A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-free Graft-versus-host Disease Prophylaxis Regimen With Post-transplantation Cyclophosphamide and Abatacept to Standard of Care
Phase: PHASE2
Conditions: GVHD, Hematologic Neoplasms
Sponsor: Dimitrios Tzachanis, MD PhD

Protocol Am 8 Dated 10Jan2022   
UCSD IIT # 180383 Abatacept 
                                        
 
 
 
 
 
 
A randomized Phase II trial comparing a calcineurin inhibitor-free graft-versus-
host disease prophylaxis regimen with post-transplantation cyclophosphamide 
and abatacept to standard of care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT number: NCT03680092 
 
Protocol Number: 
 
180383 
 
Study ID:  
 
 
IM101-701 
 
Study Drug: 
 
 
Abatacept 
 
IND Number: 
 
 
140877 
 
IND Holder:  
 
 
Dimitrios Tzachanis, MD PhD 
 
 
Funding Source:  
Bristol Myers Squibb 
 
Initial version:  
 
Version 2 Dated 15May2017 
 
Amendment:  
 
 
8 Dated 10JAN2022 
 
 
 
 
 
CONFIDENTIAL 
This material is the property of the Moores Cancer Center.  Do not disclose or 
use except as authorized in writing by the study sponsor. 
 
 
Principal Investigator:  
Dimitrios Tzachanis, MD PhD 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
ii 
                                              Associate Clinical Professor of Medicine 
UCSD Blood and Marrow Transplant Program 
3855 Health Sciences Drive 
MC 0960 
La Jolla, CA 92093-0960 
Tel: (858)534-2185 
Fax: (858)822-6844 
dtzachanis@ucsd.edu 
 
 
Co - Principal Investigator:  
Divya Koura MD, UCSD Blood and Marrow Transplant Program 
 
Biostatisticians: 
 
James M. Mirocha, MS 
829 Euclid Street 
Santa Monica, CA 90403 
Cell: 65-398-8625 
 
 
 
 
 
 
Correlative Studies: 
 
Jack Bui, MD PhD 
 
 
 
 
Director of Diagnostic Immunology, UCSD School of Medicine 
 
 
 
 
 
Gerald Morris, MD PhD 
 
 
 
 
Director, Immunogenetics and Transplantation Laboratory 
 
 
Sub-Investigator(s): 
 
 
Name 
Department/Division 
Fotios Asimakopolous MB BChir, PhD 
UCSD Blood and Marrow Transplant Program 
Edward Ball, MD 
UCSD Blood and Marrow Transplant Program 
Caitlin Costello, MD 
UCSD Blood and Marrow Transplant Program 
Aaron Goodman, MD 
UCSD Blood and Marrow Transplant Program 
Ayad Hamdan, MD  
UCSD Blood and Marrow Transplant Program 
Daniel Kaufman, MD PhD 
UCSD Blood and Marrow Transplant Program 
James Mangan, MD  
UCSD Blood and Marrow Transplant Program  
Carolyn Mulroney, MD 
UCSD Blood and Marrow Transplant Program 
Tiffany Tanaka, MD 
UCSD Blood and Marrow Transplant Program  
Parag Sanghvi, MD 
UCSD Radiation Medicine and Applied Sciences 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
iii 
  
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................1 
STUDY SUMMARY ..........................................................................................................3 
1.0 
BACKGROUND AND RATIONALE ...................................................................7 
1.1 
Disease Background ....................................................................................................... 7 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 7 
1.3 
Other Agents ................................................................................................................... 9 
1.4 
Rationale ....................................................................................................................... 10 
1.5 
Hypothesis ..................................................................................................................... 11 
1.6 
Correlative Studies ........................................................................................................ 12 
2.0 
STUDY OBJECTIVES ........................................................................................13 
2.1 
Primary Objective .......................................................................................................... 13 
2.2 
Secondary Objectives .................................................................................................... 14 
2.3 
Exploratory Objectives ................................................................................................... 14 
2.4 
Endpoints ....................................................................................................................... 14 
3.0 
PATIENT ELIGIBILITY .......................................................................................15 
3.1 
INCLUSION CRITERIA ................................................................................................. 15 
3.2 
EXCLUSION CRITERIA ................................................................................................ 16 
3.3 
REGISTRATION PROCEDURES ................................................................................. 17 
4.0 
TREATMENT PLAN ............................................................................................17 
4.1 
Treatment Dosage and Administration .......................................................................... 17 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 19 
4.3 
Concomitant Medications/Treatments ........................................................................... 20 
4.4 
Duration of Therapy ....................................................................................................... 20 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
iv 
4.5 
Duration of Follow Up .................................................................................................... 20 
4.6 
Removal of Patients from Protocol Therapy .................................................................. 21 
5.0 
STUDY PROCEDURES ......................................................................................21 
5.1 
Screening/Baseline Procedures .................................................................................... 21 
5.2 
Study visits (days +5, +14 , +28, +56, +84, +112, +140, +168, and 1 year) ................. 22 
5.3 
Blood for correlative studies will be collected: ............................................................... 23 
5.4 
Removal of Subjects from Study ................................................................................... 23 
6.0 
Study Calendar ...................................................................................................24 
7.0 
Measurement of Effect ......................................................................................27 
7.1 
Safety/tolerability ........................................................................................................... 27 
8.0 
ADVERSE EVENTS:  DEFINITIONS AND REPORTING REQUIREMENTS
 
27 
8.1 
Definitions ...................................................................................................................... 27 
8.2 
Data Collection procedures for adverse events ............................................................. 31 
8.3 
Grading and Attribution .................................................................................................. 32 
8.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 32 
8.5 
Reporting Requirements for Adverse Events ................................................................ 33 
9.0 
DRUG INFORMATION .......................................................................................36 
9.1 
Abatacept ...................................................................................................................... 36 
10.0 
STATISTICAL CONSIDERATIONS .............................................................38 
11.0 
STUDY MANAGEMENT .................................................................................43 
11.1 
Conflict of Interest .......................................................................................................... 43 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 43 
11.2 
Data Management and Monitoring/Auditing .................................................................. 43 
11.3 
Data Safety Monitoring .................................................................................................. 44 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
v 
11.4 
Adherence to the Protocol ............................................................................................. 44 
11.5 
Amendments to the Protocol ......................................................................................... 45 
11.6 
Record Retention ........................................................................................................... 45 
11.7 
Obligations of Investigators ........................................................................................... 45 
12.0 
REFERENCES .................................................................................................46 
13.0 
APPENDICES ...................................................................................................50 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
1 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
aGVHD 
Acute Graft Versus Host Disease 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
ATG 
Anti-thymocyte globulin 
BM 
Bone marrow 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
cGVHD 
Chronic Graft versus Host Disease 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr Virus 
ECOG 
Eastern Cooperative Oncology Group 
EF 
Ejection fraction 
EFS 
Event free survival 
GVHD 
Graft-Versus-Host Disease 
GVT 
Graft versus Tumor 
H&P 
History & Physical Exam 
HLA 
Human Leukocyte Antigen 
HRPP 
Human Research Protections Program 
HSCT 
Hematopoetic Stem Cell Transplantation 
IV (or iv) 
Intravenously 
MA 
Myeloablative 
MDS 
Myelodysplastic Syndrome 
MMF 
Mycophenolate Mofetil 
MRD 
HLA-identical sibling donors 
MTD 
Maximum Tolerated Dose 
MUD 
HLA matched unrelated 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
p.o. 
per os/by mouth/orally 
PBMCs 
Peripheral Blood Mononuclear Cells 
PBSC 
Peripheral Blood Stem Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
2 
 
PR 
Partial Response 
PTLD 
Post Transplant Lymphoproliferative Disease 
RIC 
Reduced Intensity Conditioning 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SSIs 
Immunosuppressants 
T Cells 
Tregs 
TBI 
Total Body Irradiation 
TCR 
T cell receptor 
ULN 
Upper limit of Normal 
VCA 
Viral capsid antigen 
VOD 
Veno-occlusive disease 
WBC 
White Blood Cells 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
3 
 
 Study Schema (Experimental Arm) 
 
 
 
 
STUDY SUMMARY 
Title 
A randomized Phase II trial comparing a calcineurin inhibitor-free graft-
versus-host disease prophylaxis regimen with post-transplantation 
cyclophosphamide and abatacept to standard of care. 
Short Title 
Abatacept and Cyclophosphamide for GVHD prophylaxis 
Protocol Number 
180383 
Phase 
Phase II 
Methodology 
Randomized, Open-Label 
Study Duration 
2 years 
Study Center(s) 
Single-center (UCSD) with potential participation of other UC centers 
through the UC Hematologic Malignancy Consortium 
Study Hypothesis 
This is a post-transplantation study comparing two GVHD prophylaxis 
regimens in patients who underwent an allogeneic stem cell 
transplantation for the treatment of a hematologic malignancy. The 
experimental GVHD prophylaxis arm consists of cyclophosphamide and 
abatacept. Cyclophosphamide induces apoptosis of activated T cells and 
abatacept (CTLA4Ig) blocks activation of T cells by inhibiting the co-
stimulatory signal. The standard of care arm consists of methotrexate and 
tacrolimus. 
Compared to the standard-of-care control arm, the experimental arm is 
much more convenient and expected to be associated with fewer 
toxicities.  
In addition there is a great theoretical potential for immunological synergy 
between cyclophosphamide and abatacept for inducing post- 
Hematopoietic Stem Cell  transplant (HSCT) immunologic tolerance that 
clinically might translate into less GVHD without increase in relapse.  
If the experimental arm looks promising, then our findings will be used for 
the design of a larger phase III trial. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
4 
 
Primary Objective 
 
To show that post HSCT cyclophosphamide + abatacept can induce 
tolerance. This clinically translates into a reduction in chronic GVHD by 
one year (compared to standard of care GVHD prophylaxis with 
methotrexate and tacrolimus). 
 
Secondary and Exploratory 
Objectives 
Secondary Objectives  
To compare the two treatment arms regarding  
GVHD- and relapse- free survival by one year 
Donor engraftment at day 28 
Grades II-IV and III-IV acute GVHD 
Chronic GVHD 
Relapse rate 
Disease free survival over the course of the study 
Overall survival 
Transplant related mortality by 1 year after transplantation 
Infections by 1 year after transplantation 
Renal insufficiency and other toxicities 
Cognitive impairment 
 
Exploratory Objectives 
 
Post-HSCT immune reconstitution studies will include measuring T cell 
and NK cell phenotype, PD-1 expression,and alloreactivity to recipient 
and third party at predetermined time points. We will compare and 
contrast the findings between the treatment and control arm and correlate 
those with disease relapse and presence of acute or chronic GVHD. 
Study population 
50 subjects with hematologic malignancies 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
5 
 
Diagnosis and Main 
Inclusion and Exclusion 
Criteria 
Inclusion criteria: 
• 
High risk hematologic malignancy justifying the need for a stem cell 
transplantation 
• 
Patient receiving either Myeloablative Busulfan/Fludarabine or TBI/Cy 
or Reduced Intensity Fludarabine/ Melphalan for conditioning 
• 
ECOG performance score 0-2 
• 
Creatinine clearance ≥ 40 (by Cockgroft-Gault) 
• 
Adequate hepatic function (total bilirubin <2.0 mg/dl, AST and ALT 
<3x ULN), 
• 
Normal cardiac function (EF > 50%) 
 
 
Exclusion criteria: 
• 
Patients with hematologic malignancies for which transplant is not the 
only curative option, such as AML with good or intermediate 
cytogenetics or molecular markers in CR1 or CML in chronic phase 
• 
Inability to identify an 8/8  or 10/10 HLA-Matched Donor (related or 
unrelated)  
• 
Prior allogeneic stem cell transplant 
• 
Active, uncontrolled infection, uncontrolled cardiac angina, 
symptomatic congestive heart failure or any other uncontrolled 
medical condition that in the opinion of the investigator will put the 
patient at increased risk by participating in this clinical trial or would 
interfere with data collection or interpretation 
• 
Life expectancy <3 months 
 
Treatment plan 
Patients will be randomized 1:1 to the experimental vs the standard of 
care arm.  
The two arms will be stratified by conditioning regimen (MA v RIC) and 
donor type (MRD vs MUD) in an effort to keep them balanced. 
 
The GVHD prophylaxis regimen on the experimental arm will consist of 
high dose Cyclophosphamide on Days +3 and +4 followed by abatacept 
for 6 months. 
The GVHD prophylaxis regimen on the standard of care arm will consist 
of methotrexate on Days +1,+3, +6 and +11 and tacrolimus. 
Study Product(s), Dose, 
Route, Regimen 
Abatacept at a dose of 10mg/kg will be administered on days  +5, +14 
and +28, +56, +84, +112, +140, +168 
Subject duration of 
participation 
1 year post-transplant 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
6 
 
Statistical Methodology 
The primary endpoint is the occurrence of moderate and severe chronic 
GVHD by one year post-HSCT. A Mantel-Haenszel test will be used to 
compare chronic GVHD risk between the two arms at 5% significance 
level. Competing risks will be treated as censoring events, including non-
relapse mortality and relapse.  This approach will test for a change in the 
cause-specific hazard ratio  for GVHD. 
 
The key secondary endpoint is GVHD- and relapse-free survival (or GRFS 
i.e. free from acute GVHD Grade III or IV, and from moderate or severe 
chronic GVHD, and from relapse or non-relapse mortality and CRFS, i.e. 
free from chronic GVHD, relapse and non-relapse mortality) by one year 
post-transplant. A stratified Cox proportional hazard model will be used to 
compare survival curves over time and estimate a two-sided  95% 
confidence interval for the hazard ratio of treatment vs. control  
 
 Additional secondary analyses: 
 
Cumulative incidence funcitons for GVHD, relapse, and non-relapse   
mortality will also be displayed, and tested for significant differences 
using  Gray’s test. 
 
Toxicities and adverse events will be summarized by arm, disease type 
and donor type. Their grade, relationship with the treatment, and severity 
will be listed.   
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
7 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Allogeneic Hematopoetic Stem Cell Transplantation (HSCT) is the only curative option for many 
malignant hematologic disorders mainly due to the graft versus leukemia effect. Infection and graft-
versus-host disease (GVHD) is a major complication of allogeneic HSCT. Limiting GVHD and 
infection rates while improving Graft Versus Tumor effect (GVT) has been the elusive “Holy Grail” 
for transplant immunology [1].  
 
The most commonly used GVHD prophylaxis regimen has been a calcineurin inhibitor (CNI) 
(cyclosporine or tacrolimus) in combination with either methotrexate, mycophenolate mofetil (MMF) 
or sirolimus[2]. Despite prophylactic measures, the incidence of acute GVHD (aGVHD) remains in 
the 40–60% range for transplants from HLA-identical sibling donors (MRD) and up to 75% for HLA 
matched unrelated (MUD) transplants[2]. The incidence of chronic GVHD (cGVHD) ranges 
between 40 and 70% and is the leading cause of mortality and morbidity in allogeneic HSCT 
survivors.  
 
The currently used CNI based GVHD prophylaxis regimens cause significant toxicity 
(nephrotoxicity, neurotoxicity, myelosuppression, hypertension, tissue microangiopathy etc.) and 
close level monitoring and frequent dose adjustments, as well as aggressive hydration and 
electrolyte replacements are needed. Furthermore it has been proposed that CNIs block the 
induction of post-transplantation tolerance [3] and thymic T cell development [4] leading therefore 
to chronic GVHD.  
 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
 
Cyclophosphamide is an alkylating agent that has been used for decades in the treatment of cancer 
and autoimmune diseases. Cyclophosphamide induces apoptosis of activated T cells but is not 
stem cell toxic [5]. Most currently used GVHD prophylaxis agents (such as cyclosporine) inhibit T 
cell activation, proliferation, and interleukin-2 (IL-2) production (thereby also blocking tolerance 
induction). Only methotrexate and cyclophosphamide can induce apoptosis of activated T cells but 
methotrexate cannot be given safely in high doses because of marrow and mucosal toxicity. 
 
High-dose cyclophosphamide has been studied as single agent prophylaxis of GVHD after 
myeloablative HLA-matched related or unrelated donor HSCT [6]. In that trial 117 patients with 
hematologic malignancies underwent a myeloablative HSCT, 78 from a matched related and 39 
from matched unrelated donor. Transplantation conditioning was oral or intravenous busulfan and 
cyclophosphamide followed by infusion of donor marrow. Cyclophosphamide was administered at 
a dose of 50mg/kg on days +3 and +4. In theory cyclophosphamide given within a short window 
after stem cell infusion can eliminate activated T cells of both host and donor origin while leaving 
memory T cells intact [5, 7]. Hematopoetic stem cells are resistant to the toxic effects of 
cyclophosphamide due to the high expression of aldehyde dehydrogenase [8]. High-dose post-
transplantation cyclophosphamide was well tolerated. The most common toxicities were 
transient mild renal dysfunction or elevations of serum liver enzymes. Hepatic veno- 
occlusive disease developed in 10 patients (9%) and was fatal in 2. Engraftment of donor cells 
occurred in 98% of patients with a median time to neutrophil recovery of 23 days for recipients of 
related donor and 25 days for recipients of unrelated donor allografts. The cumulative 
incidences of grades II–IV GVHD by day 200 after transplantation were 42 and 46% among 
recipients of related and unrelated donor grafts, respectively. The incidence of grades III–
IV GVHD for all patients was 10%. At 2 years after transplantation, the cumulative incidences 
of chronic GVHD for recipients of related and unrelated donor grafts were 9 and 11% 
respectively. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
8 
 
 
In a follow-up updated report on 139 consecutive patients (79 related and 60 unrelated) treated on 
the same study and with a median follow up of 26 months, the cumulative incidences of acute 
grades II–IV and chronic GVHD for all patients were 45 and 10%, respectively. Only three patients 
have died with refractory GVHD. Secondary systemic immunosuppressants (SSIs) were used in 
45% of all patients. The overall and event free survival for all patients at 1 year after transplantation 
were 63 and 48% respectively, and at 2 years after transplantation were 55 and 39%, respectively, 
suggesting that with the use of high-dose cyclophosphamide for GVHD prophylaxis the GVT effect 
was retained in these high-risk patients[7]. In summary this regime was effective but there was still 
a high rate of acute GVHD and need for SSIs. 
 
Another approach to GVHD prophylaxis is based on costimulation blockade. The two signal model 
of T cell activation dictates that for T cell activation to proceed two signals are required: one through 
the antigen specific T cell receptor (TCR) and the second though the non-antigen specific 
engagement of a costimulatory molecule by its counterpart on an antigen presenting cell[9]. The 
main costimulatory signal is delivered by the engagement of CD28 on the T cell by B7-1 and B7-2 
on antigen presenting cells (APCs). Engagement of the TCR in the absence of costimulation leads 
to T cell anergy and peripheral tolerance [9, 10]. Anergy is thought to be the initial stage of 
development of regulatory T lymphocytes and there is evidence that regulatory T cells abrogate 
GVHD and enhance immune reconstitution without blocking the GVT effect [11, 12]. In a clinical 
study haploidentical donor derived regulatory T cells (Tregs) followed by CD34+ cells and mature 
T cells were infused to the recipient [13]. Almost all patients engrafted, acute GVHD rate was low, 
there was no chronic GVHD, immune recovery was rapid and the GVL effect appeared preserved 
[14]. 
 
A group from Harvard conducted a clinical trial where a haploidentical marrow was infused after in 
vitro co-culture with recipient cells in the presence of CTLA4Ig, which is an antibody that blocks the 
second costimulatory signal rendering the alloreactive T cells in the culture anergic[15].  95% of 
the treated patients engrafted, the GVHD rate was low and the immune reconstitution was rapid 
resulting in very few viral infections [16].  After the in vitro treatment the frequency of helper T cells 
that were reactive against the recipient fell by one to four orders of magnitude, whereas third party 
alloreactivity remained unaffected. 
 
There are currently two FDA approved CTLA4Ig molecules for clinical use, belatacept and 
abatacept. Belatacept is a fusion protein composed of the Fc fragment of a human IgG1 
immunoglobulin linked to the extracellular domain of CTLA4. It differs from CTLA4Ig by two amino 
acid substitutions that increase the avidity for CD80 and CD86 [17]. Belatacept was rationally 
designed as CD28 blocker leading therefore to T cell anergy and tolerance upon TCR engagement.  
In addition CTLA4 by itself might play a significant role. Regulatory T cells constitutively  express 
CTLA4 and may exert at least part of their action through the engagement of B7-1 and B7-2 on 
APCs as this has been shown to lead to a tolerogenic APC phenotype [18]. A possible mechanism 
of action is the induction of indolamine-2,3-dioxygenase (IDO) expression, which results in 
exhaustion of tryptophan and appearance of the tryptophan metabolite kynurenine that is toxic for 
T lymphocytes and an anergy inducing factor[19]. 
 
Belatacept is FDA approved for the prophylaxis of organ rejection in kidney transplant instead of 
cyclosporine based on strong data from phase III trials [20-23]. Rejection prophylaxis with 
belatacept in these trials resulted in comparable patient and graft survival and superior preservation 
of renal function compared with cyclosporine.  In addition transplant biopsies suggest that 
belatacept confers a substantially different immunologic profile at the tissue level than cyclosporine 
with increased levels of markers of tolerance [24]. Belatacept was also safe and resulted in reduced 
mean blood pressures and new onset diabetes than cyclosporine at 1 year [25]. There were fewer 
deaths and serious infections than with cyclosporine with the exception of Post Transplant 
Lymphoproliferative Disease (PTLD) in EBV seronegative patients. Kidney transplantation patients 
receiving ATG/belatacept/sirolimus had a significantly higher percentage of T regs and showed a 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
9 
 
more 
potent 
anti-donor 
suppressive 
activity 
when 
with 
a 
CNI-based 
regimen 
(ATG/tacrolimus/MMF)[26].  Belatacept has not been studied in HSCT [27]. 
 
Abatacept is another CTLAIg molecule that has been approved by the FDA for the treatment of 
rheumatoid arthritis and juvenile idiopathic arthritis [28]. It was also recently shown to slow down 
the progression of diabetes type 1[29].  Similar to belatacept, abatacept also has a favorable side 
effect profile and was associated with fewer serious adverse events and serious infections when 
compared to infliximab in a randomized phase III trial [30].  
 
A “first-in-disease” feasibility trial of in vivo T cell costimulation blockade with abatacept for GVHD 
prophylaxis was reported[31]. In this trial abatacept was added to standard of care GVHD 
prophylaxis with cyclosporine and methotrexate in 10 patients undergoing matched unrelated donor 
HSCT for high-risk hematologic malignancies. Abatacept was administered at a dose of 10 mg/kg 
on days -1, +5, +14, and +28. The drug was well tolerated, and patients did not develop unexpected 
infections. No patient developed CMV disease or high-level EBV reactivation.  All patients 
engrafted, no patients developed grade IV or steroid refractory GVHD, two patients developed 
severe chronic GVHD and seven patients were alive and disease free with a median follow up of 
475 days. The pharmacokinetic parameters of abatacept in this patient population were similar to 
those in patients with Rheumatoid Arthritis. Another recently presented trial found abatacept to be 
well tolerated and effective in the treatment of steroid refractory chronic GVHD[32]. An increase in 
PD-1 expression and skewing toward Th2 cytokines were observed in responders. 
 
In a recent pilot study children with aplastic anemia underwent haploidentical transplantation with 
post-transplant high dose cyclophosphamide, abatacept and sirolimus for GVHD prophylaxis[33]. 
Outcomes were compared to a control group that received post-transplant high dose 
cyclophosphamide based GVHD prophylaxis without abatacept. The GVHD and disease-free 
survival was 80% for the children who received abatacept vs 30% who didn’t. The acute GVHD 
incidence was respectively 10.5 vs 50%.  
1.3 
Other Considerations 
 
Conditioning regimens will be administered per institutional standards. This is a GVHD prophylaxis 
study so we won’t be examining the effect of conditioning regimens. The following conditioning 
regimens are allowed on the study: 
The combination of Busulfan (Bu) and Cyclophosphamide (Cy) as a conditioning regimen is 
associated with liver toxicity and VOD [34]. Furthermore, the antitumor activity of Cy in several 
hematological malignancies is questionable. (Cyclophosphamide was originally added to Total 
Body Irradiation (TBI) for tumor lysis prevention in relapsed acute leukemia.) On the other hand 
fludarabine (Flu) does not cause VOD and it has both direct and synergistic with busulfan anti-
leukemic activity. In a study by the MD Anderson group 96 patients with AML or myelodysplastic 
syndrome (MDS; 56% with active disease at the time of transplantation) were transplanted with 
Bu/Flu conditioning regimen using Fludarabine (40 mg/m2/d for 4 days) and IV Busulfan (130 
mg/m2/d for 4 days)[35]. This regimen was well tolerated with no deaths from VOD and low 
mucositis and overall toxicity rate. The one year OS and event-free survival EFS were 65% and 
52% for all patients, and 81% and 75% for patients receiving transplants in CR. In another study 
by the same group the Bu-Flu conditioning regimen was retrospectively evaluated against BuCy 
using Bayesian methodology. In a cohort of mostly advanced patients (half of the patients were > 
CR1), the OS and EFS were significantly better in the Bu-Flu group compared with BuCy (70 vs 
59%, P = .03, and 62 vs 37%, P = .04, respectively). Similar results were observed in the subgroup 
of patients transplanted in CR[36]. The safety and efficacy of Bu-Flu were also shown in a cohort 
of patients older than 55 years[37]. In  Acute Lymphoblastic Leukemia (ALL) there is some evidence 
in favor of a TBI-based regimen [38]. For patients who will receive a RIC conditioning regimen, we 
propose the use of Fludarabine and Melphalan (140 mg/m2) which is the most widely used RIC 
regimen. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
10 
 
 
Most transplant centers prefer to use mobilized peripheral blood stem cells (PBSCs) over bone 
marrow (BM) as a stem cell source because of the ease of collection, reduced risk for the donor 
who doesn’t need to undergo general anesthesia and faster engraftment[39]. It was shown though 
in a randomized trial that PBSCs are associated with a significant increase in the risk of chronic 
GVHD compared to BM[40]. On the other hand there is evidence suggesting a reduced risk of graft 
failure and of relapse with the use of PBSCs[40, 41].  
 
 
1.4 
Rationale 
 
It was shown in the study by the Hopkins group that post-transplant high dose cyclophosphamide 
can be safely used for GVHD prophylaxis and the patients can be spared from the toxicity 
associated with CNIs and methotrexate[6]. This approach was also associated with a lower than 
expected cGVHD rate. However there was a relatively high rate of VOD (9%), acute GVHD (42% 
for MRD and 46% for MUD grade II-IV aGVHD) and an EFS at 2 years of 39%. 45% of the patients 
required secondary immunosuppression. Therefore there is clearly room for improvement.  
 
In the abatacept study [31] it was demonstrated that the use of abatacept is safe and feasible for 
patients who undergo stem cell transplantation with promising results in a limited number of patients 
studied. However, the patients still had to take a CNI and methotrexate. In addition it was recently 
shown that abatacept as a single agent is safe and effective for the treatment of chronic GVHD[32]. 
 
One of our goals is to avoid the CNI associated toxicity and the need for frequent drug level 
monitoring and dose adjustments. In addition we might be able to improve both disease and 
transplant related mortality by combining two novel safe GVHD prophylaxis regimens.  
 
The combination of cyclophosphamide and abatacept should promote tolerance given their 
immunological mechanism of action. We will examine if we can indeed promote tolerance induction. 
This will clinically translate into a low rate of chronic GVHD.  
 
Tolerance induction might also paradoxically prevent relapses [11, 12] either by reducing the need 
for nonspecific immunosuppression or through another unexplained mechanism. For instance 
costimulation blockade was shown to lead to earlier natural killer (NK) Cell recovery [31] and NK 
cell alloreactivity protects from relapse[42].  
 
Furthermore CD86 (one of CTLA4Ig’s ligands) is an activation receptor for NK cells and it has been 
shown in vitro that CTLA4Ig enhances tumor cell killing by NK cells[43, 44]. CTLA4Ig treated Donor 
Lymphocyte Infusions (DLI) were used recently in a clinical study with the aim to prevent 
relapses[45]. In this study priming of the DLI with CTLA4Ig resulted in greater proliferation of NK 
cells with mature phenotype and improved relapse free survival especially in patients with AML. 
 
 
 
We plan to enroll 50 patients with hematologic malignancies undergoing a myeloablative stem cell 
transplantation over the course of two years. The conditioning regimen will be myeloablative or RIC 
followed by the infusion of donor PBSCs. The patients will be randomized to either standard of care 
GVHD prophylaxis (MTX and tacrolimus) or the experimental arm with cyclophosphamide followed 
by abatacept. (Please refer to section 10.6 for more details on randomization.) Cyclophosphamide 
will be administered at a daily dose of 50mg/kg IV on days +3 and +4. Abatacept will be 
administered at a 10mg/kg IV dose on days +5, +14, +28, +56, +84, +112, +140,  and+168 [23].  
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
11 
 
On December 15, 2021, the Food and Drug Administration approved abatacept (Orencia, Bristol-
Myers Squibb Company) for the prophylaxis of acute graft versus host disease (aGVHD), in 
combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), in adults and pediatric 
patients 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from 
a matched or 1 allele-mismatched unrelated donor.  
Efficacy was evaluated in two studies in patients six years and older undergoing HSCT from a 
matched or 1 allele-mismatched unrelated donor.   
 
GVHD-1 (NCT 01743131) was a randomized (1:1), double-blind, placebo-controlled clinical trial of 
patients who underwent an 8 of 8 Human Leukocyte Antigen (HLA)-matched HSCT and received 
abatacept or placebo in combination with a CNI and MTX. While severe (grade III-IV) aGVHD-free-
survival assessed at Day 180 after transplantation was not significantly improved in patients who 
received Orencia compared to patients who received a placebo (HR 0.55; 95% CI 0.26, 1.18), the 
OS rate at Day 180 after HSCT was 97% (95% CI: 89%, 99%) for patients who received abatacept 
compared to 84% (95% CI: 73%, 91%) for patients who received a placebo (HR 0.33; 95% CI: 
0.12, 0.93). The moderate-severe (grade II-IV) aGVHD-free survival rate at Day 180 after HSCT 
was 50% (95% CI: 38%, 61%) for patients who received abatacept compared to 32% (95% CI: 
21%, 43%) for patients who received a placebo (HR 0.54; 95% CI: 0.35, 0.83).   
 
Additional evidence of effectiveness was provided by GVHD-2, a clinical study using data from the 
Center for International Blood and Marrow Transplant Research (CIBMTR) in patients who 
underwent a 7 of 8 HLA-matched HSCT between 2011 and 2018. This registry-based study 
analyzed outcomes of 54 patients treated with abatacept for the prophylaxis of aGVHD, in 
combination with a CNI and MTX, versus 162 patients randomly selected from the CIBMTR registry 
treated with a CNI and MTX alone. The OS rate at Day 180 after HSCT was 98% (95% CI: 78%, 
100%) for patients who received abatacept in combination with CNI and MTX compared to 75% 
(95% CI: 67%, 82%) for patients who received CNI and MTX alone. 
 
With the approval of abatacept for GVHD prophylaxis (which validates some of our hypotheses), 
the SOC for GVHD prophylaxis changed and we’ve decided to stop enrolling in the SOC arm but 
complete enrollment in the experimental arm. 
 
1.5 
Hypothesis 
 
There is a great theoretical potential for immunological synergy between cyclophosphamide and 
abatacept. Cyclophosphamide induces apoptosis of activated T cells and abatacept blocks 
activation of T cells by inhibiting the co-stimulatory signal. Therefore the combination has the 
potential of inducing immunologic tolerance that clinically might translate into less GVHD without 
increase in relapse. Furthermore abatacept activates NK cells and might enhance the graft versus 
tumor effect. Abatacept’s immunologic mechanism of action will be examined further with our 
correlative studies. 
 
Compared to the standard-of-care control arm, the experimental arm is a calcineurin inhibitor-free 
graft-versus-host disease prophylaxis regimen that is much more convenient for patient care. The 
patients on standard of care oral CNIs have to come in two to three times a week to have drug 
levels checked and the dose of the CNI needs to be adjusted accordingly. In addition, there are 
always concerns about absorption and interactions with other medications and foods with CNIs; 
the pills need to be taken precisely at the exact same time twice a day. Besides convenience, the 
experimental arm is expected to have fewer toxicities such as renal insufficiency, electrolyte 
abnormalities such as hypokalemia and hypomagnesemia requiring oral and frequently even IV 
repletion and CNS toxicity. 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
12 
 
If the experimental arm looks promising, then our findings will be used for the design of a larger 
phase III trial.  
 
1.6 
Correlative Studies 
1.6.1 
GVHD Specific Immune Cell Activity Samples 
 
This study provides a unique setting that will enable to further characterize the mechanism of action 
of abatacept. 
 
In order to assess the effect of abatacept on immune responses, we will collect peripheral blood 
samples for immunologic studies. We hypothesize that the effect of abatacept would be to prevent 
the priming or activation of allogeneic donor cells against host antigens, thereby blocking or 
ameliorating acute and/or chronic GVHD. Previous studies found that the effector phase of acute 
GVHD involves a significant increase in CD8+ T cells expressing co-stimulatory molecules CD134 
(OX40) and CD154 (CD40L)[46]. Other studies found that abatacept decreased the percentage of 
CD4+ T cells secreting IL-17 (Th17) and IFN-gamma (TH1) in the peripheral blood of patients with 
rheumatoid arthritis [47]. Notably, abatacept treated rheumatoid arthritis patients also 
demonstrated a decrease in repertoire restriction [48]. 
 
Based on these previous studies, we propose the following studies to determine how abatacept 
might influence immune cell activity, specific for GVHD, in our patient cohort. We will collect the 
following samples: 
• 
2 baseline blood samples at different timepoints from donor preferably prior to mobilization 
but ok during mobilization and at time of apheresis.  
• 
2 baseline blood samples at different timepoints from recipient prior to conditioning 
• 
Post-transplant blood samples from recipient at days +28, +100, +180 and 1 year 
(representing engrafted donor immune cells) 
• 
Post-transplant blood samples from recipient at study exit in the case of disease relapse 
 
All samples are EDTA 10 mL x 5 tubes. 
 
1 tube will be used immediately for flow cytometry studies using the following panel: 
• 
Tube 1 – lymphocytes: CD4 / HLA-DR / 7-AAD / CD8 / CD56 / CD3 
• 
Tube 2 – Treg tube: CD4 / CD127 / 7AAD / CD8 / CD25 / CD3 
• 
Tube 3 – Helper T: CXCR3 / CCR4 / 7-AAD / CCR6 / CD4 / CD3 
• 
Tube 4 – Cytotoxic T: CD45RA / CD44 / 7-AAD / CD8 / CD45RO / CD62L 
• 
Tube 5 – NK cells: CD16 / CD69 / 7-AAD / CD33 / CD56 / CD3 
• 
Tube 6 – T markers 1: CD4 / PD1 / 7-AAD / LAG-3 / CD8 / CD3 
• 
Tube 7 – T markers 2: CD4 / CTLA4 / 7-AAD / CD28 / CD8 / CD3 
• 
Tube 8 – T markers 3: CD4 / CD40L / 7-AAD / OX40 / CD8 / CD3 
• 
Tube 9 – T markers iso: CD4 / IgG / 7-AAD / IgG / CD8 / CD3 
 
4 tubes will be processed and stored in the MCC biorepository as plasma, serum, and PBMCs. 
Once the trial is close to completion, these samples will be analyzed in batched studies.. We 
hypothesize that abatacept will prevent the oligoclonal expansion of donor T cells mediating GVHD. 
Thus, we will compare recipient blood samples post-transplant with donor samples prior to 
transplant. As a functional readout, we will perform mixed lymphocyte reactions (MLRs) using donor 
samples at baseline and recipient samples after transplant as Responder Cells. Stimulator Cells 
will be recipient PBMCs collected at baseline prior to conditioning. In these studies, recipient 
plasma during abatacept treatment can be spiked in to determine whether abatacept in the plasma 
is sufficient to block MLR responses in vitro. In addition, third-party MLR studies can be performed 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
13 
 
to test if abatacept has induced suppressive cells such as T-regulatory cells. We will also directly 
examine the effect of abatacept on T-regulatory cell proliferation using intracellular Ki-67 and 
FOXP3 staining of frozen PBMCs. 
 
We envision that the studies proposed will profile the immune response to an extent that 
correlations between various immune cell parameters and clinical course can be drawn. Given that 
we will have a control cohort, we can also assign a causal effect on immune cells due to abatacept. 
 
1.6.2 
Immunogenicity Studies  
Blood samples for determination of antibodies to abatacept will be collected at timepoints 
specified below.  Samples will be assayed for presence of abatacept-sepecifc antidbodies by 
ICON Clinical Laboratories. A validated, sensitive, electrochemiluminescence assay (ECL) 
method will be used to analyze anti-abatacept antibodies in serum [61].  
 
Time Points:  
Baseline (screening) 
Days +28, +56, +84, +112, +140, +168(all timepoints +/- 7 days) 
 
Sample Collection:  
Approximately 7 mL Whole blood samples are collected to provide approximately 3 mL of serum 
for drug concentration or ADA measurement at time points specified in the protocol. Blood 
samples are collected into appropriately labeled additive-free glass tubes (note that silicone-
coated plastic tube are acceptable if non-additive glass red top tube is unavailable). Serum 
separator tubes (SST) should not be used.  
 
Processing Guidelines:  
Blood samples are allowed to clot at room temperature for at least 20 minutes for a complete clot 
to form.  Serum is separated from the whole blood within approximately 40 minutes of collection. 
Specimens should be centrifuged at 1,500 x g for approximately 10 minutes in a room 
temperature centrifuge (a refrigerated centrifuge is acceptable if available) to harvest the serum. 
After centrifugation, the upper serum layer is carefully transferred with a disposable pipette and 
equally aliquoted into 2 labeled screw capped plastic storage tubes (each with approximately 1.5 
mL of serum, one for PK analysis and one for a back-up sample for PK analysis, respectively). 
Similar samples are collected for ADA sample and backup sample as noted in the protocol. After 
centrifugation, the upper serum layer is carefully transferred with a disposable pipette and into 
one labeled screw capped plastic storage tube. If red blood cells are inadvertently drawn into the 
serum, the sample should be recentrifuged immediately and processed appropriately. Serum 
samples will be frozen in an upright position within 120 minutes of sample collection at 
approximately -70°C (-20°C is acceptable if -70°C not available at the collection site). 
 
Shipping Guidelines:  
Samples are to be shipped to ICON per the included requisition forms for processing and 
analysis.  
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
To examine if the novel combination of post transplant high dose cyclophosphamide and 
abatacept can induce tolerance. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
14 
 
2.2 
Secondary Objectives  
 
• 
To estimate the rate of other important transplant outcomes with the two GVHD prophylaxis 
strategies: 
o 
donor engraftment by day 28 
o 
Grades II-IV and III-IV acute GVHD 
o 
Chronic GVHD of all grades 
o 
Relapse rate 
o 
Disease free survival over the course of the study 
o 
Overall survival 
o 
Transplant related mortality by 1 year after transplantation 
• 
To estimate the infectious, renal, cognitive and other toxicity caused by the two GVHD 
prophylaxis strategies. 
2.3 
Exploratory Objectives 
 
Post-transplantation immune reconstitution studies will include measuring T cell and NK cell 
phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time 
points. We will compare and contrast the findings between the treatment and control arm and 
correlate those with disease relapse and presence of acute or chronic GVHD. 
 
2.4 
Endpoints  
2.4.1 
Primary 
Occurrence of (moderate and severe) chronic GVHD by one year post–transplant . Chronic 
GVHD will be diagnosed and staged according to the previously published and widely 
accepted National Institutes of Health consensus criteria [49]. Only moderate and severe 
chronic GVHD will be included.  
 
 
2.4.2 
Secondary 
 
1. GVHD- and relapse-free survival by one year post transplant. GRFS: GVHD- and relapse-
free survival will be defined as the absence of acute GVHD Grade III or IV or moderate or 
severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. 
CRFS: Chronic GVHD and relapse free survival will be defined as the absence of moderate 
or severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. 
Acute GVHD will be diagnosed and graded according to Glucksberg criteria[50].  
 
2. The rate of  donor engraftment by day 28 
The day of neutrophil engraftment is defined as the first day of three consecutive increased 
lab values on different days, after the conditioning regimen induced nadir of blood counts 
that the absolute neutrophil count is ≥ 500/microL. The day of platelet engraftment is defined 
as the first day of three consecutive increased lab values on different days, after the 
conditioning regimen induced nadir of blood counts that the platelet count is ≥ 20,000/microL 
without platelet transfusion support in the seven days prior. Chimerism will also be 
measured on Days +28, +100 and +180. Donor engraftment is defined as presence of both 
donor and platelet engraftment.  
 
3. Grades II-IV and III-IV acute GVHD  

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
15 
 
Acute GVHD will be diagnosed and graded according to Glucksberg criteria[50].  
 
4. Chronic GVHD 
 
5. Disease free survival over the course of the study 
Recurrent malignancy will be defined by standard hematologic criteria.  
 
6. Overall survival  
Proportion of patients who are alive post transplantation. 
 
7. Transplant related mortality at 1 year after transplantation 
Defined as death in the absence of recurrent malignancy.  
 
8. Infections by 1 year after transplantation 
 
Defined as Grade 3 or higher infections 
 
9. Renal insuffiency and other toxicities 
Defined as Grade 3 or higher renal insufficiency or other grade 3 or higher. 
 
10. Cognitive impairment 
Defined as change in Mini-Mental State Examination between baseline, Days +100, +180 
and one year after transplant 
 
 
 
3.0 
PATIENT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered (see 
Section 3.3 for registration requirements). 
 
3.1 
INCLUSION CRITERIA 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
16 
 
• 
High risk hematologic malignancy justifying the need for an allogeneic hematopoetic stem cell 
transplantation: AML, ALL, CML in accelerated or blast phase, MDS/MPN, NHL, Hodgkin lymphoma, 
and multiple myeloma 
• 
Patient receiving either Myeloablative Busulfan/Fludarabine or TBI/Cy or Reduced Intensity 
Fludarabine/ Melphalan for conditioning 
• 
Patient age > 18 years 
• 
ECOG performance score 0-2  
• 
Creatinine clearance >  40 (by Cockgroft-Gault) 
• 
Adequate hepatic function (total bilirubin <2.0 mg/dl, AST and ALT <3x ULN) 
• 
Normal cardiac function (EF > 50%) 
• 
Acceptable pulmonary function, FEV1 of >/= 50% of predicted and DLCO of >/= 40% predicted.  
• 
Psychological assessment, social arrangement and family support indicate reasonable expectation 
that patient will adhere to the medication regimen required after stem cell transplantation.  
• 
No clinical evidence of metastatic CNS disease 
• 
Laboratory testing for infectious disease performed on a sample collected within 30 days prior to or 
concurrently with procurement of the stem cell product. No clinical or laboratory evidence for active 
infections such as hepatitis B or C, HIV.  
• 
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, 
and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician immediately. A 
female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has 
had menses at any time in the preceding 12 consecutive months). 
• 
Ability to understand and willingness to sign a written informed consent. 
 
3.2 
EXCLUSION CRITERIA 
 
a. Patients with hematologic malignancies for which transplant is not the only curative 
option, such as AML with good or intermediate cytogenetics or molecular markers in CR1 
or CML in chronic phase 
b. Inability to identify an 8/8 or 10/10 HLA-Matched (related or unrelated) Donor 
c. Prior allogeneic stem cell transplant 
 
 
d. Active malignant disease relapse 
e. Active, uncontrolled infection, uncontrolled cardiac angina, symptomatic congestive heart 
failure or any other uncontrolled medical condition that in the opinion of the investigator 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
17 
 
will put the patient at increased risk by participating in this clinical trial or would interfere 
with data collection or interpretation 
f. 
Life expectancy <3 months 
g. Pregnancy or lactation 
h. Inability to comply with treatment regimen 
i. 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to abatacept,  
j. 
Patients may not be receiving any other investigational agents in the last 28 days  
k. 
Patients with chronic myeloid leukemia in first chronic phase. 
 
3.3 
REGISTRATION PROCEDURES 
3.3.1 Registration Process 
 
All patients must obtain a study ID number from the UCSD BMT Clinical Trials Office before 
enrollment. An eligibility check list signed by the PI or Sub-I must be faxed or emailed to the 
BMT Clinical Trials Office at 858-822-1473. Confirmation of eligibility by UCSD is not required 
prior to starting treatment.  
 
Patients will be given a unique sequential patient ID number based on the study number, and 
patient enrollment number. 
 
Oversight by the principal investigator is required throughout the entire registration process.   
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
Randomization 
Patients will be randomized to the either the standard of care or the experimental arm prior after 
enrollment and prior to initiating the conditioning regimen. 
 
 
 
4.1.2 
Pre-transplant Work-up and Intake 
Pre-transplant donor and recipient work up and intake will proceed per the institutional standard 
operating procedure (SOP). 
 
Patients age, sex, disease and disease status, donor source (sibling, unrelated), HLA matching 
and donor and recipient CMV status and blood groups will be recorded for research purposes. 
 
4.1.3 
Conditioning Regimen 
 
Conditioning regimens will be administered per institutional standard. The following conditioning 
regimens are allowed on the study: TBI/Cy, myeloablative BuFlu and RIC Flu/Mel. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
18 
 
Drug administration dates and dose received will be recorded on the study Case Report Forms 
(CRFs).  
 
Dosing will be based on institutional standard of care. 
Dosing guidelines are provided as suggestions in Appendix V. 
 
 
4.1.4 
Transplant (Day 0) 
Patients will receive donor peripheral stem cells per institutional standards. Stem cell dose will be 
recorded for research purposes, but will be at minimum 2x10^6 CD34+ cells/kg. 
 
4.1.5 
GVHD prophylaxis 
Patients were randomized to the experimental or the standard of care arm. The two arms will be 
stratified by conditioning regimen (MA vs RIC) and donor type (MRD vs MUD). 
Drug administration dates and dose received will be recorded on the study Case Report Forms 
(CRFs).   
 
On December 15 2021 the FDA approved abatacept for GVHD prophylaxis (in combination with 
Methotrexate and a CNI). Given that the SOC for GVHD prophylaxis changed, we’ve decided to 
stop enrolling in the SOC arm but complete enrollment in the experimental arm. 
 
Starting with Amendment 8 all patient will be enrolled in the experimental arm. 
 
4.1.5.1 Standard of Care arm 
Patients randomized to the standard of care arm will receive the following GVHD prophylaxis 
regimen: 
• 
Tacrolimus 0.022 mg/kg/day (using ideal body weight) starting on day -2; adjust for 
trough of 5-15 
• 
Methotrexate  
o 
For Flu/Bu and Flu/Mel: 5 mg/m2 on Days 1, 3, 6 and 11 (The methotrexate dose 
might be adjusted or held at the investigator’s discretion)  
o 
For Cy/TBI and TBI/Cy: 15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11 
(the methotrexate might be adjusted or held at the investigator’s discretion) 
 
 
Use of ATG in the standard of care arm should be avoided but will ultimately be at the investigator’s 
discretion for patient safety. It is prohibited in the experimental arm. 
4.1.5.2 Experimental arm 
Patients randomized to the experimental arm will receive the following GVHD prophylaxis regimen: 
• 
A 10mg/kg dose of abatacept (maximum dose, 1000 mg) will be given intravenously 
on days, +5, +14 , +28, +56, +84, +112, +140, +168[31].  
• 
Dosing will be based on actual body weight on the day of treatment (-1 day allowed).   
• 
The doses on days +5 and +14 will be administered on that exact day.  
• 
The other doses may be administered within a 3 day window from the planned day to 
allow for clinic closures (weekends, holidays etc). 
• 
Cyclophosphamide will be administered at a dose of 50 mg/kg/day will be given 
intravenously on days +3 and +4 after transplantation [6]. Mesna  will be administered 
on both days of cyclophosphamide administration as per institutional guidelines. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
19 
 
Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), 
unless the patient weighs more than 125% of IBW, in which case the drug will be 
dosed according to the adjusted IBW (AIBW= IBW + [(0.25) x (ABW-IBW)]).  
 
4.1.6 
Post-Transplant Treatment and Maintenance  
 
Growth factors are allowed 24-48 hr after the completion of the chemotherapy, ie on Day +13 for 
patients on the SOC arm and Day +6 on the experimental arm.   
 
Post-transplant supportive care and infection prophylaxis will be otherwise provided according to 
institutional standards. 
 
Post transplant maintenance therapies to prevent relapse will generally be allowed unless there is 
a known GVHD prophylactic effect.   
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will 
be assessed for the development of toxicity according to the Time and Events table. Toxicity will 
be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 
5.0.  
 
As busulfan, fludarabine (or TBI based regimens), abatacept and cyclophosphamide are part of the 
transplantation regimen, they will only be held if in the opinion of the investigator, the patient’s 
safety is at risk.  The reason for all dosing delays must be described in the subject’s medical record.   
 
Infusion related reactions to cyclophosphamide and abatacept have been observed and are usually 
mild and self-limited.  
 
If an anaphylactic or other serious allergic reaction to abatacept occurs, administration of abatacept 
should be stopped immediately with appropriate therapy instituted, and the use of abatacept should 
be permanently discontinued. Please refer to the Orencia (abatacept) Package Insert for further 
information. 
 
If there are grade 3 or higher nonhematologic toxicities due to abatacept, hold abatacept until grade 
2 or less, then resume dosing.  If with resumed dosing grade 3 or higher nonhematologic toxicity 
recurs, then discontinue abatacept permanently. 
 
If there is a delay of abatacept dosing by 4 weeks or more due to toxicity, abatacept will be 
discontinued. 
 
 
 
Common toxicities with abatacept 
 
Infections. 
- 
The most commonly reported side effects (occurring in one out of 100 or more of patients 
treated with drug) were headache, upper respiratory tract infection (cough sneezing, runny 
nose, nasal congestion, sore throat), nasopharyngitis (commonly known as cold), and nausea 
- 
Serious infections: pneumonia, cellulitis, urinary tract infection, bronchitis, 
diverticulitis, and acute pyelonephritis 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
20 
 
Malignancies 
- The potential role of ORENCIA in the development of malignancies in humans is unknown. One 
major safety concern with belatacept is the numerical increase of early Post-transplant 
Lymphoproliferative Disease (PTLD) in the BENEFIT trial. However, whether or not belatacept 
really increases the risk of developing PTLD is unclear. While the numbers in the belatacept 
groups were higher than in controls in the first trial, they were still very low. Given the 
spontaneous frequency of occurrence (1.6%), 14 cases in about 1000 patients is not 
unexpectedly high. Furthermore a recent meta-analysis of five Randomized Controlled Trials did 
not show a difference in PTLD. 
 
Infusion-Related Reactions and Hypersensitivity Reactions 
- 
The most frequently reported events (1%-2%) were dizziness, headache, and hypertension. 
Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with 
ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood 
pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, 
hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to 
moderate (28%). 
 
 
 
 
 
4.3 
Concomitant Medications/Treatments 
 
Concomitant use of any other immunosuppressive medications (such as cyclosporine, MMF or 
corticosteroids) for GVHD prophylaxis is prohibited.  Concurrent use of other investigational drugs 
is prohibited.  Immunosuppressive medications such as steroids may be used for the treatment of 
acute or chronic GVHD or other indications per the investigator’s discretion. If a patient develops 
acute GVHD, abatacept will be continued as scheduled up to day+168. 
 
 
Supportive care, such as hydration and pre-medications should be provide according to institutional 
standard of care and is at the discretion of the treating physician. 
4.4 
Duration of Therapy 
 
Treatment on the experimental arm will continue until the last dose of abatacept on Day +168 
after transplantation or until: 
 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s)  
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
 
 
4.5 
Duration of Follow Up 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
21 
 
Patients will be followed for 1 year after transplant or until death whichever occurs first. Patients 
removed from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event or 1 year after transplant, whichever is later.  
4.6 
Removal of Patients from Protocol Therapy 
 
Patients will be removed from therapy when any of the criteria listed in Section 5.4 apply. Notify the 
Principal Investigator, and document the reason for study removal and the date the patient was 
removed in the Case Report Form. The patient should be followed-up per protocol. 
 
4.7 
Handling of dropouts 
 
Patients in the treatment arm who drop out of the study prior to the first dose of abatacept 
will be replaced. Similarly, patients in the control arm who drop out prior to day +5 will be 
replaced.  All patients, including those who are replaced, will be included in the intent-to-
treat analysis, but replaced patients will be excluded from the as-treated analysis.  
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 90 days prior to registration unless 
otherwise stated. The screening procedures include: 
1. 
Informed Consent – The investigator must obtain documented consent from 
each potential subject prior to performing research procedures.   
2. 
Medical history - Complete medical and surgical history, history of infections 
3. 
Demographics - Age, gender and race 
4. 
Review subject eligibility criteria - All inclusion and exclusion criteria will be 
reviewed by the investigator or qualified designee to ensure that the subject 
qualifies for the trial 
5. 
Review previous and concomitant medications – The investigator or qualified 
designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject with 30 
days before starting the trial.  All concomitant medications will be recorded during 
the trial. 
6. 
Physical exam including vital signs, height and weight.  Vital signs include 
heart rate, blood pressure, respiratory rate, and temperature.   
7. 
Performance status (ECOG) - Performance status evaluated prior to study entry 
according to Appendix III. 
8. 
Adverse event assessment- See Section 6 for Adverse Event monitoring and 
reporting.  Adverse events will be graded and recorded throughout the study 
according to NCI-CTCAE Version 5.0. Toxicities will be characterized in terms 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
22 
 
including seriousness, causality, toxicity grading, and action taken with regard to 
study therapy.  All safety evaluations may be performed at any time based on the 
clinical judgement of the Investigator. 
9. 
Hematology - CBC with auto differential, platelets, coagulation 
10. 
Serum chemistries 
 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin. 
 
11.      Quantiferon 
12. 
Pregnancy test (for females of child bearing potential) 
 
See section 3.1.6.1 for definition.  
13. 
Tumor assessment 
 
Disease type specific (eg. bone marrow biopsy for leukemias, PET or CT scan for 
lymphomas, serum/urine protein electrophoresis and free light chains for multiple 
myeloma) 
14. 
Chest X ray 
15. 
EKG 
 
16. 
Echocardiogram  
 
17. 
Mini-mental status exam 
 
5.2 
Study visits (days  +5, +14,  +28, +56, +84, +112, +140, +168) 
 
History and Physical exam 
Vital signs- vital signs to be performed as clinically indicated during abatacept 
administration.  
Hematology 
Serum chemistries 
 
 
 
Toxicity assessment 
 
 
 
Mini mental status exam 
 
 
 
Disease assessment will be at the investigator’s discretion 
 
Recording of GVHD (date of diagnosis, symptoms/signs, scoring and treatment) 
 
Monitoring for CMV, EBV, and adenovirus PCR  post-transplantation. 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
23 
 
5.3 
Blood for correlative studies will be collected: 
 
• 
2 baseline blood samples at different timepoints from donor preferably prior to mobilization 
but ok during mobilization and at collection 
 
• 
2 baseline blood samples at different timepoints from recipient prior to conditioning 
 
• 
Post-transplant blood samples from recipient at days +28, +100, +180, and +365 
 
• 
Blood samples for the immunogenicity studies will be collected at screening, days +28, 
+56, +84, +112, +140, +168 (all timepoints +/- 7 days)  
 
5.4 
Removal of Subjects from Study 
 
Patients can be taken off the study treatment and/or study at any time at their own request, or they 
may be withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation will be documented and may include: 
• 
Patient voluntarily withdraws from treatment (follow-up permitted)  
• 
Patient withdraws consent (termination of treatment and follow-up) 
• 
Patient is unable to comply with protocol requirements 
• 
Patient demonstrates disease progression (unless continued treatment with study drug is 
deemed appropriate at the discretion of the investigator) 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe 
• 
Treating physician judges continuation on the study would not be in the patient’s best 
interest 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event) 
• 
Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study 
• 
If a research subject cannot be located to document survival after a period of 1 year, the 
subject may be considered “lost to follow-up.”  
 
 
 
 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
24 
 
 
6.0 
Study Calendar: Experimental Arm 
 
Period/Procedure 
Screening 
Treatment  
  
  
 -90  to -1  
  
  
Post Transplant  
End of 
treatment  
Day 
  
+3 
+4 
+5 
+14 
+28 
+56 
+84 
+100 
+112 
+140 
+168 
+180 
+365 
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Treatment  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Conditioning 
Regimen  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Stem cell Infusion  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cyclophosphamide  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Abatacept6 
  
  
  
X 
X 
X 
X 
X 
  
X 
X 
X 
  
  
  
Clinical 
Procedures  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of Eligibility 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam7 
X 
  
  
x  
x  
x  
x  
x  
X 
x  
x  
x  
X 
X 
X 
Performance 
Status (ECOG)7 
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
Vital Signs, 
Weight7, 8 
X 
  
  
x  
x  
x  
 x 
x  
X 
x  
x  
x  
X 
X 
X 
Height  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECHO 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Chest X-ray 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
GVHD Assessment  
  
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
Tumor 
Assessments (as 
indicated for 
disease)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone Marrow 
Biopsy (Leukemia)7 
X 
  
  
  
  
  
  
  
X10 
  
  
  
 
 
 
  
 -90  to -1  
 
  
  
End of 
treatment  

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
25 
 
Post Transplant  
Day 
  
+3 
+4 
+5 
+14 
+28 
+56 
+84 
+100 
+112 
+140 
+168 
+180 
+365 
  
PET/CT or CT 
(Lymphoma)7 
X 
  
  
  
  
  
  
  
X10 
  
  
  
 
 
 
Serum/Urine 
Protein 
Electrophoresis 
(MM)7 
X 
  
  
  
  
  
  
  
 X10 
 
  
  
  
X 
X 
Free Light Chains 
(MM)7 
X 
  
  
  
  
  
  
  
X10  
 
  
  
  
X 
X 
Laboratory 
Procedures  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC7 
X 
  
  
x  
x  
x  
x  
 x 
x  
X 
x  
x  
x  
X 
X 
PT7 
X 
  
  
 
 
 
  
  
 
 
 
  
 
 
 
PTT7 
X 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
CMP7 
X 
  
  
x  
x  
x  
 x 
 x 
x  
X 
x  
x  
x  
X 
X 
Quantiferon 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CMV, EBV, and 
adenovirus PCR 
post-
transplantation7  
 
 
 
 
 
X 
  
  
X  
 
 
 
 
 
 
Immunogenicity 
samples5 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Research labs 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Chimerism11 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Study 
Assessments  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Events 
  
  
  
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 
X 
Mini-Mental Status 
Exam7 
X 
  
  
  
  
 
 
  
X 
 
 
 
X 
X 
X 
 
 
Blood samples 
1. 2 baseline blood samples at different timepoints from donor preferably prior to mobilization but ok during mobilization and at collection 
2. 2 baseline blood samples at different timepoints from recipient prior to conditioning 
3. Post-transplant blood samples from recipient at days +28, +100, +180 (+/- 7 days) and 1 year  (+/- 14 days) 
4. Blood samples to be checked if disease relapse 
5. Sent to central lab, collected at screening, days +28, +56, +84, +112, +140, +168 (all timepoints +/- 7 days)  
6. Beginning on Day +28, Abatacept may be administered within +/- 3 day window 
7. Beginning on Day +28, procedures may be performed within +/- 7 day window 
8. Dosing weight for the first two doses of Abatacept (Days +5 & +14) may be taken within -1 day window. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
26 
 
9. Vital signs to be collected as clinically indicated during Abatacept administration. Vital signs include heart rate, blood pressure, 
respiratory rate, and temperature.   
10. The window for the first post-transplant assessment is between Day +60 and Day +120 
11. The window for chimerism is +/- 10 days 
12. The window for 1 year and End of treatment visits is +/- 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
27 
 
 
7.0 
Measurement of Effect 
Acute GVHD will be diagnosed and graded according to the Glucksberg Criteria [50]. (Appendix 
II) 
 
Chronic GVHD will be diagnosed and staged according to the previously published and widely 
accepted National Institutes of Health consensus criteria [49] (Appendix I) 
 
The day of neutrophil engraftment is defined as the first day of three consecutive lab values on 
different days, after the conditioning regimen induced nadir of blood counts that the absolute 
neutrophil count is ≥ 500/microL. The day of platelet engraftment is defined as the first day of three 
consecutive lab values on different days, after the conditioning regimen induced nadir of blood 
counts that the platelet count is ≥ 20,000/microL without platelet transfusion support in the seven 
days prior. Chimerism will also be measured on Days +28, +100 and +180. Donor engraftment is 
defined as presence of both donor and platelet engraftment.  
 
Recurrent malignancy will be defined by standard disease specific criteria and it is recommended 
to be proven by biopsy (bone marrow for leukemia/ myeloma, lymph node for lymphoma).  
Event free survival is defined as survival in the absence of recurrent malignancy. 
 
Transplant related mortality is defined as death in the absence of recurrent malignancy. 
 
7.1 
Safety/tolerability 
Analyses will be performed for all patients after the initiation of the conditioning regimen. The 
study will use the CTCAE version 5.0 for reporting of adverse events 
http://ctep.cancer.gov/reporting/ctc.html) (Appendix IV). 
8.0 
ADVERSE EVENTS:  DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 
Definitions 
Definition of Adverse Event (AE): Any untoward medical occurrence or worsening of a preexisting 
medical condition associated with the use of a drug in humans, whether or not considered drug 
related. Therefore, an AE can be ANY unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE.  

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
28 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
• 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] 
as part of an annual reporting requirement.  
• 
Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. All 
non-serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 30 days following the last dose of 
study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as 
such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
Potential Drug Induced Liver Injury (DILI)  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as:  

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
29 
 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
8.1.1 Unanticipated Problems: An unanticipated problem involving risk to subjects or others 
(UP) is defined as any unexpected incident, event, or problem that is related or possibly related to 
the research and poses greater risk of harm than was previously known to an individual or group 
of individuals (including research subjects, research staff, or others not directly involved in the 
research). 
 
Examples of Unancipated Problems may include: 
• Adverse Events 
• Subject complaints 
• Medication or device errors 
• Other errors in the conduct of the research 
• Protocol deviations or violations 
• Protocol exceptions (changes made to the research without prior approval in order to eliminate 
apparent immediate harm to subjects) 
• Breach of confidentiality 
• Billing problems that pose unanticipated financial risk to subjects 
8.1.2 Serious Adverse Event (SAE):  Any adverse event that results in ANY of the following 
outcomes: 
1) 
Death 
2) 
A life-threatening adverse drug experience 
3) 
Inpatient hospitalization or prolongation of existing hospitalization (for >24 hours). (see 
NOTE below) 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
5) 
A congenital anomaly/birth defect 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
7) 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
30 
 
 
The following hospitalizations are not considered SAEs:  
- 
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
- 
elective surgery, planned prior to signing consent 
- 
admissions as per protocol for a planned medical/surgical procedure 
- 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
- 
Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases. 
- 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
- 
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
 
8.1.3 
Severity vs. Seriousness:  Severity is not synonymous with seriousness. SAE is 
based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. SAEs need to fulfill additional reporting process (reported to 
corporate global drug safety group or pharmacovigilence group, regulatory authorities, IRBs).  On 
the other hand, Severity of an AE is a point on a scale of intensity of the adverse event in 
question. See Section 8.3 below for the severity grading system.  
Pregnancy:   
 
If, following initiation of abatacept, it is subsequently discovered that a study participant is 
pregnant or may have been pregnant at the time of the abatacept exposure, including during at 
least 5 half-lives after abatacept administration, abatacept will be permanently discontinued.  
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either the 
CIOMS, MedWatch, or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures.   
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.   
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the CIOMS, 
MedWatch or appropriate Pregnancy Surveillance Form.  A BMS Pregnancy Surveillance Form 
may be provided upon request.  
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS.  Information on this pregnancy will be collected on the Pregnancy Surveillance Form.  In 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
31 
 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must give written permission for disclosure of this information.  
 
8.1.4 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
8.1.5 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
X-rays, and any other potential safety assessments, whether or not these procedures are 
required by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, 
and reported accordingly.  
 
8.2 
Data Collection procedures for adverse events 
The principal investigator is responsible for evaluating all adverse events, obtaining 
supporting documents, and determining that documentation of the event is adequate. 
He/she is responsible for determining the seriousness, severity, and relationship of the 
adverse event to the investigational drug. The principal investigator may delegate these 
duties to sub-investigators and must assure that these sub-investigators are qualified to 
perform these duties under the supervision of the principal investigator. All adverse 
events will be documented in the subject’s source and recorded on Case Report Form(s).  
 
The term of the adverse event should reflect the diagnosis rather than its symptoms, 
when available.  In the event of death, the cause of death should be recorded as the 
adverse event. The detailed description of the event will include appropriately graded 
severity of the adverse event and its relationship to the study drug. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE.  
 
Events that do not meet the definition of an AE include: 
 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.  
• 
The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
32 
 
8.3 
Grading and Attribution 
Grading (severity grading):  Terminology Criteria for Adverse Events will be evaluated 
using the following criteria (The NCI Common Toxicity Criteria, Version 4.0 shall be 
used):  
 
 
• 
Grade 1 - Mild: Awareness of symptom, but easily tolerated; usually transient 
requiring no special treatment; does not interfere with usual status or activities  
• 
Grade 2 – Moderate:  May be ameliorated by simple therapeutic measures; may 
interfere with usual activities  
 
• 
Grade 3 – Severe:  Incapacitating, inability to perform usual activities  
 
• 
Grade 4 – Life-threatening/Disabling: Subject was at risk of death or significant 
disability at the time of the event  
• 
Grade 5 – Death related to AE 
 
Attribution is an assessment of the relationship between the AE/SAE and the medical 
intervention. Although all of the drugs used in this study have been used in man before, 
this combination of drugs has not, therefore the phase 1 study is considered a “first in 
human” study and therefore all adverse events should be considered relevant to 
determining dose-limiting toxicities and to reporting unless the event can clearly 
be determined to be unrelated to the study drug.  Relationship of the adverse event to 
the investigational drug will be determined by the principal investigator, or qualified 
designee, and will be categorized as:  
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention1 
Unrelated 
The AE is clearly 
NOT related to the 
intervention 
Unlikely 
The AE is 
doubtfully related 
to the intervention 
Related to 
investigational 
agent/intervention1 
Possible 
The AE may be 
related to the 
intervention 
Probable 
The AE is likely 
related to the 
intervention 
Definite 
The AE is clearly 
related to the 
intervention 
1NOTE: AEs listed as possibly, probably, or definitely related to the investigational 
agent/intervention are considered to have a suspected reasonable causal relationship to the 
investigational agent/intervention.  For routine, adverse event reporting purposes, 
“Attribution” defines the relationship between the adverse event and the investigational 
agent(s)/intervention.  Additional Instructions and Guidelines that can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/cdus_ig_3r4.pdf.   
8.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5.0).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5.0. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
33 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
8.5 
Reporting Requirements for Adverse Events 
8.5.1 
Routine Reporting 
All serious adverse events (SAE) regardless of causality must be documented 
according to the table outlined in Section 8.3 
 
 
Contact for Expedited reporting –  
 
Dimitrios Tzachanis, MD PhD 
Tel: 858-822-6600 
Pager: 619-290-8792 
 
 
 
 
Email: dtzachanis@ucsd.edu 
 
Divya Koura, MD 
Tel: 858-822-6600 
Pager: 619-290-8079 
Email: dkoura@ucsd.edu 
 
 
Serious adverse events, occurring after the informed consent is signed but prior 
to the initial dose of abatacept will be collected as part of the subject’s medical 
history/baseline symptoms but will only be reportable if they are considered by 
the Investigator to be causally related to required research procedures.  Non-
serious adverse events (AEs) and serious adverse events (SAEs) will be 
collected throughout the treatment period maintenance phase and for 30 days 
after discontinuing abatacept or if otherwise classified as possibly related to 
study intervention.  Events occurring during this period must be followed until 
resolution or death unless in the Investigator’s opinion, the condition is unlikely to 
resolve due to the patient’s underlying disease. SAEs must be reported to 
oversight agencies as described below 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
34 
 
8.5.2 
Reporting to the FDA 
8.5.3 
Reporting to the IRB 
 
The Principal Investigator must be notified within 24 hours of learning of any serious adverse 
events, regardless of attribution, occurring during the study or within 30 days of the last 
administration of the study drug. Serious Adverse Event (SAE) reporting will be in accordance 
with the UCSD IRB Regulations and Code of Federal Regulation Title 21 Volume 5 Part 312.32.   
MedWatch forms will be utilized for reporting purposes.  For a copy of the form, go to 
http://www.fda.gov/medwatch/getforms.htm. 
 
All SAEs from outside institutions must be reported to: 
UCSD BMT Clinical Trials Office 
3855 Health Science Drive MC0698 
La Jolla, CA, 92093 
Phone: 858-822-6390/6396/6397 
Fax 858-822-6398 
within 24 hours of learning of its occurrence, even if it is not felt to be treatment related.  Follow-
up information about a previously reported SAE must be sent to the UCSD BMT Clinical Trials 
Office as soon as complete details of the SAE are known. 
 
If the SAE is death, and is determined to be possibly, probably or definitely related to the 
investigational drug or any research related procedure, the event must be reported to the UCSD 
DSMB Chair by the UCSD Clinical Trials Office within 24 business hours.  The reporting 
procedure is by personal communication via phone or with written documentation of the one to 
one communication via e-mail, with a copy of the e-mail to DSMB Administrator and DSMB 
Coordinator.   
 
Follow-up data should describe whether the event has resolved or continues, if and how it was 
treated, and whether the patient continued or discontinued study participation. 
 
The UCSD Human Research Protections Program (HRPP) must be notified within 10 business 
days of “any unanticipated problems involving risk to subjects or others” (UPR). 
 
The following events meet the definition of UPR: 
1. 
Any serious event (injuries, side effects, deaths or other problems), which in the opinion 
of the Principal Investigator was unanticipated, involved risk to subjects or others, and was 
possibly related to the research procedures. 
2. 
Any serious accidental or unintentional change to the IRB-approved protocol that alters 
the level of risk. 
3. 
Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject. 
4. 
Any new information (e.g., publication, safety monitoring report, updated sponsor safety 
report), interim result or other finding that indicates an unexpected change to the risk/benefit ratio 
for the research. 
5. 
Any breach in confidentiality that may involve risk to the subject or others. 
6. 
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved 
by the Principal Investigator. 
 
Routine Reporting 
 
The UCSD HRPP will be notified of any adverse events that are not unanticipated problems 
involving risk to subjects or others (non-UPRs) at the time of the annual Continuing Review. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
35 
 
8.5.4 
Reporting by and to the Drug Manufacturer 
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate 
in the study through 30* days of discontinuation of dosing must be reported to BMS Worldwide 
Safety, whether related or not related to study drug. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, are collected, including those thought to be associated with protocol-specified 
procedures. The investigator should report any SAE occurring after these aforementioned time 
periods, which is believed to be related to study drug or protocol-specified procedure. 
• 
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
• 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
• 
If the BMS safety address is not included in the protocol document (eg, multicenter studies where 
events are reported centrally), the procedure for safety reporting must be reviewed/approved by the 
BMS Protocol Manager. Procedures for such reporting must be reviewed and approved by BMS 
prior to study activation. 
• 
An appropriate SAE form (USA = Medwatch form) should be used to report SAEs to BMS . The 
BMS protocol ID number must be included on whatever form is submitted by the 
Sponsor/Investigator.  
o 
The MedWatch form is available at: 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pd
f 
• 
For studies with long-term follow-up periods in which safety data are being reported, include the 
timing of SAE collection.  
• 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms).  
o 
Frequency of reconciliation should be every 3 months and prior to the database lock or 
final data summary.  
o 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation 
report.  
o 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data 
elements listed on the GPV&E reconciliation report will be used for case identification 
purposes.  
If the Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS. 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously described in 
the IB). An event meeting these criteria is termed a Suspected, Unexpected Serious Adverse 
Reaction (SUSAR). Investigator notification of these events will be in the form of a SUSAR Report.  
o 
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of efficacy 
that poses significant hazard to study subjects, clinically significant safety finding from a 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
36 
 
nonclinical (eg, animal) study, important safety recommendations from a study data monitoring 
committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. 
o 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 
sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.  
o 
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
• 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on eMedWatch form & pregnancies must be reported on 
a Pregnancy Surveillance Form or can be submitted on the aforementioned SAE form to BMS. 
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports 
should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) using the same 
procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/.  The website will instruct you 
where to send the SAE forms. 
 
9.0 
DRUG INFORMATION 
9.1 
Abatacept 
9.1.1 
Abatacept Description 
ORENCIA (abatacept) is a soluble fusion protein that consists of the extracellular domain 
of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified 
Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). 
Abatacept is produced by recombinant DNA technology in a mammalian cell expression 
system. The apparent molecular weight of abatacept is 92 kilodaltons. 
ORENCIA is supplied as a sterile, white, preservative-free, lyophilized powder for 
parenteral administration. Following reconstitution with 10 mL of Sterile Water for 
Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH 
range of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept, 500 
mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium chloride for 
administration. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
37 
 
9.1.2 
CLINICAL PHARMACOLOGY 
Mechanism of Action  
Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by 
binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction 
provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T 
lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of 
patients with RA. In vitro, abatacept decreases T cell proliferation and inhibits the 
production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat 
collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-
collagen antibody production, and reduces antigen specific production of interferon-γ. The 
relationship of these biological response markers to the mechanisms by which ORENCIA 
exerts its effects in RA is unknown. 
 
Pharmacodynamics 
 
In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed 
in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid 
factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The 
relationship of these biological response markers to the mechanisms by which ORENCIA 
exerts its effects in RA is unknown. 
 
Pharmacokinetics and Drug Metabolism 
 
Healthy Adults and Adult RA The pharmacokinetics of abatacept were studied in healthy 
adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 
10 mg/kg intravenous infusions (see Table 3). 
 
 
The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be 
comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of 
abatacept showed proportional increases of Cmax and AUC over the dose range of 2 
mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by 
day 60 with a mean (range) trough concentration of 24 (1 to 66) mcg/mL. No systemic 
accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at 
monthly intervals in RA patients. 
Population pharmacokinetic analyses in RA patients revealed that there was a trend toward 
higher clearance of abatacept with increasing body weight. Age and gender (when 
corrected for body weight) did not affect clearance. Concomitant MTX, NSAIDs, 
corticosteroids, and TNF blocking agents did not influence abatacept clearance. 
No formal studies were conducted to examine the effects of either renal or hepatic 
impairment on the pharmacokinetics of abatacept. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
38 
 
 
Juvenile Idiopathic Arthritis 
In patients 6 to 17 years of age, the mean (range) steady-state serum peak and trough 
concentrations of abatacept were 217 (57 to 700) and 11.9 (0.15 to 44.6) mcg/mL. 
Population pharmacokinetic analyses of the serum concentration data showed that 
clearance of abatacept increased with baseline body weight. The estimated mean (range) 
clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 (0.20 to 1.12) 
mL/h/kg. After accounting for the effect of body weight, the clearance of abatacept was not 
related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were 
also shown not to influence abatacept clearance. 
 
9.1.3 
Dosage form 
 
Commercial marketed formulation will be provided  
9.1.4 
Preparation and Administration Instructions 
 
For detailed preparation and administration instructions please refer to the most current 
Investigator’s Brochure version. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
This is a prospective, randomized phase 2 trial of the safety and efficacy of high dose 
cyclophosphamide and abatacept vs. standard of care GVHD prophylaxis. The study will enroll 50 
patients with hematologic malignancy who are eligible for allogeneic peripheral blood stem cell 
transplant (PBSCT) following conditioning with Busulfan and Fludarabine (or a TBI based regimen 
for ALL) from a matched related donor (MRD) or matched unrelated donor (MUD). 
 
On December 15 2021 the FDA approved abatacept for GVHD prophylaxis (in combination with 
Methotrexate and a CNI). Given that the SOC for GVHD prophylaxis changed, we’ve decided to 
stop enrolling in the SOC arm but complete enrollment in the experimental arm. 
 
Starting with Amendment 8 all patient will be enrolled in the experimental arm. 
 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
 
Compared to the standard-of-care control arm, the experimental arm is a Calcineurin inhibitor-free 
graft-versus-host disease prophylaxis regimen that is much more convenient for patient care. 
Besides convenience, the experimental arm is expected to have lower chronic GVHD incidence, 
fewer toxicities such as renal insufficiency, electrolyte abnormalities and mainly hypokalemia and 
hypomagnesemia requiring oral and frequent IV repletion and CNS toxicity.  It is expected that 
disease relapse will be unaffected by this new regimen, compared to standard of care. 
 
10.2 
STATISTICAL HYPOTHESES 
 
The primary hypothesis is that post transplantation cyclophosphamide + abatacept will reduce the 
risk of moderate and severe chronic GVHD by one year compared to standard of care GVHD 
prophylaxis with methotrexate and CNI. 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
39 
 
  
In addition, there is a key secondary hypothesis: 
 
High dose cyclophosphamide and abatacept will not significantly lower the GVHD- and-relapse 
free survival rate at one year post transplant. Due to sample size limitations, this will be assessed 
as a secondary endpoint of major interest, using descriptive statistics. 
 
Additional secondary hypotheses are that the overall safety profile of cyclophosphamide + 
abatacept will be favorable compared to standard of care GVHD prophylaxis with methotrexate 
and CNI. 
 
10.3 
10.3 
ANALYSIS DATASETS 
 
For intent-to-treat analysis, all patients who are randomized will be used in comparisons. Please 
refer to section 10.6 for details on randomization. For as-treated analysis, analysis data sets will 
be limited only to the experimental arm patients who have had at least one dose of abatacept and 
the control arm patients who have stayed on treatment for at least 5 days post transplant.  
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
 
The proportion of subjects experiencing adverse events, serious adverse events, and treatment 
delays/modifications will be summarized by arm, disease type and donor type.  
Event rates and survival rates at one year will be estimated by arm and 95% confidence intervals 
will be presented per arm. Competeing risks will be treated as censoring events when estimating 
cause-specific hazard rates.  To compare two arms, a Mantel-Haenszel test or Cox regression will 
be used for a proportion, treating competeing risks as censoring events; in case of rare cell 
frequencies, a stratified Fisher’s exact test may be used instead. A  log rank test will be used to 
compare a survival outcome between the two arms. Test for homogeneity among strata will be 
performed using a logrank test; if there is a significant difference among the strata, a stratified 
logrank test will be used to compare treatment vs. control; otherwise a non-stratified logrank test 
will be performed to compare the two arms.  Logistic regression models, multiple linear models or 
Cox models will be used if there is need to adjust for covariates.  Cumulative incidence curves for 
of relapse, non-relapse mortality, and GVHD will also be estimated and tested for significant 
differences using Gray's test.  
Unless otherwise indicated, all tests will be two-sided at the 5% significance level.   
 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
The primary endpoint is the occurrence of moderate and severe chronic GVHD by one year post-
transplant. A Mantel-Haenszel test will be used to compare chronic GVHD risk between the two 
arms while taking into account the two stratification factors: conditioning regimen (MA vs RIC) 
and donor type (MRD vs MUD), using a two-sided test at the 5% significance level. In this 
analysis, competing risks will be treated as censoring events, including non-relapse mortality and 
relapse.  This approach, which is equivalent to testing for a change in the hazard ratio in a 
stratified Cox regression model,  will test for an change in the cause-specific hazard ratio  for 
GVHD, as suggested by Pintle (2002) and in Kalbfliesch and Prentice (2002; Ch 8 p 257 and 
example 8.2)  
 
10.4.3 ANALYSIS OF SECONDARY EFFICACY  ENDPOINTS 
The key secondary endpoint is GVHD- and relapse-free survival (GRFS i.e. free from acute 
GVHD Grade III or IV, and from moderate or severe chronic GVHD, and from relapse or non-

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
40 
 
relapse mortality and CRFS, i.e. free from chronic GVHD, relapse and non-relapse mortality) by 
one year post-transplant. A stratified Cox proportional hazard model will be used to compare 
survival curves over time and estimate a two-sided  95% confidence interval for the hazard ratio 
of treatment vs. control [52].  Stratified Cox models will first be built to stratify on conditioning 
regimen and donor types. A test for homogeneity among strata will be performed using a logrank 
test. If there is not a significant difference among the strata, a non-stratified Cox model will be 
used to increase power [53] The proportional hazard assumption will be assessed based on 
weighted residuals [54].  
 
We will also test for any change in the cause-specific hazard ratio for relapse or non-relapse 
mortality, using the same approach as above.  Cumulative incidence funcitons for GVHD, 
relapse, and non-relapse mortality will also be displayed, and tested for significant differences 
using Gray’s test. 
 
Please refer to section 10.4.1 for more details about the analysis for other secondary endpoints. 
 
10.4.4 SAFETY ANALYSES 
Toxicities and adverse events will be summarized by arm, disease type and donor type. Their 
grade, relationship with the treatment, and severity will be listed.  Treatment delays/modifications 
will also be reported. 
 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
Patients who drop out of the study early will be reported; their follow-up time will be calculated 
and early dropouts reasons will be listed.   
 
10.4.6 BASELINE DESCRIPTIVE STATISTICS 
Baseline characteristics will be compared between the two arms to see if the randomization is 
successful. 
 
10.4.7 SAFETY STOPPING RULES 
There will be a continuously monitored safety stopping rule applied to deaths related to the 
experimental treatment (cyclophosphamide and abatacept). .  The rule uses an exact sequential 
Pockock boundary [60].  It will be applied sequentially as subjects enroll in the experimental arm of 
the study.   The stopping rule will be assessed after each subject has passed 100 days post-
transplant. We assume UCSD experience is a ~20% transplant related mortality at 1 year, occurring 
with uniform hazard rate over the year; this translates to approximately 7% morality by 100 days.  
The stopping rule is designed to stop early with probability 60% if 100-day experimental treatment 
related mortality is 10% or higher.   
 
 
 
The trial will be stopped if the number of treatment related deaths is equal to or exceeds bn out 
of n patients with completed follow-up. 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
1 1 1 1 1 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
3 3 3 4 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
41 
 
 
After each patient on the experimental arm reaches 100 days on post-transplant, data will be 
updated in the study database and a formal report will be issued documenting the status of the 
stopping rule.  Enrollment will be suspended during the time period that the stopping rule is being 
updated (between day 100 and issuance of the report).  If the number of experimental treatment 
related deaths bn out of the first n enrolled patients exceeds the number in the table above, the 
study will be halted due to safety concerns. 
 
The operating characteristics of the stopping rule are given below, where  
Θ = the mortality rate 
Y = the number of deaths  
N = the number of patients enrolled prior to stopping 
φ* = the actual probability of early stopping (hitting the boundary) 
E[ ] denotes the expected value (mean) 
SD[ ] denotes the standard deviation 
 
θ 
φ* 
E[Y] 
SD[Y] 
E[N] 
SD[N] 
0.10 
0.5987 
1.39 
0.77 
13.94 
10.29 
0.20 
0.9233 
1.41 
0.68 
7.04 
7.49 
0.30 
0.9919 
1.20 
0.49 
4.02 
4.45 
0.40 
0.9995 
1.09 
0.31 
2.71 
2.65 
 
 
In addition to this formal rule focused on early mortality events, the Moores Cancer Center DSMC 
will review this study twice per year. In addition to the usual summary of adverse events, the DSMC 
report will include comparative cumulative incidence curves of treatment related mortality and of 
aGVHC (grade III and IV), compared between treatment and control arms.  Non-treatment related 
mortality and death from any cause will be considered competing events, respectively, in these 
analyses.   The DSMC will consider these curves in their decision whether to continue the study.  
 
[35, 36, 55, 56]. 
 
10.4.8 SAFETY REVIEW 
Safety data will be summarized and sent to the team for review every other month. The study 
may be stopped early due to excessive or unexpected number of serious adverse events.  
  
 
10.4.9 ADDITIONAL SUB-GROUP ANALYSES 
Additional subgroup analyses may be considered such as patients with good adherence; however 
these will be considered exploratory.  
10.4.10 MULTIPLE COMPARISON/MULTIPLICITY 
There is only one primary endpoint for this study. All the results from secondary endpoints will be 
considered exploratory. Thus, no adjustment will be done for multiple testing.  
 
10.4.11 TABULATION OF INDIVIDUAL RESPONSE DATA 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
42 
 
10.4.12 EXPLORATORY ANALYSES 
Advanced statistical modeling techniques including logistic regression models, multiple linear 
models or Cox models may be applied in exploratory analyses where the stratification factors will 
be adjusted.  
 
10.5 
SAMPLE SIZE AND POWER 
 
 Considering the comparison of the primary endpoint between the two arms ( occurrence of 
moderate and severe chronic GVHD by one year post transplant), with 25 patients per arm, at a 
type I error rate of 0.05, using a two-sided test on the treatment effect from Cox regression, and 
assuming that all strata have similar odds ratios, we will have 82% power to detect a significant 
difference if the incidence is 10% in the experimental arm and 50% in the control arm, and the 
incidence of competing risk from non-relapse mortality or relapse is 20% in each arm. Based on 
data observed from published studies [57,58, 59] without or with the use of Abatacept, we believe 
these incidence estimates are feasible for this study. This computation was done using the 
approach in Pintilie (2002). 
 
Considering confidence intervals for the hazard rate of the key secondary endpoint, note that we 
expect to see on the order of 10 events in the control arm, with hazard rates in the range of 0.6 to 
0.8.  In this range of values, the width of an two sided 95% confidence interval ranges from about 
0.7 to 1.0.  While these are wide confidence intervals, they should provide a reasonable 
preliminary estimate of the comparability of the two approaches.  In summary, while we 
acknowledge the limitations of the small proposed sample size,  we feel that useful information 
will be gained. 
 
These power calculations were done in PASS 14 (version 14.0.3)s[57]. 
 
On December 15 2021 the FDA approved abatacept for GVHD prophylaxis (in combination with 
Methotrexate and a CNI). Given that the SOC for GVHD prophylaxis changed, we’ve decided to 
stop enrolling in the SOC arm but complete enrollment in the experimental arm. 
 
Starting with Amendment 8 all patient will be enrolled in the experimental arm. 
 
New Power Analysis 
 
Power analysis will utilize the Fisher exact test with a 2-sided 0.05 significance level. 
Primary outcome: occurrence of moderate and severe chronic GVHD by 1 year post transplant. 
Note: Because this is a Phase II trial, the 2-sided significance level could be 0.10 or 0.20. 
 
 
Original Power for comparing event rates of 10% in ABA versus 50% in SOC with 25 in each 
arm, using the Fisher exact test: Power = 82.9% (0.829).  I will use the Fisher approach below. 
 
New Power for the same event rate comparison (10% v 50%) 
Allowing the sample size in ABA to increase, starting at N = 25  
(holding constant N = 15 in SOC) 
N in ABA N in SOC Power 
25 
15 
0.684 
30 
15 
0.723 
35 
15 
0.751 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
43 
 
40 
15 
0.773 
45 
15 
0.790 
50 
15 
0.803 
 
 
 
We’ll plan on enrolling a total of 25 patient on the experimental arm. We have already enrolled 15 patients 
on the SOC arm. 
 
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
We expected to accrue all the 50 patients within a year at UCSD. All the patients will be followed 
for one year after transplant. The total duration of this study will be about two years.  
 
Stratified randomization using permuted blocks of size 4 will be performed to randomize 
participants to the experimental or control arm. There are two stratification factors: conditioning 
regimen (MA vs RIC) and donor type (MRD vs MUD). Randomization will be performed prior to 
the use of any study related drug which includes the conditioning therapy to be used for the 
control arm.  
 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must  disclose 
the conflict to the IRB and in the subject’s informed consent form.  All investigators will 
follow the Institutional conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Once 
this essential information has been provided to the patient and the investigator is assured 
that the patient understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing an IRB-approved consent form. 
 
11.2 
Data Management and Monitoring/Auditing 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
44 
 
11.3 
Data Safety Monitoring 
 
Safety data will be summarized and sent to the team for review bi-monthly. The study 
may be stopped early due to excessive or unexpected number of serious adverse events.  
 
In addition to adverse event monitoring and clinical oversight by the Study Chair, site 
principal investigator and co-investigators, quality assurance of the study will be 
performed by the UCSD Moores Cancer Center Clinical Trials Office internal monitor. 
Monitoring intervals will be every 6 months.   
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring 
Board (DSMB) to provide oversight in the event that this treatment approach leads to 
unforeseen toxicities. Data from this study will be reported annually and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the date of first and most recent patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study. 
11.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
11.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form 
must be completed within five (5) business days of making the change.  
11.4.2 Protocol Exceptions 
Planned exceptions to the protocol that are more than logistical (e.g., minor 
changes to the study schedule for an individual subject)and/or have the potential 
to affect the subject’s safety or study integrity may not be implemented without 
prior approval from the IRB. In this case, the PI should submit a Protocol 
Exception request. 
11.4.3 Other Protocol Deviations/Violations 
 
Logistical deviations from the protocol (e.g., minor changes to the study schedule 
for an individual subject) do not require prior IRB approval unless the deviation 
has the potential to affect the subject’s safety. Such planned deviations that do 
not affect the subject’s safety should be noted in the subject’s research record. 
 
Unintentional deviations from the protocol that might affect subject safety or 
study integrity should be reported to the IRB within 10 days from when the 
investigator becomes aware that such a deviation has occurred. In this case, a 
Protocol Deviation report must be submitted to the IRB. 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
45 
 
All submissions should include a description of the plan to avoid similar 
deviations in the future. 
 
11.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
46 
 
12.0 
REFERENCES 
  
 
1. 
Appleman, L.J., et al., Induction of immunologic tolerance for allogeneic hematopoietic 
cell transplantation. Leuk Lymphoma, 2002. 43(6): p. 1159-67. 
2. 
Ram, R., et al., Prophylaxis regimens for GVHD: systematic review and meta-analysis. 
Bone Marrow Transplant, 2009. 43(8): p. 643-53. 
3. 
Li, Y., et al., Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis 
of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med, 1999. 
5(11): p. 1298-302. 
4. 
Jenkins, M.K., R.H. Schwartz, and D.M. Pardoll, Effects of cyclosporine A on T cell 
development and clonal deletion. Science, 1988. 241(4873): p. 1655-8. 
5. 
Luznik, L., R.J. Jones, and E.J. Fuchs, High-dose cyclophosphamide for graft-versus-host 
disease prevention. Curr Opin Hematol, 2010. 17(6): p. 493-9. 
6. 
Luznik, L., et al., High-dose cyclophosphamide as single-agent, short-course prophylaxis 
of graft-versus-host disease. Blood, 2010. 115(16): p. 3224-30. 
7. 
Durakovic, N., et al., Secondary Systemic Immunosuppressants (SSI) After Myeloablative 
HLA Matched Related And Unrelated Bone Marrow Transplantation (BMT) Using High 
Dose Cyclophosphamide (HiCy) As Sole GVHD Prophylaxis. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation, 2010. 16(2): p. S161-S162. 
8. 
Jones, R.J., et al., Assessment of aldehyde dehydrogenase in viable cells. Blood, 1995. 
85(10): p. 2742-6. 
9. 
Tzachanis, D., et al., Intrinsic and extrinsic regulation of T lymphocyte quiescence. Leuk 
Lymphoma, 2004. 45(10): p. 1959-67. 
10. 
Kuklina, E.M., Molecular mechanisms of T-cell anergy. Biochemistry (Mosc), 2013. 
78(2): p. 144-56. 
11. 
Nguyen, V.H., et al., The impact of regulatory T cells on T-cell immunity following 
hematopoietic cell transplantation. Blood, 2008. 111(2): p. 945-53. 
12. 
Jones, S.C., G.F. Murphy, and R. Korngold, Post-hematopoietic cell transplantation 
control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-
versus-leukemia response. Biol Blood Marrow Transplant, 2003. 9(4): p. 243-56. 
13. 
Di Ianni, M., et al., Tregs prevent GVHD and promote immune reconstitution in HLA-
haploidentical transplantation. Blood, 2011. 117(14): p. 3921-8. 
14. 
Di Ianni, M., et al., Immunoselection and clinical use of T regulatory cells in HLA-
haploidentical stem cell transplantation. Best Pract Res Clin Haematol, 2011. 24(3): p. 
459-66. 
15. 
Guinan, E.C., et al., Transplantation of anergic histoincompatible bone marrow 
allografts. N Engl J Med, 1999. 340(22): p. 1704-14. 
16. 
Davies, J.K., et al., Outcome of alloanergized haploidentical bone marrow 
transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies. Blood, 
2008. 112(6): p. 2232-41. 
17. 
Larsen, C.P., et al., Rational development of LEA29Y (belatacept), a high-affinity variant 
of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant, 2005. 5(3): p. 
443-53. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
47 
 
18. 
Tzachanis, D., et al., Blockade of B7/CD28 in mixed lymphocyte reaction cultures results 
in the generation of alternatively activated macrophages, which suppress T-cell 
responses. Blood, 2002. 99(4): p. 1465-73. 
19. 
Mellor, A.L. and D.H. Munn, IDO expression by dendritic cells: tolerance and 
tryptophan catabolism. Nat Rev Immunol, 2004. 4(10): p. 762-74. 
20. 
Vincenti, F., et al., Three-year outcomes from BENEFIT, a randomized, active-
controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant, 
2012. 12(1): p. 210-7. 
21. 
Larsen, C.P., et al., Belatacept-based regimens versus a cyclosporine A-based regimen in 
kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT 
studies. Transplantation, 2010. 90(12): p. 1528-35. 
22. 
Vincenti, F., et al., A phase III study of belatacept-based immunosuppression regimens 
versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant, 
2010. 10(3): p. 535-46. 
23. 
Durrbach, A., et al., A phase III study of belatacept versus cyclosporine in kidney 
transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant, 
2010. 10(3): p. 547-57. 
24. 
Furuzawa-Carballeda, J., et al., Infiltrating cellular pattern in kidney graft biopsies 
translates into forkhead box protein 3 up-regulation and p16INK4alpha senescence 
protein down-regulation in patients treated with belatacept compared to cyclosporin A. 
Clin Exp Immunol, 2012. 167(2): p. 330-7. 
25. 
Charpentier, B., Belatacept: a novel immunosuppressive agent for kidney transplant 
recipients. Expert Rev Clin Immunol, 2012. 8(8): p. 719-28. 
26. 
Bestard, O., et al., Costimulatory blockade with mTor inhibition abrogates effector T-cell 
responses allowing regulatory T-cell survival in renal transplantation. Transpl Int, 2011. 
24(5): p. 451-60. 
27. 
Fuchs, E.J., Haploidentical transplantation for hematologic malignancies: where do we 
stand? Hematology Am Soc Hematol Educ Program, 2012. 2012: p. 230-6. 
28. 
Furst, D.E., et al., Updated consensus statement on biological agents for the treatment of 
rheumatic diseases, 2012. Ann Rheum Dis, 2013. 72 Suppl 2: p. ii2-34. 
29. 
Orban, T., et al., Co-stimulation modulation with abatacept in patients with recent-onset 
type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet, 2011. 
378(9789): p. 412-9. 
30. 
Schiff, M., et al., Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a 
phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients 
with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis, 
2008. 67(8): p. 1096-103. 
31. 
Koura, D.T., et al., In Vivo T Cell Costimulation Blockade with Abatacept for Acute 
Graft-versus-Host Disease Prevention: A First-in-Disease Trial. Biol Blood Marrow 
Transplant, 2013. 19(11): p. 1638-49. 
32. 
Nahas, M.R., et al., Phase I clinical trial evaluating abatacept in patients with steroid-
refractory chronic graft-versus-host disease. Blood, 2018. 
33. 
Jaiswal, S.R., et al., T cell costimulation blockade promotes transplantation tolerance in 
combination with sirolimus and post-transplantation cyclophosphamide for 
haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol, 
2017. 43-44: p. 54-59. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
48 
 
34. 
Blaise, D. and L. Castagna, Do different conditioning regimens really make a difference? 
Hematology Am Soc Hematol Educ Program, 2012. 2012: p. 237-45. 
35. 
de Lima, M., et al., Once-daily intravenous busulfan and fludarabine: clinical and 
pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for 
allogeneic stem cell transplantation in AML and MDS. Blood, 2004. 104(3): p. 857-64. 
36. 
Andersson, B.S., et al., Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares 
favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant 
conditioning therapy in AML/MDS. Biol Blood Marrow Transplant, 2008. 14(6): p. 672-
84. 
37. 
Alatrash, G., et al., Myeloablative reduced-toxicity i.v. busulfan-fludarabine and 
allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or 
myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow 
Transplant, 2011. 17(10): p. 1490-6. 
38. 
Khaled, S.K., S.H. Thomas, and S.J. Forman, Allogeneic hematopoietic cell 
transplantation for acute lymphoblastic leukemia in adults. Curr Opin Oncol, 2012. 
24(2): p. 182-90. 
39. 
Appelbaum, F.R., Pursuing the goal of a donor for everyone in need. N Engl J Med, 
2012. 367(16): p. 1555-6. 
40. 
Anasetti, C., et al., Peripheral-blood stem cells versus bone marrow from unrelated 
donors. N Engl J Med, 2012. 367(16): p. 1487-96. 
41. 
Mielcarek, M., et al., Long-term outcomes after transplantation of HLA-identical related 
G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow. Blood, 2012. 
119(11): p. 2675-8. 
42. 
Velardi, A., Natural killer cell alloreactivity 10 years later. Curr Opin Hematol, 2012. 
19(6): p. 421-6. 
43. 
Peng, Y., et al., CD86 is an activation receptor for NK cell cytotoxicity against tumor 
cells. PLoS One, 2013. 8(12): p. e83913. 
44. 
Martin-Fontecha, A., et al., Triggering of murine NK cells by CD40 and CD86 (B7-2). J 
Immunol, 1999. 162(10): p. 5910-6. 
45. 
Jaiswal, S., et al., A Novel Approach Towards Natural Killer Cell Immunotherapy 
Following Haploidentical Transplantation: CTLA4Ig Primed Donor Lymphocyte 
Infusions (DLI). Biology of Blood and Marrow Transplantation. 24(3): p. S76-S77. 
46. 
Paz Morante, M., et al., Activation-associated phenotype of CD3 T cells in acute graft-
versus-host disease. Clin Exp Immunol, 2006. 145(1): p. 36-43. 
47. 
Pieper, J., et al., CTLA4-Ig (abatacept) therapy modulates T cell effector functions in 
autoantibody-positive rheumatoid arthritis patients. BMC Immunol, 2013. 14: p. 34. 
48. 
Imberti, L., et al., Reduced T-cell repertoire restrictions in abatacept-treated rheumatoid 
arthritis patients. J Transl Med, 2015. 13: p. 12. 
49. 
Filipovich, A.H., et al., National Institutes of Health consensus development project on 
criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging 
working group report. Biol Blood Marrow Transplant, 2005. 11(12): p. 945-56. 
50. 
Glucksberg, H., et al., Clinical manifestations of graft-versus-host disease in human 
recipients of marrow from HL-A-matched sibling donors. Transplantation, 1974. 18(4): p. 
295-304. 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
49 
 
51. 
Snyder, D.S., et al., Fractionated total body irradiation and high-dose etoposide as a 
preparatory regimen for bone marrow transplantation for 99 patients with acute 
leukemia in first complete remission. Blood, 1993. 82(9): p. 2920-8. 
52. 
D'Agostino, R.B., Sr., J.M. Massaro, and L.M. Sullivan, Non-inferiority trials: design 
concepts and issues - the encounters of academic consultants in statistics. Stat Med, 
2003. 22(2): p. 169-86. 
53. 
Feng, C., H. Wang, and X.M. Tu, Power Loss of Stratified Log-Rank Test in 
Homogeneous Samples. International Journal of Quality, Statistics, and Reliability, 2010. 
2010: p. 4. 
54. 
Grambsch, P.M. and T.M. Therneau, Proportional hazards tests and diagnostics based 
on weighted residuals. Biometrika, 1994. 81(3): p. 515-526. 
55. 
Lee, J.H., et al., Randomized trial of myeloablative conditioning regimens: busulfan plus 
cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol, 2013. 31(6): p. 701-9. 
56. 
Rambaldi, A., et al., Busulfan plus cyclophosphamide versus busulfan plus fludarabine as 
a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients 
with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. 
Lancet Oncol, 2015. 16(15): p. 1525-1536. 
57. 
PASS 14 Power Analysis and Sample Size Software. NCSS, L.K., Utah, USA, 
ncss.com/software/pass. 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
50 
 
13.0 
APPENDICES 
 
Appendix I Diagnosis and Scoring of chronic GVHD according to the NIH consensus 
criteria[49] 
 
The diagnosis of chronic GVHD requires the following:  
1. Distinction from acute GVHD. 
2. Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 1 
distinctive manifestation confirmed by pertinent biopsy or other relevant tests. 
3.  Exclusion of other possible diagnoses. 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
51 
 
 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
52 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
53 
 
Appendix II Acute GVHD grading [50] 
 
Grading of acute graft-versus-host disease 
 
Organ Stage Description 
 
Skin 
1 
Maculopapular rash over <25 percent of body area 
 
2 
Maculopapular rash over 25 to 50 percent of body area 
 
3 
Generalized erythroderma 
4 
Generalized erythroderma with bullous formation and often with desquamation 
Liver 
1 
Bilirubin 2.0 to 3.0 mg/dL; SGOT 150 to 750 international units 
 
2 
Bilirubin 3.1 to 6.0 mg/dL 
 
3 
Bilirubin 6.1 to 15.0 mg/dL 
 
4 
Bilirubin >15.0 mg/dL 
 
Gut 
1 
Diarrhea >30 mL/kg or >500 mL/day 
 
2 
Diarrhea >60 mL/kg or >1000 mL/day 
 
3 
Diarrhea >90 mL/kg or >1500 mL/day 
4 
Diarrhea >90 mL/kg or >2000 mL/day; or severe abdominal pain with or without 
ileus 
 
 
 
Glucksberg grade 
 
I – Stage 1 or 2 skin involvement; no liver or gut involvement; ECOG PS 0 
II – Stage 1 to 3 skin involvement; Grade 1 liver or gut involvement; ECOG PS 1 
III – Stage 2 or 3 skin, liver, or gut involvement; ECOG PS 2 
IV – Stage 1 to 4 skin involvement; Stage 2 to 4 liver or gut involvement; ECOG PS 3 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
54 
 
Appendix III ECOG Performance Status Scale 
 
 
SCORE DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
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. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 

 
 
 
Protocol Am 8 Dated 10Jan2022  UCSD IIT # 180383 Abatacept 
 
 
55 
 
Appendix IV: NCI CTC Version 5.0 
 
Toxicity will be scored using NCI CTC Version 5.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 5.0 can be downloaded from the CTEP 
homepage: (http://ctep.cancer.gov).  All appropriate treatment areas have access to a copy of 
the CTC Version  
 
 
 
 
Appendix V Suggestions for dosing of conditioning regimens 
 
Dosing will be based on patients' actual weight up to 120% of ideal body weight, above which it will 
be based on adjusted ideal body weight (ideal weight plus 50% of the difference between ideal and 
actual weight). 
 
Myeloablative regimen: 
• 
Fludarabine 40 mg/m2 IV over 30 minutes daily for 4 days (day -6, -5, -4, -3) followed by: 
• 
Busulfan 130 mg/m2 IV over 3 hours daily (day -6, -5, -4, -3) 
• 
Both fludarabine and busulfan are infused via a controlled-rate infusion pump through a 
central venous catheter. [35].   
 
Cyclophosphamide/TBI   
• 
Cyclophosphamide 60 mg/kg IV over 2 hours daily x 2 (Day -5, -4) 
o 
Consider a cyclophosphamide dose of 50mg/kg for patients who will receive 
PTCy 
• 
Mesna 50 mg/kg continuous infusion IV over 24 hours q24h x 2 doses each day on (Day 
-5, -4).  
First dose is 30 min prior to cyclophosphamide.  
• 
Total body irradiation 2.0 Gy bid on (Day -3, -2, -1) for a total of 12.0 Gy.  
 
TBI/Cyclophosphamide 
       •     Total body irradiation 2.0 Gy BID on (Day -6, -5, -4) for a total of 12.0 Gy. 
       •     Cyclophosphamide 60 mg/kg IV over 2 hours daily x 2. (Day -3, -2) 
       •     Mesna 50 mg/kg continuous infusion IV over 24 hours q24h x 2 doses each day on (Day 
-3, -2). 
              First dose is 30 min prior to cyclophosphamide. 
 
Reduced Intensity Conditioning regimen: 
• 
Fludarabine 30 mg/m2 will be given IV over 30 minutes  daily for 4 days (Day -6,-5,-4,-3) 
• 
Melphalan 140 mg/m2 via central line over 15 minutes x 1 on Day -2