Strategies for the treatment of disease relapse in these patients include the cessation of 
post-transplantation immune suppression medication, salvage chemotherapy with or without 
irradiation, a second allogeneic HCT, or the infusion of donor leukocytes (DLI).  Despite these 
interventions few patients beyond those with chronic myelogenous leukemia (CML) can be 
returned to durable remissions and the overall survival (OS) at 2 years following disease relapse 
was < 20% [19, 20].  Given that disease relapse is relatively common after transplant, and that 
few if any patients can be returned to durable remission once relapse has occurred, a desired 
goal would be to improve the transplant strategy and avoid the serious problem of post-transplant 
disease relapse.  
2.4 Graft Versus Tumor Reactions 
A major mechanism of cancer eradication following allogeneic HCT is the immunological-based 
recognition of residual host tumor cells by donor-derived immune cells contained in the donor 
graft.  This phenomenon, termed graft-versus-tumor (GVT) reactions, is supported by various 
lines of evidence.  The initial observations in support of GVT reactions stemmed from studies that 
used T-cell depleted (TCD) donor grafts whereby graft-versus-host disease (GVHD) was 
eliminated; however, without donor T-cells in the donor inoculum patients suffered a high 
incidence of disease recurrence [21].  The importance of GVT reactions was further demonstrated 
by improved disease control and fewer relapses following HLA identical sibling (allogeneic) 
transplantation compared to syngeneic (identical twin) transplantation for patients with 
hematologic malignancies [22].  The three year probability for relapse of leukemia was 
substantially higher following syngeneic compared to allogeneic HCT in acute myelogenous 
leukemia (AML) (52% vs 16%) and CML (40% vs 7%) following treatment using full dose 
transplant conditioning regimens [22].  The increased risk of relapse in syngeneic transplants 
counterbalanced the beneficial effect of the lack of GVHD.  Perhaps the most compelling 
evidence comes from the observation that the infusion of donor leukocytes obtained from the 
original donor in patients who have disease relapse following allogeneic HCT resulted in a GVT 
effect (23).  
2.5 Reduced Intensity Transplant Conditioning 
Following the recognition that a main mechanism of disease control after allogeneic HCT is by 
donor derived immune mediated GVT reactions, multiple groups, including our own at Stanford,  
developed reduced intensity transplant conditioning (RIC) regimens that shifted the burden of 
disease control from high doses of chemoradiotherapy to the donor immune system [23-25]).  The 
low intensity transplant conditioning has allowed older patients and those with medical 
co-morbidities to proceed with transplant whereas, before these patients were excluded from 
allogeneic transplantation as the full dose conditioning regimens were associated with prohibitive 
toxicities.  As a consequence of the low-dose conditioning, host hematopoietic and immune cells 
persist and result in a state of mixed hematopoietic and lymphoid chimerism (MC) that may 
convert to full donor chimerism (FDC) over a variable time course (13, 28-30).  Importantly, the 
achievement of early (before Day 60) FDC appears to be a necessary precondition for disease 
control ([26, 27].  We and others have reported that irrespective of the specific type of RIC 
regimen used, the relapse risk is significantly higher in patients with persistent MC compared to 
those with FDC, and likely reflects tolerance of donor cells to recipient tissues (13, 28-30).  In a 
report detailing the outcomes of 111 allogeneic HCT recipients from HLA-matched and single 


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v5.  10August  2020 
antigen mismatch donors following TLI-ATG conditioning for leukemia and lymphoma there was a 
very low incidence of severe (Grade 2 to4) acute GVHD ( < 5%), and a low incidence of 
non-relapse related mortality at 1 year ( < 5%) (13).  Whereas almost all patients who failed to 
achieve FDC experienced disease relapse, the actuarial event free survival was more than 55% in 
the patients who achieved > 95% donor type chimerism, with observations extending up to 
6 years (13).  
2.6 Rationale to include very low-dose TBI in NMA TLI-ATG conditioning  
Low-dose TBI (doses of 50, 100, 150 and 200 cGy) is well established to improve 
donor hematopoietic stem cell (HSC) engraftment due to targeting of marrow HSC niches.[28] 
Engraftment is dose-dependent with more robust engraftment at higher doses.  Yet increasing 
the dose of TBI is balanced by the risk of aggravating GVHD as higher doses (> 150 cGy) of 
TBI which may increase GVHD development by promoting intestinal inflammation with 
subsequent release of DAMPS and PAMPS.[29] It is hypothesized that in the current protocol 
the addition of one very low-dose (80 cGy) of TBI as a substitute for the last dose of TLI will help 
promote donor HSC engraftment due to its ability to help clear marrow niche space yet avoid the 
widespread intestinal inflammation typically associated with higher doses of TBI.  Improved donor 
cell engraftment is associated with reduced rates of post-transplant disease relapse and 
improving donor cell engraftment without increasing GVHD is a significant goal of transplantation. 
2.7 Study Rationale 
The persistence of mixed hematopoietic cell chimerism is associated with a significantly high risk 
of disease relapse after allogeneic HCT [13, 28-30].  Once the patient’s disease has relapsed 
after allogeneic HCT, the likelihood for long-term survival is poor.  Therefore, a strategy that can 
help promote conversion of mixed to complete hematopoietic cell chimerism prior to disease 
relapse, and does not promote significant GVHD has the potential to help improve the outcomes 
of allotransplant recipients by reducing the risk of disease relapse.  The goal of the current 
proposed trial will be to determine if the addition of very low-dose TBI to standard TLI-ATG 
conditioning therapy will increase the proportion of patients with FDC at Day 28 post-transplant, 
without reducing tolerability or increasing transplant morbidity.  We hypothesize that the addition 
of very low-dose TBI at 80 cGy to TLI-ATG will result in at least a 30% increase in the proportion 
of patients with FDC in the CD3 subset at Day 28 post-HCT.  This study will follow a single-arm 
Simon 2-stage trial principle.  In Simon stage 1, we will enroll 11 patients, and if 
5 or fewer patients respond, defined as ≥ 95% donor chimerism in the CD3 compartment at 
Day 28, we will stop for futility.  If 6 or more respond in Simon stage 1, then in stage 2 we will 
continue to enroll a full sample of 20 patients and declare success if a total of 11 or more patients 
respond.  The primary endpoint will be the determination of the rate of conversion from mixed to 
complete donor chimerism.  Secondary endpoints will include the risk of acute and chronic GVHD, 
freedom from disease progression, event-free and overall survival, and the relapse rate.  The goal 
is to improve the rate of attaining complete chimerism without increasing the risk of GVHD.  If 
following the Simon 2-stage trial the results are encouraging, we will expand our experience to a 
broader trial to determine if the TLI/ATG/low-dose TBI is associated with significantly lower rates 
of disease relapse.  


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v5.  10August  2020 
2.8 Study Design 
This is a single institution open-labeled single treatment study evaluating the safety and efficacy 
of very low-dose TBI added to TLI-ATG conditioning in adults undergoing allogeneic HCT from 
related and unrelated donors.  Enrollment of 20 patients is expected to be completed in less than 
2 years.  The study will involve a single non-randomized intervention arm of administering TBI 
80 cGy on Day -1 of standard TLI ATG conditioning.  The total duration of patient study 
participation is 12 months.  Per regular medical care for HSC transplant patients, all recipients will 
be followed long term and tracked via the Stanford BMT patient database for overall survival;  
event-free survival;  and late complications such as but not limited to relapse;  late chronic GVHD;  
and infections. 
3. PARTICIPANT SELECTION AND PRE-ENROLLMENT REQUIREMENTS 
Inclusion and Exclusion Criteria are provided on the Eligibility Checklist, following, and which may 
be extracted for use in screening potential subjects.  
The following Participant Eligibility Checklist will be completed in its entirety for each subject prior 
to registration.  The completed, signed, and dated checklist will be retained in the subject’s 
study file, and the study’s Regulatory Binder.  
Pursuant to Stanford Medicine SOP “Confirmation of Participant Eligibility in Clinical Trials,” the 
treating Physician (investigator);  the Study Coordinator;  and an Independent Reviewer will verify 
that the subject’s eligibility is accurate;  complete;  and legible in source records.  A description of 
the eligibility verification process will be included in the EPIC or other Electronic Medical Record 
progress note.  


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v5.  10August  2020 
Participant Eligibility Checklist 
For each prospective study participant that is screened, this checklist will be printed, the results 
recorded, and filed in the respective subject binder or file.  It is anticipated that not all prospective 
study participants will be enrolled.  
I. 
Protocol Information  
Protocol Title: Very Low-dose Total Body Irradiation in Combination with Total 
Lymphoid Irradiation and anti-Thymocyte Globulin to Improve Donor 
Engraftment in Patients Undergoing Non-Myeloablative Hematopoietic 
Cell Transplantation  
eProtocol number: 
OnCore number: 
IRB-47407  
BMT330 
Principal 
Investigator: Robert Lowsky, MD 
II. 
Subject Information  
Subject name / Unique ID: 
/ 
Gender  
  Male   
 Female   


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v5.  10August  2020 
III. 
Study Information  
3.1  
Patient Inclusion Criteria (patients must have all of the following). 
Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
1. ≥ 18 years old 
 
 
 
2. Has a HLA-matched or single allele-mismatched adult 
sibling donor or unrelated donor 
 
 
 
3. Has a myeloid or lymphoid malignant disease that will be 
treated with TLI and ATG reduced-intensity conditioning for 
allogeneic transplant [any of the following:  acute myeloid 
leukemia (AML);  myelodysplastic syndrome (MDS);  
myeloproliferative disease syndrome (MPD)];  chronic 
lymphocytic leukemia (CLL);  B or T-cell non-Hodgkin 
lymphoma (NHL);  Hodgkin lymphoma (HL);  or chronic 
myelomonocytic leukemia (CMML) 
 
 
 
4. Patients who due to age, pre-existing medical conditions, 
or, prior therapy are considered to be at high-risk for 
regimen-related toxicity associated with fully ablative 
transplant conditioning, and therefore reduced intensity 
conditioning is recommended. Or patients for whom RIC 
allotransplant is recommended that is in keeping with 
standard of care in the transplant community 
 
 
 
5. Ability to understand and the willingness to sign a written 
informed consent document.  Patients must have signed 
informed consent to participate in the trial. 
 
 
 
3.2  
Patient Exclusion Criteria (excluded if any of the following) 
Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
1. Uncontrolled bacterial, viral or fungal infection defined as 
currently taking medication and progression of clinical 
symptoms 
 
 
 
2. Progressive hemato-lymphoid malignancy despite 
conventional therapy 
 
 
 
3. Chronic myelogenous leukemia (CML)  
 
 
 
4. Active CNS involvement of the underlying malignancy if 
previously documented CNS involvement 
 
 
 
5. HIV-positive 
 
 
 
6. Pregnant or lactating  
 
 
 
7. Prior malignancy (EXCEPTION:  diagnosed > 5 years ago 
without evidence of disease, OR treated ≤ 5 years ago but 
have a greater than 50% chance of life expectancy of 
≥ 5 years for that malignancy). 
 
 
 


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v5.  10August  2020 
Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes 
No 
Supporting 
Documentation * 
8. Have a psychiatric disorder(s) or psychosocial 
circumstance(s) which in the opinion of the primary 
physician would place the patient at an unacceptable risk 
from transplant. 
 
 
 
9. Organ dysfunction defined as follows: 
i. 
Left ventricular ejection fraction (LVEF) < 30%, or 
uncontrolled cardiac failure  
ii. Diffusing capacity of lung for carbon monoxide (DLCO) 
< 40% predicted 
iii. Total bilirubin > 3 mg/dL 
iv. SGOT or SGPT > 4 x ULN 
v. Creatinine > 2 mg/dL and an estimated creatinine 
clearance < 40 mL/min  
vi. Poorly-controlled hypertension despite multiple 
antihypertensive medications 
 
 
 
10. Karnofsky Performance Status (KPS) < 60% 
 
 
 
* All subject files must include supporting documentation to confirm subject eligibility.  The method 
of confirmation can include, but is not limited to, laboratory test results, radiology test results, 
subject self-report, and medical record review.  


IRB-47407  
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v5.  10August  2020 
V. 
Statement of Eligibility  
By signing this form of this trial I verify that this subject is:  
 eligible / 
 ineligible for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the IRB of record, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.  
Study Coordinator printed name: 
Date:  
Signature: 
 
Investigator printed name: 
Date:  
Signature: 
 
Triple-check reviewer printed name: 
Date:  
Signature: 


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3.3 Informed Consent Process 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  All potential risks associated with 
the use of TLI;  ATG; , low-dose TBI;  immunosuppressive drugs;  and allogeneic hematopoietic 
cell infusions will be discussed as objectively as possible.  It will be explained that patients offered 
this protocol have an underlying malignancy that render them either at high risk of relapse or that 
will result in life expectancies of several months to no more than one to two years with 
conventional treatments.  These patients would be unlikely to benefit from, or tolerate an 
autologous transplant, and are at high risk of early transplant mortality from conventional 
allogeneic transplant.  Informed consent from the patient will be obtained using a form approved 
by the Administrative Panel on Human Subjects in Medical Research of the Stanford University 
Medical Center.  The participant will receive a copy of the signed and dated consent document.  
The original signed copy of the research consent document must be retained in the 
subject’s research file.   
3.4 Study Timeline 
It is expected the study will accrue 10 to 15 patients per year and therefore the target goal of 
20 patients will be completed within 2 years of the study opening.   
Patients will be followed for 12 months after the mobilized PBSC infusion on Day 0.  Patients’ 
End-of-Study Visit will be scheduled for approximately Day 360 post-PBSC infusion, +/- 8 weeks.  
Therefore, it is expected the study will be complete within 48 months of opening.  Per regular 
medical care for HSC transplant patients, all recipients will be followed long-term and tracked via 
the Stanford BMT patient database for overall survival;  event-free survival;  and late 
complications such as but not limited to relapse;  late chronic GVHD;  and infections.  


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4. 
TREATMENT PLAN 
The full procedure schedule is described in Section 7 Study Calendar. 
4.1 
Study Treatment Schedule 
Transplant Schedule (See also Section 7 Study Calendar) 
Week 1 
Monday 
Day -11 
Tuesday 
Day -10 
Wednesday 
Day -9 
Thursday 
Day -8 
Friday 
Day -7 
Saturday 
Day -6 
Sunday 
Day -5 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy 
Rest 
Rest 
ATG **** 
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
 
 
Week 2 and beyond 
Monday 
Day -4 
Tuesday 
Day -3 
Wednesday 
Day -2 
Thursday 
Day -1 * 
Friday 
Day 0 
Saturday 
Day +1 
Day 28 
+/- 5 days 
Day 56 
+/- 5 days 
Day 90 
+/- 5 days 
TLI 
120 cGy 
TLI  
120 cGy 
TLI  
120 cGy 
TLI  
120 cGy 
Mobilized 
PBMC 
 
  
 
 
 
Start Tac 
0.05 mg/kg 
oral BID***  
 
TBI 80 cGy 
Start 
MMF ** 
 
 
 
 
 
 
 
 
 
 
PB STRs 
PB STRs 
PB STRs 
* 
As a guideline 5 hour interval will be provided between TLI and TBI on Day -1.  No lung blocks will be used for TBI.  
The dose rate with be ≤ 2 Gy/minute.  The Pre-HCT radiation oncology consultation will include simulation for both 
TLI and TBI and should be scheduled as such 
** 
MMF 15 mg/kg PO BID for matched related donors;  15 mg/kg PO q8 hours for unrelated donors (URDs) or 
mismatched related donors. Physician discretion can round up or round down MMF to the nearest 250m/dose. 
*** Tac starting dose is a recommended guideline yet based on Physician/APP discretion this start dose can be 
modified, typically lowered due to concern about drug-drug interaction and possible Tac toxicity. 
**** ATG dosing is based on actual weight yet if >15kg above ideal body weight the ordering MD has the discretion to 
dose ATG based on actual weight or dose based on adjusted weight, both are acceptable. 
4.2 Criteria for Removal from Study  
All adverse events will be reviewed by Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC) and patients will be removed from the study for the following reasons: 
• 
Non-compliance with the protocol (defined as inability to receive all scheduled treatments, 
follow-up appointments, and tests) 
• 
Patient request to withdraw from the study 
4.3 Alternatives 
Alternative therapies will be discussed with each patient and would potentially include allogeneic 
transplantation using TLI and ATG conditioning without TBI or allogeneic transplantation using 


IRB-47407  
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v5.  10August  2020 
other transplant conditioning or other investigational therapies, or best of care non-transplantation 
therapy. 
4.4 Compensation 
There will be no compensation for participation on study. 
5. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
5.1 
Adverse Events 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a number 
of life threatening disorders, including cancer.  In this setting, a very large number of Grade 1, 2 
and 3 adverse events (AEs) are expected to occur, regardless of whether or not a patient is 
participating in a research study.  In order to minimize the “background noise” and to focus on 
clinically significant, meaningful adverse events useful in the assessment of proposed trial the 
following AE reporting schema is proposed.  This schema is intended to capture all AEs that are 
clinically significant and/or impactful, but minimize “not informative” AE collection. 
• 
Grade 4 and higher AEs will be collected and documented with causality attribution on an 
adverse event log (AE log), and all AEs meeting the criteria of “serious” as defined at 
21CFR§312.32(a), including any that are otherwise Grade 1, 2 or 3 will be collected; 
identified as serious; and documented on an AE log, including causality attribution. 
o An adverse event is considered serious if it fulfills one of the following criteria per 
21CFR§312.32(a): 
▪ 
Results in death. 
▪ 
Life threatening (patient at risk of death at the time of the event). 
▪ 
Requiring new inpatient hospitalization or prolongation of existing 
hospitalization. 
▪ 
Resulting in persistent or significant disability. 
▪ 
Other medical events that may not be immediately life threatening or result 
in death or hospitalization by may jeopardize the patient or require 
intervention to prevent one of the outcomes listed above 
• 
Laboratory values without a clinical consequence or outcome will not be tracked as 
adverse events, unless deemed serious. 
• 
Grade 1-3 AEs not meeting these criteria will not be collected, except as follows.  Grade 1 
to 3 AEs resulting in subject termination or withdrawal from the study will be collected. 
All Serious Adverse Events (SAEs) will be tracked until resolution or at least 60 
days after the study treatment.5.2 
Adverse Event Reporting 
All serious adverse events (SAEs) as outlined in section above  and meeting the criteria specified 
in 21CFR§312.32(c)(1) that occur from start of transplant conditioning through to day +90 post 
transplant will be collected.  SAEs related to study treatment will be collected through the Week 
52 follow up visit. All SAEs will be reported to in accordance with the established practices of the 
Stanford Division of Blood and Marrow Transplantation, as well the IRB and DSMC.  The 
collected AEs will be documented in the adverse event log.   


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v5.  10August  2020 
6. 
DATA CAPTURE  
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study, in accordance with the 
established practices of the Stanford Division of Blood and Marrow Transplantation.  
The trial completed enrollment and is closed to patient accrual. The trial remains open for patient 
observation and determination of the trial’s secondary outcomes.   
Time is needed for patients to complete this period of observation. Once all the patients have 
passed the last time point of observation the study PI will analyze the data in context of BMT Core 
Group B which includes Drs. Ying Lu and John Tamaresis. The outcomes will be uploaded to 
Clinical trials.gov.  
There is no data specific for this trial that extends beyond what the extensive and comprehensive 
bmt database already collects. This data will be reviewed by the study PI and Core B for accuracy 
before it is finalized in BMTcore.   


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v5.  10August  2020 
7. 
STUDY CALENDAR 
 
Pre-enrollment 
requirements 
Day -11, 
-10, -9,  
-8, -7 
Day -4 Day -3 Day -2 Day -1 Day 0 
Day 28 +/- 
7 days 
Day 56 +/- 
14 days 
Day 90 +/- 
14 days 
Day 180 +/- 
4 weeks  
Day 360 +/- 
8 weeks 
Day-180 
to -13 
Day -42 
to -12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Donor evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
B-HCG a 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Medical history 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Concurrent meds 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Physical exam 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Vital signs b 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Performance status 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Central venous 
catheter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
Serum chemistry c 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
STR analysis k 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
TLI e 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
TAC f 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ATG g 
 
 
X 
 
 
 
 
 
 
 
 
 
 
TBI h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PBSC Infusion 
 
 
 
 
 
 
 
X 
 
 
 
 
 
MMF i 
 
 
 
 
 
 
 
X 
 
 
 
 
 
SAE evaluation 
 
 
 
 
 
 
 
X - Weekly from Day 0 through Day 90 
 
 
Disease Status 
Assessment  j 
X 
 
 
 
 
 
 
 
 
X 
X 
as indicated 
X 
as indicated 


IRB-47407  
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v5.  10August  2020 
a: 
Pregnancy test for women of childbearing potential only.  
b: 
Temperature, blood pressure, and pulse.  
c: 
Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium 
e: 
TLI:  Total lymphoid irradiation, 120 cGy.  
f: 
TAC:  Tacrolimus 
g: 
ATG:  Anti thymocyte globulin, 1.5 mg/kg with solumedrol 1.0 mg/kg.  
h: 
TBI:  Total body irradiation, 80 cGy.  
i: 
MMF:  Mycophenolate mofitel, by mouth.   
j 
Response assessment as per disease histology, and may include CT, PET, and/or MRI imaging, and bone marrow biopsy or 
aspiration (refer to Appendix B), and is typically performed around Day 90 post-transplant (Day 0).  
k: 
Short tandem repeat (STR) analysis (by comparison to subject’s pre-study HLA analysis) on Day 28 +/- 7 days;  
Day 56 +/- 14 days;  Day 90 +/- 14 days;  Day 180 +/- 4 weeks;  Day 360 +/- 4 weeks, and thereafter as per standard of care.  
 


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8. 
MEASUREMENTS and STATISTICAL METHODS 
Our extensive experience with the TLI ATG conditioning for allogeneic HCT in cancer patients 
showed a 30 to 40% incidence of FDC at Day 90, with a 95% confidence interval of 10 to 49%.  
The non-relapse mortality (NRM) was 3% (95% CI:  0 to 14%) at 100 days and 6% (95% CI:  
1 to 28%) at 1 year.  The incidence of acute GVHD by Day 100 was 6% (0.7 to 22%). 
8.1  
Primary and Secondary Outcome measures 
The primary outcome is to determine the proportion of patients with full dose donor 
chimerism (FDC) at Day 28 following TLI/ATG/TBI conditioning.  FDC is defined as achieving 
≥ 95% donor type in the CD3+ lineage within 28 days of donor cell infusion.  
The secondary outcome measures include time-to-disease progression assessed at 1 year after 
hematopoietic cell transplantation (HCT);  overall survival (OS) at 1 year;  and event-free survival 
(EFS) at 1 year;  and non-relapse mortality at 1 year.  The incidence of acute and chronic GVHD 
following the infusion of allogeneic CD8+ memory T-cells will be assessed at 1 year after HCT. 
Recipients will be monitored for HCT toxicities and the rates of GVHD as per the study calendar.  
STR analysis will be performed on Day 28 +/- 7 days and per the study calendar thereafter.  The 
level of tumor burden will be evaluated at 3 months after transplant and at 6 and 12 months as 
clinically indicated by standard imaging and blood evaluation procedures specific for the patient 
disease (refer to Appendix B). 
Beyond 12 months and per regular medical care for HSC transplant patients, all recipients will be 
followed long-term and tracked via the Stanford BMT patient database for overall survival;  
event-free survival;  and late complications such as but not limited to relapse;  late chronic GVHD;  
and infections.  
9. 
REGULATORY CONSIDERATIONS 
This study evaluates an approved therapy (anti-thymocyte globulin, ATG) and an established 
radiotherapy procedure (low-dose total body irradiation, TBI).  The study therapy is considered to 
not represent an increase in risk over that described in the ATG labeling, and on this basis, is 
considered to be an IND-exempt investigation.  
9.1 
Institutional Review of Protocol 
The protocol, the informed consent and all forms of participant information related to the study 
(eg, advertisements used to recruit participants) will be reviewed and approved by the Stanford 
IRB and Stanford Cancer Center Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to all 
participating investigators. 
9.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Center Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine whether 
the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 


IRB-47407  
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v5.  10August  2020 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
9.3 
Data Management Plan 
The Protocol Director, or his designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  The Stanford BMT 
data monitoring team along with the study coordinator will collect the information required in the 
Study calendar of events and maintain records for data analysis.  The data will be reviewed by the 
study PI for accuracy against source document data. 
9.4 Confidentiality  
Patient records will be kept in a secure location at Stanford University Medical Center accessible 
only to research authorized personnel.  Patient identity will be kept as confidential as possible as 
required by law.  The patient will not be identified by name, social security number, address, 
telephone number, or any other personal direct identifier.  Study patients will be assigned an 
identification code.  Information about the code will be kept in a secure location and access limited 
to research study personnel.  The results of this study may be presented at scientific or medical 
meetings or published in scientific journals, however patient identity will not be disclosed.  
Personal data included in the investigators’ database will be maintained in compliance with all 
applicable laws and regulations.  
10. 
STATISTICAL CONSIDERATIONS 
10.1  Statistical Analysis 
The sample size determination for the clinical trial will follow a single arm Simon 2-stage trial 
principle.  The null hypothesis that the true response rate is 
 will be tested against a 
one-sided alternative (
).  In the first stage, 
 patients will be accrued.  If there are 
 or fewer responses in these 
 patients, the study will be stopped.  Otherwise, 
 additional patients will be accrued for a total of 
.  The null hypothesis will be 
rejected if 
 or more responses are observed in 
 patients.  This design yields a 
type I error rate of 
 and power of 
 when the true response rate is 
.  
We plan to use a dose of 80 cGy of TBI on Day -1 of HCT.  It is fully expected that this low-dose 
will be safe and not provoke or increase the risk of GVHD or other complications.  Patients will be 
evaluated for toxicities, defined as new Grade 3 to 4 toxicities, according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v.5 and Grade 3 to 4 GVHD (Appendix A) 
during the 90 days following HCT.   
10.2  Stopping Rule  
Based on preclinical data, we do not believe the TBI at such a low-dose will aggravate GVHD, 
and we do not expect additional regimen-related toxicities at this dose.  Patients will not be 
enrolled into Stage 2 until all patients in Stage 1 have reached 90 days post-transplant.  Patients 
will not be enrolled into Stage 2 until all patients in Stage 1 have reached 90 days post-transplant. 
The study will be terminated if the number of subjects who experience a “stopping event” (defined 
as Grade 4 GVHD) is 2, 3 or 4 among (respectively) the first 6, 12, or 18 patients.  This rule is 
based on stopping if the lower 80% confidence limit for the true probability of a “stopping event” 


IRB-47407  
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v5.  10August  2020 
exceeds 12% (the maximal acceptable rate) at any look.  The rule is implemented with a 
forward-looking interpretation, so that if the number of events hits the boundary for the current 
look at any time, the study will stop.  Subjects will not be enrolled into Stage 2 until all subjects in 
Stage 1 have reached 90 days post-transplant without triggering the stopping rule, and enrollment 
will be delayed if necessary at each stopping rule milestone, to ensure that subject 7, 13, and 19 
are not enrolled until the stopping rule at (respectively) 6, 12, and 18 is cleared (for example, 
if there has been one stopping event in the first 5 subjects, enrollment is paused until patient 6 
reaches 90 days without an event.   
The stopping rule described above, which we have used in many studies, controls the 
"false alarm" rate.  We do not generally calculate the "true alarm rate" at probabilities exceeding 
the max acceptable rate, because we do not think it is informative.  It is well-understood that the 
small samples in phase 1 and 2 generally do not provide precise upper bounds for the probability 
of unwanted effects, so the purpose of stopping rules is to protect the patients enrolled in the 
study, as far as possible, consistent with the inherent risks of early phase studies and the 
potential benefit.  If the stopping rule is not triggered even though the true risk is substantially 
greater than the max acceptable rate, then the actual harm has been limited to the extent possible 
in an early phase trial.  
10.3  Sample Size  
Twenty patients will be required to complete the study.  
10.4 Accrual estimates 
Approximately 10 to 15 patients will be enrolled annually.  Time to complete enrollment will be 
2 years.  Overall time to initiate, conduct, and complete the trial will be about 4 years. 


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v5.  10August  2020 
11. 
REFERENCES 
1. 
Burnett, A.K., et al., The value of allogeneic bone marrow transplant in patients with acute 
myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J 
Haematol, 2002. 118(2): p. 385-400. 
2. 
Suciu, S., et al., Allogeneic compared with autologous stem cell transplantation in the 
treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first 
complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 
trial. Blood, 2003. 102(4): p. 1232-40. 
3. 
Burnett, A.K., et al., Randomised comparison of addition of autologous bone-marrow 
transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: 
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Leukaemia Working Parties. Lancet, 1998. 351(9104): p. 700-8. 
4. 
Levi, I., et al., Meta-analysis of autologous bone marrow transplantation versus 
chemotherapy in adult patients with acute myeloid leukemia in first remission. Leuk Res, 
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5. 
Zittoun, R.A., et al., Autologous or allogeneic bone marrow transplantation compared with 
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Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J 
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6. 
Barry, E., et al., Favorable outcome for adolescents with acute lymphoblastic leukemia 
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7. 
Schiffer, C.A., Differences in outcome in adolescents with acute lymphoblastic leukemia: a 
consequence of better regimens? Better doctors? Both? J Clin Oncol, 2003. 21(5): p. 
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8. 
Snyder, D.S., et al., Long-term follow-up of 23 patients with Philadelphia 
chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow 
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Milligan, D.W., et al., Guidelines on the management of acute myeloid leukaemia in adults. 
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Yanada, M., et al., Efficacy of allogeneic hematopoietic stem cell transplantation depends 
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11. 
Reiffers, J., et al., Allogeneic vs autologous stem cell transplantation vs chemotherapy in 
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Gyurkocza, B., et al., Nonmyeloablative allogeneic hematopoietic cell transplantation in 
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Kohrt, H.E., et al., TLI and ATG conditioning with low risk of graft-versus-host disease 
retains antitumor reactions after allogeneic hematopoietic cell transplantation from related 
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14. 
Gutierrez-Aguirre, C.H., et al., Outpatient reduced-intensity allogeneic stem cell 
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15. 
Corradini, P., et al., Allogeneic stem cell transplantation following reduced-intensity 
conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: 
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16. 
Rezvani, A.R., et al., Nonmyeloablative allogeneic hematopoietic cell transplantation in 
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17. 
Rezvani, A.R., et al., Non-myeloablative allogeneic haematopoietic cell transplantation for 
relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol, 2008. 
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18. 
Cook, G., et al., Outcome following Reduced-Intensity Allogeneic Stem Cell 
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Mielcarek, M., et al., Outcomes among patients with recurrent high-risk hematologic 
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Oran, B., et al., Treatment of AML and MDS relapsing after reduced-intensity conditioning 
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Slavin, S., et al., Nonmyeloablative stem cell transplantation and cell therapy as an 
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Giralt, S., et al., Engraftment of allogeneic hematopoietic progenitor cells with purine 
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McSweeney, P.A., et al., Hematopoietic cell transplantation in older patients with 
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26. 
Childs, R., et al., Engraftment kinetics after nonmyeloablative allogeneic peripheral blood 
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28. 
Xu, H., et al., CD45 congenic bone marrow transplantation: evidence for T cell-mediated 
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29. 
Zeiser, R. and B.R. Blazar, Pathophysiology of Chronic Graft-versus-Host Disease and 
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30. 
Martin, P.J., et al., Reporting of adverse event data in hematopoietic stem cell 
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APPENDIX A:  Glucksberg clinical stage and grade of acute GVHD 
 


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v5.  10August  2020 
APPENDIX B. 
RESPONSE CRITERIA by DISEASE HISTOLOGY 
AML Response Criteria (Cheson, et al.  2003) 
 
In this study Day of assessment is 12 weeks and 24 weeks post stem cell infusion.  For patients who are in a pathologically confirmed remission prior to 
infusion, a bone marrow biopsy and/or aspirate are not required; disease can be followed by confirmatory CBCs 


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v5.  10August  2020 
NHL Response Criteria (Cheson, et al.  2007) 
 
    In this study, the day of assessment is 12 weeks and 24 weeks after stem cell infusion. 
 


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CLL Response Criteria (Hallek, et al.  2008) 
 
  In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion. 


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MDS Response Criteria (Cheson, et al. 2006)