Clinical trial NCT02208037
Conditions: Acute Leukemia Chronic Myelogenous Leukemia Myelodysplasia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Lymphoma, B-Cell Lymphoma, Follicular Lymphoma, Large B-Cell, Diffuse Hodgkin's Lymphoma
Keywords: Acute Lymphoblastic Leukemia/Lymphoma Acute Myelogenous Leukemia Mantel-Cell Lymphoma Hematopoietic Transplant GVHD Prophylaxis
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2014-08-01; Completion date: 2017-10-01
Enrollment: 279 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.

Detailed description:
GVHD is a complication that can occur after a bone marrow or stem cell transplant. The transplant recipient's body is attacked by the newly introduced cells. Only about 40% of patients with acute GVHD have durable responses when treated with corticosteroid therapy. A strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an effective approach to improve survival after allogeneic transplantation.

GVHD incidence can be decreased with various treatment plans. Early transplants were done using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later shown to work better than methotrexate. Then doctors discovered that the combined use of cyclosporine and methotrexate worked even better than either agent alone. More recently, other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been conducted to compare available treatment combinations for related and unrelated donors. The combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis.

However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II clinical trial will compare each intervention arm with a Tac/MTX control.

This study will enroll people who have a cancer of the blood or lymph glands and a stem cell transplant is a treatment option. The study will take at least two years and will include 270 participants - 90 participants in each of three treatment groups. The purpose of this study is to compare three combinations of medications to see whether one or more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.

Arms: arm 1: Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib. arm 2: Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc. arm 3: Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Interventions: intervention 1: Tacrolimus (ARM with Methotrexate) intervention 2: Tacrolimus (ARM with MMF and Cyclophosphamide) intervention 3: Methotrexate (ARM with Maraviroc) intervention 4: Methotrexate (ARM with Bortezomib) intervention 5: Maraviroc intervention 6: Bortezomib intervention 7: Mycophenolate mofetil intervention 8: Cyclophosphamide
Intervention descriptions: intervention 1: Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels. The dose should be adjusted accordingly to maintain a suggested level of 5-15 ng/mL. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. intervention 2: Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. Serum levels of tacrolimus will be measured at Day 7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD. intervention 3: Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of maraviroc. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. intervention 4: Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of bortezomib. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. intervention 5: Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to hematopoietic stem cell infusion, and continue until Day 30 post HSCT. If the patient requires a two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day. intervention 6: Bortezomib will be administered at the dose of 1.3 mg/m2 based upon actual body weight (ABW) as an approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous administration of bortezomib is not allowed on this protocol. intervention 7: MMF will be given at a dose of 15 mg/kg three times a day (TID) based upon ABW with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day 5 and discontinue after the last dose on Day 35, or may be continued if active GVHD is present. intervention 8: Hydration prior to cyclophosphamide may be given according to institutional standards.

Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide.

Cyclophosphamide \[50 mg/kg ideal body weight (IBW); if ABW \< IBW, use ABW\] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the HSCT) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).

Protocol documents:
Prot_000.pdf: 
 
 
A Multi-center Phase II Trial Randomizing Novel 
Approaches for Graft-versus-Host Disease Prevention 
Compared to Contemporary Controls 
(Posted on clinicaltrials.gov as NCT02208037) 
 
BMT CTN PROTOCOL 1203 
Version 3.0 
Study Chairpersons 
Javier Bolaños-Meade, MD1; John Koreth, MBBS, DPhil2; Ran Reshef, MD3 
 
Protocol Team 
 
Amin Alousi, MD4 
Joseph H. Antin, MD2 
Nancy Geller, PhD5 
Shernan Holtan, MD8 
Brent Logan, PhD6 
David Jacobsohn, MD7 
Richard J. Jones, MD1  
Margaret MacMillan, MD8 
Adam Mendizabal, PhD9 
Marco Mielcarek, MD10 
Marcelo Pasquini, MD6(Protocol 
Officer) 
Joseph Pidala, MD11 
David Porter, MD3 
Joel Reed, MA, MPH9 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
IND # 119524 
 
1Johns Hopkins University 
2Dana Farber Cancer Institute 
3Columbia University 
4MD Anderson Cancer Center 
5National Heart, Lung, and Blood Institute 
6CIBMTR/Medical College of Wisconsin 
7Children’s National Medical Center 
8University of Minnesota 
9The EMMES Corporation 
10Fred Hutchinson Cancer Research Center 
11H. Lee Moffitt Cancer Center 
12University of Pennsylvania 
 
 
__________________________________  
__________________________________ 
Approval Signature (Protocol Chair/Officer) 
 
Approval Signature (Protocol Chair/Officer) 
 


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Core Study Participants: 
 
 
 
Affiliate Study Participants: 
Baylor College of Medicine  
BMT Program at Northside Hospital 
Case Western Reserve University Consortium  
   University Hospitals of Cleveland 
   Oregon Health & Sciences University 
   Cleveland Clinic 
City of Hope National 
Dana Farber Consortium 
   Brigham & Women’s Hospital 
   Massachusetts General Hospital 
H. Lee Moffitt Cancer Center 
Johns Hopkins University 
Memorial Sloan-Kettering Cancer Center 
Ohio State Consortium 
Ohio State University 
Roswell Park Cancer Institute 
University of North Carolina 
Virginia Commonwealth University 
Stanford University 
University of Florida Consortium 
   University of Florida 
   Emory University Medical Center 
University of Michigan Consortium 
   Mayo Clinic, Rochester, MN  
University of Nebraska Consortium 
   University of Kansas 
University of Minnesota 
University of Pennsylvania Cancer Center 
University of Texas, MD Anderson Cancer Center 
Washington University, Barnes Jewish Hospital 
Karmanos Cancer Institute/BMT 
Loyola University 
Medical University of South Carolina 
Texas Transplant Institute 
University of Iowa 
University of Utah 
 
 
 
 


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PROTOCOL SYNOPSIS – BMT CTN 1203 PROTOCOL 
 
A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease 
Prevention Compared to Contemporary Controls 
 
Co-Principal Investigators: 
Javier Bolaños -Meade, MD; John Koreth, MBBS, DPhil;  
Ran Reshef, MD 
 
Study Design: 
The study is designed as a Phase II, multicenter trial that 
randomizes patients to one of three GVHD prophylaxis 
approaches comparing each to a contemporary control. 
 
Primary Objective: 
The primary objective of the randomized trial is to compare one 
year GVHD/relapse or progression-free survival (GRFS) after 
hematopoietic stem cell transplantation (HSCT) between each 
of three novel GVHD prophylaxis approaches and a 
contemporary control from the Center for International Blood 
and Marrow Transplant Research (CIBMTR) database. An 
event for this time to event outcome is defined as grade III-IV 
acute 
GVHD, 
chronic 
GVHD 
requiring 
systemic 
immunosuppressive treatment, disease relapse or progression, or 
death by any cause.. 
 
Secondary Objectives: 
Secondary objectives are to describe for each treatment arm: 
rates of grade II-IV and III-IV acute GVHD, visceral acute 
GVHD, chronic GVHD, immunosuppression-free survival at 
one year, hematologic recovery (neutrophil and platelet), donor 
cell engraftment, disease relapse or progression, transplant-
related mortality, rates of Grade  3 toxicity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0; incidence of infections; immune reconstitution and 
overall survival.  
 
Eligibility Criteria: 
Eligible patients are between 18 and 75 years undergoing HSCT 
for treatment of acute leukemia, chronic myelogenous leukemia 
or myelodysplasia with no circulating blasts and with less than 
5% blasts in the bone marrow; chronic lymphocytic 
leukemia/small lymphocytic lymphoma, follicular lymphoma; 
marginal zone lymphoma; Hodgkin’s Lymphoma, diffuse large 
B cell lymphoma or, mantle cell lymphoma sensitive to 
chemotherapy who are eligible for an allogeneic transplant. 
Patients must have a related or unrelated peripheral blood 
stem cell donor. Sibling donor must be a 6/6 match for 
HLA-A and -B at intermediate (or higher) resolution, and -
DRB1 at high resolution using DNA-based typing, and must 


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be willing to donate peripheral blood stem cells and meet 
institutional criteria for donation. Unrelated donor must be 
a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing. Unrelated donor must 
be willing to donate peripheral blood stem cells and be 
medically eligible to donate stem cells according to NMDP 
criteria. Patients are eligible only if receiving a reduced 
intensity conditioning (RIC) regimen.  
 
Treatment Description: 
Patients will be randomized to receive one of the three specified 
regimens: 
Tacrolimus 
(Tac)/Methotrexate 
(Mtx) 
with 
bortezomib 1.3 mg/m2 IV daily Days +1, +4 and +7 post HSCT; 
Tac/Mtx with maraviroc 300 mg PO twice a day from Day -3 to 
30 post HSCT; or cyclophosphamide (Cy) 50 mg/kg Day +3 
and +4, followed by Tac and mycophenolate mofetil (MMF).  
Tac will be maintained at therapeutic doses for a minimum of 
90 days in all arms.  Methotrexate will be dosed at 15 mg/m2 
Day +1, and 10 mg/m2 Days +3, 6 and 11 in the maraviroc and 
bortezomib arms. MMF will be dosed at 15 mg/kg every 8 
hours from Day +5 to Day +35 in the Tac/MMF/Cy treatment 
arm.     
 
Accrual Objective: 
The clinical trial will enroll 270 patients or 90 per arm.  Patients 
will be compared to a minimum of 270 controls from the 
CIBMTR who received Tac/Mtx alone.  
 
Accrual Period: 
The estimated accrual period is 30 months. 
 
Study Duration: 
Patients will be followed for 1 year following HSCT. 
 
Interim Analysis: 
There will be no interim analyses for efficacy. An interim 
analysis for futility will be conducted based on the 6 month 
GRFS when 30 patients in each arm have 6 months of follow-up 
available.  If fewer than 14 are alive and GVHD/relapse free 
among the first 30 patients on an arm, closure of the study arm 
for futility will be considered.   
 
Stopping Guidelines: 
Monitoring of the key safety endpoint of death will be 
conducted   monthly. The rate of mortality will be monitored up 
to 100 days post-randomization separately in each of the three 
treatment arms.  At least three events must be observed in order 
to trigger review for consultation with the DSMB.  
 
 
 


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STUDY SCHEMA 
Aim:  To determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and 
relapse free survival at one year after transplant.  
Inclusion Criteria 
1. Age 18-75 years (patient is older than 18.0 and less 
than 76.0 years old) 
2. Patients with acute leukemia, chronic myelogenous 
leukemia, or myelodysplasia with no circulating 
blasts and with less than 5% blasts in the bone 
marrow. 
3. Patients with chronic lymphocytic leukemia/small 
lymphocytic lymphoma; follicular, marginal zone, 
diffuse large B-cell, Hodgkin’s Lymphoma, or 
mantle cell lymphoma with chemo-sensitive disease 
at time of transplant. 
4. Recipients of reduced intensity conditioning. 
5. Patients must have a related or unrelated peripheral 
blood stem cell donor. Sibling donor must be a 6/6 
match for HLA-A and -B at intermediate (or higher) 
resolution, and -DRB1 at high resolution using 
DNA-based typing, and must be willing to donate 
peripheral blood stem cells and meet institutional 
criteria for donation. Unrelated donor must be a 7/8 
or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing. Unrelated donor 
must be willing to donate peripheral blood stem cells 
and be medically cleared to donate stem cells 
according to NMDP criteria. 
6. Cardiac function: Ejection fraction ≥ 45% 
7. Estimated creatinine clearance greater than 50 
mL/minute (using the Cockcroft-Gault formula and 
actual body weight) 
8. Pulmonary function: DLCO ≥ 40% (adjusted for 
hemoglobin) and FEV1 ≥ 50%  
9. Liver function: total bilirubin < 1.5x the upper limit 
of normal and ALT/AST < 2.5x the upper normal 
limit. Patients who have been diagnosed with 
Gilbert’s Disease are allowed to exceed the defined 
bilirubin value of 1.5x the upper limit of normal. 
10. Female subjects (unless postmenopausal for at least 
1 year before the screening visit, or surgically 
sterilized), agree to practice two effective methods of 
contraception or agree to complete abstain from 
heterosexual intercourse from the time of signing the 
informed consent through 12 months post transplant. 
11. Male subjects (even if surgically sterilized), of 
partners of women of childbearing potential must 
agree to practice effective barrier contraception or 
abstain from heterosexual intercourse from the time 
of signing the informed consent through 12 months 
post transplant. 
12. Signed informed consent. 
 
Exclusion Criteria 
1. Prior allogeneic transplant 
2. Karnofsky Performance Score  < 70% 
3. Active CNS involvement by malignant cells 
4. Patients with uncontrolled bacterial, viral or fungal 
infections (currently taking medication and with 
progression or no clinical improvement) at time of 
enrollment. 
5. Presence of fluid collection (ascites, pleural or pericardial 
effusion) that interferes with methotrexate clearance or 
makes methotrexate use contraindicated 
6. Patients with transformed lymphoma (e.g., Richters 
transformation arising in follicular lymphoma or chronic 
lymphocytic leukemia). 
7. Patients seropositive for the human immunodeficiency 
virus (HIV). 
8. Patient with active Hepatitis B or C determined by 
serology and/or NAAT. 
9. Patients with hypersensitivity to bortezomib, boron or 
mannitol. 
10. Patients with ≥ grade 2 sensory peripheral neuropathy. 
11. Myocardial infarction within 6 months prior to enrollment 
or New York Heart Association (NYHA) Class III or IV 
heart failure (see Appendix D), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities.  Prior to study entry, any 
ECG abnormality at screening must be documented by the 
investigator as not medically relevant 
12. Female patients who are lactating or pregnant 
13. Patients with a serious medical or psychiatric illness likely 
to interfere with participation in this clinical study  
14. Patients with prior malignancies, except resected basal cell 
carcinoma or treated cervical carcinoma in situ.  Cancer 
treated with curative intent ≥ 5 years previously will be 
allowed.  Cancer treated with curative intent < 5 years 
previously will not be allowed unless approved by the 
Protocol Officer or one of the Protocol Chairs.  
15. Planned use of ATG or alemtuzumab in conditioning 
regimen. 
16. Planned post-transplant therapy (including use of TKIs)  
17. Inability to withhold agents that may interact with hepatic 
cytochrome P450 enzymes (CYP3A4), or glutathione S-
transferases involved in bortezomib and/or busulfan 
metabolism during day -5 through day +7. It is acceptable 
to use alternative non-interacting medications during this 
period, and then resume prior medications. 
18. Patients with secondary acute myeloid leukemia arising 
from myeloproliferative disease, including CMML, with 
evidence 
of 
active 
myeloproliferative 
features 
or 
myelofibrosis in the background. 


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Immunosuppression Taper: 
Patients without GVHD 
Tacrolimus 
- 
Taper to initiate at least Day 90 and 
completely off at Day 180.  
 
MMF 
- 
Discontinued on Day +35 without a 
taper. 
 
Primary endpoint: 
- GVHD/relapse or progression-free survival (GRFS) by 1 
year: this time to event outcome is defined as grade III-IV 
acute GVHD, chronic GVHD requiring systemic treatment, 
disease relapse or progression, or death by any cause.   
Secondary endpoints: 
- Grades II-IV and III-IV acute GVHD 
- Incidence of visceral GVHD (liver or gut) 
- Chronic GVHD  
- Immunosuppression-free survival at 1 years 
- Hematologic recovery (neutrophil and platelet)  
- Donor cell engraftment 
- Disease relapse or progression 
- Transplant-related mortality 
- Toxicity and rates of infections 
- Disease-free and overall survival 
 
 
 
 
 
Conditioning Regimens 
Reduced Intensity/Non-myeloablative* 
Flu/Bu (≤ 8 mg/Kg) 
Flu/Mel (≤ 150 mg/m2) 
Flu/Cy/TBI 
Flu/TBI (200cGy) 
Flu/Cy 
*No anti-thymocyte globulin or alemtuzumab is allowed in 
the conditioning regimen 
 
 


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Outline of Treatment Plan 
 
 
 
 
CIBMTR control eligibility 
Transplants performed in the U.S. 
Centers not participating in BMT CTN 1203 and agree to provide supplemental information 
Age 18-75 years 
Transplants for malignant disease using RIC and a PBSC graft 
GVHD prophylaxis with Tac/MTX without additional agents 
Age 18-75 years 
Controlled Malignant Diseases 
RIC 
Related or Unrelated PBSC Donor 
Tac/MTX/ 
Bortezomib 
Tac/MTX/ 
Maraviroc 
Tac/MMF/ 
Cyclophosphamide 
 
Tac/MTX CIBMTR 
Controls 


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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Introduction .................................................................................................................... 1-1 
1.2. 
Tacrolimus, Methotrexate and Bortezomib (Tac/MTX/Bort) ................................... 1-2 
1.2.1. 
Bortezomib .................................................................................................................. 1-2 
1.2.2. 
Bortezomib Mechanism of Action .............................................................................. 1-2 
1.2.3. 
Bortezomib and Graft-versus-Host-Disease: Preclinical Data .................................... 1-3 
1.2.4. 
Bortezomib Clinical Pharmacokinetics and Pharmacodynamics ................................ 1-3 
1.2.5. 
Clinical Experience with Bortezomib ......................................................................... 1-4 
1.2.6. 
Clinical Experience with Bortezomib for GVHD Prophylaxis ................................... 1-4 
1.3. 
Tacrolimus, Methotrexate and Maraviroc (Tac/MTX/MVC) ................................... 1-5 
1.3.1. 
CCR5 and CCR5 inhibitors ......................................................................................... 1-5 
1.3.2. 
Maraviroc .................................................................................................................... 1-5 
1.3.3. 
Maraviroc Mechanism of Action and Safety Studies ................................................. 1-5 
1.3.4. 
CCR5 Inhibition and GVHD ....................................................................................... 1-6 
1.3.5. 
Phase I/II Study of Maraviroc in GVHD Prophylaxis ................................................ 1-7 
1.4. 
Tacrolimus, Mycophenolate Mofetil and Cyclophosphamide (Tac/MMF/Cy) ...... 1-10 
1.4.1. 
Rationale of Post-transplant Cyclophosphamide ...................................................... 1-10 
1.4.2. 
Post-transplant Cyclophosphamide in Haploidentical Donor Transplants ............... 1-10 
1.4.3. 
Post-transplant Cy as GVHD Prophylaxis ................................................................ 1-11 
1.5. 
Benchmark Analysis and Composite Endpoint ........................................................ 1-12 
1.6. 
Rationale ....................................................................................................................... 1-15 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Specific Objectives .............................................................................. 2-1 
2.2.1. 
Hypothesis ................................................................................................................... 2-1 
2.2.2. 
Study Objectives ......................................................................................................... 2-1 
2.3. 
Patient Eligibility ........................................................................................................... 2-1 
2.3.1. 
Inclusion Criteria ......................................................................................................... 2-1 
2.3.2. 
Exclusion Criteria........................................................................................................ 2-2 
2.3.3. 
Eligibility for the Control Arm ................................................................................... 2-3 
2.4. 
Treatment Plans ............................................................................................................. 2-4 
2.4.1 
Conditioning Regimens ............................................................................................... 2-4 
2.4.2 
Hematopoietic Stem Cell Transplantation .................................................................. 2-6 
2.4.3 
Tacrolimus/Methotrexate/Bortezomib ........................................................................ 2-7 
2.4.4 
Tacrolimus/Methotrexate/Maraviroc .......................................................................... 2-9 
2.4.5 
Tacrolimus/Mycophenolate Mofetil/Cyclophosphamide.......................................... 2-11 
2.5 
Supportive Care ........................................................................................................... 2-12 
2.5.1 
Growth Factors .......................................................................................................... 2-12 
2.5.2 
Blood Products .......................................................................................................... 2-12 
2.5.3 
Prophylaxis Against Infections ................................................................................. 2-12 
2.5.4 
Intravenous Immune Globulin (IVIG) ...................................................................... 2-12 


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2.6 
Participant Risks .......................................................................................................... 2-13 
2.6.1 
Therapy Toxicities .................................................................................................... 2-13 
2.6.2 
Tacrolimus................................................................................................................. 2-13 
2.6.3 
Methotrexate ............................................................................................................. 2-13 
2.6.4 
Bortezomib ................................................................................................................ 2-13 
2.6.5 
Maraviroc .................................................................................................................. 2-15 
2.6.6 
Mycophenolate mofetil (MMF) ................................................................................ 2-16 
2.6.7 
Cyclophosphamide .................................................................................................... 2-16 
2.7 
Study Drug Supply ....................................................................................................... 2-17 
2.7.1 
Tacrolimus, Methotrexate, Cyclophosphamide and Mycophenolate Mofetil ........... 2-17 
2.7.2 
Bortezomib and Maraviroc ....................................................................................... 2-17 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
Acute GVHD ............................................................................................................... 3-1 
3.2.2. 
Chronic GVHD ........................................................................................................... 3-1 
3.2.3. 
1-year Immunosuppression-free Survival ................................................................... 3-1 
3.2.4. 
Hematologic Recovery ................................................................................................ 3-2 
3.2.5. 
Donor Cell Engraftment .............................................................................................. 3-2 
3.2.6. 
Disease Relapse or Progression .................................................................................. 3-2 
3.2.7. 
Transplant-related Mortality ....................................................................................... 3-3 
3.2.8. 
Toxicity ....................................................................................................................... 3-3 
3.2.9. 
Infections ..................................................................................................................... 3-4 
3.2.10. 
Disease-Free Survival ................................................................................................. 3-4 
3.2.11. 
GVHD-Free Survival .................................................................................................. 3-4 
3.2.12. 
Overall Survival .......................................................................................................... 3-4 
4. 
PATIENT ENROLLMENT AND EVALUATIONS .................................................. 4-1 
4.1. 
Approaching Patients, Eligibility Screening and Obtaining Consent ....................... 4-1 
4.2. 
Transplant Protocol Registration ................................................................................. 4-1 
4.3. 
Randomization ............................................................................................................... 4-1 
4.4. 
Treatment Scheduling ................................................................................................... 4-1 
4.5. 
Patient Evaluation .......................................................................................................... 4-1 
4.6. 
Study Monitoring ........................................................................................................... 4-2 
4.6.1. 
Patient Assessments .................................................................................................... 4-2 
4.6.2. 
Criteria for Forms Submission .................................................................................... 4-6 
4.6.3. 
Reporting Patient Deaths............................................................................................. 4-6 
4.7. 
Adverse Event Reporting Requirements ..................................................................... 4-7 
4.7.1. 
Definitions ................................................................................................................... 4-7 
4.7.2. 
BMT CTN Adverse Event Reporting Guidelines ....................................................... 4-7 
4.7.3. 
Additional Adverse Event Reporting Requirements for Patients Randomized to the 
Tacrolimus/Methotrexate/Bortezomib Arm ................................................................ 4-8 
4.7.4. 
Adverse Event Reporting for Patients Randomized to the Tacrolimus/Methotrexate/ 
Maraviroc Arm ............................................................................................................ 4-8 


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4.7.5. 
Procedures for Reporting Exposure to Bortezomib or Maraviroc During Pregnancy 
and Birth Events .......................................................................................................... 4-8 
4.8. 
CIBMTR Data Reporting.............................................................................................. 4-8 
4.9. 
Registration of CIBMTR Controls ............................................................................... 4-9 
4.9.1. 
Selection of Control Arm Participating Transplant Centers ....................................... 4-9 
4.9.2. 
Enrollment procedure for the control arm ................................................................... 4-9 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1 
Study Design ................................................................................................................... 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Randomization ............................................................................................................ 5-1 
5.1.3. 
Primary Endpoint ........................................................................................................ 5-1 
5.1.4. 
Primary Hypothesis ..................................................................................................... 5-1 
5.2. 
Sample Size and Power Considerations ....................................................................... 5-2 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-5 
5.3.1. 
Interim Analysis for Efficacy ...................................................................................... 5-5 
5.3.2. 
Interim Analysis for Futility........................................................................................ 5-5 
5.3.3. 
Guidelines for Safety Monitoring ............................................................................... 5-5 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-6 
5.5. 
Analysis of Primary Endpoint ...................................................................................... 5-7 
5.6. 
Analysis of Secondary Endpoints ................................................................................. 5-7 
5.6.1. 
Acute GVHD ............................................................................................................... 5-7 
5.6.2. 
Chronic GVHD ........................................................................................................... 5-8 
5.6.3. 
Immunosuppression-Free Survival at One Year ......................................................... 5-8 
5.6.4. 
Hematologic Recovery ................................................................................................ 5-8 
5.6.5. 
Donor Cell Engraftment .............................................................................................. 5-8 
5.6.6. 
Disease Relapse or Progression .................................................................................. 5-8 
5.6.7. 
Transplant-related Mortality ....................................................................................... 5-8 
5.6.8. 
Toxicity ....................................................................................................................... 5-9 
5.6.9. 
Infections ..................................................................................................................... 5-9 
5.6.10. 
Disease-free Survival .................................................................................................. 5-9 
5.6.11. 
GVHD-Free Survival .................................................................................................. 5-9 
5.6.12. 
Overall Survival .......................................................................................................... 5-9 
5.7. 
Safety Analysis ............................................................................................................... 5-9 
5.8. 
Selection of Promising Approaches .............................................................................. 5-9 
 
 
LIST OF APPENDICES 
APPENDIX A 
 
HUMAN SUBJECTS 
APPENDIX B 
 
INFORMED CONSENTS 
APPENDIX C 
 
LABORATORY PROCEDURES 
APPENDIX D 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
OF CARDIAC DESIGN  


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APPENDIX E 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
APPENDIX F 
KARNOFSKY PERFORMANCE STATUS SCALE 
APPENDIX G 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
APPENDIX H 
 
KNOWN ANTICIPATED RISKS OF BORTEZOMIB 
APPENDIX I 
 
PRODUCT COMPLAINTS FOR BORTEZOMIB 
APPENDIX J 
 
ADVERSE EVENT REPORTING 
APPENDIX K 
 
REFERENCES 
 
 
 


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CHAPTER 1 
 
 
1. BACKGROUND AND RATIONALE 
 
1.1. Introduction 
 
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after 
allogeneic hematopoietic stem cell transplantation (HSCT).  Clinically significant grade II-IV 
acute GVHD occurs in 34-40% of patients undergoing HLA-matched related donor HSCT, 47-
52% of HLA-matched unrelated donor HSCT, and is further increased in those lacking HLA-
matched donors.1, 2, 3, 4 
 
GVHD is thought to be mediated by donor-derived T cells that are reactive against recipient 
antigens expressed in the context of the major histocompatibility complex (MHC or HLA). 
These antigens, termed minor histocompatibility antigens (mHA), are small peptides with 
immunogenic single nucleotide polymorphisms (SNPs) capable of eliciting potent T cell immune 
responses upon presentation by antigen presenting cells (APCs).  A number of these mHAs have 
been identified.5  In fact, mismatches of known mHA among HLA identical donor-recipient pairs 
have been associated with the development of GVHD after stem cell transplantation.6  
 
Approximately 40% of patients with acute GVHD will have durable responses to corticosteroid 
therapy; there has been little change in this response rate over the past 20 years, despite addition 
or substitution of other immunosuppressive drugs to GVHD treatment regimens.7  The prognosis 
of the 60% of patients without long-lasting response is poor.8  A strategy that minimizes the 
incidence of GVHD, without other adverse effects, would be an effective approach to improve 
survival after allogeneic transplantation. 
 
GVHD incidence can be decreased with various pharmacologic agents.  Early transplants were 
done using post-transplant methotrexate to prevent GVHD; in the 1980s cyclosporine was shown 
to be superior to methotrexate and in 1986 the combined use of cyclosporine and methotrexate 
was shown to be superior to single agent prophylaxis. 9  More recently, other calcineurin-
inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to 
favorable toxicity profiles in comparison with cyclosporine.10, 11 
 
Phase III trials comparing tacrolimus/methotrexate versus cyclosporine/methotrexate for related 
and unrelated donors have been performed. In the unrelated donor setting, the incidence of grade 
II-IV acute GVHD was 56% among the 46 patients randomized to tacrolimus arm versus 74% 
among the 63 patients randomized to cyclosporine arm.
12   The combination of 
tacrolimus/methotrexate remains a standard for GVHD prophylaxis, despite its limited efficacy. 
 
However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current 
clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and 
bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and 
tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy).  This randomized 
Phase II clinical trial will compare each intervention arm with a Tac/MTX control.   


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1.2. Tacrolimus, Methotrexate and Bortezomib (Tac/MTX/Bort) 
 
1.2.1. Bortezomib 
 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  Bortezomib 
is currently approved by the United States Food and Drug Administration (US FDA) for the 
treatment of patients with multiple myeloma (MM).  It is also indicated for the treatment of 
patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.   
 
1.2.2. Bortezomib Mechanism of Action 
 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways.  The antineoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition 
of expression of genes that control cellular adhesion, migration, and angiogenesis.  Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and 
the extent to which each affected pathway is critical to the inhibition of tumor growth could also 
differ.  Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro 
and in vivo assays.13  In addition, bortezomib has cytotoxic activity in a variety of xenograft 
tumor models, both as a single agent and in combination with chemotherapy and 
radiation.14,15,16,17,18,19,20,21,22,23,24,25,26  Notably, bortezomib induces apoptosis in cells that over 
express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional 
chemotherapeutics.27 
 
The mechanisms of action leading up to apoptosis have been more clearly defined and include 
initiation of the unfolded protein response and direct/indirect effects on various molecular targets 
including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, 
transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis factors, and 
many others.  Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of 
nuclear factor B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell 
growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.28,29,30,31,32,33,34,35 
 
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor 
B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects. 36   Bortezomib also has 
immunomodulatory effects relevant to allogeneic HSCT.  The proteasome, acting via NF-kB, 
plays an important role in cytokine signaling and the generation of cell mediated immune 
responses via T cell activation, proliferation and apoptosis.37, 38, 39  Bortezomib also attenuates 
TLR4 mediated antigen-presenting cell activation, with reduced cytokine production and 
immunostimulatory activity. 40   In the allogeneic setting, bortezomib preferentially and 
specifically depletes alloreactive T lymphocytes.41  It however spares human regulatory T cells 
(Treg) that act to suppress inappropriate immune responses underlying GVHD.42  Given the 
immunomodulatory effects of bortezomib on APCs, alloreactive T lymphocytes and Tregs, as 


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well as its anti-tumor effects and its lack of hematopoietic stem cell toxicity, it is an attractive 
candidate for control of GVHD after allogeneic transplantation. 
 
1.2.3. Bortezomib and Graft-versus-Host-Disease: Preclinical Data 
 
In murine models of severe acute GVHD involving fully-HLA mismatched myeloablative 
HSCT, bortezomib administered early after stem cell infusion protected against GVHD without 
impairing engraftment.43, 44  In a model intended to induce less severe GVHD, mice receiving 
bortezomib had 100% survival with no animal developing GVHD, while control animals all 
succumbed to GVHD prior to Day 50 post-transplantation.43  
 
Additionally, in other in-vivo murine models combination bortezomib/sirolimus synergistically 
reduced GVHD risk without hampering graft-versus-leukemia effect.  
 
1.2.4. Bortezomib Clinical Pharmacokinetics and Pharmacodynamics 
 
The clinical pharmacology characterization of bortezomib has been determined from Phase 1 
studies in subjects with solid tumors and hematological malignancies, and confirmed in Phase 2 
studies in subjects with multiple myeloma. 
 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed plasma 
concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 patients with multiple 
myeloma and creatinine clearance values >50 mL/min participating in a pharmacokinetics study.  
In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 
106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.  The mean 
elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours.  
Bortezomib is eliminated more rapidly following the first dose.  Mean Total Body Clearances 
were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, 
respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 
1.3 mg/m2, respectively.  Clinical experience has shown that the change in clearance does not 
result in overt toxicity from accumulation in this multi-dose regimen in humans. 
 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition of 
20S activity) occurred within 1-hour post dose.  At the therapeutic dose of 1.3 mg/m2 in subjects 
with multiple myeloma, the mean proteasome inhibition at 1-hour post dose was approximately 
61%. 
 
The time course of proteasome inhibition in subjects is characterized by maximum inhibition 
observed within the first hour after administration, followed by partial recovery of proteasome 
activity over the next 6 to 24 hours to within 50% of the pretreatment activity.  On the Day 1, 4, 
8, and 11 schedule variable (10%–30%) levels of proteasome inhibition have been observed at 
next scheduled dosing.  In theory, this advantage allows cells to recover proteasome activity for 
normal cellular housekeeping functions between doses. 
 


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The relationship between bortezomib plasma concentrations and proteasome inhibition can be 
described by a maximum effect (Emax) model.  The Emax curve is initially very steep, with small 
changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating to large 
increases in the percent inhibition (0–60%).  After that, a plateau occurs where marginal 
increases of proteasome inhibition are observed in spite of large changes in plasma bortezomib 
concentrations.45  
 
1.2.5. Clinical Experience with Bortezomib 
 
To date, more than 436,000 patients have been treated with bortezomib, including patients 
treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the US NCI 
Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
Bortezomib has been commercially available since 13 May 2003. 
 
1.2.6. Clinical Experience with Bortezomib for GVHD Prophylaxis 
 
In a Phase I trial in patients with refractory hematologic malignancies, the MTD for a twice 
weekly for 4 weeks of a 42 day cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, 
hyponatremia, hypokalemia, fatigue, and malaise.46  The toxicity was greatest during the third 
and fourth weeks of therapy.  In the 3-week schedule of bortezomib monotherapy (4 doses, given 
on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 
subjects with Grade 3 diarrhea and 1 with peripheral sensory neuropathy).  Therefore, the MTD 
at this schedule was 1.3 mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses of 
bortezomib monotherapy in patients with advanced solid tumors, the MTD was 1.6 mg/m2/dose 
and DLT included hypotension, tachycardia, diarrhea, and syncope.45  
 
In the allogeneic HSCT context, a Phase I/II clinical trial (DFCI protocol 06-065) of a regimen 
of bortezomib plus standard tacrolimus/methotrexate for GVHD prophylaxis after 
fludarabine/busulfan-based RIC HSCT with 1-2 locus HLA-mismatched donors (HLA-A, -B, -C; 
-DQB1, -DRB1).  Bortezomib MTD was 1.3 mg/m2 administered on Days +1, +4 and +7 after 
stem cell infusion.  Phase I results indicated minimal toxicity (rapid engraftment, zero non-
relapse mortality in the first year) and excellent acute GVHD control with the bortezomib-based 
regimen.47  Phase I/II results demonstrated that the grade II-IV acute GVHD rate at Day 180 was 
22% and no patients developed grade IV acute GVHD. Additionally, 2-year probabilities of non-
relapse mortality and relapse were 11% and 38% respectively in a population receiving HLA-
mismatched unrelated donor HSCT.48  Consequently, the combination of bortezomib, tacrolimus 
and methotrexate appears suitable for prospective multicenter evaluation.  
 
 


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1.3. Tacrolimus, Methotrexate and Maraviroc (Tac/MTX/MVC) 
 
1.3.1. CCR5 and CCR5 inhibitors 
 
CCR5 is a chemokine receptor. Its natural ligands are CCL3, CCL4 and CCL5, also known as 
macrophage inflammatory protein-1-alpha (MIP-1), MIP-1 and regulated and normal T cell 
expressed and secreted (RANTES). CCR5 is expressed on subsets of T-cells, dendritic cells and 
macrophages.  It is a G-protein coupled receptor with 7 transmembrane domains.49  CCR5 is a 
major co-receptor for HIV entry into host cells,50, 51 and a common polymorphism (32-CCR5) 
results in deletion and frame-shift and a non-functional receptor, leading to protection against 
HIV infection.  
 
1.3.2. Maraviroc 
 
Maraviroc (SELZENTRY™ – Pfizer, formerly UK-427,857) is the first FDA-approved drug in 
its class of CCR5-antagonists.  It is a highly specific small molecule antagonist of CCR5, 
developed for the treatment of HIV-1 infection.  Two pivotal Phase III trials (MOTIVATE-1 and 
MOTIVATE-2) have shown that in HIV patients maraviroc was able to produce a significant 
decrease in viral load and an increase in CD4 count.52, 53, 54  
 
1.3.3. Maraviroc Mechanism of Action and Safety Studies 
 
Maraviroc is a true antagonist of the CCR5 receptor.  It creates an allosteric conformational 
change in the extracellular domain of the receptor and prevents binding of all 3 ligands (CCL3-
5).  It is not a partial agonist and does not trigger any calcium influx or internalization of the 
receptor.  Pharmacokinetic studies showed that drug absorption is rapid, bioavailability is 23-
33% due to a 1st pass effect in the liver with maximum concentrations achieved 1–4 h after 
dosing.  Absorption is decreased with food but no efficacy data determined any difference in 
outcome so the drug is given without food restrictions.55  
 
Maraviroc is a substrate of cytochrome P450, family 3, subfamily A4.  Its level is affected by 
inducers and suppressors of the cytochrome P450 such as rifampin, antiretroviral medications 
and certain azoles, mainly ketoconazole and itraconazole.  The drug itself is not a significant 
inhibitor or inducer of any known metabolic pathway, and studies were conducted to guide the 
dosing in patients who are taking inhibitors or inducers of CYP3A455.  Therefore, the 
recommended dose is determined by concomitant medications.  Patients on strong inhibitors of 
CYP3A4 should take 150 mg bid, patients on strong inducers of CYP3A4 should take 600 mg 
bid and all other patients should take 300 mg bid. 
 
Phase I trials showed postural hypotension to be a dose-limiting side effect when a 600 mg dose 
was given to healthy volunteers.  No effects on blood counts, immunoglobulin levels or 
lymphocyte subset numbers were observed in Phase I/II studies. 
 
The safety of maraviroc has not been specifically studied in patients with significant underlying 
liver disorders.  Several cases of hepatotoxicity and hepatic failure with allergic features have 
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Phase III studies in HIV patients showed mild side effects.  Liver enzyme and bilirubin elevation 
occurred in 9.2% as opposed to 6.2% in the placebo groups.  These findings, together with 
reports of hepatotoxicity with other CCR5 antagonists, led the FDA to mandate a black box 
warning for hepatotoxicity.  Discontinuation of maraviroc should be considered in any patient 
with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is 
suspected or with increased liver transaminases combined with rash or other systemic symptoms 
of potential hypersensitivity (e.g. pruritic rash, eosinophilia or elevated IgE).  There are limited 
data in patients with hepatitis B/C infection, although such patients were not excluded from 
clinical trials in HIV patients. Special caution should be exercised when treating these patients 
with maraviroc.  
 
A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in subjects with 
severe renal impairment (CLcr < 30 ml/min, n=6) and end-stage renal disease (ESRD) to healthy 
volunteers (n=6).  Results show that dialysis had a minimal effect on exposure in subjects with 
ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the 
range observed in single maraviroc 300 mg dose studies in healthy volunteers with normal renal 
function.  Therefore, no dose adjustment is necessary in patients with renal impairment receiving 
maraviroc without a potent CYP3A4 inhibitor.  Dose adjustment is necessary in patients with 
renal impairment receiving maraviroc with potent CYP3A4 inhibitors. 
 
Maraviroc does not affect any major metabolic pathway. In particular, it does not affect the 
levels of drugs that are metabolized by the CYP450-3A4 system. In the phase I/II study, no 
significant interaction was noted with tacrolimus and tacrolimus dosing was standard. 
 
The drug is available in oral form only.  The commercially-available formulation is in pill form 
and a maraviroc solution is available for clinical research, although the solution will not be 
available for the BMT CTN 1203 study. 
 
1.3.4. CCR5 Inhibition and GVHD 
 
Blocking CCR5 in a GVHD murine model reduced the number of CD8+ lymphocytes that 
infiltrated the liver and prevented clinical GVHD.56  The entry of T-cells into Peyer’s patches 
was also dependent on CCR5.57  GVHD models also support the role of CCR5 ligands in the 
recruitment of cytotoxic T-cells into tissues.58 
 
Retrospective epidemiologic data support an association between CCR5 and GVHD.  A 
European study analyzed 186 recipients and 163 donors of SCT, and revealed that recipient Δ32 
was a protective factor for acute GVHD of any grade.  Δ32 in the donor did not predict outcome 
but the combination of Δ32 in both donor and recipient was protective (0/11 patients had 
GVHD).59  Another study used the NMDP sample repository and revealed that the H1/H1 
haplotype, which leads to high CCR5 expression, was associated with severe GVHD.60  
 
 


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1.3.5. Phase I/II Study of Maraviroc in GVHD Prophylaxis 
 
At the University of Pennsylvania, a Phase I/II clinical trial was conducted to study the role of 
maraviroc when added to conventional GVHD prophylaxis following RIC SCT.61  The trial 
enrolled 38 subjects (Table 1.3a), who received a standard RIC regimen of fludarabine and 
busulfan followed by the infusion of a peripheral blood stem cell (PBSC) graft from either a 
matched related or unrelated donor.  Single-antigen mismatched donors were acceptable. In 
addition to standard tacrolimus and methotrexate (MTX) prophylaxis, all patients received 
maraviroc from Day -2 to Day+30.   
 
TABLE 1.3a: PATIENT CHARACTERISTICS 
 
N=38 
Dose levels, n: 
150 mg bid 
300 mg bid 
7 
31 
Recipient age, median (range) 
62 (21-74) 
Recipient age>60, n (%) 
26 (68) 
Recipient gender: M/F, % 
60.5 / 39.5 
Comorbidity Index, n (%): Low 
Intermediate 
High 
21 (55) 
13 (34) 
4 (11) 
Diagnosis, n: 
Acute Myelogenous Leukemia 
Myelodysplastic Syndrome 
Non-Hodgkin Lymphoma 
Myeloproliferative Disease/Myelofibrosis 
Aplastic Anemia/Multiple 
Myeloma/Hodgkin/Chronic Myeloid 
Leukemia-Blast Crisis/Chronic 
Lymphocytic Leukemia 
15 
6 
8 
4 
1 each 
 
 
 
Donor, n(%): 
Matched related 
Matched unrelated 
Single-antigen mismatched 
13 (34) 
19 (50) 
6 (16) 
Donor age, median (range) 
38 (20-68) 
 
 
 


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Maraviroc dose level verification 
 
Studies in normal volunteers and HIV 
patients have established safe and effective 
doses of maraviroc and defined the 
expected drug interactions when the drug 
is administered together with inducers and 
inhibitors of CYP450 3A4.  In order to 
verify the dose level in patients undergoing 
allogeneic SCT, detailed pharmacokinetics 
and safety data were studied from 13 
subjects at 2 dose levels (summarized in 
Figure 1.3a); the 300 mg bid (n=6) and  
150 mg bid (n=7) doses resulted in mean 
Cavg (AUC/dosing interval) of 536 and 
118 ng/ml, respectively.  The results for 
the 300 mg bid dose were high compared 
to data from HIV trials, likely due to drug 
interactions; however, 3/7 patients at 150 mg bid did not reach the targeted minimum Cavg  
(100 ng/ml), while the higher dose level resulted in adequate Cavg in 6/6 patients.  Significant 
drug-related toxicity was not seen in either dose levels.  It was concluded that 300 mg bid should 
be the Phase II dose.   
 
Maraviroc safety 
 
Maraviroc was well tolerated and significant drug-related adverse events were not identified. 
Prompt engraftment was seen in all subjects with no primary graft failures.  Four subjects 
encountered delayed graft failure, three of them due to progressive primary myelofibrosis.  The 
frequency of microbiologically confirmed infections and CMV reactivations was not different 
than expected.  Patterns of donor-recipient chimerism were typical for RIC HSCT. 
 
Adverse events were similar to the expected toxicity of RIC HSCT.  One patient died within the 
first 30 days from septic shock and bacteremia.  The drug was briefly held in 7 patients due to 
grade 3 LFT abnormalities (n=2) or grade 3–4 mucositis (n=5). LFT abnormalities did not recur 
when the drug was restarted in both patients.  The adverse event profile was similar to the 
expected toxicity observed in patients undergoing RIC HSCT. 
 
Maraviroc efficacy 
 
As of January 2012 the median follow up was 19.6 months (range 13.8 – 34.8).  A final analysis 
for the primary end-point demonstrated that the cumulative incidence rates of acute GVHD grade 
II-IV and III-IV at Day 100 were 14.7% and 2.9% respectively.  By Day 100 all cases of acute 
GVHD involved only the skin without liver or intestinal involvement.  These results were 
compared with a well-matched cohort of patients (n=48), who underwent RIC HSCT with 
Tac/MTX prophylaxis but without maraviroc between 2009-2011 at Penn (Reshef, unpublished 
data).  This cohort included patients who underwent RIC HSCT prior to or after the completion 
 
Figure 1.3a Summary of pharmacokinetic data at 2 time 
points on 2 dose levels in comparison with known data in HIV 
trials. 


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of the maraviroc trial, or during its interim analyses.  These comparisons are summarized in 
Table 1.3b and Figure 1.3b and demonstrate a significant decrease in GVHD of the gut (8.8% vs. 
27.1%; P=0.02) and liver (2.9% vs. 14.6%; P=0.05), leading to a lower cumulative incidence of 
grade III-IV GVHD (5.9% vs. 20.8%; P=0.03).  The rates of skin GVHD were unaffected by 
maraviroc and the cumulative incidence of grade II-IV GVHD was lower but did not reach 
statistical significance (23.6% vs. 35.4; P=0.24).  Significant differences in non-relapse 
mortality, relapse and survival rates were not observed, but non-relapse mortality was 
numerically lower (11.7% vs. 19.1%; P=0.35).  In summary, this Phase I/II clinical trial showed 
low rates of GVHD, a significant decrease in visceral GVHD, leading to low rates of severe 
GVHD without adversely affecting the relapse rate. These results are sufficiently encouraging to 
proceed to multicenter testing. 
 
TABLE 1.3b: CUMULATIVE INCIDENCE RATES (+/- STANDARD ERRORS) OF ACUTE 
GVHD IN PATIENTS WHO RECEIVED TAC/MTX+MARAVIROC IN COMPARISON WITH A 
CONTROL GROUP OF PATIENTS WHO RECEIVED STANDARD PROPHYLAXIS WITH 
TAC/MTX 
 
Day 100 
Day 180 
 
Tac/MTX+ 
maraviroc 
Tac/MTX 
P 
Tac/MTX+ 
maraviroc 
Tac/MTX 
P 
 
CI Rate 
S.E. 
CI 
Rate 
S.E. 
CI Rate 
S.E. 
CI Rate 
S.E. 
Grade II-IV 
GVHD 
14.7 
6.2 
18.8 
5.7 
0.62 
23.6 
7.4 
35.4 
7 
0.24 
Grade III-IV 
GVHD 
2.9 
2.9 
8.3 
4 
0.27 
5.9 
4.1 
20.8 
5.9 
0.03 
Gut GVHD 
0 
0 
12.5 
4.8 
0.009 
8.8 
5.0 
27.1 
6.5 
0.02 
Liver GVHD 
0 
0 
8.3 
4 
0.04 
2.9 
2.9 
14.6 
5.2 
0.05 
Skin GVHD 
14.7 
6.2 
18.9 
5.7 
0.62 
32.4 
8.2 
32.6 
7.1 
0.99 
 
 


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1.4. Tacrolimus, Mycophenolate Mofetil and Cyclophosphamide (Tac/MMF/Cy) 
 
1.4.1. Rationale of Post-transplant Cyclophosphamide 
 
High dose cyclophosphamide is a potent immunosuppressor that has been successfully used to 
prevent GVHD in unrelated, HLA-matched sibling and haploidentical bone marrow/PBSC 
transplants in single center as well as in multi-center studies.62, 63, 64, 65, 66  Cyclophosphamide 
administered early post HSCT preferentially kills allo-reactive T cells while sparing resting, non 
allo-reactive T cells leading to suppression of GVHD as well as graft rejection.67 
 
1.4.2. Post-transplant Cyclophosphamide in Haploidentical Donor Transplants 
 
Based on promising pre-clinical results at Johns Hopkins, a Phase I/II clinical trial of 
haploidentical BMT to treat high-risk hematologic malignancies was initiated in 1999.  
Following a non-myeloablative regimen of fludarabine, cyclophosphamide, and low-dose TBI, 
GVHD prophylaxis consisted of cyclophosphamide (Cy) given on Days +3 and +4 post-
transplant, tacrolimus, and mycophenolate mofetil (MMF).64 Primary graft failure occurred in 
13% of patients, and was fatal due to infection in one patient in whom autologous hematopoiesis 
failed to occur.  In general, complete T-cell engraftment was observed by Day +28 or the grafts 
were rejected.  Cumulative incidences of grades II-IV and grades III-IV acute GVHD by Day 
200 were 34% and 6%, respectively.  There was lower incidence of extensive chronic GVHD 
among recipients of two versus one dose of post-transplantation Cy (5% versus 25%; p=.05).  
There was no difference in the incidence of severe acute GVHD with one or two doses of post-
transplant Cy.  The cumulative incidences of non-relapse mortality and relapse at 1 year were 
Figure 1.3b Cumulative incidence rates of acute GVHD (panel A) and organ-specific GVHD 
(panel B) in patients who received maraviroc in addition to standard Tac/MTX (n=35) in a Phase 
I/II trial in comparison with patients treated with Tac/MTX alone (n=48) during the same time 
period. 


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Figure 1.3c: Treatment schema of patients undergoing haploidentical donor 
transplants in the BMT CTN 0603 clinical trial. 
15% and 51%, respectively. Actuarial overall and event-free survivals (EFS) at two years after 
transplantation were 36% and 26%, respectively.  Patients with lymphoid malignancies appeared 
to have an improved EFS compared to those with myeloid malignancies (p=.02). 
 
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) sponsored a multi-
center Phase II trial of haploidentical BMT (BMT CTN 0603) for high-risk hematologic 
malignancies modeled after the Hopkins approach.  This was published along with a similar 
study using cord grafts without post transplant Cy (BMT CTN 0604).62  The 1-year probabilities 
of overall and progression-free survival were 54% and 46% after cord transplantation and 62% 
and 
48% 
after 
haploidentical bone 
marrow 
transplantation.  The 
Day +56 cumulative 
incidence 
of 
neutrophil recovery 
was 94% after dUCB 
and 
96% 
after 
haploidentical 
marrow.  The 100-
day cumulative incidence of grade II-IV acute GVHD was 40% with cord blood and 32% with 
haploidentical bone marrow.  The 1-year cumulative incidences of non-relapse mortality and 
relapse after cord transplantation were 24% and 31%, respectively; corresponding rates after 
haploidentical bone marrow transplantation were 7% and 45%. 
 
1.4.3. Post-transplant Cy as GVHD Prophylaxis 
 
Post-transplant Cy as GVHD prophylaxis was developed initially for haploidentical bone 
marrow transplantation after nonablative conditioning but, recently, several small studies have 
extended the approach to myeloablative conditioning and to PBSC transplantation.  To date, 
haploidentical nonablative transplantation with post-transplant Cy has used bone marrow as the 
graft source.  Use of PBSC instead of marrow may allow wider applicability of this approach but 
there is concern about higher risks of acute and chronic GVHD due to the 5-10-fold higher 
number of T-cells in the allograft. Recently, groups in Houston and Seattle/London reported 
small studies in which PBSC were substituted for bone marrow with post transplant Cy in the 
haploidentical donor setting.65, 68  In both studies, the incidences of severe acute GVHD, chronic 
GVHD and non-relapse mortality at 1 year with PBSC were comparable to the rates seen with 
bone marrow.  
 
Also, experience in HLA-matched siblings is being explored. Kasamon et al published on 10 
patients receiving nonablative transplants for lymphoma69 and Bolaños-Meade on 3 patients with 
sickle cell disease66. Kasamon’s patients also received rituximab and Bolaños-Meade’s received 
antithymocyte globulin.  Rates of GVHD and transplant related mortality were very low.  
Therefore, the inclusion of post-transplant high dose Cy with MMF and tacrolimus as GVHD 
prophylaxis after a non-ablative conditioning regimen seems to be justified. 
 


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1.5.  Benchmark Analysis and Composite Endpoint 
 
In order to better evaluate the efficacy of novel approaches for GVHD prophylaxis, a benchmark 
analysis was performed using data from the Center for International Blood and Marrow 
Transplant Research (CIBMTR) for patients who received a RIC HSCT.  
 
The CIBMTR maintains an outcomes registry that prospectively collects data from all centers 
performing allogeneic HSCTs and almost all centers performing autologous HSCTs in the 
United States and about 100 non-US centers. Centers must report all consecutive patients and 
provide longitudinal follow-up on those patients according to set timelines that include a 
pretransplant report, a 100 day report, a 6 month report and an annual report through 6 years post 
transplant followed by a biannual report in perpetuity. Data are reported on two tracks: a 
“Transplant Essential Data” track and a “Comprehensive Report Form” track.  Centers provide a 
pretransplant Transplant Essential Data form for all patients.  Data from this form are used to 
select patients for the Comprehensive Report Form track using a weighted random selection that 
over selects patients with rare diseases or procedures or for the purposes of specific studies.  For 
example, most patients on BMT CTN trials are selected for the Comprehensive Report Form 
track so that data collected by the CIBMTR can supplement clinical trial data collected through 
AdvantageEDC and can allow for long-term follow-up of trial patients for specific late effects of 
treatment. Longitudinal data are collected for patients on both the Transplant Essential Data and 
Comprehensive Report Form Track; the data differ in quantity and granularity.  Data quality is 
ensured by computerized error checks and on-site audits. 
 
The objective of the benchmark analysis was to select promising approaches to be further studied 
and to explore novel endpoints that could not only assess GVHD, but also the complex 
relationships between relapse and GVHD as well as prolonged use of immune suppression. The 
control population selected from the CIBMTR database was comprised of patients who received 
HSCT in a US center from 2006 to 2009 and who received tacrolimus and methotrexate as their 
sole GVHD prophylaxis. Data from single institution studies of the three agents to be tested in 
this protocol were also studied. Populations differed according to disease, donor, conditioning 
intensity, disease risk and patient age. Each institutional cohort was compared with the CIBMTR 
controls, adjusting for differences in baseline populations using multivariate regression 
techniques.  Table 1.5a summarizes the results of both univariate and multivariate analyses.   
 
 


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Table 1.5a: UNIVARIATE AND MULTIVARIATE RESULTS FROM THE 
BENCHMARK ANALYSIS 
Outcome 
 
Tac+MTX 
Control 
(95%CI) 
Post Cy 
(95%CI) 
Tac+MTX+ 
Bortezomib 
(95%CI) 
Tac+MTX+ 
Maraviroc 
(95%CI) 
Grade III-IV 
Acute 
GVHD  
HR 
 
1.00 
0.90 
(0.58-1.4) 
0.48 
(0.22-1.01) 
0.91 
(0.4-2.05) 
 Incidence at 6 mo 
(95%CI) 
25% 
(23-26%) 
23% 
(15-33%) 
14% 
(6-25%) 
13% 
(3-29%) 
CGVHD 
HR 
 
1.00 
0.24 
(0.14-0.41) 
0.73 
0.49-1.1) 
0.29 
(0.12-0.69) 
Incidence at 12 mo 
(95%CI) 
45% 
(43-46%) 
13% 
(7-20%) 
43% 
(28-58%) 
19% 
(7-35%) 
Overall 
Survival 
HR 
 
1.00 
1.07 
(0.82-1.4) 
0.53 
(0.34-0.83) 
0.80 
(0.46-1.4) 
Probability at 12 mo 
(95%CI) 
60% 
(58-61%) 
57% 
(47-66%) 
79% 
(66-88%) 
64% 
(47-77%) 
Disease free 
survival 
HR 
1.00 
1.21 
(0.94-1.56) 
0.67 
(0.44-1.02) 
1.20 
(0.76-1.91) 
Probability at 12 mo 
(95%CI) 
52% 
(51-53%) 
46% 
(37-55%) 
67% 
(51-78%) 
46% 
(29-61%) 
HR=Hazard Ratio, CI=Confidence Interval. The event for overall survival was death and the event for disease free survival 
was death or relapse. A hazard ratio (HR) greater than 1 implies that a specific group has more events at any time compared 
to the Tac+MTX Control reference group (indicated by a HR of 1.00). 
 
 
We also were interested in evaluating a composite endpoint that would better reflect reductions 
in either or both acute and chronic GVHD as well as the sometimes opposite effects of reducing 
GVHD on transplant-related mortality and relapse. First the prognostic impact of acute GVHD 
was investigated as a time dependent covariate. Grades 3 and 4 but not grade 2 acute GVHD 
were significantly associated with survival (Table 1.5b) 
 
 


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Table 1.5b: IMPACT OF MAXIMUM GRADE OF ACUTE GVHD AS A TIME-
DEPENDENT COVARIATE ON MORTALITY 
Max Grade 
Acute GVHD 
N 
RR (95% CI) 
p-value 
0-1 
1815 
1.00 
2 
863 
1.02 (0.9-1.15) 
0.779 
3 
609 
1.34 (1.17-1.52) 
<0.001 
4 
246 
3.39 (2.88-3.99) 
<0.001 
RR=relative risk; CI=confidence interval 
 
Using this information and considering the potential impact of these regimens on chronic GVHD 
(Table 1.5a), we computed the composite endpoint of Grade 3/4 acute GVHD-free, chronic 
GVHD-free, relapse-free survival (GVHD/relapse-free survival or GRFS).  The GRFS endpoint 
was calculated for the patients in the CIBMTR Tac+MTX control group (see above) who 
received RIC HSCT from 2006 to 2009 and who fulfilled the eligibility for the planned BMT 
CTN 1203 trial (N=628).  The one year probability of GRFS was 23% (95% CI, 20-26%).  This 
rate was used as the baseline rate for power and sample size calculations for this clinical trial. 
We also investigated whether GRFS rates differed by disease, for the diseases allowed in the 
trial.  Table 1.5c demonstrates one year GRFS rates by disease and the hazard ratio for the 
inverse of GRFS in each disease group compared to patients with AML, adjusting for other 
patient characteristics in multivariate analysis. 
 
Table 1.5c: ONE YEAR GRFS BY DISEASE 
Disease 
1 year GRFS 
Hazard Ratio 
p-value 
Acute Myelogenous Leukemiaa  
25% 
1.00 
-- 
Acute Lymphoblastic Leukemiaa 
24% 
1.04 (0.69-1.56) 
0.848 
Chronic Myeloid Leukemiab 
25% 
1.11 (0.79-1.57) 
0.537 
Myelodysplastic Syndromec 
12% 
1.55  (1.18-2.04) 
0.002 
Chronic Lymphocytic Leukemiad 
16% 
1.42 (1.11-1.82) 
0.005 
Non-Hodgkin Lymphomad 
30% 
0.89 (0.70-1.12) 
0.305 
aIn first or subsequent remission; bchronic or accelerated phase; c< 5% blasts; dchemosensitive 
 
Patients transplanted for myelodysplastic syndrome and those transplanted for chronic 
lymphocytic leukemia had higher risks of treatment failure than patients transplanted for other 
diseases; however the reasons for treatment failure differed in these two groups.  Rates of grade 
III-IV acute GVHD were higher in patients with chronic lymphocytic leukemia than in patients 
with other diseases; rates of disease relapse were higher in patients with myelodysplastic 
syndrome than in patients with other diseases.  For analysis of this trial, disease will be 
categorized as low risk (acute leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma) or 
high risk (chronic lymphocytic leukemia or myelodysplastic syndrome) and randomization will 
be stratified based on risk status. 
 


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1.6. Rationale 
 
This multicenter Phase II clinical trial will evaluate three novel GVHD prophylaxis approaches 
for their efficacy in improving the proportion of patients who do not develop severe acute 
GVHD, chronic GVHD that requires systemic therapy and disease progression or relapse by one 
year post-transplant.  All treatment arms will be compared to a contemporary control group from 
the CIBMTR database in which all patients received the most commonly used GVHD 
prophylaxis regimen, Tac+MTX.  The results of this study will identify the most promising 
approach(es) to be tested in a Phase III trial. Selection of the most promising therapy(ies) will be 
made based on the magnitudes of difference in the primary endpoint between each intervention 
group and the control. 


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CHAPTER 2 
 
 
2. STUDY DESIGN 
 
2.1.  Study Overview 
 
This is a Phase II randomized, open label, multicenter trial to identify the most promising GVHD 
prophylaxis approach(es) for patients with malignant disease receiving an allogeneic PBSC 
transplant after a RIC regimen.  Patients will be randomized to one of three new strategies: 
Tac/MTX/Bortezomib, Tac/MTX/Maraviroc or Tac/MMF/Cy.  The primary endpoint of 
GVHD/relapse or progression-free survival post-transplant will be compared to a non-
randomized contemporary Tac/MTX control group collected through the CIBMTR to identify 
which agents are promising relative to control.  The control group of patients will not be 
individually matched to patients randomized to one of the treatment arms; rather they will be 
selected to satisfy similar eligibility requirements and multivariate regression analysis will be 
used to adjust for potential differences in the groups.  Comparisons among the three randomized 
arms will also be used to guide selection of the most promising agent for further study.   
 
2.2. Hypothesis and Specific Objectives 
 
2.2.1. Hypothesis 
 
At least one of the three treatment approaches will have promising GRFS compared to the 
control group, which is anticipated to have a rate of GRFS by 1 year of 23%.  
 
2.2.2. Study Objectives  
 
The primary objective of the randomized trial is to compare one year GVHD/relapse or 
progression-free survival (GRFS) after HSCT between each of three novel GVHD prophylaxis 
approaches and a contemporary control. An event for this time to event outcome is defined as 
grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, 
disease relapse or progression, or death by any cause. Secondary objectives are to describe rates 
of grade II-IV and III-IV acute GVHD, visceral acute GVHD and chronic GVHD; 
immunosuppression-free survival rate at one year; neutrophil and platelet engraftment; donor cell 
engraftment, immune reconstitution, disease relapse or progression; transplant-related mortality; 
rates of Grade  3 toxicity according to the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0; incidence of infections; and overall survival.  
 
2.3. Patient Eligibility  
 
2.3.1. Inclusion Criteria 
1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old) 
2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no 
circulating blasts and with less than 5% blasts in the bone marrow. 


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3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, 
marginal zone, diffuse large B-cell, Hodgkin’s Lymphoma,or mantle cell lymphoma with 
chemosensitive disease at time of transplantation 
4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a) 
5. Patients must have a related or unrelated peripheral blood stem cell donor as 
follows: 
a.  Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) 
resolution, and -DRB1 at high resolution using DNA-based typing, and must be 
willing to donate peripheral blood stem cells and meet institutional criteria for 
donation. 
b. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing. Unrelated donor must be willing to donate 
peripheral blood stem cells and be medically cleared to donate stem cells 
according to NMDP criteria. 
6. Cardiac function: Ejection fraction at rest ≥ 45% 
7. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault 
formula and actual body weight) 
8. Pulmonary function: DLCO ≥ 40% (adjusted for hemoglobin) and FEV1 ≥ 50%  
9. Liver function: total bilirubin < 1.5 x the upper limit of normal and ALT/AST < 2.5x the 
upper normal limit. Patients who have been diagnosed with Gilbert’s Disease are allowed 
to exceed the defined bilirubin value of 1.5x the upper limit of normal. 
10. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or 
surgically sterilized), agree to practice two (2) effective methods of contraception at the 
same time, or agree to completely abstain from heterosexual intercourse, from the time of 
signing the informed consent through 12 months post transplant (see Section 2.6.4 for 
definition of postmenopausal). 
11. Male subjects (even if surgically sterilized), of partners of women of childbearing 
potential must agree to one of the following: practice effective barrier contraception (see 
Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from 
the time of signing the informed consent through 12 months post transplant. 
12. Signed informed consent 
 
2.3.2. Exclusion Criteria 
1. Prior allogeneic transplant 
2. Karnofsky Performance Score < 70% 
3. Active CNS involvement by malignant cells 
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking 
medication and with progression or no clinical improvement) at time of enrollment. 


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5. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with 
methotrexate clearance or makes methotrexate use contraindicated 
6. Patients with transformed lymphoma (e.g., Richters transformation arising in follicular 
lymphoma or chronic lymphocytic leukemia) 
7. Patients seropositive for the human immunodeficiency virus (HIV) 
8. Patient with active Hepatitis B or C determined by serology and/or NAAT 
9. Patients with hypersensitivity to bortezomib, boron or mannitol 
10. Patients with ≥ grade 2 sensory peripheral neuropathy 
11. Myocardial infarction within 6 months prior to enrollment or New York Heart 
Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities.  Prior to study entry, any ECG 
abnormality at screening must be documented by the investigator as not medically 
relevant. 
12. Female patients who are lactating or pregnant 
13. Patients with a serious medical or psychiatric illness likely to interfere with participation 
in this clinical study 
14. Patients with prior malignancies except resected basal cell carcinoma or treated cervical 
carcinoma in situ.  Cancer treated with curative intent ≥ 5 years previously will be 
allowed.  Cancer treated with curative intent < 5 years previously will not be allowed 
unless approved by the Protocol Officer or one of the Protocol Chairs. 
15. Planned use of ATG or alemtuzumab in conditioning regimen.  
16. Planned post-transplant therapy (including use of TKIs).  
17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes 
(CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan 
metabolism during day -5 through day +7. It is acceptable to use alternative non-
interacting medications during this period, and then resume prior medications. 
18. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, 
including CMML, with evidence of active myeloproliferative features or myelofibrosis in 
the background.  
 
2.3.3. Eligibility for the Control Arm 
 
Patients in the control arm will be identified from patients prospectively reported to the CIBMTR 
from U.S centers not enrolling to the BMT CTN 1203 study and which agree to participate in 
this study.  Control patients will not be individually matched to patients on one of the 
randomized treatment arms, but rather will satisfy similar eligibility requirements.  Patients will 
need to fulfill the same inclusion criteria for the clinical trial according to Section 2.3.1, plus the 
following: 
 


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1. Receive Tac/MTX as the sole GVHD prophylaxis approach 
2. Receive the same regimens as specified in Table 2.4a 
3. Receive PBSC as the graft source 
 
Exclusion criteria for the controls: 
1. Karnofsky Performance Score < 70% 
2. Active CNS involvement by malignant cells 
3. Patients with uncontrolled bacterial, viral or fungal infections (currently taking 
medication and with progression or no clinical improvement) at time of enrollment 
4.  Patients seropositive for the human immunodeficiency virus (HIV) 
5. Patient with active Hepatitis B or C determined by serology and/or NAAT 
 
Data for all eligible patients in centers agreeing to participate as control centers will be used to 
constitute the control database for this study. 
 
2.4. Treatment Plans 
 
It is recommended that adjusted ideal body weight be used when calculating conditioning 
regimen chemotherapy doses..  
 
Ideal Body Weight (IBW) Formulas: 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
Adjusted Ideal Body Weight Formula: 
 
AIBW = IBW + [(0.25) x (ABW - IBW)] 
 
2.4.1 Conditioning Regimens 
 
Eligible patients will receive a reduced intensity or nonmyeloablative conditioning regimen 
according to Table 2.4a.  Other regimens deemed to be RIC and not included in Table 2.4a, 
might be considered after review by the protocol chairs/officer.  
 
 


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TABLE 2.4a: CONDITIONING REGIMENS1 
Reduced Intensity Conditioning 
Nonmyeloablative Conditioning 
Fludarabine/Busulfan (Flu/Bu) 
• Fludarabine (120-180 mg/m2) 
• Busulfan (≤8 mg/kg PO or 6.4 mg/kg IV) 
 Fludarabine/Cyclophosphamide (Flu/Cy) 
• 
Fludarabine (90-120 mg/m2) 
• 
Cyclophosphamide (120 mg/kg or 2250 mg/m2) 
Fludarabine/Melphalan ( Flu/Mel) 
• 
Fludarabine (120-180 mg/m2) 
• 
Melphalan (≤150 mg/m2) 
Fludarabine /Total Body Irradiation (Flu/TBI) 
• 
Fludarabine (90 mg/m2) 
• 
TBI (200 cGy) 
 
Fludarabine/ Cyclophosphamide/TBI 
(Flu/Cy/TBI) 
• 
Fludarabine (150 mg/m2) 
• 
TBI (200 cGy) 
• 
Cyclophosphamide (29 mg/kg)  
1Addition of antithymocyte globulin or alemtuzumab is not allowed.  
 
Fludarabine and busulfan (Flu/Bu) 
 
The recommended Flu/Bu regimen is the following:  
• Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) 
Busulfan Options 
Busulfan without PK - Days -5 to -4: Busulfan (4 mg/kg/day PO or 3.2 mg/kg/day IV or 
130 mg/m2/day IV; total dose of 8 mg/kg or 6.4 mg/kg or 260 mg/m2 respectively) 
 
OR  
Busulfan with PK – Days -6 to -3: Busulfan 100 mg/m2/day IV daily for 4 days to target 
an AUC of 4000 μMol*min/day (course AUC of 16,000 μMol*min). A test dose may be 
administered prior to Day -6 per institutional standards. 
The sequence of fludarabine and busulfan administration will be done according to 
institutional standards as long as the prescribed doses are the same as the 
recommended regimen above. For patients receiving busulfan doses according to 
pharmacokinetics, targeting doses to area under the curve of 4000μMol/min or less 
is allowed. For CNS seizure prophylaxis, the use of Keppra is allowed. Phenytoin 
and other potent CYP3A4 inducers are not allowed for seizure prophylaxis to avoid 
drug interactions.. 
 
Fludarabine and melphalan (Flu/Mel) 
 
The recommended Flu/Mel regimen is the following: 
• Days -5 to -2: Flu (30 mg/m2/day, total dose of 120 mg/m2) 
• Day -1: Mel (140 mg/m2) 
 


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The sequence of fludarabine and melphalan administration will be done according to institutional 
standards as long as the prescribed doses are the same as the recommended regimen above.  
Dividing the dose of melphalan into two days is allowed.  
 
Fludarabine and cyclophosphamide (Flu/Cy) 
 
The recommended Flu/Cy regimen is the following:  
• Days -5 to -3: Flu (30 mg/m2/day, total dose of 90 mg/m2) 
• Days -4 to -2:  Cyclophosphamide (750 mg/m2/day, total dose of 2250 mg/m2) 
Alternatively: 
•  Days -3 to -2: Cyclophosphamide (60 mg/kg/day, total dose of 120 mg/kg) 
 
The sequence of fludarabine and cyclophosphamide administration will be done according to 
institutional standards as long as the prescribed doses are the same as the recommended regimen 
above.  Addition of rituximab conditioning in patients with lymphoproliferative disease is 
allowed.  Dose and intervals of rituximab conditioning can be determined according to 
institutional guidelines.  However, rituximab use after stem cell infusion is not permitted.  
 
Fludarabine and total body irradiation (Flu/TBI) 
 
The recommended Flu/TBI regimen is the following:  
• Days -5 to -3: Flu (30 mg/m2/day, total dose of 90 mg/m2) 
• Day 0:  TBI 200 cGY (pre-stem cell infusion) 
 
Fludarabine, total body irradiation and cyclophosphamide (Flu/Cy/TBI) 
 
The recommend Flu/Cy/TBI regimen is the following: 
• Days -6 to -5: Cy (14.5 mg/kg/day, total dose of 29 mg/kg) 
• Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) 
• Day -1: TBI 200 cGY 
 
2.4.2 Hematopoietic Stem Cell Transplantation 
 
Mobilized PBSC is the only allowed graft source for patients enrolled in this clinical trial.  
 
Donors will undergo G-CSF mobilization according to local institutional and donor center 
practices.  PBSC will be collected by apheresis according to local institutional guidelines.  
Plasma and red cell depletion are allowed for volume reduction or ABO incompatibility but any 
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The target stem cell dose is between 2 x 106/kg and 10 x 106/kg (actual body weight) CD34+ 
cells. The maximum CD34+ cell dose is 10 x 106/kg.    
 
Up to two leukapheresis procedures may be performed to obtain the minimum CD34+ cell target.  
If, after two leukapheresis procedures, fewer than 2 x 106/kg CD34+ cells have been collected, 
transplant centers will have the discretion to continue PBSC cell harvesting or to proceed to bone 
marrow harvesting to obtain sufficient cells.  If bone marrow harvesting is needed in order to 
meet the desired cell dose, the transplant center needs to notify the Protocol Coordinator, Chairs 
or Officer.   
 
If more than 10 x 106/kg CD34+ stem cells are collected, the excess will either be discarded or 
cryopreserved for future use, but will not be administered to the patient. 
 
PBSC will be administered on Day 0 to all patients according to individual institutional 
guidelines after appropriate processing and quantification has been performed by the local 
laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion 
occurs over two days, Day 0 is the day the last infusion is completed. Sites should avoid infusion 
after 4pm because this complicates the administration of Bortezomib if dose modifications are 
required due to toxicity. If modifications are required, late infusion of the stem cell source could 
alter the calendar schedule and result in either a missed dose or a protocol violation.  
 
2.4.3 Tacrolimus/Methotrexate/Bortezomib 
 
Tacrolimus 
 
Tacrolimus will be given per institutional practices, orally at a dose of 0.05 mg/kg or 
intravenously at a dose of 0.03 mg/kg starting Day -3. The dose of tacrolimus may be rounded to 
the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels. The 
dose should be adjusted accordingly to maintain a suggested level of 5-15 ng/mL. If patients are 
on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose 
and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be 
initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate 
of tapering will be done according institutional practices but patients should be off tacrolimus by 
Day 180 post HSCT if there is no evidence of active GVHD.  
 
Dose reductions should be made if toxicity is present or whole blood levels are above the  
recommended range, in the absence of toxicity.  Patients with severe intolerance of tacrolimus 
may be placed on cyclosporine (trough level of 200-400 ng/mL) or sirolimus (trough level of 3-8  
ng/mL). 
 
Methotrexate 
 
Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus 
on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell 
infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic 
stem cell infusion and at least 30 minutes after the first dose of bortezomib. Dose reduction of 


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MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum 
levels or development of oral mucositis is allowed according to institutional practices.  
 
Bortezomib 
 
Bortezomib will be administered at the dose of 1.3 mg/m2 (based upon actual body weight) as an 
approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell 
infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous 
administration of bortezomib is not allowed on this protocol. 
 
Bortezomib dose modifications: 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI Common 
Toxicity Criteria for Adverse Events (CTCAE), Version 4.0 
Neuropathic pain and peripheral sensory neuropathy are to be managed as described in Table 
2.4b. 
Table 2.4b:  Management of Patients With VELCADE-Related Neuropathic Pain and/or Peripheral 
Sensory or Motor Neuropathy  
Severity of Peripheral Neuropathy Signs and 
Symptomsa  
Modification of Dose and Regimen 
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or parasthesias) without pain or loss of 
function 
No action 
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities or 
Daily Living [ADL]b) 
Reduce VELCADE to 1.0 mg/m2 
Grade 2 with pain or Grade 3 (severe symptoms; 
limiting self care ADLc) 
Withhold VELCADE therapy until toxicity resolves. 
When toxicity resolves reinitiate with a reduced dose of 
VELCADE at 0.7 mg/m2 (missed dose days will not be 
made up). 
Grade 4 (life-threatening consequence; urgent 
intervention indicated) 
Discontinue VELCADE 
Source:  VELCADE USPI issued January 2012. 
Abbreviations: ADL = activities of daily living 
a   Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
b   Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, 
managing money, etc 
c   Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Patients with mild hepatic impairment (bilirubin ≤ 1.5  ULN) do not require dose adjustment.    
If a patient develops moderate or severe hepatic impairment with bilirubin ≥ Grade 2 (> 1.5 -3.0 
X ULN) after exposure to Bortezomib, the dose should be held until the toxicity returns to < 
Grade 2. Restarting Bortezomib must be done at the next lower dose level as below.  


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Once bortezomib is reduced for any toxicity, the dose may not be re-escalated. 
If after bortezomib has been held, the toxicity does not resolve, then bortezomib must be 
discontinued. 
If the toxicity resolves, as described above, bortezomib may be restarted at the same schedule the 
patient was on prior to holding therapy, and the dose must be reduced by approximately 25% as 
follows: 
• If the patient was receiving 1.3 mg/m2, reduce the dose to 1 mg/m2. 
• If the patient was receiving 1 mg/m2, reduce the dose to 0.7 mg/m2. 
 
2.4.4 Tacrolimus/Methotrexate/Maraviroc 
 
Tacrolimus 
 
Tacrolimus will be given per institutional practices, orally at a dose of 0.05 mg/kg or 
intravenously at a dose of 0.03 mg/kg starting Day -3. The dose of tacrolimus may be rounded to 
the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels. The 
dose should be adjusted accordingly to maintain a suggested level of 5-15 ng/mL. If patients are 
on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose 
and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be 
initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate 
of tapering will be done according to institutional practices but patients should be off tacrolimus 
by Day 180 post HSCT if there is no evidence of active GVHD.  
 
Dose reductions should be made if toxicity is present or whole blood levels are above the  
recommended range, in the absence of toxicity.  Patients with severe intolerance of tacrolimus 
may be placed on cyclosporine (trough level of 200-400 ng/mL) or sirolimus (trough level of 3-8  
ng/mL). 
 
Methotrexate 
 
Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus 
on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell 
infusion. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic 
stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation 
of conditioning regimen, high serum levels or development of oral mucositis is allowed 
according to institutional practices.  
 
Maraviroc 
 
Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to 
hematopoietic stem cell infusion, and continue until Day 30 post HSCT.  If the patient requires a 
two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day (on 
day 29). There are no food restrictions.  
 


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Maraviroc dose modifications 
 
The dose of maraviroc for patients who are not taking strong inhibitors or inducers of CYP 450 
is 300 mg twice daily. The dose will be adjusted in patients who take specific concomitant 
medications based on Table 2.4c. In particular, the use of anti-seizure medications that induce 
CYP 450 is allowed (with maraviroc dose adjustment) only if patients are taking them 
chronically. The use of these medications (carbamazepine, phenobarbital, and phenytoin) as anti-
seizure prophylaxis during conditioning is not allowed. 
 
 
TABLE 
2.4c: 
MARAVIROC 
DOSING 
REGIMEN 
WITH 
CONCOMITANT MEDICATIONSConcomitant Medications  
Dose of Maraviroc  
Potent CYP3A inhibitors (with or without a potent CYP3A inducer)1: 
ketoconazole, itraconazole, clarithromycin 
150 mg twice daily  
Potent CYP3A inducers (without a potent CYP3A inhibitor): 
Rifampin, carbamazepine, phenobarbital, and phenytoin  
600 mg twice daily  
1 Both voriconazole and posaconazole are moderate CYP3A inhibitors and do not require dose adjustment of 
maraviroc. Pharmacokinetic data on maraviroc and voriconazole combination demonstrated no need for dose 
reduction of maraviroc.  
 
Renal dysfunction does not require a dose modification in patients who receive maraviroc  
300 mg twice daily and the drug should not be held in severe renal dysfunction or in patients 
undergoing renal replacement therapy. In patients who receive maraviroc 600 mg twice daily or 
150 mg twice daily due to concomitant medications, the drug should be held in severe renal 
failure (CrCl <30 mL/min), and restarted when the CrCl ≥ 30 at the same dose level due to lack 
of data for these dose levels and according to the approved prescribing information. Renal 
function will be calculated using the Cockcroft-Gault formula and actual body weight. 
 
Maraviroc dose reduction of 50% will take place if the following requirement is met: 
 
Symptoms of postural hypotension such as dizziness, syncope or loss of consciousness together 
with evidence for postural hypotension defined as a decrease in supine to standing blood 
pressure of at least 10 mmHg (diastolic) or 20 mmHg (systolic) or a standing systolic blood 
pressure lower than 90 mmHg.  The drug must be held until symptomatic hypotension resolves 
prior to reducing the dose. 
 
The following events will mandate holding maraviroc therapy: 
• Grade 3 or higher liver toxicity not attributable to other causes such as infection, GVHD, 
toxicity from other drugs or sinusoid obstructive syndrome/veno-occlusive disease. 
• Other non-hematologic grade 3 or higher toxicity, which is not attributable to other 
causes such as GVHD, infection, disease relapse and chemotherapy toxicity. 
• Severe mucositis, nausea or other complications that precludes administration of an oral 
medication.  
• Persistent symptomatic postural hypotension after reduction to 150 mg twice daily dose. 


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The drug should be restarted at the same dose after recovery of related toxicities to grade 2 or 
lower or identification of an alternative cause for these toxicities. 
 
GVHD does not require holding maraviroc therapy unless other criteria are met (e.g., grade 3 
liver toxicity). 
 
2.4.5 Tacrolimus/Mycophenolate Mofetil/Cyclophosphamide 
 
Tacrolimus 
 
Tacrolimus will be given per institutional practices, orally at a dose of 0.05 mg/kg or 
intravenously at a dose of 0.03 mg/kg starting Day +5.  Serum levels of tacrolimus will be 
measured at Day 7 and then should be checked weekly thereafter, and the dose adjusted 
accordingly to maintain a suggested level of 5-15 ng/mL.  Tacrolimus taper can be initiated at a 
minimum of 90 days post HSCT if there is no evidence of active GVHD.  The rate of tapering 
will be done according to institutional practices but patients should be off tacrolimus by Day 180 
post HSCT if there is no evidence of active GVHD.  
 
Dose reductions should be made if toxicity is present or whole blood levels are above the  
recommended range, in the absence of toxicity.  Patients with severe intolerance of tacrolimus 
may be placed on cyclosporine (trough level of 200-400 ng/mL) or sirolimus (trough level of 3-8  
ng/mL). 
 
Mycophenolate mofetil (MMF) 
 
MMF will be given at a dose of 15 mg/kg TID (based upon actual body weight) with the 
maximum total daily dose not to exceed 3 grams (1g TID, IV or PO).  MMF prophylaxis will 
start Day 5 and discontinue after the last dose on Day 35, or may be continued if active GVHD is 
present.  
 
Cyclophosphamide 
 
Hydration prior to cyclophosphamide may be given according to institutional standards.  A 
recommended approach is as follows:  Patients are instructed to increase fluids overnight before 
cyclophosphamide administration.  Hydration with normal saline at 3 ml/kg/hr IV will be started 
2 hours prior to cyclophosphamide, then the rate will be reduced to 2 ml/kg/hr for 1 hour pre-
cyclophosphamide and continued at 2 ml/kg/hr for 8 hours post-cyclophosphamide. 
 
Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-
cyclophosphamide or administered per institutional standards.  Mesna dose will be based on the 
cyclophosphamide dose being given.  The total daily dose of Mesna is equal to 80% of the total 
daily dose of cyclophosphamide.   
 
Cyclophosphamide [50 mg/kg IBW; if ABW < IBW, use ABW] will be given on Day 3 post-
transplant (between 60 and 72 hours after the start of the PBSC infusion) and on Day 4 post-


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transplant (approximately 24 hours after Day 3 cyclophosphamide).  Cyclophosphamide will be 
given as an IV infusion over 1-2 hours (depending on volume). 
 
It is crucial that no immunosuppressive agents are given prior to transplant, or until 24 
hours after the completion of the post-transplant cyclophosphamide.  This includes 
corticosteroids as anti-emetics. 
 
2.5  Supportive Care 
 
All supportive care will be given in keeping with the BMT CTN Manual of Procedures and local 
institutional practice.  Supportive care will be administered in a similar fashion to subjects 
randomized to all three arms of the study. 
 
2.5.1 Growth Factors 
 
G-CSF may be given per institutional guidelines. 
 
2.5.2 Blood Products 
 
Transfusion thresholds for blood product support will be consistent with the BMT CTN MOP 
and standard institutional guidelines.  All blood products will be irradiated. 
 
2.5.3 Prophylaxis Against Infections 
 
Patients will receive infection prophylaxis according to institutional guidelines. Infection 
prophylaxis will include, but is not limited to, agents or strategies (e.g., PCR screening and 
preemptive therapy) to reduce the risk of bacterial, herpes simplex, CMV, HHV-6, EBV, 
Pneumocystis jiroveci, and fungal infections: 
• Antifungal therapy: Prophylaxis with fluconazole or other antifungal agents can be given 
as per local institutional guidelines.   
o Fluconazole, voriconazole and other azoles are expected to increase serum 
tacrolimus levels, therefore, dosages of tacrolimus should be adjusted 
accordingly. These drugs also interact with bortezomib and it is recommended to 
avoid using them from Day 0 to Day +7 among patients who are randomized to 
bortezomib. 
 
• CMV: CMV monitoring will be done according to institutional guidelines. It is 
recommended that weekly assessment for CMV be done through Day 60 post-transplant. 
Any reactivation and/or CMV disease will be captured in this study. An Infection form 
must be submitted in AdvantageEDC.   
 
2.5.4 Intravenous Immune Globulin (IVIG) 
 
IVIG administration will be according to local institutional standard practice. 


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2.6  Participant Risks 
 
2.6.1 Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.   
 
2.6.2 Tacrolimus 
 
Tacrolimus side effects include:  
• Cardiovascular: hypertension 
• Neurologic: confusion, dizziness, insomnia, seizures, tremors, changes in how clearly one 
can think 
• Gastrointestinal: nausea, vomiting 
• Hematologic: microangiopathic hemolytic anemia, thrombocytopenia 
• Endocrine and metabolic: hypomagnesemia, hypokalemia, hypocalcemia, hyperlipidemia 
• Miscellaneous: unwanted hair growth, changes in vision, liver problems, reversible renal 
insufficiency, infections and post-transplant lymphoproliferative disorders  
 
2.6.3 Methotrexate 
 
The most frequently reported adverse reactions associated with methotrexate use as GVHD 
prophylaxis include: 
 
• Neurologic: fever, dizziness, chills, undue fatigue 
• Gastrointestinal: ulcerative stomatitis, nausea, abdominal distress, diarrhea 
• Hematologic:  leucopenia, anemia, and suppressed hematopoiesis (leading to infection) 
• Miscellaneous: abnormal liver tests, kidney failure, and pulmonary complications after 
transplantation  
 
2.6.4 Bortezomib 
 
To date, more than 436,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. 
 
Prescribing physicians and health care practitioners are referred to their locally approved product 
label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and 
Precautions. 
 


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The known anticipated risks of bortezomib therapy are presented in Appendix H. These risks are 
grouped according to the combined frequency observed in an integrated analysis of AEs in 
sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-
day schedule, in patients with multiple myeloma and mantle cell lymphoma. 
 
The most common Bortezomib side effects include: 
• Hematologic: anemia, neutropenia, thrombocytopenia, leucopenia, lymphopenia  
• Neurologic: asthenia, dizziness, anxiety, syncope, headache, insomnia, fever, rigors, 
chills, sensory peripheral neuropathy, and leukoencephalopathy, including reversible 
posterior leukoencephalopathy syndrome 
• Pulmonary: cough, dyspnea, pleural effusion, pneumonitis, interstitial pneumonia, edema 
acute respiratory distress syndrome (ARDS) 
• Cardiovascular: hypotension, tachycardia, atrial fibrillation, palpitation, congestive heart 
failure, bradycardia, atrial flutter, atrioventricular block, arrhythmia, cardiac failure, 
cardiac arrest, pericardial effusion, pericarditis  
• Infectious: reactivations of herpes zoster, opportunistic infections  
• Gastrointestinal: weight loss, decreased appetite, anorexia, constipation, dehydration, 
diarrhea, heartburn, dyspepsia, stomatitis, nausea, vomiting, ileus, GI perforation, acute 
pancreatitis 
• Metabolic: hyperglycemia, hypoglycemia, hyponatremia, hypokalemia, hypercalcemia 
• Renal: renal failure 
• Neuromuscular and skeletal: arthralgias, back pain, bone pain, muscle cramp and 
myalgias 
• Miscellaneous: rash, hemorrhage, blurred vision, deafness, hepatitis, hyperbilirubinemia 
Other medical events of interest that are considered not causally related to bortezomib 
include hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib.  Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
 
Additional details on the potential risks of bortezomib may be found in the current 
Investigator’s Brochure. 
 
 


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Bortezomib Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner.  Non-sterilized female patients of 
reproductive age and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
 
Female patients must meet 1 of the following: 
• Postmenopausal for at least 1 year before the screening visit. Postmenopausal is defined 
as the time after which a woman has experienced twelve (12) consecutive months without 
a menstrual period.   
• Surgically sterile 
• If they are of childbearing potential (i.e., not postmenopausal or surgically sterile), agree 
to practice 2 effective methods of contraception from the time of signing the informed 
consent form through 12 months post-transplant, or agree to completely abstain from 
heterosexual intercourse. It is strongly recommended that at least 1 of these 2 methods be 
‘highly effective’ (see Table 2.6). 
Table 2.6 Methods of Contraception 
Highly Effective Methods 
Other Effective Methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended. 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to one (1) of 
the following: 
• Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug,  
• Completely abstain from heterosexual intercourse. 
 
2.6.5 Maraviroc 
 
Maraviroc side effects include: 
• Neurologic: fever, dizziness (including postural dizziness), insomnia, anxiety, 
consciousness disturbances, depression, pain 
• Dermatologic: rash, pruritus, folliculitis, skin neoplasms (benign), erythema, acne 


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• Pulmonary: upper respiratory tract infection, cough, bronchitis, sinusitis, breathing 
abnormality, respiratory tract/sinus disorder 
• Cardiovascular: Vascular hypertensive disorder 
• Endocrine and metabolic: lipodystrophy 
• Gastrointestinal: Appetite disorders, constipation 
• Genitourinary: Urinary tract/bladder symptoms, genital warts 
• Hematologic: Neutropenia (grades 3/4) 
• Hepatic: Transaminases increased (grades 3/4), bilirubin increased (grades 3/4) 
• Neuromuscular and skeletal: Joint disorders, parasthesia, sensory abnormality, myalgia, 
peripheral neuropathy 
• Ocular: Conjunctivitis, infection/inflammation 
• Miscellaneous: Herpes infection, sweat gland disturbances, influenza 
 
2.6.6 Mycophenolate mofetil (MMF) 
 
MMF side effects include: 
• Neurologic: headache, tremors, insomnia, dizziness, excessive fatigue, weakness  
• Cardiovascular: tachycardia 
• Pulmonary: dyspnea 
• Gastrointestinal: nausea, vomiting, dyspepsia, abdominal pain, diarrhea, hematemesis and 
hematochezia 
• Hematologic: Neutropenia, thrombocytopenia, unusual bruising, and anemia 
• Endocrine and metabolic: hyperlipidemia 
• Miscellaneous: rash, edema, change in vision, infection, second cancers, teratogenicity, 
miscarriage, limited effectiveness of birth control, and progressive multifocal 
leukoencephalopathy (PML). 
 
2.6.7 Cyclophosphamide 
 
Cyclophosphamide side effects include:  
• Gastrointestinal: nausea, vomiting, anorexia, mucositis, stomatitis, abdominal pain, 
diarrhea 
• Cardiovascular: cardiomyopathy, fluid weight gain/edema 
• Hematologic: myelosuppression, hemolytic anemia 


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• Miscellaneous: skin rash, alopecia, hemorrhagic cystitis, pulmonary toxicity, temporary 
lethargy, secondary cancers, gonadal function impairment, sterility, and damage to fetus 
if taking drug while pregnant 
 
2.7 Study Drug Supply 
 
2.7.1 Tacrolimus, Methotrexate, Cyclophosphamide and Mycophenolate Mofetil  
 
Tacrolimus, methotrexate, cyclophosphamide and mycophenolate mofetil are commercially 
available agents and will be administered as described in Section 2.4. 
 
2.7.2 Bortezomib and Maraviroc 
 
Bortezomib will be provided by Millennium Pharmaceuticals, Inc. and distributed by the BMT 
CTN 1203 Central Pharmacy directly to transplant centers. Maraviroc will also be provided by 
the study and distributed by the BMT CTN 1203 Central Pharmacy directly to transplant centers. 
 
BORTEZOMIB 
 
Drug Supply, Preparation, Handling and Storage: 
Bortezomib for Injection (supplied by Millennium Pharmaceuticals, Inc.) is a sterile lyophilized 
powder for reconstitution and is supplied in vials containing bortezomib and mannitol at a 1:10 
ratio.  For example, vials containing 3.5mg of bortezomib contain 35mg of mannitol. 
 
Vials containing lyophilized Bortezomib for Injection will be stored according to the label 
requirements.  For the United States, store at USP Controlled Room Temperature which is 25ºC 
(77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF).  To date, stability data indicate that 
the lyophilized drug product is stable for at least 18 months when stored under the recommended 
conditions.  Stability studies are ongoing, and Millennium Pharmaceuticals, Inc. will notify the 
investigator should this information be revised during the conduct of the study. 
 
Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling Bortezomib solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations.  The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area immediately 
and thoroughly with soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes.  Always contact a physician after any 
form of body contact. All materials that have been used for preparation will be disposed of 
according to standard practices. A log must be kept of all disposed materials. 
 
Drug is available in sterile, single use vials containing 3.5 mg of Bortezomib. The vials are not 
patient specific.  Each vial of Bortezomib for Injection will be reconstituted under a laminar flow 
biological cabinet (hood) within eight hours before dosing.  For intravenous infusions, 
reconstitution must be with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection USP 
with a concentration of 1 mg/mL.  Prior to reconstitution the vials will remain in the cartons to 


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protect them from light.  Dissolution is completed in approximately 10 seconds.  The 
reconstituted solution is clear and colorless, with a final pH of 5 to 6.  Reconstituted Bortezomib 
will be administered promptly and in no case more than 8 hours after reconstitution.   
 
Administration: 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).   
 
The drug will be prepared under the supervision of a pharmacist, or appropriately qualified and 
trained personnel.  The amount (in mg) of drug to be administered will be determined based on 
body surface area.  Body surface area is to be calculated based on body weight using institutional 
standards.  Any discrepancy between the calculated dose and dose administered and the 
reason for the discrepancy must be recorded in the source documents. 
 
The appropriate amount of Bortezomib will be drawn from the injection vial and administered as 
an intravenous (IV) push over 3 to 5 seconds followed by a standard saline flush or through a 
running IV line.  Vials are for single use administration.   
 
There must be at least 72 hours between each dose of bortezomib. 
 
Drug Ordering: 
Bortezomib will be supplied to participating centers from the BMT CTN 1203 Central Pharmacy. 
Refer to the BMT CTN 1203 Study Drug Guide for additional information regarding study drug 
supply and ordering, or contact the BMT CTN 1203 DCC Protocol Coordinator. 
 
Drug Accountability: 
Accountability for the drug at all study sites is the responsibility of the principal investigator.  
The investigator will ensure that the drug is used only in accordance with this protocol.  Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and return to the BMT CTN 1203 Central Pharmacy or disposal of the drug (if 
applicable and if approved by Millennium) will be maintained by the clinical site.  
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient 
numbers.   
 
Drug Destruction: 
Investigational bortezomib (expired or end of study) will be destroyed on site according to the 
institution’s standard operating procedure. Be sure to document removal and destruction on drug 
accountability logs. 
 
MARAVIROC 
 
Drug Supply, Preparation, Handling and Storage: 
Maraviroc (Selzentry) is manufactured by Pfizer, Inc. 
 


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Maraviroc will be supplied in 150 mg and 300 mg tablets and will be stored according to the label 
requirements.  For the United States, store at USP Controlled Room Temperature which is 25ºC 
(77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF).   
 
Administration: 
Drug will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).   
 
Maraviroc will be dispensed under the supervision of a pharmacist, or appropriately qualified 
and trained personnel.  The amount (in mg) of drug to be administered will be per protocol 
Section 2.4.4.1 (Maraviroc) and Section 2.4.4.2 (Maraviroc Dose Modifications). Maraviroc can 
be taken with or without food. Tablets should be swallowed whole. However, if necessary they 
may be crushed and administered to the patient in a liquid or pudding.   
 
Drug Ordering: 
Maraviroc will be supplied to participating centers from the BMT CTN 1203 Central Pharmacy. 
Refer to the BMT CTN 1203 Study Drug Guide for additional information regarding study drug 
supply and ordering, or contact the BMT CTN 1203 DCC Protocol Coordinator. 
 
Drug Accountability: 
Accountability for the drug at all study sites is the responsibility of the principal investigator.  
The investigator will ensure that the drug is used only in accordance with this protocol.  Drug 
accountability records indicating the drug’s delivery date to the site, inventory at the site, use by 
each patient, and return to the central pharmacy or disposal of the drug will be maintained by the 
clinical site.  Accountability records will include dates, quantities, lot numbers, expiration dates, 
and patient numbers.   
 
Drug Destruction: 
Investigational maraviroc (expired or end of study) will be destroyed on site according to the 
institution’s standard operating procedure. Be sure to document removal and destruction on drug 
accountability logs. 
 


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CHAPTER 3 
 
 
3. STUDY ENDPOINTS 
 
3.1. Primary Endpoint 
 
The primary endpoint is GVHD/relapse or progression-free survival (GRFS).  All randomized 
patients and patients in the contemporary CIBMTR control will be analyzed for this endpoint.  
An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD 
requiring systemic immunosuppressive treatment, disease relapse or progression, or death by any 
cause.  Patients will be followed up for at least one year for this endpoint. 
 
Use of systemic immunosuppressive therapy for treatment of chronic GVHD is at the discretion 
of the treating physicians.  The event of interest is the development of chronic GVHD severe 
enough to warrant any additional systemic treatment(s).  Also, continuation of study-mandated 
GVHD prophylaxis beyond Day 180 in the presence of chronic GVHD will also be considered 
an event with time to event determined as date of chronic GVHD onset.   
 
3.2. Secondary Endpoints 
 
3.2.1. Acute GVHD 
 
Cumulative incidences of grade II-IV and III-IV acute GVHD will be determined.  Acute GVHD 
will be graded according to the BMT CTN MOP.  The time of onset of acute grades II-IV and 
III-IV acute GVHD will be recorded, as well as the maximum grade achieved.  This endpoint 
will be evaluated through 180 days post HSCT.  Within the acute GVHD endpoint, the 
proportion of patients with visceral involvement (liver or gut) will be described.  
 
3.2.2. Chronic GVHD 
 
The cumulative incidence of chronic GVHD will be determined.  Data will be collected directly 
from providers and chart review according to the recommendations of the NIH Consensus 
Conference.  Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD 
involvement.  Liver and pulmonary function test results, and use of systemic therapy for 
treatment of chronic GVHD will also be recorded.  These data will allow calculation of the NIH 
global severity scores of mild, moderate and severe chronic GVHD, which has been associated 
with transplant related mortality and overall survival.  Assessment of chronic GVHD will occur 
up to one year post HSCT.  
 
3.2.3. 1-year Immunosuppression-free Survival 
 
Patients who are alive, relapse-free, and do not need ongoing immune suppression to control 
GVHD at one year post HSCT are considered successes for this endpoint.  Immune suppression 
is defined as any systemic agents used to control or suppress GVHD.  Corticosteroid doses of 
>10 mg present will be considered active systemic immune suppression treatment.  Patients who 


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discontinued immune suppression < 15 days prior to the 1-year time point will be considered to 
be on immune suppression for this endpoint.  
 
3.2.4. Hematologic Recovery 
 
Hematologic recovery will be assessed according to neutrophil and platelet counts recovery after 
HSCT. Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC)  
≥ 500/mm3 for three consecutive measurements on three different days.  The first of the three 
days will be designated the day of neutrophil recovery.  The competing event is death without 
neutrophil recovery.  For patients who never drop ANC below 500/mm3, the date of neutrophil 
recovery will be Day +1 post HSCT.  
 
Platelet recovery is defined by two different metrics: the first day of a sustained platelet count 
>20,000/mm3 or >50,000/mm3 with no platelet transfusion in the preceding seven days.  The first 
day of sustained platelet count above these thresholds will be designated the day of platelet 
engraftment.  For patients who never drop their platelet count below 20,000/mm3 or 50,000/mm3, 
the date of platelet recovery will be Day +1 post HSCT.  
 
3.2.5. Donor Cell Engraftment 
 
Donor cell engraftment will be assessed with donor/recipient chimerism studies.  Chimerism 
may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 
or CD15 fraction.  For the purpose of this protocol, mixed chimerism is defined as the presence 
of donor cells, as a proportion of total cells to be < 95% but > 5% in the bone marrow or 
peripheral blood.  Full donor chimerism is defined as ≥ 95% of donor cells. Mixed and full 
chimerism will be evidence of donor cell engraftment.  Donor cells of ≤ 5% will be considered as 
graft rejection.  The proportion of patients with each level of chimerism described above will be 
described as part of this outcome.  For sorted blood cell fractions, CD3+ donor cell chimerism 
will be used to define the donor/recipient chimerism status.  
 
3.2.6. Disease Relapse or Progression 
 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pretransplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy.  Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation.  The 
event is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy.  
 
Acute leukemia and MDS – Relapse will be diagnosed when there is: 
- 
Reappearance of leukemia blast cells in the peripheral blood; or, 
- 
>5% blasts in the bone marrow, not attributable to another cause (e.g. bone marrow 
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- 
The appearance of previous or new dysplastic changes (MDS specific) within the bone 
marrow with or without falling donor chimerism; or  
- 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid or 
- 
The reappearance of cytogenetic abnormalities present prior to transplantation 
 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
- 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site will only be considered relapsed or progressive disease after 
confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
- 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules).  To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by  50% and to a size of 1.5 x 1.5 cm or 
more than 1.5 cm in the long axis.  
 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (<1.5 cm in its long axis by CT). 
 
- 
In addition to the criteria above, patients with CLL who present in complete remission 
prior to transplantation may fulfill the relapse definition if there is reappearance of 
circulating malignant cells that are phenotypically characteristic of CLL.  
 
Institution of any therapy to treat persistent, progressive or relapsed disease, including the 
withdrawal of immunosuppressive therapy or donor lymphocyte infusion, will be 
considered evidence of relapse/progression regardless of whether the criteria described 
above were met.  
 
3.2.7. Transplant-related Mortality 
 
The cumulative incidence of TRM will be estimated at Days 100, 180, and 1 year after HSCT.  
An event for this endpoint is death without evidence of disease progression or recurrence. 
Disease progression or recurrence will be considered competing events. 
 
3.2.8. Toxicity 
 
All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention 
arm.  The proportion of patients developing grade ≥ 3 AE across intervention arms will be 
compared.  


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3.2.9. Infections 
 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for 
each intervention arm.  The cumulative incidence of CMV reactivation in the first 100 days post 
HSCT will be described.  All Grade 2 and 3 infections will be reported according to the BMT 
CTN MOP.  
 
3.2.10. Disease-Free Survival 
 
Disease free survival is the time from date of transplant to death or relapse/progression, 
whichever comes first.  The event for this endpoint is relapse/progression or death.  Patients alive 
and disease free will be censored at last follow-up.  
 
3.2.11. GVHD-Free Survival 
 
An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD 
requiring systemic immunosuppressive treatment, or death by any cause.  The time for this 
GVHD-free survival endpoint is the time from date of transplant to death or grade 3/4 acute 
GVHD or chronic GVHD requiring immunosuppressive treatment, whichever comes first.  
Patients alive without experiencing an event will be censored at last follow-up. 
 
3.2.12. Overall Survival 
 
Overall survival is defined as the time interval between date of transplant and death from any 
cause or for surviving patients, to last follow-up.  The event for this endpoint is death from any 
cause.   
 
 


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CHAPTER 4 
 
 
4. PATIENT ENROLLMENT AND EVALUATIONS 
 
4.1. Approaching Patients, Eligibility Screening and Obtaining Consent 
 
Subjects will be approached for this study after the decision to proceed with transplantation is 
made and a suitable HLA-matched PBSC donor is identified. Patients willing to participate in the 
trial will sign an Institutional Review Board approved consent form.   Transplant physicians will 
evaluate the patient eligibility for randomization onto this study (see Section 2.2).  Eligibility 
criteria will be verified and ineligible patients will proceed off study and no further follow-up 
will be obtained.  Transplant center personnel will record the documentation of patient consent in 
EMMES AdvantageEDCSM (Electronic Data Capture, an Internet-based data entry system) and 
patients will be registered through AdvantageEDC. 
 
4.2. Transplant Protocol Registration 
 
Before randomization occurs, the transplant center must state through AdvantageEDC which 
conditioning regimen will be used for the enrolled subject.  Such a registration step will avoid 
potential biases that preferential use of a certain regimen on one treatment arm could confer to 
the study.  At this stage, the transplant center will also verify that the patient is still a candidate 
for transplantation, and eligible for the trial.   
 
4.3. Randomization 
 
Once the subject is deemed eligible and has given written informed consent, and the transplant 
center has confirmed patient eligibility and registered the patient’s conditioning regimen, 
randomization occurs.  Patients should be randomized as close as possible to the initiation of the 
conditioning regimen, and preferably within 7 days of and not more than 14 days from the 
initiation of conditioning. If there is a delay in conditioning, certain pre-transplant evaluations 
will have to be repeated. Refer to section 4.6.1 Patient Assessments-pre-transplant evaluations.  
 
4.4. Treatment Scheduling 
 
Treatment should be initiated as soon as possible after randomization.  This will prevent subject 
attrition prior to HSCT for reasons such as disease progression.  Consequently, all treatments 
related to the transplant should be scheduled PRIOR to randomization. This includes planning an 
admission date and ensuring that the PBSC donor can be mobilized and undergo apheresis in a 
coordinated fashion with the planned transplant.   
 
4.5. Patient Evaluation 
 
The patient pre-transplant evaluation must be completed within three weeks (≤21 days) of 
randomization. If an unexplained delay in treatment occurs and the initiation of conditioning is 
greater than 14 days after randomization, some pre-transplant evaluations may need to be 


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repeated. See section 4.6.1 Patient Assessments-pre-transplant evaluations. This step is necessary 
because patient organ function, infection status and status of malignancy may vary over time.  
This evaluation will protect patients with a new contraindication to transplant from initiating 
transplant therapy at an unsafe time. 
 
4.6. Study Monitoring 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.6a.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
 
TABLE 4.6a: FOLLOW-UP SCHEDULE 
 
Study Visit 
Target Day Post-Transplant 
Baseline 
 42 days from conditioning 
1 week 
7  2 days 
2 week 
14  2 days 
3 week 
21  2 days 
4 week 
28  2 days 
5 week 
35  2 days 
6 week 
42  2 days 
7 week 
49  2 days 
8 week 
56  2 days 
9 week 
63  2 days 
100 day 
100  7 days 
4 month 
120  7 days 
5 month 
150  7 days 
6 month 
180  14 days 
9 month 
270  days 
12 month 
365  14 days 
 
4.6.1. Patient Assessments 
 
Table 4.6b summarizes patient clinical assessments over the course of the study.  
 


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TABLE 4.6b: PATIENT CLINICAL ASSESSMENTS 
 
Study Assessments/  
Testing 
Baseline 
7 
14 
21 
28 
35 
42 
49 
56 
63 
100 
120 
150 
180 
270 
365 
History, physical exam, weight and height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky performance status (see Appendix F) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
HCT-Specific Comorbidity Index score (see Appendix G) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (donor and recipient) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC1, differential, platelet count, and blood chemistries2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Estimated creatinine clearance3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease titers4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG and LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO and FEV1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disease evaluation5 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Chest x-ray or chest CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVHD assessments7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessments8 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Chimerism9 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Blood samples for future research (see Appendix C)10 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
1CBC with differential performed three times weekly from Day 0 until ANC > 500/mcL for three days and platelet count > 20,000/mcL after nadir, while 
hospitalized.  CBC then performed weekly through Day 63 post-transplant and every other week through Day 100 post-transplant, then at Days 180, 270 and 
365 post-transplant. 
2Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST and ALT. Blood chemistries performed twice weekly until hospital 
discharge.  Blood chemistries performed weekly after hospital discharge until Day 63 post-transplant, then every other week through Day 100 post-
transplant, and then at Days 180, 270 and 365 post-transplant. 
3Estimated creatinine clearance is calculated using the Cockcroft-Gault formula and actual body weight. 
4Infectious disease titers include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and 
HTLV I/II antibody, and varicella zoster. 
5Evaluation of the malignant disease: For acute leukemia, CML and MDS this includes a bone marrow aspirate and biopsy. For lymphomas this includes 
imaging studies, which will be done according to institutional practices, or the same as prior to transplant, for matter of comparison.  
6Pregnancy test must be performed < 30 days before the start of the transplant conditioning regimen. Pregnancy test is required for females of child-bearing 
potential and may be performed per institutional practices. 


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7GVHD assessments performed weekly from Day 7 until Day 63 post-transplant, and then at Days 100, 120, 150, 180, 270, and 365.  The GVHD assessment 
will include a review of all abnormalities experienced during the entire assessment period and the highest grade for each abnormality (whether attributed 
to GVHD or not) during the assessment period will be recorded on the Acute GVHD form, the Follow-up GVHD form, and the Chronic GVHD Provider 
Survey in AdvantageEDC. 
8The toxicity assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for each toxicity during 
the assessment period will be recorded on the Toxicity form in AdvantageEDC. 
9Chimerism may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 or CD15 fraction. The actual measurement dates 
may be within +/- 7 days of the recommended time points. 
10The pre-transplant baseline sample must be collected prior to the initiation of the transplant conditioning regimen. 
 


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Pre-transplant evaluations 
 
The following observations must be completed within three weeks (<21 days) of patient 
randomization, and within (≤) 35 days of conditioning. If the initiation of conditioning is 
greater than 14 days from randomization then pre-transplant evaluations must be completed 
according to institutional practice, unless otherwise indicated.  
• History, physical examination, height and weight. 
• Karnofsky performance status and HCT-Specific Comorbidity Index score. 
• CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, AST and ALT. 
• Estimated creatinine clearance, using the Cockcroft-Gault formula and actual body 
weight. 
• Infectious disease titers to include: CMV antibody, Hepatitis panel (HepA Ab, HepB 
SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and 
HTLV I/II antibody, and varicella zoster. 
• EKG and LVEF (may be performed < 56 days prior to patient randomization). 
• Pulmonary function tests, including DLCO and FEV1 (may be performed < 56 days prior 
to patient randomization).Disease evaluation for patients with acute leukemia, CML or 
MDS includes a bone marrow aspirate and biopsy for pathology and cytogenetics. A 
bone marrow biopsy must be performed ≤21 days prior to randomization and must 
be repeated if not within 35 days prior to the initiation of the transplant 
conditioning regimen. 
• Disease evaluation for patients with lymphomas includes imaging studies for matters of 
comparison post-transplant., the types of which may be determined according to the 
center’s institutional practices. Imaging studies must be done within (≤) 42 days prior 
to patient randomization, and if the initiation of conditioning is greater than 14 days 
from randomization (or ≥ 56 days from last imaging) then should be repeated 
according to the center’s standard requirements.  
• Chest X-ray or chest CT. 
• Pregnancy test per institutional practices for females of child-bearing potential. NOTE: 
pregnancy test must be performed < 30 days prior to enrollment and must be 
repeated if not within 30 days prior to the initiation of the transplant conditioning 
regimen. 
• Pre-transplant donor and recipient samples for post-transplant chimerism studies. 
• Pre-transplant blood samples for future research (prior to initiation of conditioning).  
 
Post-transplant evaluations 
 
The following observations will be made according to Table 4.6b: 


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• History and physical exam to assess GVHD and other morbidity weekly through Day 63 
post-transplant, then at  Days 100, 120, 150, 180, 270 and 365 post-transplant. GVHD 
will be monitored in accordance with BMT CTN guidelines as specified in the BMT 
CTN Manual of Procedures (BMT CTN MOP). GVHD assessments from Day 7 through 
Day 63 post-transplant, and then at Days 100, 120, 150, 180, 270, and 365 post-
transplant. 
• Assessment for toxicities at Days 28, 56, 100, 180, 270 and 365 post-transplant. 
• CBC with differential performed at least three times a week from Day 0 until ANC > 
500/L for 3 days and platelet count > 20,000/L for 3 days (while hospitalized only) 
after nadir is reached.  Thereafter, CBC weekly until Day 63 post-transplant, then every 
other week through Day 100 post-transplant, and then at Days 180, 270 and 365 post-
transplant. 
• Serum creatinine, bilirubin, alkaline phosphatase, ALT and AST, twice a week until 
hospital discharge and then weekly until Day 63 post-transplant, then every other week 
through Day 100 post-transplant, and then at Days 180, 270 and 365 post-transplant. 
• Chimerism studies performed at Days 28 and 100 post-transplant. Chimerism may be 
evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 
or CD15 fraction. The actual measurement dates may be within +/- 7 days of the 
recommended time points.   
• Disease evaluation of the malignant disease at Days 100, 180 and 365 post-transplant: 
For acute leukemia, CML and MDS this includes a bone marrow aspirate and biopsy for 
pathology and cytogenetics. For lymphomas this includes imaging studies, which will be 
done according to institutional practices and the same as prior to transplant, for matter of 
comparison. 
• Pulmonary function tests, including DLCO and FEV1 at Day 365 post-transplant. 
• Data on occurrence of infections and recorded as per the BMT CTN MOP. 
• Blood samples for optional future research to be collected at Days 35, 100, 180 and 365 
post-transplant (Appendix C).  
 
4.6.2. Criteria for Forms Submission 
 
Criteria for timeliness of submission for all study forms are detailed in the Data Management 
Handbook and User’s Guide.  Forms that are not entered into AdvantageEDC within the 
specified time will be considered delinquent.  A missing form will continue to be requested 
either until the form is entered into the AdvantageEDC and integrated into the Data and 
Coordinating Center’s (DCC) master database, or until an exception is granted and entered into 
the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
4.6.3. Reporting Patient Deaths 
 


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Recipient death information must be entered into AdvantageEDC within 24 hours of knowledge 
of the patient’s death.  If the cause of death is unknown at that time, it need not be recorded at 
that time.  However, once the cause of death is determined, the form must be updated in 
AdvantageEDC. 
 
4.7. Adverse Event Reporting Requirements 
 
Reporting of adverse events on the BMT CTN 1203 trial has unique requirements due to the 
addition of bortezomib and maraviroc as part of this protocol. Adverse event reporting 
requirements are summarized below and further described in Appendix J. 
 
4.7.1. Definitions 
 
Adverse Event:  An Adverse Event (AE) is defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease that is temporally associated 
with the use of a medical treatment or procedure regardless of whether it is considered related to 
the medical treatment or procedure. 
 
Expectedness: An adverse event can be Expected or Unexpected  
• Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
• Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
 
4.7.2. BMT CTN Adverse Event Reporting Guidelines 
 
It is BMT CTN policy that AEs must be reported even if the investigator is unsure whether a 
relationship exists between the adverse event and the use of the study treatment. Reporting of 
AEs for BMT CTN 1203 will be consistent with the BMT CTN Manual of Procedures. 
Additional requirements specific to this protocol are outlined below and in Appendix J.  
 
In BMT CTN studies, expected adverse events are reported via the web-based electronic data 
capture system, AdvantageEDC. Events are captured on calendar-driven case report forms (e.g., 
Toxicity 
and 
Hematology/Chemistry) 
or 
event-driven 
case 
report 
forms 
(e.g., 
Relapse/Progression, Secondary Graft Failure, and Death).  
 
Unexpected, grades 3-5 AEs, irrespective of the attribution of the event to the study drug 
/procedure/treatment, will be reported through the expedited AE reporting system via 
AdvantageEDC, and will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0.  The BMT CTN 1203 protocol has three distinct 
interventions to which patients are randomized. Determination of expectedness for events 
occurring on each treatment arm will be at the discretion of the investigator as described in 


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Appendix J, section J.3. Unexpected, grades 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business 
days of knowledge of the event.  The NHLBI Data and Safety Monitoring Board will receive 
summary reports of all adverse experiences at least twice yearly. 
 
4.7.3. Additional Adverse Event Reporting Requirements for Patients Randomized to the 
Tacrolimus/Methotrexate/Bortezomib Arm 
 
Millennium Pharmaceuticals, Inc. (MPI) is supplying bortezomib for this study and a description 
of additional adverse event reporting requirements for this study, detailed in Appendix J apply 
to any patient who is randomized to receive bortezomib as part of the GVHD prophylaxis 
regimen. The additional adverse event reporting period for bortezomib begins with the first dose 
(Day +1) and continues until 30 days after the last dose of bortezomib (Day +7 plus 30 days = 
Day +37). Along with the additional adverse event reporting requirements, any adverse event 
reported through the expedited AE reporting system will include the investigator’s assessment of 
relationship to bortezomib (unrelated, unlikely, possible, probable, or definite). 
 
4.7.4. Adverse Event Reporting for Patients Randomized to the Tacrolimus/Methotrexate/ 
Maraviroc Arm 
 
Patients randomized to the maraviroc arm will have all unexpected grade 3-5 AEs reported 
throughout the course of the study, including the investigator’s assessment of relationship to 
maraviroc (unrelated, unlikely, possible, probable, or definite). 
 
4.7.5. Procedures for Reporting Exposure to Bortezomib or Maraviroc During Pregnancy and 
Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while taking bortezomib or 
maraviroc for this study, she must inform the Investigator immediately and permanently 
discontinue study drug.  The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported within 24 hours of the Investigator’s knowledge of the pregnancy. The event must be 
reported through the expedited AE reporting system via AdvantageEDC (Adverse Event forms).  
 
The Investigator will follow the subject until completion of the pregnancy, and must report the 
outcome of the pregnancy and neonatal status as a follow-up to the original expedited AE report 
in AdvantageEDC. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the Investigator must also immediately report the pregnancy as detailed above. Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
4.8. CIBMTR Data Reporting 
 
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all 
consecutive hematopoietic stem cell transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR).  


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Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database 
(SCTOD).  (Note: Federal legislation requires submission of these forms for all US allotransplant 
recipients.)  Enrollment in BMT CTN 1203 must be indicated on the SCTOD pre-transplant 
registration form.  Additionally, CIBMTR pre- and post- transplant Comprehensive Report 
Forms must also be submitted for all patients enrolled on this trial. CIBMTR forms will be 
submitted directly to the CIBMTR at the times specified on the Form Submission Schedule.  
 
4.9. Registration of CIBMTR Controls 
 
This clinical trial will compare outcomes from patients enrolled in the intervention arms to a 
contemporary control from the CIBMTR. Selection of the controls will start by the selection of 
transplant centers, which will not be the same centers participating in the enrollment of patients 
in the intervention arms.  
 
4.9.1. Selection of Control Arm Participating Transplant Centers 
 
CIBMTR research centers with experience in submitting comprehensive report forms to the 
CIBMTR will be eligible to participate in the study. Additionally, participating centers will need 
to agree to participate in this study and to submit all CIBMTR and supplemental report forms 
required for this study reported according to the pre-specified schedule.  
 
4.9.2. Enrollment procedure for the control arm 
 
Data reported on pre-transplant Transplant Essential Data forms to CIBMTR by participating 
centers will be monitored on a weekly basis to screen patients who fulfill the eligibility criteria. 
Control patients who fulfill eligibility criteria (Section 2.2.3) and who have signed a consent to 
allow their data to be used for research will be assigned to the CIBMTR comprehensive data 
reporting track (CRF–track) and centers will be notified. Forms due requirements for the CRF 
track will be implemented. Expected data reporting will be same as what routinely is collected by 
the CIBMTR from patients in the CRF-track, including basic recipient information, disease 
specific and infusion information, and follow-up at 100 days, 6 months and at 1 year. All 
required data for the primary end point analysis is included in the CIBMTR data reporting forms.  
Supplemental data collection related to immune suppression use will be collected along with the 
1 year follow up form. CIBMTR data from control patients will be reviewed systematically for 
elements of the primary endpoint. 
 
Timely data reporting will be a requirement for the control patients and reporting compliance 
will be monitored quarterly. A minimum of 270 controls will be targeted in order to ensure 
sufficient patients comparable to the randomized population for the comparison.  
 
 


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CHAPTER 5 
 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1 Study Design 
 
The study is designed as a Phase II randomized, open label, multicenter trial to identify the most 
promising GVHD prophylaxis approach(es) for allogeneic transplant recipients with malignant 
disease using a reduced intensity conditioning regimen.  Patients will be randomized to one of 
three promising new strategies: Tac/MTX/Bortezomib, Tac/MTX/Maraviroc or Tac/MMF/Cy.  
The primary endpoint of GRFS will be compared to a non-randomized concurrent Tac/MTX 
control group collected through the CIBMTR to identify which agents are promising on the basis 
of their efficacy relative to control.  The control group of patients will not be individually 
matched to patients randomized to one of the treatment arms; rather, they will satisfy similar 
eligibility requirements and multivariate regression will be used to adjust for potential 
differences in the groups.  Estimates of primary and secondary endpoints for the three 
randomized arms will also be used to guide selection of the most promising agent(s) for further 
study.  The target enrollment is 540 patients (270 patients across the 3 treatment arms and 270 
CIBMTR contemporary controls). 
 
5.1.1. Accrual 
 
It is estimated that 30 months of accrual will be necessary to enroll the targeted sample size.  
Both Core and Affiliate Centers will enroll patients on this study.  Accrual will be reported by 
race, ethnicity, gender, and age. 
 
5.1.2. Randomization 
 
All patients will be randomized within 7 days prior to the initiation of conditioning therapy.  
Randomization will be performed in a 1:1:1 ratio using random block sizes for the three arms.  
Randomization will be stratified by donor type/HLA mismatching (Matched Sibling vs. Matched 
Unrelated vs. Mismatched Unrelated) and by disease risk (High vs Low, see Section 1.5). 
 
5.1.3. Primary Endpoint 
 
The primary endpoint is time to GRFS from the time of transplant.  All transplanted patients will 
be followed for the primary endpoint for at least one year; however the primary endpoint will be 
analyzed as a time to event endpoint. The primary analysis will be performed using a modified 
intent-to-treat principle and will be performed among transplanted patients only.  
 
5.1.4. Primary Hypothesis 
 
The primary objective of the study is to determine which if any of the three GVHD prophylaxis 
strategies have promising GRFS compared to a non-randomized CIBMTR control group.  To 
address this objective, the hazard ratio (HR) for GRFS will be estimated for each treatment arm 


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compared to the control group, after adjustment for patient characteristics as described in Section 
5.5. The hypotheses of interest for each comparison to control are: 
 
H0: HR=1 vs. Ha: HR<1. 
 
5.2. Sample Size and Power Considerations 
 
Sample size and power considerations are based on the comparison of each treatment group 
(n=90 patients) to the concurrent nonrandomized CIBMTR control cohort (n=270 patients).  A 
treatment is considered promising relative to the control if its HR relative to control, after 
adjustment for covariates, is significant at the one-sided significance level of 0.05.  We are using 
one-sided testing since this is a phase 2 trial to identify whether one of these agents is promising 
relative to the control, and we are not interested in detecting treatments that are worse than 
control since they would not be pursued further.  Control rates for GRFS are expected to be 
approximately 23% by one year, based on a recent analysis of CIBMTR data, although we 
considered control rates at one year as high as 35%.  In addition to the final analysis, an interim 
analysis for futility will be conducted after 30 patients in each group have 6 months of follow-up, 
anticipated to be approximately 50% through the accrual period assuming uniform accrual over 
30 months.  If fewer than 14 patients are alive and GVHD/relapse free at 6 months, closure of the 
study arm for futility will be considered.   
 
The operating characteristics of this study design, including the impact of the futility stopping 
rule, were determined in a simulation study.  GRFS was assumed to follow an exponential 
distribution, and follow-up was censored at one year for all patients. The probability of GRFS by 
one year was assumed to be 23% or 35% for the control group, while probabilities of GRFS for 
the treatment groups were 5%, 10%, or 20% higher at one year, depending on the scenario.  
Probabilities of stopping for futility were calculated for each arm, along with the expected 
sample size (ExpN) assuming uniform accrual over 30 months.  Final probabilities of identifying 
a treatment as promising relative to control were estimated, along with the probability of 
identifying at least one treatment as promising.  This latter probability is the same as the 
Familywise Type I error rate when all the treatments have the same GRFS.  Finally, we included 
the probabilities of selecting a particular treatment arm as the winner, among those identified as 
promising, based on having the lowest HR relative to control.  However, this is for illustrative 
purposes only, since it is possible that multiple treatments may be identified as good candidates 
for further study in a follow on phase 3 trial.  This probability is most interpretable when there is 
clear separation in outcomes between the best treatment and the other treatments.  The 
simulation results are shown in Table 5.2 below.  Adjustment for covariates was not incorporated 
into the simulation study, although it will be used in the final analysis. 
 
This study design has 81-87% power to identify a treatment as promising when its GRFS at one 
year is 15% better than control.  The probability of stopping an arm for futility is approximately 
37% for treatment arms which are no better than control, when the control is correctly specified 
(23% at one year).  If the control rates are higher, there is less impact of the futility boundary, 
with a 6% likelihood of stopping an arm for futility when it has the same outcome as the control.  
If none of the treatments has GRFS better than the control, the overall (Familywise) type I error 
rate is approximately 11-13%.  When the best treatment has GRFS which is 15% better than the 


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other two arms, the probability of correct selection of the winner based on having the best 
observed outcomes is over 80%.  This means that there is at least an 80% chance that the truly 
best treatment will have the best observed outcomes.   When the GRFS for the best treatment is 
only 10% better than the other two treatments, there is a 75-81% chance of correctly selecting 
the winner.   


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TABLE 5.2: OPERATING CHARACTERISTICS OF STUDY DESIGN 
 
GRFS at 1 Year 
Probability of Stopping 
for Futility 
Individual Power 
Overall 
Probability of Selection 
as Best 
Control 
A 
B 
C 
A 
B 
C 
A 
B 
C 
Power 
A 
B 
C 
ExpN 
0.23 0.23 0.23 0.23 38.3% 37.0% 37.4% 
4.1% 
3.9% 
4.2% 
10.9% 
3.8% 
3.5% 
3.7% 
222.6 
0.23 0.38 0.23 0.23 
3.0% 38.0% 37.4% 86.9% 
4.4% 
4.0% 
87.3% 86.5% 
0.4% 
0.4% 
237.1 
0.23 0.38 0.38 0.38 
3.2% 
3.2% 36.5% 86.0% 86.2% 
4.0% 
97.0% 48.6% 48.3% 
0.1% 
252.0 
0.23 0.38 0.38 0.23 
3.1% 
3.2% 
3.3% 86.8% 86.0% 86.9% 
99.2% 33.4% 32.4% 33.4% 
266.0 
0.23 0.38 0.33 0.33 
3.2% 
8.8% 
8.6% 86.0% 58.8% 58.3% 
95.2% 61.7% 17.2% 16.3% 
261.3 
0.23 0.38 0.28 0.28 
3.1% 19.3% 18.9% 86.1% 24.5% 24.6% 
89.8% 80.7% 
4.5% 
4.6% 
252.7 
0.35 0.35 0.35 0.35 
5.8% 
6.0% 
6.0% 
4.4% 
4.9% 
4.7% 
12.6% 
4.0% 
4.4% 
4.3% 
262.5 
0.35 0.50 0.35 0.35 
0.2% 
5.5% 
5.6% 81.3% 
4.6% 
4.5% 
82.0% 80.8% 
0.6% 
0.6% 
265.3 
0.35 0.50 0.50 0.35 
0.2% 
0.2% 
5.9% 81.4% 80.8% 
4.2% 
94.4% 46.9% 47.3% 
0.2% 
267.4 
0.35 0.50 0.50 0.50 
0.2% 
0.1% 
0.2% 81.5% 81.7% 81.0% 
98.0% 33.2% 33.2% 31.6% 
269.8 
0.35 0.50 0.45 0.45 
0.1% 
0.5% 
0.6% 82.5% 52.4% 52.6% 
92.8% 59.7% 16.5% 16.6% 
269.5 
0.35 0.50 0.40 0.40 
0.1% 
2.0% 
2.2% 81.0% 20.6% 20.9% 
85.1% 75.2% 
5.1% 
4.8% 
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5.3. Interim Analysis and Stopping Guidelines 
 
5.3.1. Interim Analysis for Efficacy 
 
There will be no interim analyses for efficacy. 
 
5.3.2. Interim Analysis for Futility 
 
An interim analysis for futility will be conducted based on the 6 month GRFS when 30 patients 
in each arm have 6 months of follow-up available.  If fewer than 14 are alive and GVHD/relapse 
free among the first 30 patients on an arm, closure of the study arm for futility will be 
considered.  This futility stopping rule is meant to be a guidance only, based on an anticipated 6 
month GRFS in the control group of 45-50%; the DSMB may also consider other factors, such as 
the risk characteristics of these patients, when deciding whether to follow the futility stopping 
rule.  A futility stopping rule which incorporates a direct comparison to the concurrent CIBMTR 
controls along with risk adjustment is not feasible because of the different sources for data 
collection. However, if a futility rule is triggered so that the DSMB is considering dropping an 
arm for futility, a comparison with CIBMTR controls may be considered before a final decision 
to drop an arm is made.   
 
5.3.3. Guidelines for Safety Monitoring 
 
Monitoring of a key safety endpoint will be conducted monthly, and if rates significantly exceed 
pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised.  Policies 
and composition of the DSMB are described in the BMT CTN's Manual of Procedures.  The 
stopping guideline serves as trigger for consultation with the DSMB for additional review. 
 
The key safety endpoint for this study is mortality.  The rate of mortality will be monitored up to 
100 days post-randomization separately in each of the three treatment arms.  At least three events 
must be observed in order to trigger review.  The expected probability of 100 day mortality after 
a reduced intensity conditioning transplant is 10-15%, based on CIBMTR data.  Each month, the 
null hypothesis that the 100-day mortality rate is less than or equal to 15% is tested.  An 
extension of the sequential probability ratio test (SPRT) for censored exponential data will be 
used for monitoring, as described in greater detail below and in Appendix E. 
 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations for a treatment arm.  The SPRT can be represented graphically.  At each monthly 
interim analysis, the total time on study is plotted against the total number of endpoints (e.g., 
patients experiencing death).  The continuation region of the SPRT is defined by two parallel 
lines.  Only the lower boundary will be used for monitoring to protect against excessive 100-day 
mortality.  If the graph falls below the lower boundary, the SPRT rejects the null hypothesis, and 
concludes that there are more events than predicted by the observed time on study.  Otherwise, 
the SPRT continues until enrollment reaches the maximum of 90 patients. 
 
This procedure assumes a censored exponential distribution for the time until death during the 
first 100 days, and censors follow-up time after 100 days.  Only deaths that occur on or before 


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the patient has been followed for 100 days are counted.  Total time on study is computed as time 
from registration to death, or to 100 days, whichever comes first, summed for all patients on 
study. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The tests to be used in this protocol were developed from the following SPRT:   
• A SPRT contrasting 15% versus 30% 100-day rate of mortality results in decision 
boundaries with a common slope of 13.310 and a lower intercept of –42.278, with 
nominal type I and II errors of 7% and 15%, respectively. 
 
The actual operating characteristics of the truncated test, shown in Table 5.3, were determined in 
a simulation study that assumed uniform accrual of 90 individuals over a 30 month time period, 
and exponential time to failure after randomization.   
 
TABLE 5.3:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
 
Day 100 MORTALITY 
 
True 100-Day Rate 
15% 
25% 
30% 
Probability Reject Null 
0.046 
0.650 
0.917 
Mean Month Stopped 
32.3 
21.3 
14.4 
Mean # Endpoints in 100 Days 
13.1 
14.4 
11.6 
Mean # Patients Enrolled 
87.6 
60.5 
42.5 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 5% of 
the time when the true 100-day mortality rate is 15%, and 92% of the time when the rate is 30%.  
This corresponds to a type I error rate of  = 0.05 and a type II error rate of  = 0.08.  When the 
true 100-day mortality rate is 30%, on average, the DSMB will be consulted 14 months after 
opening, when 12 events have been observed in 42 patients. 
 
5.4. Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, disease 
specific risk categories, hematopoietic cell transplant comorbidity index (HCT CI), donor type 
and HLA matching, donor/recipient CMV status, donor/recipient sex match, donor/recipient 
ABO match, and conditioning regimen.  Between group comparisons will be performed for 
continuous variables via a Kruskal-Wallis test and for categorical variables, via the chi-square 
test. 
 


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5.5. Analysis of Primary Endpoint 
 
Kaplan-Meier curves along with 90% confidence intervals will be constructed to estimate GRFS 
probabilities for each treatment group as well as the control.  The primary analysis will consist of 
a comparison of GRFS among transplanted patients for each treatment arm to the control group, 
based on a multivariate Cox regression model.  The following factors will be included in the 
regression model: age, disease, donor type/HLA matching.  In addition, a stepwise model 
building strategy with a significance level of 0.1 will be used to consider additional factors from 
the list of demographic/baseline characteristics.  A significance level of 0.05 (one-sided) will be 
used for the hazard ratio of each treatment arm relative to the control to determine whether a 
treatment should be considered promising for further study.  Confidence intervals for the hazard 
ratio using a 90% confidence level will also be constructed for each hazard ratio.  The 
familywise type I error rate over all the comparisons to the control is expected to be 
approximately 10-11% based on simulations in Section 5.2. This familywise type I error rate can 
be interpreted as the probability of incorrectly identifying at least one of the treatments as 
promising when they all have identical GRFS compared to the control.  Direct statistical 
comparison of GRFS among the randomized treatment arms will not be conducted, since the 
study is not powered for these comparisons.   
 
5.6. Analysis of Secondary Endpoints 
 
Since this is a Phase II trial, most of the analysis of secondary endpoints will involve estimation 
with 90% confidence intervals rather than formal statistical comparisons.  All secondary 
endpoints will be described from the time of transplantation; however, the number of patients 
randomized but dropping out prior to transplantation will also be described by treatment arm.  
No direct statistical comparisons among the randomized treatment arms will be conducted, since 
the study is not powered for these comparisons.  For a select set of endpoints (acute and chronic 
GVHD, TRM, relapse, DFS, and survival) which are components of the composite primary 
endpoint, an analysis comparing each treatment arm to the control group will be conducted.  To 
alleviate concerns about multiple testing, these secondary analyses for a particular treatment 
group will only be performed if the primary endpoint is significantly different between that 
treatment group and the control group.  Details of the analyses of secondary endpoints are given 
below.   
 
5.6.1. Acute GVHD 
 
Incidence of acute GVHD grade II-IV and grade III-IV up to 180 days will be estimated with 
90% confidence intervals for each treatment group as well as the control using the cumulative 
incidence estimate, treating death prior to aGVHD as a competing event.  A multivariate Cox 
regression model for the cause-specific hazard of aGVHD will be used to compare the treatment 
groups with the control group, after adjustment for baseline characteristics as described for the 
primary endpoint.   
 
 


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5.6.2. Chronic GVHD 
 
Incidence of chronic GVHD up to 1 year will be estimated with 90% confidence intervals for 
each treatment group as well as the control using the cumulative incidence estimate, treating 
death prior to chronic GVHD as a competing event.  A multivariate Cox regression model for the 
cause-specific hazard of chronic GVHD will be used to compare the treatment groups with the 
control group, after adjustment for baseline characteristics as described for the primary endpoint.   
 
5.6.3. Immunosuppression-Free Survival at One Year 
 
Proportions of patients alive, relapse free, and off immune suppression at one year will be 
described for each treatment group and for the control, along with 90% confidence intervals.  If 
there is censoring prior to one year, multistate models will be constructed to estimate these 
probabilities.  Agreement between this endpoint and the primary endpoint of GRFS will be 
described using cross-tabulation frequencies and assessed using the Kappa statistic.   
 
5.6.4. Hematologic Recovery 
 
Probabilities of neutrophil recovery by Day 28 and Day 100 will be described with 90% 
confidence intervals for each treatment group using the cumulative incidence estimate, treating 
death as a competing event.  Similarly, probabilities of platelet recovery by Day 60 and Day 100 
will be described with 90% confidence intervals for each treatment group using the cumulative 
incidence estimate, treating death as a competing event.   
 
5.6.5. Donor Cell Engraftment 
 
Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized 
treatment arms will be described numerically as median and range for those evaluable as well as 
according to proportions with full (>95%), mixed (5-95% donor cells), graft rejection (<5%), or 
death prior to assessment of donor chimerism.  Incidence of secondary graft failure (chimerism 
<5% after initial donor cell engraftment) will be described for each arm using frequencies. 
 
5.6.6. Disease Relapse or Progression 
 
Incidence of disease relapse or progression up to 1 year will be estimated with 90% confidence 
intervals for each treatment group as well as the control using the cumulative incidence estimate, 
treating death prior to disease relapse as a competing event.  A multivariate Cox regression 
model for the cause-specific hazard of relapse or progression will be used to compare the 
treatment groups with the control group, after adjustment for baseline characteristics as described 
for the primary endpoint.   
 
5.6.7. Transplant-related Mortality 
 
Incidence of transplant-related mortality (TRM) up to 1 year will be estimated for each treatment 
group as well as the control using the cumulative incidence estimate, treating disease relapse or 
progression as a competing event.  A multivariate Cox regression model for the cause-specific 


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hazard of TRM will be used to compare the treatment groups with the control group, after 
adjustment for baseline characteristics as described for the primary endpoint.   
 
5.6.8. Toxicity 
 
All Grade  3 toxicities will be tabulated by grade for each randomized treatment arm, by type of 
toxicity as well as the peak grade overall.  Toxicity frequencies will be described for each time 
interval as well as cumulative over time.   
 
5.6.9. Infections 
 
The number of infections and the number of patients experiencing infections will be tabulated for 
each randomized treatment arm by type of infection, severity, and time period after transplant.   
 
5.6.10. Disease-free Survival 
 
Kaplan-Meier curves will be constructed to estimate disease free survival probabilities for each 
treatment group as well as the control.  A multivariate Cox regression model for the risk of death 
or relapse/progression will be used to compare the treatment groups with the control group, after 
adjustment for baseline characteristics as described for the primary endpoint.   
 
5.6.11. GVHD-Free Survival 
 
Kaplan-Meier curves will be constructed to estimate GVHD free survival probabilities for each 
treatment group as well as the control.  A multivariate Cox regression model for the risk of death 
or GVHD will be used to compare the treatment groups with the control group, after adjustment 
for baseline characteristics as described for the primary endpoint.   
 
5.6.12. Overall Survival 
 
Kaplan-Meier curves will be constructed to estimate overall survival probabilities for each 
treatment group as well as the control.  A multivariate Cox regression model for the risk of death 
will be used to compare the treatment groups with the control group, after adjustment for 
baseline characteristics as described for the primary endpoint.   
 
5.7. Safety Analysis 
 
All reported serious adverse events potentially associated with study drugs will be carefully 
examined with respect to the severity and relationship to the study drugs.  Adverse events will be 
graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0.   
 
5.8. Selection of Promising Approaches  
 
The objective of the Phase II trial is to identify promising agents to be tested on a Phase III 
setting.  Determination of whether a treatment is promising relative to control is based on 
identifying a significant effect relative to control on the primary endpoint using a 5% one-sided 


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significance level, and not on secondary analyses.  Among those identified as promising relative 
to control using this criterion, the actual selection of promising agents for future study may also 
consider toxicities, secondary endpoints, and the magnitude of effect on the primary end point 
compared to the control cohort.  Note that more than one approach might be identified as 
promising relative to control on the primary endpoint and be selected for further study.  
 


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APPENDIX A 
 
HUMAN SUBJECTS 
 


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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
Candidates for the study will be identified as described in Chapter 4 of the protocol.  The 
Principal Investigator or his/her designee at each transplant center will contact the candidates, 
provide them with information about the purpose of the study and obtain consent.  The BMT 
CTN will provide a template of the consent form to each center.  Each center will customize the 
template according to their local requirements and submit it for review by the local Internal 
Review Board (IRB).  The DCC will verify the adequacy of the consent forms prior to 
submission to the IRB.  Each center must provide evidence of IRB approval. 
 
 
2. 
Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the network.  
 
 
3. 
Participation of Women and Minorities 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of leukemia 
and lymphoma in these groups.  Centers will be notified if their rates differ significantly from 
those expected and asked to develop appropriate recruitment reports. 
 
 


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APPENDIX B 
 
CONSENT FORMS 
 
 
 
PATIENT INFORMED CONSENT 


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Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
Your Name:  
________________________________ 
 
 
Study Title:  
A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-
versus-Host Disease Prevention Compared to Contemporary Controls 
 
Protocol: 
 
BMT CTN 1203 
 
Principal 
Investigator:   
Insert local PI information 
 
 
Sponsor:   
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN).  
 
 
1. Introduction 
We invite you to join this clinical trial, also known as a research study.  We are doing this study 
because we want to compare three new combinations of medications to see which is better at 
preventing Graft-versus-Host Disease (GVHD). You are being asked to join this study because: 
1. You have a disease that can be treated by a peripheral blood stem cell transplant; and 
2. Your doctor plans on using a reduced-intensity conditioning regimen for your transplant. 
 
This study will take at least two (2) years and will include 270 participants – 90 participants in 
each of three (3) treatment groups.  
 
This Consent Form will tell you about the purpose of the study, the possible risks and benefits, 
other options available to you, and your rights as a participant in the study.  
Everyone who takes part in research at [insert facility name] should know that: 
▪ Being in any research study is voluntary. 
▪ You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 


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▪ If you join the study, you can quit the study at any time.  
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
▪ You can ask questions now or any time during the study. 
▪ Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends. It is your decision to be in the study. If you decide to join, please 
sign and date the end of the Consent Form. 
 
You and your doctor will discuss other treatment choices if you do not want to participate in this 
study. 
 
 
2. Study Background 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are providing staff support and money for this research study. The 
BMT CTN and the NIH will make decisions about how to manage the study.  
 
A stem cell transplant is a standard therapy for blood cancers such as acute and chronic 
leukemias, lymphoma and myelodysplastic disorders.  A common problem that may occur after a 
stem cell transplant is a condition known as GVHD.  The word “graft” refers to the donor blood 
cells that you will receive during your transplant.  The word “host” refers to the person (in this 
case, you) receiving the cells.  GVHD is a complication where the donor graft attacks and 
damages some of your (the transplant recipient's) tissues.   
• GVHD can cause skin rash, intestinal problems such as nausea, vomiting, or diarrhea,   
• It may also damage your liver and cause hepatitis or jaundice.   
• GVHD may also increase your risks of infection. 
 
 
3. Study Purpose 
We are inviting you to take part in this study because you have a cancer of the blood or lymph 
glands and a stem cell transplant is a treatment option. 
The purpose of this study is to compare three combinations of medications to see whether one or 
more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent 
GVHD. These combinations of medication in this study are: 
Treatment Group A: Tacrolimus, methotrexate and bortezomib 
Treatment Group B: Tacrolimus, methotrexate and maraviroc 
Treatment Group C: Tacrolimus, mycophenolate mofetil and cyclophosphamide 


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Doctors want to know which combination (A, B or C) is better, or if they give the same results. 
The current standard of care for preventing GVHD is Tacrolimus/Methotrexate. This 
combination is not available on this study. The study will help doctors make choices about 
medications to prevent GVHD for future transplant patients. 
 
 
4. Right to Ask Questions and/or Withdraw 
You have the right to ask questions about the study at any time.  If you have questions about 
your rights as a participant or you want to leave the study, please contact:  
[insert contact info] 
Being in this study is voluntary. You can choose not to be in this study or leave this study at any 
time. If you choose not to take part or leave this study, it will not affect your regular medical care 
in any way.  
 
Your study doctor and study staff will be available to answer any questions that you may have 
about taking part in or leaving this study.  
 
 
5. Study Treatment and Tests  
We will check your health before you start treatment, while you receive treatment, and for one 
year after transplant.   
 
Before You Begin the Study 
Before you begin the study, you will need to have several exams, tests or procedures to find out 
if you can be in the study. All patients participating in this study need to have a matched donor. 
These exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These include: 
• Medical history 
• Physical examination, including height and weight 
• Blood and urine tests 
• Heart function tests, including EKG and ejection fraction 
• Lung (pulmonary) function tests 
• Tests to evaluate your cancer, including a bone marrow aspirate/biopsy if you have acute 
leukemia, chronic myelogenous leukemia or myelodysplastic syndrome, and imaging 
studies if you have lymphoma.   
• Chest X-ray or chest CT 
• A pregnancy test if you are a woman able to have children. If you are pregnant, you will 
not be able to take part in this study. 


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• Optional blood samples for future research (see Section 19: Blood Samples for Future 
Research). 
 
Study Participation 
If you decide to join the study, your participation will last for 1 year after your transplant. We 
will ask you to sign this Consent Form and you will get a copy of the signed form to keep.  
 
Before the Transplant 
Before your transplant, your doctor will choose from one of several conditioning regimens.  The 
conditioning regimen prepares your body for transplant.  It uses treatments such as chemotherapy 
and radiation to destroy the cancer cells and the cells that make up your immune system.  Your 
doctor will decide which conditioning regimen you will receive before you are assigned to one of 
the three (3) treatment groups.  
 
Randomization  
We will use a computer to randomly assign you to 1 of 3 treatment groups. You will have an equal 
chance of being placed in 1 of the 3 groups.  Neither you nor your doctor or study investigator will 
have any control over which treatment group you will be assigned.  
 
During Your Transplant 
The treatments that are used to prevent GVHD either start before or after the infusion of stem cells. 
These treatments are a combination of immune suppressing drugs and a standard component of the 
transplant. 
The 3 treatment groups being included in this study are outlined below:  
Treatment Group A: Tacrolimus, methotrexate and bortezomib 
• 
Tacrolimus will be given daily per institutional standards, as a pill by mouth or by 
intravenous infusion (through your vein), beginning three (3) days before your 
transplant. The amount of drug given will slowly be decreased over time and 
eventually stopped.  This process occurs over several months. 
• 
Methotrexate will be given by intravenous infusion (through your vein) on four 
(4) different days (1, 3, 6 and 11) after your transplant. 
• 
Bortezomib will be given by intravenous push (3-5 second shot in your vein) on 
three (3) different days (1, 4 and 7) after your transplant. 
Treatment Group B: Tacrolimus, methotrexate and maraviroc group 
• Tacrolimus will be given daily per institutional standards, as a pill by mouth or by 
intravenous infusion (through your vein), beginning three (3) days before your 
transplant. The amount of drug given will slowly be decreased over time and 
eventually stopped.  This process occurs over several months. 
• Methotrexate will be given by intravenous infusion (through your vein) on four 
(4) different days (1, 3, 6 and 11) after your transplant. 


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• Maraviroc will be given as a pill by mouth twice a day, beginning three (3) days 
before your transplant and will continue for 30 days after your transplant. 
Treatment Group C: Tacrolimus, mycophenolate mofetil and cyclophosphamide 
group 
• Tacrolimus will be given daily per institutional standards, as a pill by mouth or by 
intravenous infusion (through your vein), beginning on day five (5) after your 
transplant. The amount of drug given will slowly be decreased over time and 
eventually stopped.  This process occurs over several months. 
• Mycophenolate mofetil will be given daily by intravenous infusion (through your 
vein) or as a pill by mouth three times a day, beginning on Day 5 after your 
transplant, and will continue for 30 days. Your doctor may decide to continue this 
drug if active GVHD is present. 
• Cyclophosphamide will be given by intravenous infusion (through your vein), 
over 1-2 hours, on Day 3 and Day 4 after your transplant. 
 
Peripheral Blood Stem Cell Transplant 
On your transplant day, the stem cells will be given to you through your catheter, like a blood 
transfusion. The cells will travel to your bone marrow where they will start to make healthy, new 
blood cells after several weeks.  
 
Health Evaluations After the Transplant 
We will test (evaluate) your health during the study. These tests and how often they are 
scheduled are standard care for patients receiving an allogeneic transplant. They would be done 
even if you were not part of this study. You will be watched closely for any signs and symptoms 
of GVHD.  
• Physical exam to assess toxicities, and infections weekly until Day 63 and then at Days 
100, 120, 150, 180, 270 and 365. 
• Physical exam to assess GVHD weekly starting Day 7 until Day 63 and then at Days 100, 
120, 150, 180, 270 and 365. 
• Routine blood tests (cell counts, liver and kidney function) weekly until Day 63 and then 
at Days 100, 180, 270 and 365. 
• Blood or bone marrow tests to find the amount of donor cells in your body on Days 28 
and 100. This is also called chimerism.  
• Disease evaluation tests to see how much cancer you have after treatment on Days 100, 
180 and 365. 
• Lung (pulmonary) function tests on Day 365. 
• Optional blood samples for future research on Days 35, 100, 180 and 365 (see Section 
19: Blood Samples for Future Research). 
 


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6. Risks and Discomforts 
You will have side effects while on the study.  Side effects can range from mild to serious.  
The risks and discomforts of participating in this study will be similar to what you may have 
with stem cell transplant if you do not participate in this study, but you might do better or worse 
than on standard transplant treatment.  Your health care team may give you medicines to help 
lessen side effects such as feeling sick to your stomach (nausea).  In some cases, side effects can 
be long lasting or may never go away.  
Risks and Toxicities Related to Medications  
All immune suppressive drugs, except for bortezomib and maraviroc, are commonly used in 
allogeneic hematopoietic cell transplantation.  
 
Table 1- Risks and Side Effects  
Likely 
What it means: This type of side effect is expected to occur in more than 
20% of patients. This means that 21 or more patients out of 100 might get 
this side effect. 
Less Likely 
What it means: This type of side effect is expected to occur in 20% of 
patients or fewer. This means that 20 patients or fewer out of 100 might get 
this side effect. 
Rare, but 
Serious 
What it means: This type of side effect does not occur very often – in fewer 
than 2% of patients – but is serious when it occurs. This means that 1 or 2 
patients (or fewer) out of 100 might get this side effect. 
 
Bortezomib (Velcade®) 
Likely 
Less Likely 
Rare, but Serious 
▪ Anemia 
▪ Decreased platelet count 
with increased risk of 
bleeding 
▪ Feeling weak, tired and 
generally uncomfortable 
▪ Fever, with shaking 
chills 
▪ Anorexia – loss of 
appetite 
▪ Constipation 
▪ Diarrhea 
▪ Nausea 
▪ Vomiting 
▪ Abdominal pain 
• Decreased white blood cell 
count with risk of infection 
• Difficulty sleeping 
• Skin rash with itching and 
redness 
• Low blood pressure 
• Changes in heart beat that 
can cause you to feel light-
headed, dizzy, faint, short of 
breath, or have chest pain 
• Heartburn, dyspepsia 
• Bleeding (GI, 
pulmonary/upper respiratory) 
• Blood in the urine 
• Coughing up blood 
• Syndrome associated with 
high blood pressure 
characterized by headache, 
confusion, seizures, and 
vision loss associated with 
imaging findings 
• Hepatitis and liver failure 
• Inflammation of the 
intestines, stomach, or 
pancreas 
• Inflammation and fluid 
build-up in and around the 
lungs 


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Likely 
Less Likely 
Rare, but Serious 
▪ Painful feelings or 
numbness and tingling 
in hands and feet 
 
 
• Pneumonia and bronchitis 
 
• Confusion  
• Anxiety 
• Painful sores of the mouth 
and/or throat 
• Changes in the way things 
taste 
• Abnormal liver tests 
• Blurred vision 
• Inflammation of the eye 
• Aches and pains in muscles, 
joints and the bone in the 
arms and legs 
• Muscle weakness 
• Cough 
• Shortness of breath 
• Headache 
• Nose bleeds 
• Changes in blood sugar 
• Lowered amount of 
potassium and sodium in 
your blood 
• Increase in the amount of 
calcium in your blood 
• Flu-like symptoms such as 
chills, sore throat, runny nose 
and sinus and throat 
infections 
• Swelling or fluid build-up in 
the arms and legs, feeling 
dizzy and weight gain 
• Herpes virus such as shingles 
• New or worsening heart 
failure 
• Infections of the bladder, 
sinuses, throat, stomach and 
intestines and skin 
• Fungal infections in the 
mouth and throat 
• Life-threatening infections in 
the blood 
• Inflammation of the layers 
surrounding your heart or 
collection of fluid around the 
heart 
• Loss of hearing 
• Bleeding in the brain 
• Loss of some to all vision in 
one or both eyes 
• Encephalopathy or brain 
dysfunction that can lead to 
death 
• Allergic reactions that may 
include skin swelling and/or 
swelling of the face or throat 
and could be severe or life-
threatening 
• Severe, life-threatening or 
deadly rash with skin peeling 
and mouth sores 
• Pain, redness, swelling and 
infection in the area of the 
skin where bortezomib is 
injected 
• Pain in the mouth and throat 
when swallowing 
• Intestinal obstruction 
• Fast death of cancer cells that 
may let toxin into the blood 
and injure organs, such as the 
kidneys 
• Severe muscle weakness and 
paralysis 
 
 
 


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Cyclophosphamide (Cytoxan®) 
Likely  
Less Likely 
Rare, but Serious 
▪ Decreased white blood cell 
count with increased risk of 
infection 
▪ Temporary hair loss 
▪ Nausea 
▪ Vomiting 
▪ Loss of appetite 
▪ Sores in mouth or on lips 
▪ Diarrhea 
▪ Stopping of menstrual periods 
in women 
▪ Decreased sperm production 
in men 
▪ Decreased platelet count 
(mild) with increased risk of 
bleeding 
 
▪ Anemia 
▪ Temporary tiredness 
▪ Damage to the fetus if 
you become pregnant 
while taking drug 
▪ Abdominal pain 
▪ Skin rash 
▪ Bleeding in the bladder 
 
▪ Scarring of lung 
tissue, with cough and 
shortness of breath 
▪ Severe heart muscle 
injury and death at 
very high doses 
▪ New (secondary) 
cancers 
 
 
 


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Maraviroc (Selzentry®) 
Likely 
Less Likely 
Rare, but Serious 
▪ Fever, cough 
and flu-like 
symptoms 
▪ Rash and 
redness of the 
skin 
▪ Upper 
respiratory 
infections 
 
▪ Fever 
▪ Dizziness 
▪ Insomnia 
▪ Anxiety 
▪ Depression 
▪ Itching 
▪ Benign skin tumors 
▪ High blood pressure 
▪ Decrease appetite 
▪ Constipation 
▪ Low white blood counts with increase 
risk of infections 
▪ Joint pain 
▪ Excessive sweating 
▪ Nerve damage causing numbness, 
tingling, burning 
▪ Muscle pain 
▪ Bladder irritation 
▪ Acne 
▪ Abnormal liver tests 
▪ Herpes infections 
▪ Eye infections/inflammation 
▪ Breathing abnormalities 
▪ Genital warts 
▪ Abnormal growth or change of fat in 
the body 
▪ Loss of consciousness 
(fainting) 
▪ Rash affecting the 
whole body 
▪ Allergic reactions 
associated with liver 
damage and jaundice 
 
 


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Methotrexate 
Likely 
Less Likely 
Rare, but Serious 
▪ Decreased white blood 
cell count with increased 
risk of infection. 
▪ Fatigue 
▪ Infections 
 
▪ Nausea/Vomiting 
▪ Irritation or sores in the 
lining of the throat or 
mouth 
▪ Diarrhea 
▪ Abdominal discomfort 
▪ Fever 
▪ Chills 
▪ Anemia 
▪ Abnormal liver tests 
▪ Kidney failure 
▪ Dizziness 
▪ Scarring of the lungs 
 
 
Mycophenolate Mofetil (MMF, Cellcept®) 
Likely  
Less Likely 
Rare, but Serious 
▪ Miscarriage 
▪ Birth defects 
▪ Diarrhea 
▪ Damage to unborn baby 
▪ Limited effectiveness of birth 
control 
▪ Stomach pain 
▪ Upset stomach 
▪ Nausea/Vomiting 
▪ Headache 
▪ Tremors 
▪ Low white blood cell count 
with increased risk of 
infection 
▪ Increased blood cholesterols 
▪ Decreased platelet count 
with increased risk of 
bleeding 
▪ Swelling of the hands, feet, 
ankles, or lower legs 
▪ Anemia 
▪ Rash 
▪ Difficulty falling 
asleep or staying 
asleep 
▪ Dizziness 
▪ Difficulty breathing 
▪ Unusual bruising 
▪ Fast heartbeat 
▪ Excessive tiredness 
▪ Weakness 
▪ Blood in stool 
▪ Bloody vomit 
▪ Change in vision 
▪ Encephalopathy or 
brain dysfunction that 
can lead to death 
▪ 
New (secondary) 
cancers 
 
 
 


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Tacrolimus (FK506, Prograf®) 
Likely 
Less Likely 
Rare, but Serious 
▪ Kidney problems 
▪ Loss of magnesium, calcium, 
potassium 
▪ High blood pressure 
▪ Tremors 
▪ Increases in cholesterol and 
triglyceride 
▪ Decreased platelet count with 
increased risk of bleeding 
▪ Infections 
 
▪ Nausea 
▪ Vomiting 
▪ Liver problems 
▪ Changes in how 
clearly one can 
think 
▪ Insomnia 
▪ Unwanted hair 
growth 
▪ Confusion 
▪ Seizures 
▪ Changes in vision 
▪ Dizziness 
▪ Red blood cell 
destruction 
It is very important that you do not eat grapefruit or drink grapefruit juice while taking 
Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight.  
 
Risks and Toxicities Related to Transplant 
The following problems may occur as a result of stem cell transplantation. These risks may occur 
whether a transplant was done as part of the study or not:  
Slow recovery of blood counts. The red blood cells, white blood cells, and platelets can be slow 
to recover after blood or marrow transplant. Until your blood counts recover, you will need 
blood and platelet transfusions, and will be at risk for bleeding and infections. To speed the 
recovery of the white cells as much as possible you may receive Filgrastim.   
Graft failure. The stem cells (the “graft”) may fail to grow inside your body. Past experience 
suggests that there can be up to a 10-15% chance of graft failure. If graft failure occurs, this may 
result in low blood counts for a long period of time. If your counts do not recover, you may need to 
receive a second transplant. Graft failure can be fatal. 
Graft-Versus-Host Disease (GVHD). GVHD results from cells in the graft recognizing your body 
as foreign and attacking it. In most cases, GVHD can be successfully treated. Sometimes GVHD is 
severe or difficult to treat and may lead to death. You will be watched closely for this complication 
and given drugs to prevent and/or treat it.  
Acute GVHD may produce skin rash, nausea, vomiting, diarrhea, abdominal pain, abnormalities of 
liver function, and an increased risk of infection. Chronic GVHD may produce skin rashes, hair 
loss, thickened dry skin, dry eyes, dry mouth, liver disease, weight loss, diarrhea, and an increased 
risk of infection. To confirm the diagnosis of acute or chronic GVHD, you may be asked to have a 
biopsy (a small sample of your tissue to look at under the microscope) of your skin, gut, or, rarely, 
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Other complications. Other complications may include: 
a. Damage to the vital organs in your body. The transplant could cause problems in any body 
organ such as the heart, lungs, liver, gut, kidneys and bladder, or brain. The kidneys and the 
liver are most likely to be damaged. Some patients will experience serious lung problems from 
infections or the chemotherapy and radiation.  
b. Serious infections. Full and complete recovery of your immune system may take many months. 
During this time, there is an increased risk of infections.  You will be prescribed certain drugs to 
reduce the chance of those infections. However, these treatments do not always work. If you 
have an infection, you may have to stay in the hospital longer or be re-hospitalized after 
transplant. Although most infections can be successfully treated, some infections may result in 
death.  
c. Relapse of disease or a new blood cancer. Your leukemia or lymphoma may come back even 
if the transplant is initially successful. In rare cases, a new blood cancer may develop from the 
donor cells. Cyclophosphamide can cause damage to blood cells, which may result in a blood 
cancer such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The 
blood cancer usually develops 2-10 years after treatment, or 6 years on average. The risk of 
developing a new blood cancer after allogeneic blood or marrow transplant is probably less 
than 2%. If cancer develops in your donor’s blood cells, you may require additional treatment 
with chemotherapy or another blood or marrow transplant. 
d. Risk to the unborn. The treatments in this study have not been proven to be safe at any stage of 
pregnancy. Therefore, if you are pregnant or nursing, you are not eligible for this study. Women 
who can become pregnant must use effective birth control while receiving chemotherapy, TBI, 
and drugs to prevent GVHD, and for 1 year after transplant. Effective birth control is defined as 
the following: 
1. Refraining from all acts of vaginal sex (abstinence)  
2. Consistent use of birth control pills 
3. Injectable birth control methods (Depo-Provera, Norplant) 
4. Tubal sterilization or male partner who has undergone a vasectomy 
5. Placement of an IUD (intrauterine device) 
6. Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam 
every time you have sex. 


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Reproductive Risks  
The drugs used in this research study may damage your reproductive organs, affect your ability to 
have children or possibly cause birth defects if you take them while you are pregnant. It is 
important that a woman is not pregnant or breast-feeding and does not become pregnant during 
the course of the study.  
It is important that both women who can become pregnant and their male partners use 
birth control for  
1 year after transplantation while on this study. 
If you are a woman and can become pregnant, you will need to take a pregnancy test before you 
start the study. You should discuss ways to prevent pregnancy while you are in the study. 
Women who have gone through puberty may find that their menstrual cycle becomes irregular or 
stops permanently. This does not mean that you cannot become pregnant. You must still use an 
effective method of birth control during your transplant and continue until you are finished with 
your GVHD prevention treatment. 
If you are a man, your body may not be able to produce sperm (become sterile). You should talk 
with your doctor about banking your sperm before having a transplant. 
Please check with your doctor to understand more about these risks. 
Additional Information about Bortezomib (Velcade®) 
▪ The effect of Velcade® on reproduction and its safety in pregnancy are unknown. If you 
are a woman capable of becoming pregnant [anyone who has not undergone a 
hysterectomy (removal of the womb), has not had both ovaries removed or has not been 
post-menopausal (stopped menstrual periods) for more than 24 months in a row], you 
must have a negative pregnancy test before beginning treatment. In addition, you must 
not be breastfeeding a baby during this study. 
▪ If you think that you have become pregnant or may have fathered a child while taking 
part in this study you must tell the study doctor immediately. The study doctor will advise 
you of the possible risks to your unborn baby and discuss options for managing the 
pregnancy with you. You should also notify the doctor managing your pregnancy that the 
mother/father received a study drug called Velcade®. 
▪ If you are a woman and you become pregnant during your participation in this study, 
your treatment with Velcade® will be stopped and you may be withdrawn from some of 
the study procedures but not from follow-up by your study doctor. The study doctor will 
ask for your permission to stay in contact with you throughout the length of the 
pregnancy. 
▪ If you are a man and your partner becomes pregnant, the study doctor will ask for your 
partner’s permission to collect information about her pregnancy and the health of the 
baby. 
▪ Laboratory tests show that Velcade® may damage DNA. Based on this information, it is 
possible that Velcade® may cause infertility in men and women. 


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Additional Information about MMF 
▪ MMF could be damaging to an unborn baby if you are pregnant or become pregnant 
while receiving the drug.  
▪ MMF can make birth control pills less effective and increase your chances of becoming 
pregnant while you are taking it. 
▪ If you could become pregnant, you must use 2 effective forms of birth control for 4 
weeks before starting MMF, during treatment, and for one year after transplantation. 
If you think you might be pregnant or could be become pregnant prior to enrollment, you should 
not join this study. 
Unforeseen Risks  
New risks might appear at any time during the study. These risks might be different from what is 
listed in this Consent Form. We will promptly tell you about new information that may affect 
your decision to take part in the study. We may learn new things about reduced-intensity 
transplants that might make you want to stop being in the study. We will let you know if this 
happens and you can decide if you want to continue in the study.  
Other Treatments or Medications 
Some medicines react with each other, and it is important that you tell the study doctor or staff 
about any other drugs, treatments, or medicines you are taking.  This includes non-prescription 
medications, vitamins and herbal treatments.  
It is also important that you tell the study staff about any changes to these medications during 
your participation in the study. 
For more information about risks and side effects, ask your study doctor. 
 
 
7. Alternative Treatments 
Participation in this study is optional. If you choose not to take part, you may still receive an 
allogeneic transplant to treat your disease.  The treatment and evaluations you would receive 
could be very similar to what would receive if you join this study.  
Your study doctor will talk with you about your options. If you decide not to participate in this 
study, your medical care will not be affected in any way. 
Your other choices may include: 
▪ Treatment with other drugs, radiation, or a combination of drugs and radiation without a 
transplant. 
▪ An allogeneic blood or marrow transplant that is not part of the study, or another type of 
transplant 
▪ Participation in another clinical trial, if available (check with your doctor) 


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▪ No treatment for your blood cancer at this time 
▪ Comfort care 
 
Every treatment option has benefits and risks. Talk with your doctor about your treatment 
choices before you decide if you will take part in this study. 
 
 
8. Possible Benefits 
Taking part in this study may or may not make your health better.  The information from this 
study will help doctors learn more about medications used to prevent GVHD. 
 
 
9. New Information Available During the Study 
During this research study, the study doctors may learn about new information about the study 
drugs or the risks and benefits of the study.  If this happens, they will tell you about the new 
information.  The new information may mean that you can no longer participate in the study, or that 
you may not want to continue in the study.  
If this happens, the study doctor will stop your participation in the study and will offer you all 
available care to suit your needs and medical conditions. 
 
 
10. Privacy, Confidentiality and Use of Information  
Your confidentiality is one of our main concerns. We will do our best to make sure that the 
personal information in your medical record is kept private. However, we cannot guarantee total 
privacy. All your medical and demographic (such as race and ethnicity, gender and household 
income) information will be kept private and confidential. (Name of Transplant Center) and the 
organizations listed below will not disclose your participation by any means of communication 
to any person or organization, except by your written request, or permission, or unless required 
by federal, state or local laws, or regulatory agencies.  
 
Individuals authorized by the organizations below will have access to your research and medical 
information. They may use this information for inspections or audits to study the outcomes of 
your treatment, or for required reporting to regulatory authorities (such as to the FDA for serious 
adverse events). In agreeing to participate, you consent to such inspections and to the copying of 
parts of your records, if required by these organizations. 
▪ The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
▪ The Center for International Blood and Marrow Transplant Research (CIBMTR) 
▪ The National Marrow Donor Program (NMDP) 


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▪ The Food and Drug Administration (FDA) 
▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN DCC)  
▪ Millennium Pharmaceuticals, Inc., supplier of bortezomib 
 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 
Information that does not include personally identifiable information about this clinical trial has 
been or will be submitted, at the appropriate and required time, to the government-operated 
clinical trial registry data bank, which contains registration, results, and other information about 
registered clinical trials. 
This data bank can be accessed by you and the general public at www.ClinicalTrials.gov.  
Federal law requires clinical trial information for certain clinical trials to be submitted to the data 
bank. 
 
 
11. Ending Your Participation 
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time.  If you choose not to take part or leave this study, your regular medical care will not be 
affected in any way.  Tell your doctor if you are thinking about stopping or decide to stop.  He or 
she will tell you how to stop safely. 
 
The study doctor or the study sponsor may stop the study at any time, and we may ask you to 
leave the study.  We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the treatment.  If we ask you to leave the study, the reasons will be 
discussed with you.  Possible reasons to end your participation in this study include: 
▪ You do not meet the study requirements.  
▪ You need a medical treatment not allowed in this study. 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
▪ You are having serious side effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or take study drugs as directed. 
▪ The study is stopped for any reason. 
If you decide to leave this study after taking the study treatment, or are asked to leave by your 
doctor for medical reason, you will need to come back to the doctor’s office for tests for your 
safety.  Even if you leave the study, the information collected from your participation will be 
included in the study evaluation, unless you specifically ask that it not be included. 
 
 


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12. Physical Injury as a Result of Participation  
It is important that you tell your doctor, __________________ [investigator's name(s)] or study 
staff if you feel that you have been injured because of taking part in this study.  You can tell the 
doctor in person or call him/her at __________________ [telephone number]. 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.  
In case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
 
13. Compensation or Payment 
You will not be paid for your participation in the research study.  You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. Your participation in this research study may contribute to the development of 
commercial products from which Millennium Pharmaceuticals, Inc. (manufacturer of 
bortezomib) or others, may derive an economic benefit.  You will have no rights to any patents 
or discoveries arising from this research, and you will receive no economic benefit. 
 
 
14. Costs and Reimbursements 
Most of the visits for this research study are standard medical care for patients undergoing 
allogeneic transplants and will be billed to your insurance company.  You and/or your health 
plan/insurance company will need to pay for some or all of the costs of standard treatment in this 
study 
The drug bortezomib is being provided by the manufacturer (Millennium Pharmaceuticals, Inc.), 
free of charge. The drug maraviroc is being provided by the study, free of charge. 
You or your insurance will not be charged for optional blood samples for research on this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
 
15. Ethical Review 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
 


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Version 3.0 dated July 17, 2015 
 
 
B-19 
 
16. For More Information 
If you need more information about this study, or if you have problems while you are participating 
in this study, you can contact the study doctor or his/her staff.  They can be reached at the telephone 
numbers listed here: 
[Insert name and contact details] 
 
 
17. Contact Someone about Your Rights 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact:  
[Insert appropriate contact details] 
For questions about your rights while taking part in this study, call the __________[name of 
center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  
 
 
18.  Blood Samples for Research (Optional) 
This section of the informed consent form is about future research studies that will be done 
using blood samples from people who are taking part in the main study described above.  
You may give small blood samples for these future research studies if you want to.  You can 
still be a part of the main study even if you say “no” to giving blood samples for future 
research studies.  You can say "yes" or "no" to giving blood samples for future research 
studies.  Please mark your choice at the end of this section. 
 
We would like to have five (5) small blood samples for future research.  If you agree, these 
samples will be drawn before you begin the conditioning regimen for your transplant (3 
teaspoons or 16 mL), and at 4 different times after your transplant: on Days 35, 100, 180 and 365 
(10 teaspoons or 40 mL each). These samples will be kept and may be used in research to learn 
more about immune reconstitution, GVHD, cancer and other diseases.  Usually the blood can be 
drawn from a vein in your arm at the same time as other blood collections. When the samples are 
given to investigators for research, no information about your name, address, phone number or 
other information that will let the researcher know who you are will be provided. 
 
The samples collected for research purposes will be sent to the BMT CTN Repository.  The 
samples will be labeled with unique codes that do not contain information that could identify 
you.  A link to this code does exist.  The link is stored at the Data and Coordinating Center for 
the Blood and Marrow Transplant Clinical Trials Network (BMT CTN DCC).  The staff at the 
Repository where your sample is being stored does not have a link to this code.  Your research 
samples will continue to be stored at the BMT CTN Repository until they are used up for 
approved research. 


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Version 3.0 dated July 17, 2015 
 
 
B-20 
 
Genome-Wide Association Studies: 
DNA from your stored blood samples might be used in genome-wide association (GWA) 
studies for a future project either done or supported by the National Institutes of Health 
(NIH).  Genome-wide association studies are a way for scientists to find genes that have a 
role in human disease or treatment. Each study can look at hundreds of thousands of genetic 
changes at the same time. 
 
  If your coded samples are used in such a study, the researcher is required to add your test 
results and sample information into a public research database.  This public database is called 
the NIH Genotype and Phenotype Database and it is managed by the National Center for 
Biotechnology Information (NCBI).  The NCBI will never have any information that would 
identify you, or link you to your information or research samples, although the results of 
genetic studies could theoretically include identifying information about you.  
 
Genetic Information Nondiscrimination Act: 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  Health 
insurance companies and group health plans may not request your genetic information that we 
get from this research.  This means that they must not use your genetic information when making 
decisions regarding insurability.  Be aware that this new federal law will not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
 
Things to Think About:  
• The choice to let us have blood samples for future research is up to you.  No matter what 
you decide to do, it will not affect your care.  
 
• If you decide now that your blood can be kept for research, you can change your mind at 
any time.  Just contact your study doctor and let him or her know that you do not want us 
to use your blood sample.  Then any blood that remains will no longer be used for 
research.  
 
• In the future, people who do research on these blood samples may need to know more 
about your health.  While the study doctor or others involved in running this study may 
give the researchers reports about your health, it will not give them your name, address, 
phone number, or any other information that will let the researchers know who you are.  
 
• Sometimes blood is used for genetic research (about diseases that are passed on in 
families).  Even if your blood is used for this kind of research, the results will not be put 
in your health records.  
 
• Your blood will be used only for research and will not be sold.  The research done with 
your blood may help to develop new products in the future.  


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Version 3.0 dated July 17, 2015 
 
 
B-21 
 
• Reports about research done with your blood will not be given to you or your doctor.  
These reports will not be put in your health record.  The research will not have an effect 
on your care.  
 
Benefits: 
The research that may be done with your blood is not designed specifically to help you.  The 
benefits of research using blood include learning more about what causes GVHD, cancer and 
other diseases, how to prevent them, and how to treat them.  
 
Risks: 
There is a small risk of an infection or fainting from the blood draw.  
 
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
Making Your Choice: 
Please read each sentence below and think about your choice.  After reading each sentence, 
please indicate your choice below.  If you have any questions, please talk to your doctor or nurse, 
or call our research review board at ___________________.  
 
No matter what you decide to do, it will not affect your care. 


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Version 3.0 dated July 17, 2015 
 
 
B-22 
Statement of Consent 
The purpose of storing blood samples for future research, the procedures involved, and the risks 
and benefits have been explained to me.  I have asked all the questions I have at this time and I 
have been told whom to contact if I have more questions.  I have been told that I will be given a 
signed copy of this consent form to keep. 
I understand that I do not have to allow the use of my blood  for research.  If I decide to not let 
you store research samples now or in the future, it will not affect my medical care in any way. 
I voluntarily agree that  blood samples may be collected and that my blood and related 
information can be stored indefinitely by the BMT CTN Repository for research to learn about, 
prevent, or treat GVHD, cancer, or other health problems.  I also understand that my DNA and 
health information may or may not be used in genome-wide association studies.  
 I do agree to give blood samples for future research. 
 I do not agree to give blood samples for future research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
                                               
 
 


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated July 17, 2015 
 
 
B-23 
Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes 
 
A. Purpose:   
As a research participant, I authorize the Principal Investigators and the researcher’s staff to 
use and disclose my individual health information for the purpose of conducting the research 
study:  
A Multi-Center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host 
Disease Prevention Compared to Contemporary Controls 
 
B. Individual Health Information to be Used or Disclosed:  
My individual health information that may be used or disclosed to do this research includes:  
▪ Demographic information (for example: date of birth, sex, weight).  
▪ Medical history (for example: diagnosis, complications with prior treatment). 
▪ Findings from physical exams. 
▪ Laboratory test results obtained at the time of work up and after transplant (for example: 
blood tests, biopsy results).  
 
C. Parties Who May Disclose My Individual Health Information:  
The researcher and the researcher’s staff may collect my individual health information from: 
[List hospitals, clinics or providers from which health care information can be requested]. 
 
D. Parties Who May Receive or Use My Individual Health Information:  
The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the following 
parties: 
 
Principal Investigators and the researchers’ staff 
Dr. Javier Bolaños-Meade, Co-Principal Investigator  
Dr. John Koreth, Co-Principal Investigator  
Dr. Ran Reshef, Co-Principal Investigator 
 
Study Sponsors  
▪ National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH),  
▪ Blood and Marrow Transplant Clinical Trials Network (BMT CTN), Data and 
Coordinating Center 
 
                                                 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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Version 3.0 dated July 17, 2015 
 
 
B-24 
Other organizations 
▪ U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) 
▪ U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments. 
▪ Millennium Pharmaceuticals, Inc., supplier of bortezomib 
 
E. Right to Refuse to Sign this Authorization:  
I do not have to sign this Authorization.  If I decide not to sign the Authorization, I will not 
be allowed to participate in this study or receive any treatment related to research that is 
provided through the study.   
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
 
F. Right to Revoke:   
I can change my mind and withdraw this authorization at any time by sending a written 
notice to the Principal Investigator to inform the researcher of my decision.  
If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study.  No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure:  
My individual health information disclosed under this authorization may be subject to re-
disclosure outside the research study and no longer protected. 
Examples include potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
 
H. This authorization does not have an expiration date. 
 
 
 


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Version 3.0 dated July 17, 2015 
 
 
B-25 
I have read and understood this Consent Form.  The nature and purpose of the research study has 
been explained to me. 
▪ I have had the chance to ask questions, and understand the answers I have been given.  I 
understand that I may ask questions at any time during the study. 
▪ I freely agree to be a participant in the study. 
▪ I understand that I may not directly benefit from taking part in the study. 
▪ I understand that, while information gained during the study may be published, I will not 
be identified and my personal results will stay confidential. 
▪ I have had the chance to discuss my participation in this research study with a family 
member or friend. 
▪ I understand that I can leave this study at any time, and doing so will not affect my 
current care or prevent me from receiving future treatment. 
▪ I understand that I will be given a copy of this signed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Counseling Physician 
 
 
 
Date 
 
 
 
 
 
 
 
 
                                                                
Signature of Counseling Physician 
 
    
 
Date 
 
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 
 


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GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
C-2 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
OPTIONAL RESEARCH SPECIMENS 
 
Patients consenting to the optional future research will have samples collected for future research 
supporting the protocol, including assessment of immune reconstitution.  All research sample 
aliquots will be given unique bar code designations that cannot be linked back to the 
participant’s name or other identifying information. Laboratory test results, clinical information, 
etc., associated with the coded samples are provided to the Investigator only after completion of 
the protocol.  Samples sent to researchers cannot be linked with any remaining samples at the 
repository. 
 
Patient samples will be collected both prior to the initiation of treatment and at Days 35, 100, 
180 and 365 post-treatment time points as specified in the table on the next page. All research 
samples will be collected and shipped same-day to the BMT CTN Repository for processing and 
sample aliquot storage. Sample collection and shipping procedures are detailed in the BMT CTN 
1203 Laboratory Sample Guide. 


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GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
C-3 
 
Optional Research Samples 
Subjects 
Research 
Sample 
Type 
Time Points 
[Total Blood 
Volume] 
Sample 
Quantity 
Stored 
Material 
Sample 
Processing 
& Storage 
Site 
Aliquots Stored 
Purpose 
270 Patients 
 
Patients encouraged 
to co-enroll on 
BMT CTN 1202 
Biomarkers Study 
Peripheral 
Blood 
Pre-Transplant 
(prior to initiation 
of conditioning 
regimen) 
 
16 mL 
6 mL 
EDTA 
Whole Blood 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL whole blood aliquots; 
stored at -80º C 
Undefined Future Research 
(Genomic DNA Isolation) 
10 mL 
Serum 
Clot Tube 
Serum 
BMT CTN 
Repository 
Maximum 
10 aliquots 
~ 0.5 mL aliquots; stored at  
-80º C 
Undefined Future Research 
(Proteomic) 
Post-Transplant 
Days 35, 100, 180, 
and  365 
 
40 mL 
10 mL 
Serum 
Clot Tube 
Serum 
BMT CTN 
Repository 
Maximum 
10 aliquots 
~ 0.5 mL aliquots; stored at  
-80º C 
Undefined Future Research 
(Proteomic) 
30 mL 
Heparin 
Viable PBMC 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL aliquots containing ~ 
2.5-5.0 x 106 PBMC; 
controlled-rate frozen and 
stored in LN2 
Undefined Future Research 
(Cell-Functional & Gene 
Expression) 
 
 
Windows for Submitting Optional Research Samples 
Day 0 (Prior to Initiation of 
Conditioning) 
Day 35 (±2) 
Day 100 (±7)  
Day 180 (±14)  
Day 365 (±14) 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
D-1 
APPENDIX D 
 
NEW YORK HEART ASSOCIATION (NYHA)  
CLASSIFICATION OF CARDIAC DISEASE 
 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
D-2 
APPENDIX D 
 
NEW YORK HEART ASSOCIATION (NYHA)  
CLASSIFICATION OF CARDIAC DISEASE 
 
The following table presents the NYHA classification of cardiac disease. 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
E-1 
APPENDIX E 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC  
FOR CENSORED EXPONENTIAL DATA 
 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
E-2 
APPENDIX E 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H


:
0
 versus
1
1 :


H
 decides in favor of 
1
H  or 
0
H if 
c
Ln 
 
or 
c
Ln 
, respectively, where 


n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 
c is 
determined to have the size .  When the sample size is not fixed in advance, further 
improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The SPRT 
continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling and 
decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H as soon 
as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities 

and of 
rejecting 
0
H when 
0


, and of accepting 
0
H when 
1


, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, 
j=0,1, the SPRT with error probabilities  and minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
.  If, in 
addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function 
)
,
( 
x
f
, with monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1


 
has non-decreasing power function. 
 
For the SPRT with error probabilities 

and , the SPRT boundaries are given approximately 
by 

/)
1( 

A
 and 
)
1
/(




B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O



 where 
)
(
h
is the non-trivial solution to the equation 

1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E



provides the average sample number 
for an arbitrary .  The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var

.  Thus 
we will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
E-3 
Derivation of the SPRT for Uncensored Exponential Survival Times 
 
For example, we wish to construct a sequential test for the composite null hypothesis that the rate 
of TRM at 180 days is less than or equal to 5% versus the alternative hypothesis that it is greater 
than or equal to 5%.  For the derivation of the uncensored SPRT, we will require that the type I 
error of the test be less than 10%, and that the test provide 90% power to reject the null 
hypothesis under a specified alternative that the true rate is 10%.  A maximum sample size of 
250 patients will be permitted. 
 
Let us assume that the survival times, 
nT
T
T
,...,
,
2
1
, are completely observed (uncensored) and are 
i.i.d. with exponential density function 
T
e
T
f





)
,
(
.  These assumptions will be relaxed to 
incompletely observed data subsequently.  In the exponential parameterization, a 180-day 
survival rate of 95% translates into a mean survival of 9.747 years (

0

.1026), and 90% 
translates into a mean survival of 4.746 years (

1

.2107). 
 
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case, 


o
H


:
0
 .1026 versus
1
1 :


H
 = .2107.  However, since the log-likelihood ratio for the 
exponential, 








n
i
n
i
n
i
i
i
i
T
n
x
f
x
f
)
(
))
log(
)
(log(
)
,
(
log
)
;
(
log
0
1
0
1
0
1






, is a 
monotone function of 
n
i
iT , the power of the test is non-decreasing in .  Thus the SPRT is a 
one-sided level .10 test of a composite null (
1026
.
:
0


o
H


) versus a composite alternative (
2107
.
:
1


o
H


), with power of 
90
.
1


 at the selected alternative 


1


.2107. 
 
The SPRT can be represented graphically.  The continuation region is bounded by two parallel 
lines with common slope 



)
log
/(log
)
(
0
1
0
1




0.150, and intercepts 


)
log
/(log
log
0
1


A
3.05 and 


)
log
/(log
log
0
1


B
-3.05 for the lower and upper bounds, respectively.  As each 
individual unit is put on trial and observed to fail, the current sample size, n,  is plotted against 
the cumulative sum of failure times.  When this graph crosses the upper boundary, the null 
hypothesis is rejected. 
 
The maximum sample size of 250 patients requires that the SPRT be truncated.  We choose to 
truncate the SPRT by declaring that if the test has failed to terminate after 250 patients, that the 
null hypothesis will be accepted.  Since the probability that the untruncated SPRT would reject 
the null at a sample size of 250 is negligible, it makes little difference how the final boundary 
value is selected, and this rule is chosen for simplicity.   
 
Derivation of a Modified SPRT for Censored Exponential Data 
 
The assumption of uncensored exponential survival times is flawed.  However, we consider it 
reasonable to assume the hazard for TRM is constant over the first 180 days post-transplant, and 


BMT CLINICAL TRIALS NETWORK 
GVHD Prophylaxis Protocol – 1203 
Version 3.0 dated July 17, 2015 
 
 
E-4 
we will restrict our attention to this time interval.  Furthermore, it is not practical to conduct a 
clinical study by putting each individual on trial, and waiting until that individual is observed to 
fail.  We relax our assumptions as follows.  Firstly, each individual’s time on study will be 
computed as time from transplant to failure, or to the 180 day time point, whichever comes first.  
Secondly, we will put individuals on trial as soon as they become available, without waiting for 
the previous individual to fail. 
 
Let us consider the impact of relaxing these assumptions one at a time.  In a fixed sample size 
trial with uncensored exponential failure times, mean survival time is estimated by the sample 
mean of the failure times, or total time on study divided by the number of individuals enrolled.  
When censoring is introduced, the estimate becomes the total time on study divided by the 
number of observed (non-censored) failures.  This suggests that in an exponential SPRT test 
modified to incorporate censoring, we replace the observed failure times, 
nT
T
T
,...,
,
2
1
, with 
censored failures times, 
nx
x
x
,...,
,
2
1
, and the current sample size, n , with the number of observed 
failures, d .   
 
Now we relax the second assumption, and put individuals on trial as soon as they become 
available, without waiting for the previous individual to fail.  Assume that three years are 
required for accrual of 250 patients to the study, and that the final analysis takes place 180 days 
after the last patient is entered.  Putting all of this together, we propose a modified truncated 
SPRT, where at any interim time point, s , ranging from 0 to 3 years 180 days, the number of 
observed failures, d(s), is plotted against the sum of observed time on study, 
n
i
i s
X
)
(
.  In 
practice, monitoring will be scheduled monthly after the start of enrollment to the study.  A 
further modification to the SPRT was to only use the upper boundary for stopping since the 
primary focus of the monitoring is to protect against unacceptable 180-day TRM rates. 
 
Operating Characteristics of the Modified SPRT Test for Censored Exponential Data 
 
Recall that the uncensored SPRT targeted a drop in TRM-free survival at Day 180 from 95% to 
90%, with type I and II errors of 10% and 10%.  Since only the upper boundary is used for 
monitoring, the continuation region of the test was bounded above by a line with a slope of 0.150 
and intercept of 3.05.  In our example, the sample size is large enough that the reduction in 
power due to truncation of the test is negligible compared to the increase in power because the 
modified SPRT, lacking a lower boundary, cannot stop early to “accept” the null hypothesis.  In 
order to maintain type I error, we raise the upper boundary to make it harder to cross.  Under the 
further assumption of uniform accrual over a three year period, and monthly interim analyses 
over the course of the study, the operating characteristics of the modified SPRT were obtained 
from a simulation study.  These simulation show that an intercept of 4.02, corresponding to 
setting parameters 

 and to 10% and 10%, result in empirical type I and II error rates of 10% 
and 10%.   
 


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Version 3.0 dated July 17, 2015 
 
 
E-5 
Table E-1   Operating Characteristics of Sequential Testing Procedures from a 
Simulation Study with 100,000 Replications 
 
True 180-Day Rate 
5% 
10% 
Probability Reject Null 
0.095 
0.903 
Mean Month Stopped 
41.0 
20.2 
Mean # Endpoints in 180 days 
11.8 
11.6 
Mean # Patients Enrolled 
240.8 
135.4 
 
While the motivation for this testing procedure is largely heuristic rather than theoretical, the 
simulation results validate the approach.  When the true rate of TRM on or before Day 180 was 
5%, the test crossed the lower boundary in 9484 of 100,000 replications, for an estimated type I 
error rate of 9.5%.  When the true rate of TRM on or before Day 180 was 10%, the test failed to 
cross the boundary in the in 9742 of 100,000 replications, for an estimated type II error rate of 
9.7%.  In this setting, on average, the boundary will be crossed at 20.2 months. 
 
It is interesting to note that the SPRT derived above for exponential failure times with censoring 
at 180 days, has operating characteristics which are similar to those of a more traditional SPRT, 
derived for binomial variates with success probability equal to the 180 day failure rate.  Using 
time to failure rather than a simple binary indicator of failure, leads to little improvement in 
power when failure times are censored relatively soon after entry on study.  We speculate that if 
the constant hazard rate over the first 180 days were high, the exponential test would reject faster 
than the binomial test, but have not conducted simulation studies to demonstrate this. 
 


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F-1 
APPENDIX F 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
 


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Version 3.0 dated July 17, 2015 
 
 
F-2 
APPENDIX F 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of disease. 
 
Able to carry on normal activity; no 
special care needed. 
90 
Able to carry on normal activity, minor signs or 
symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal activity 
or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of assistance 
needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, but 
death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 
 
 


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APPENDIX G 
 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 


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G-2 
APPENDIX G 
 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
 
Comorbidities 
Definition 
Score 
Migraine/headache 
 
0 
Osteoporosis 
 
0 
Osteoarthritis 
 
0 
Hypertension 
 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCo and/or FEV1 >80% or 
Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dl 
0 
Endocrine 
 
0 
Bleeding 
 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
 
0 
Arrhythmia 
 
1 
Myocardial 
Coronary artery disease, congestive HF, history of 
medically documented MI, EF50% 
1 
Mild hepatic 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular 
accident 
1 
Morbid obesity 
 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
 
1 
Infection 
Requiring continuation of treatment after Day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica 
 
2 
Moderate pulmonary 
DLCo and/or FEV1 66-80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN 
3 
Severe pulmonary 
DLCo and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 


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Version 3.0 dated July 17, 2015 
 
 
H-1 
APPENDIX H 
 
KNOWN ANTICIPATED RISKS OF BORTEZOMIB 
 


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Version 3.0 dated July 17, 2015 
 
 
H-2 
APPENDIX H 
 
KNOWN ANTICIPATED RISKS OF BORTEZOMIB 
 
 
Table 1 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival haemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, oedema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 


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Table 1 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinaemia, hepatitis* 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis, 
bactaeremia*, cellulitis, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, 
fungal oesophagitis 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumour lysis syndrome* 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo, headache 


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Version 3.0 dated July 17, 2015 
 
 
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Table 1 Known Anticipated Risks of Bortezomib by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Common  
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrome, 
posterior reversible encephalopathy syndrome  
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 16. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is deemed medically important and so is included. 
Effective MedDRA update to version 14.0, the term ‘reversible posterior leukoencephalopathy syndrome’ updated to ‘posterior 
reversible encephalopathy syndrome (PRES)’. 
 
 


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H-5 
Table 2 Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class Preferred Term 
Observed Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
 
Optic neuropathy 
Rare 
 
Blindness 
Rare  
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
Rare 
Progressive multifocal leukoencephalopathy 
Very rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 


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Version 3.0 dated July 17, 2015 
 
 
H-6 
Table 2 Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class Preferred Term 
Observed Incidencea 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 16. 
a Incidence is assigned using the following convention:  very common ( 1/10); common ( 1/100 and  1/10); uncommon ( 1/1000 
and  1/100); rare ( 1/10,000 and  1/1000 ); very rare ( 1/10,000, including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a Preferred Term of Interstitial 
lung disease. 


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Version 3.0 dated July 17, 2015 
 
 
I-1 
APPENDIX I 
 
PRODUCT COMPLAINTS FOR BORTEZOMIB 
 


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Version 3.0 dated July 17, 2015 
 
 
I-2 
APPENDIX I 
 
PRODUCT COMPLAINTS FOR BORTEZOMIB 
 
 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
quality representative. 
 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
MedComm Solutions (see below) and report the event. 
 
For Product Complaints or Medication Errors,  
call MedComm Solutions at 
1-866-835-2233 (US and International)  
 
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint or medication error results in an Unexpected, Grade 3-5 Adverse Event, then the 
appropriate forms in AdvantageEDC should be completed (refer to Section 4.7 Adverse Event 
Reporting). 
 
 
 


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Version 3.0 dated July 17, 2015 
 
 
J-1 
APPENDIX J 
 
ADVERSE EVENT REPORTING REQUIREMENTS  
 


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated July 17, 2015 
 
 
J-2 
APPENDIX J 
 
ADVERSE EVENT REPORTING 
 
J.1 Adverse Event Reporting 
 
Adverse events (AEs) will be collected on calendar-driven forms and event-driven forms in 
AdvantageEDC.   
 
The calendar-driven forms are those that appear in the AdvantageEDC Forms Grid for each 
enrolled patient at designated time points (e.g., Day 28 post transplant) throughout the course of 
the study. Completion of a calendar-driven form is expected by the Target Date for the given 
assessment period.  
 
Calendar-driven forms for the BMT CTN 1203 study are as follows:   
• Toxicity Form: this form documents all expected toxicities for the BMT CTN 1203 
study; each toxicity is also assigned a grade, based on the NCI CTCAE Version 4.0. 
• Hematology/Chemistry 
Form: 
this 
form 
documents 
selected 
hematology 
(CBC/differential) and blood chemistry results. 
• Follow-Up Status Form: this form documents the status of each patient at various 
intervals on the study. 
 
Event-driven forms must be completed when a certain event triggers the appearance of the form 
in the AdvantageEDC Forms Grid. Most often the event-driven form is triggered by information 
entered on the Follow-up Status Form. Event-driven forms for the BMT CTN 1203 study are as 
follows: 
• Re-Admission/Hospitalization Form: this form documents all hospital admissions, 
including the admission for transplant for this study.  
• Infection Form: this form documents infections from the Day 0 (date of transplant) 
through the 1-year post-transplant follow-up period.  
• Secondary Graft Failure Form: this form captures the details associated with secondary 
graft failure. DO NOT report secondary graft failure as an Unexpected, Grade 3-5 
Adverse Event. 
• Progression/Relapse Form: the form captures detailed information associated with 
progression or relapse of the primary disease. DO NOT report progression or relapse as 
an Unexpected, Grade 3-5 Adverse Event. 
• Death Form: this form documents the death of a patient from the time of study 
enrollment and randomization through the 1-year post-transplant follow-up period.  
• Bortezomib SAE Screening Form: this form captures basic information on all SAEs 
only for patients randomized to the bortezomib arm from the first dose of bortezomib 
through 30 days after the last dose. 


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J-3 
• Adverse Event Forms: this series of forms captures details on adverse events that are 
both unexpected and grades 3-5, based on the NCI CTCAE Version 4.0, regardless of 
attribution to any of the study interventions. These forms are also used to collect 
information on any SAE event required by the additional adverse event reporting 
requirements. These events will be reviewed by the Medical Monitor at the BMT CTN 
Data and Coordinating Center (DCC) within 2 business days of receiving the summary of 
the adverse event from the transplant center. If the Medical Monitor requires additional 
information to make his/her assessment, the transplant center will have 4 business days to 
respond to the request for additional information. 
 
J.2 Reporting Expected Toxicities 
 
Expected toxicities for all patients enrolled on BMT CTN 1302 will be collected on the BMT 
CTN 1203 Calendar-Driven Toxicity Form.  
 
J.3 Reporting Unexpected, Grade 3-5 Adverse Events 
 
All Unexpected, Grade 3-5 Adverse Events should be reported for every patient enrolled on 
the study from the time of enrollment until 1 years post transplant. Additional Adverse 
Event reporting applies to patients dependent on the treatment received on the study. 
Determination of the expectedness of adverse events should be differentiated between the arms 
at the discretion of the investigator. For example, sweat gland disturbances would be an expected 
risk associated with maraviroc, but the investigator should assess the expectedness for a patient 
experiencing sweat gland disturbances randomized to the bortezomib arm.  
 
 
J.4 Additional Reporting Requirements for Patients Randomized to the Tacrolimus/ 
Methotrexate/Bortezomib from the 1st dose of Bortezomib through 30 Days After the 
Last Dose.  
 
This section outlines the adverse event reporting requirements for all patients randomized to the 
Tacrolimus/Methotrexate/Bortezomib from the first dose  
 
Millennium Pharmaceuticals, Inc. (MPI) is supplying bortezomib for all patients who are 
randomized to receive tacrolimus/methotrexate/bortezomib as GVHD prophylaxis on this study. 
MPI has adverse event reporting requirements for all patients who receive study bortezomib. 
 
In addition to the standard BMT CTN guidelines for reporting adverse events (see Chapter 
4, Section 4.7), MPI is requiring the reporting of all Serious Adverse Events (SAEs) that occur 
after the initial dose of study bortezomib (Day +1), during treatment, and within 30 days of 
the last dose of study bortezomib (Day +7 plus 30 days).  This includes events meeting the 
definition of a Serious Adverse Event, per 21 CFR 312.32, as follows: 
 
Serious Adverse Event: A serious adverse event (SAE) is any adverse event that results in one 
of the following outcomes, regardless of causality and expectedness:  


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Version 3.0 dated July 17, 2015 
 
 
J-4 
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Medical and scientific judgment should be exercised in deciding whether expected reporting is also 
appropriate in situations other than those listed above.  For example, important medical events may 
not be immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the outcomes listed in the definition above (eg, 
suspected transmission of an infectious agent by a medicinal product is considered a Serious 
Adverse Event). Any event is considered a Serious Adverse Event if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact. 
 
J.4.1 Reporting Timelines for Events Occuring During Bortezomib Reporting Period 
 
• Fatal and Life-Threatening events must be reported in AdvantageEDC within 24 hours, 
of the investigator’s observation or awareness of the event. 
• All Other Serious events (non-fatal/non-life-threatening) must be reported in 
AdvantageEDC within 3 calendar days of the investigator’s observation or awareness of 
the event. 
 
J.4.2 How to Report Serious Adverse Events During Bortezomib Reporting Period 
 
All SAEs from the first dose of bortezomib through 30 days after the last dose will be reported in 
AdvantageEDC by completing theBortezomib SAE Screening Form. .  All SAEs also require 
completion of the Adverse Event Forms (AE1-AE6), unless any of the following SAEs are 
determined to be unrelated or unlikely related to the bortezomib, then the Adverse Event Forms 
are not required: 
 


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Version 3.0 dated July 17, 2015 
 
 
J-5 
• Neutropenia 
• Thrombocytopenia 
• Anemia 
• Minor bleeding episodes (i.e. epistaxis) 
• Graft-versus-host disease (GVHD) 
• Graft failure 
• Hepatic veno-occlusive disease (VOD) 
• Thrombotic microangiopathy (TMA)  
 
Accurate completion of the Bortezomib SAE and/or Adverse Event forms will allow the DCC to 
provide MPI with the details they require to fully understand each event, so it is critical that all 
fields are filled in and comprehensive supporting source documents for the event (PHI redacted) 
are uploaded to the appropriate forms. 
 
If an adverse event does not meet the criteria of an SAE, it will require reporting on the Adverse 
Event form if it is both unexpected and grade 3-5 based on the BMT CTN standard reporting 
guidelines. 
 
J.4.3 Frequently Asked Questions 
 
Below are some examples of anticipated questions with regard to the reporting requirements 
detailed above. These questions do not cover all possible scenarios, therefore it is important to 
contact the BMT CTN Adverse Event or 1203 Protocol Coordinator should there be any 
questions or concerns regarding the reporting of an event and whether the event meets the MPI 
reporting requirements. 
• Since hospitalization is considered an SAE, should the patient’s admission for 
transplant be reported as an SAE?  NO. Admissions that are scheduled to occur during 
the study period, bu planned prior to study entry are not considered SAEs given the 
disease existed before the person was enrolled in the trial and provided that it did not 
deteriorate in an unexpected manner during the trial. The SAE reporting requirements 
also begin with the first dose of study drug (bortezomib on Day +1), so the admission for 
transplant will occur before this reporting begins. Among patients who undergo the 
transplant procedure as outpatients and have scheduled hospitalization at time they 
become neutropenic in the absence of fever, an SAE report is not required, unless the 
neutropenia prolongs the scheduled hospitalization.    
• Is neutropenia and/or thrombocytopenia associated with the preparative regimen 
and experienced during the transplant admission considered a life-threatening 
event? NO. Pancytopenias associated with transplant are not considered life-threatening 
events for the purposes of these reporting requirements. If patients are discharged after 
the transplant, followed as outpatients, and then re-hospitalized for neutropenic fever 
prior to day 37, SAE reporting will be required.  
• During the transplant admission a patient becomes critically ill (e.g., pneumonia 
requiring intubation). Does this event need to be reported as an SAE? YES. Even 
though the patient is already hospitalized, this is a life-threatening event that required 
intervention and likely prolonged hospitalization. 


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• A patient is discharged from the hospital post-transplant on Day +32, and is then re-
admitted 2 days later for diarrhea and nausea. Should this re-admission be reported 
as an SAE?  Possibly. Even though the subsequent hospitalization falls within the 
reporting period (Day +7 plus 30 days) the reason for admission is likely GVHD. If the 
GVHD is determined to be unrelated or unlikely related to the bortezomib, only the 
Bortezomib SAE screening form is required. If the GVHD is determined to be possibly, 
probably or definitely related to bortezomib, then an SAE should be reported on both the 
Bortezomib SAE screening form and the Adverse Event forms. If the work up is negative 
for GVHD of the gastrointestinal tract, then an SAE should be reported. 
• A patient is discharged from the hospital post-transplant, and is then re-admitted 
for nausea, vomiting and diarrhea on Day +40. Should this hospitalization be 
reported as an SAE?  It is not required that this event be reported as an SAE since the 
admission occurred outside of the reporting period (Day +7 plus 30 days). However, if 
the investigator has a reason to believe that the event is life-threatening and there is no 
evidence of GVHD, the event may be reported at the discretion of the investigator. 
 
J.5 Reporting Requirements for Patients Randomized to Tacrolimus/ 
Methotrexate/Bortezomib Beginning 30 days After the Last Dose of Bortezomib 
 
This section outlines the adverse event reporting requirements for all patients beginning 30 days 
after the final dose of bortezomib until 1 year post transplant. 
 
Table J-1 lists adverse events and toxicities for this study, as well as the form in AdvantageEDC 
that is used to document the event.  
 
TABLE J-1: ADVERSE EVENTS FOR BMT CTN 1203 BEGINNING 30 DAYS AFTER 
THE LAST DOSE OF BORTEZOMIB BY ORGAN SYSTEM 
Adverse Event 
Collection Type 
Collection Form1 
AUDITORY DISORDERS 
Hearing loss 
Calendar-Driven 
Toxicity 
BLOOD AND LYMPHATIC DISORDERS 
Anemia 
Calendar-Driven 
Toxicity  
Neutropenia 
Calendar-Driven 
Toxicity  
Thrombocytopenia 
Calendar-Driven 
Toxicity 
Thrombotic thrombocytopenic 
purpura/ Thrombotic 
microangiopathy 
Calendar-Driven 
Toxicity 
CARDIAC DISORDERS 
Cardiac arrhythmia 
Calendar-Driven 
Toxicity 
Hypertension 
Calendar-Driven 
Toxicity 
Hypotension 
Calendar-Driven 
Toxicity 
Left ventricular systolic dysfunction 
Calendar-Driven 
Toxicity 
Myocardial infarction 
Calendar-Driven 
Toxicity 
New or worsening heart failure 
Calendar-Driven 
Toxicity 
Pericardial effusion 
Calendar-Driven 
Toxicity 


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J-7 
Adverse Event 
Collection Type 
Collection Form1 
Pericarditis 
Event-Driven 
Adverse Event Form 
Peripheral edema 
Calendar-Driven 
Toxicity 
Restrictive cardiomyopathy 
Calendar-Driven 
Toxicity 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Calendar-Driven 
Toxicity 
Anorexia 
Calendar-Driven 
Toxicity 
Constipation 
Calendar-Driven 
Toxicity 
Diarrhea 
Calendar-Driven 
Toxicity 
Dysgeusia (taste alteration) 
Calendar-Driven 
Toxicity 
Dyspepsia (heartburn) 
Calendar-Driven 
Toxicity 
Gastroenteritis 
Calendar-Driven 
Toxicity 
Intestinal obstruction 
Event-Driven 
Adverse Event Form 
Nausea 
Calendar-Driven 
Toxicity 
Oral mucositis 
Calendar-Driven 
Toxicity 
Vomiting 
Calendar-Driven 
Toxicity 
GENERAL DISORDERS 
Fatigue 
Calendar-Driven 
Toxicity 
Fever 
Calendar-Driven 
Toxicity 
HEPATOBILIARY/PANCREAS DISORDERS 
Abnormal liver function tests 
Calendar-Driven 
Toxicity 
Hepatitis 
Event-Driven 
Adverse Event Form 
Liver failure 
Event-Driven 
Adverse Event Form 
Pancreatitis 
Calendar-Driven 
Toxicity 
HEMORRHAGIC DISORDERS 
Intracranial 
Event-Driven 
Adverse Event Form 
Gastrointestinal 
Calendar-Driven 
Toxicity 
Genitourinary 
Calendar-Driven 
Toxicity 
Pulmonary/Upper respiratory 
Calendar-Driven 
Toxicity 
IMMUNE SYSTEM DISORDERS 
Allergic reaction 
Event-Driven 
Adverse Event Form 
Anaphylaxis (swelling of the skin 
and/or swelling of the face or throat) 
Event-Driven 
Adverse Event Form 
INFECTIONS 
Fungal infections of the  mouth and 
throat 
Event-Driven 
Infection 
Herpes virus/shingles 
Event-Driven 
Infection 
Infections of the bladder, sinuses, 
throat, stomach and intestines, and 
skin 
Event-Driven 
Infection 
Sepsis 
Event-Driven 
Infection 
METABOLISM AND NUTRITION DISORDERS 
Hypercalcemia 
Calendar-Driven 
Toxicity  
Hyperglycemia 
Calendar-Driven 
Toxicity  


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J-8 
Adverse Event 
Collection Type 
Collection Form1 
Hypoglycemia 
Calendar-Driven 
Toxicity  
Hypokalemia 
Calendar-Driven 
Toxicity  
Hyponatremia 
Calendar-Driven 
Toxicity 
Tumor lysis syndrome 
Event-Driven 
Adverse Event Form 
MUSCULOSKELETAL AND TISSUE DISORDERS 
Arthralgia 
Calendar-Driven 
Toxicity 
Myalgia 
Calendar-Driven 
Toxicity 
Muscle weakness (generalized or 
specific area) 
Calendar-Driven 
Toxicity 
NERVOUS SYSTEM DISORDERS 
Anxiety 
Calendar-Driven 
Toxicity 
Confusion 
Calendar-Driven 
Toxicity 
Depression 
Calendar-Driven 
Toxicity 
Dizziness 
Calendar-Driven 
Toxicity 
Encephalopathy 
Event-Driven 
Adverse Event Form 
Headache 
Calendar-Driven 
Toxicity 
Insomnia 
Calendar-Driven 
Toxicity 
Neuropathy 
Calendar-Driven 
Toxicity 
Reversible posterior 
leukoencephalopathy syndrome 
(PRES) 
Calendar-Driven 
Toxicity 
Seizure 
Calendar-Driven 
Toxicity 
Severe muscle weakness/paralysis 
Event-Driven 
Adverse Event Form 
Somnolence 
Calendar-Driven 
Toxicity 
Syncope (fainting) 
Calendar-Driven 
Toxicity 
OCULAR/VISUAL DISORDERS 
Blurred vision 
Calendar-Driven 
Toxicity 
Conjunctivitis 
Calendar-Driven 
Toxicity 
Sudden loss of vision 
Event-Driven 
Adverse Event Form 
RENAL DISORDERS 
Cystitis Non-infective 
Calendar-Driven 
Toxicity 
Acute kidney injury 
Calendar-Driven 
Toxicity 
Chronic kidney disease 
Calendar-Driven 
Toxicity 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Bronchitis 
Calendar-Driven 
Infection 
Cough 
Calendar-Driven 
Toxicity 
Dyspnea 
Calendar-Driven 
Toxicity 
Hypoxia 
Calendar-Driven 
Toxicity 
Pleural effusion 
Calendar-Driven 
Toxicity 
Pneumonia 
Calendar-Driven 
Infection 
Sinusitis 
Calendar-Driven 
Toxicity 
Sore throat 
Calendar-Driven 
Toxicity 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 


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J-9 
Adverse Event 
Collection Type 
Collection Form1 
Pruritis 
Calendar-Driven 
Toxicity 
Rash 
Calendar-Driven 
Toxicity 
Hyperhidrosis (excessive sweating) 
Calendar-Driven 
Toxicity 
VASCULAR DISORDERS 
Capillary leak syndrome 
Calendar-Driven 
Toxicity 
Thromboembolic event 
Calendar-Driven 
Toxicity 
OTHER 
Pregnancy 
Event-Driven 
Adverse Event Form 
Other unexpected grade 3-5 AE 
Event-Driven 
Adverse Event Form  
 
1Events determined to be at least possibly related to bortezomib that occur more than 30 days 
from the last dose may be reported via the Bortezomib SAE Screening Form and Adverse Event 
Form at the discretion of the investigator.  
 
J.6 Reporting Requirements for All BMT CTN 1203 Participants 
 
This section outlines the reporting requirements for all participants enrolled on BMT CTN 1203 
from enrollment through 1 year post transplant..  
 
For patients randomized to Tacrolimus/Methotrexate/Bortezomib and 
Tacrolimus/MMF/Maraviroc, an assessment of relationship to Bortezomib and Maraviroc is 
required in addition to an assessment of relationship to transplant.  
 
Figure J-2 provides a decision tree for any adverse event that occurs on a patient randomized to 
any of the 3 treatment arms. 
 
 
 


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated July 17, 2015 
 
 
J-10 
FIGURE J-2: DECISION TREE FOR ADVERSE EVENTS FOR BMT CTN 1203  
Did the Adverse Event occur in a patient who has received 
bortezomib?
Did this event occur within the required reporting period 
(i.e., beginning with the first dose of bortezomib and 
through 30 days after the last dose of bortezomib)?
Does this event meet the criteria of a serious adverse event 
(death, life-threatening, hospitalization, significant 
diasability/incapacity, congenital anomaly or birth defect or 
other important medical event)?
Yes
No
No
Is this a Grade 3–5 event, per version CTCAE 4.03?
Yes
No
1)Complete 
the 
Bortezomib 
SAE 
Screening 
form. 
No
Yes
Is the event unlikely or unrelated to 
bortezomib?
No
Yes
No further reporting required.
Is the event unexpected?
Yes
You must 
complete AE1 – 
AE5 forms in 
AdvantageEDC to 
report this event.
This event does not 
require reporting on 
AE1-AE5 forms in 
AdvantageEDC. Consult 
forms guide, calendar-
driven and event-driven 
forms for reporting 
requirements on other 
forms.
No
No
Yes
Yes
2) Is the event neutropenia, 
thrombocytopenia, anemia, a minor 
bleeding episode (i.e. epistaxis), graft-
versus-host-disease (GVHD), graft 
failure, hepatic veno-occlusive disease 
(VOD) or thrombotic microangiopathy 
(TMA)?


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Version 3.0 dated July 17, 2015 
 
 
K-1 
APPENDIX K 
 
REFERENCES 
 


BMT CLINICAL TRIALS NETWORK 
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K-2 
APPENDIX K 
 
REFERENCES 
 
 
                                                 
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posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641-650. 
65 Raj, K., Streetly, M., Kazmi, M., Harringon, E., Getzendaner, L. C., Lee, S. J., and O'Donnell, 
P. V. Peripheral Blood Progenitor Cell (PBPC) Transplantation from Haploidentical Donors 
Following Reduced Intensity Conditioning (RIC) for High-Risk Hematologic Malignancies. 
Biology of blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation 18[2], S331. 2-1-2012. 
66 Bolaños-Meade J, Fuchs EJ, Luznik L et al. HLA-haploidentical bone marrow transplantation 
with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell 
disease. Blood. 2012;120:4285-4291. 
67 Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host 
tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47:65-
77. 
68 Ciurea SO, Mulanovich V, Saliba RM et al. Improved early outcomes using a T cell replete 
graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. 
Biol Blood Marrow Transplant. 2012;18:1835-1844. 
69 Kasamon, Y. L., Jones, R. J., Gocke, C. D., Bolaños-Meade, J., Swinnen, L. J., Blackford, A., 
Gladstone, D. E., Fuchs, E. J., and Ambinder, R. F. Nonmyeloablative Allogeneic (Allo) BMT 
for B-Cell Lymphoma with Posttransplant Rituximab: Donor Selection by Prioritizing 
FCGR3A-158 Polymorphism Over HLA Matching. Blood . 2012. 

SAP_001.pdf: 
1 
 
BMT CTN #1203 Statistical Analysis Plan (SAP) 
Version 0.01 
Drafted by: Raphael Fraser & Mat Makowski on 11/09/2016 
 Reviewed by DCC STAT Committee on:  
Reviewed by the protocol team on: 
Finalized on:  
 
Protocol  
BMT CTN #1203 A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-
versus-Host Disease Prevention Compared to Contemporary Controls 
Protocol Synopsis  
BMT CTN protocol #1203 is a Phase II, multi-center trial designed to compare the treatment 
effects in three arms of GVHD prophylaxis to contemporary controls.  The three arms are: (1) 
Tacrolimus (Tac)/Methotrexate (Mtx) with bortezomib 1.3 mg/m2 IV daily Days +1, +4 and +7 
post HSCT, (2) Tac/Mtx with maraviroc 300 mg PO twice a day from Day -3 to 30 post HSCT, 
and (3) cyclophosphamide (Cy) 50 mg/kg Day +3 and +4, followed by Tac and mycophenolate 
mofetil (MMF).   
The primary objective of the randomized trial is to compare one year GVHD/relapse or 
progression-free survival (GRFS) after hematopoietic stem cell transplantation (HSCT) between 
each of three novel GVHD prophylaxis approaches and a contemporary control from the Center 
for International Blood and Marrow Transplant Research (CIBMTR) database.  Secondary 
objectives are to describe for each treatment arm the following:   
• Incidence of grade II-IV and III-IV of acute GVHD up to 180 days 
• Incidence of chronic GVHD up to 1 year 
• Immunosuppression-free survival at 1 year 
• Hematologic Recovery (neutrophil and platelet) 
• Donor cell engraftment 
• Disease relapse or progression 
• Transplant-related mortality at days 100, 180, and 1 year 
• Proportion of grade 3 or more toxicities according to the CTCAE 


2 
 
• Incidence of infections 
• Disease-free survival 
• GVHD-free survival 
• Overall survival 
The target enrollment is 540 patients. This includes 90 randomized patients to each of the 3 
treatment arms and 270 non-randomized CIBMTR contemporary controls.  Participants will be 
accrued over a 30 month period then followed for an additional year post HSCT.   
 
Study Treatment 
All patients will be randomized within 7 days prior to the initiation of conditioning therapy. 
Randomization will be stratified by donor type/HLA mismatching (Matched Sibling vs. Matched 
Unrelated vs. Mismatched Unrelated) and by disease risk. Patients will be randomized to receive 
one of the three specified regimens: Tacrolimus (Tac)/Methotrexate (Mtx) with bortezomib 1.3 
mg/m2 IV daily Days +1, +4 and +7 post HSCT; Tac/Mtx with maraviroc 300 mg PO twice a 
day from Day -3 to 30 post HSCT; or cyclophosphamide (Cy) 50 mg/kg Day +3 and +4, 
followed by Tac and mycophenolate mofetil (MMF).  Tac will be maintained at therapeutic 
doses for a minimum of 90 days in all arms.  Methotrexate will be dosed at 15 mg/m2 Day +1, 
and 10 mg/m2 Days +3, 6 and 11 in the maraviroc and bortezomib arms. MMF will be dosed at 
15 mg/kg every 8 hours from Day +5 to Day +35 in the Tac/MMF/Cy treatment arm.    
 


3 
 
 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old) 
2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no 
circulating blasts and with less than 5% blasts in the bone marrow. 
3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, 
marginal zone, diffuse large B-cell, Hodgkin’s Lymphoma,or mantle cell lymphoma with 
chemosensitive disease at time of transplantation 
4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a) 
5. Patients must have a related or unrelated peripheral blood stem cell donor as 
follows: 
a.  Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) 
resolution, and -DRB1 at high resolution using DNA-based typing, and must be 
willing to donate peripheral blood stem cells and meet institutional criteria for 
donation. 


4 
 
b. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing. Unrelated donor must be willing to donate 
peripheral blood stem cells and be medically cleared to donate stem cells 
according to NMDP criteria. 
6. Cardiac function: Ejection fraction at rest ≥ 45% 
7. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault 
formula and actual body weight) 
8. Pulmonary function: DLCO ≥ 40% (adjusted for hemoglobin) and FEV1 ≥ 50%  
9. Liver function: total bilirubin < 1.5 x the upper limit of normal and ALT/AST < 2.5x the 
upper normal limit. Patients who have been diagnosed with Gilbert’s Disease are allowed 
to exceed the defined bilirubin value of 1.5x the upper limit of normal. 
10. Female subjects (unless postmenopausal for at least 1 year before the screening visit, or 
surgically sterilized), agree to practice two (2) effective methods of contraception at the 
same time, or agree to completely abstain from heterosexual intercourse, from the time of 
signing the informed consent through 12 months post transplant (see Section 2.6.4 for 
definition of postmenopausal). 
11. Male subjects (even if surgically sterilized), of partners of women of childbearing 
potential must agree to one of the following: practice effective barrier contraception (see 
Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from 
the time of signing the informed consent through 12 months post transplant. 
12. Signed informed consent 
 
Exclusion Criteria 
1. Prior allogeneic transplant 
2. Karnofsky Performance Score < 70% 
3. Active CNS involvement by malignant cells 
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking 
medication and with progression or no clinical improvement) at time of enrollment. 
5. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with 
methotrexate clearance or makes methotrexate use contraindicated 
6. Patients with transformed lymphoma (e.g., Richters transformation arising in follicular 
lymphoma or chronic lymphocytic leukemia) 
7. Patients seropositive for the human immunodeficiency virus (HIV) 
8. Patient with active Hepatitis B or C determined by serology and/or NAAT 
9. Patients with hypersensitivity to bortezomib, boron or mannitol 
10. Patients with ≥ grade 2 sensory peripheral neuropathy 


5 
 
11. Myocardial infarction within 6 months prior to enrollment or New York Heart 
Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities.  Prior to study entry, any ECG 
abnormality at screening must be documented by the investigator as not medically 
relevant. 
12. Female patients who are lactating or pregnant 
13. Patients with a serious medical or psychiatric illness likely to interfere with participation 
in this clinical study 
14. Patients with prior malignancies except resected basal cell carcinoma or treated cervical 
carcinoma in situ.  Cancer treated with curative intent ≥ 5 years previously will be 
allowed.  Cancer treated with curative intent < 5 years previously will not be allowed 
unless approved by the Protocol Officer or one of the Protocol Chairs. 
15. Planned use of ATG or alemtuzumab in conditioning regimen.  
16. Planned post-transplant therapy (including use of TKIs).  
17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes 
(CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan 
metabolism during day -5 through day +7. It is acceptable to use alternative non-
interacting medications during this period, and then resume prior medications. 
18. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, 
including CMML, with evidence of active myeloproliferative features or myelofibrosis in 
the background.  
 
Eligibility for the Control Arm 
Patients in the control arm will be identified from patients prospectively reported to the CIBMTR 
from U.S centers not enrolling to the BMT CTN 1203 study and which agree to participate in 
this study.  Control patients will not be individually matched to patients on one of the 
randomized treatment arms, but rather will satisfy similar eligibility requirements.  Patients will 
need to fulfill the same inclusion criteria for the clinical trial, plus the following: 
1. Receive Tac/MTX as the sole GVHD prophylaxis approach 
2. Receive the same regimens as specified in Table 2.4a of the protocol 
3. Receive PBSC as the graft source 
 
Exclusion Criteria for the controls 
1. Karnofsky Performance Score < 70% 
2. Active CNS involvement by malignant cells 


6 
 
3. Patients with uncontrolled bacterial, viral or fungal infections (currently taking 
medication and with progression or no clinical improvement) at time of enrollment 
4.  Patients seropositive for the human immunodeficiency virus (HIV) 
5. Patient with active Hepatitis B or C determined by serology and/or NAAT 
 
Response Variables and Data Collection Time Points 
Participants are evaluated for progression and disease status assessments at study entry at day 
100, day 180 and day 365 post transplant.  Disease relapse/progression is reported on event-
driven forms.  GVHD assessments are performed weekly from day 7 until day 63 post-transplant, 
and then at days 100, 120, 150, 180, 270, and 365 post-transplant.   
Randomization  
All patients will be randomized within 7 days prior to the initiation of conditioning therapy.  
Randomization will be performed in a 1:1:1 ratio using random block sizes for the three arms.  
Randomization will be stratified by donor type/HLA mismatching (Matched Sibling vs. Matched 
Unrelated vs. Mismatched Unrelated) and by disease risk (High vs. Low, see Section 1.5 of the 
protocol). 
Time Line  
The study opened for accrual in September 2014 and completed accrual in June 2016.   There 
were no interim analyses planned for efficacy.  An interim analysis for futility was planned based 
on the 6 month GRFS when 30 participants in each arm have 6 months of follow-up available.  
The interim analysis for futility was conducted and presented at the DSMB meeting in April 
2016.  The database for the study will be locked after completion of participants’ 1-year follow 
up and data review by Endpoint Review Committee (ERC).  The ERC is planning to begin 
adjudicating cases in Fall 2016. 
General Statistical Considerations 
Sample Size and Power Calculations 
Sample size and power considerations are based on the comparison of each treatment group 
(n=90 patients) to the concurrent nonrandomized CIBMTR control cohort (n=270 patients).  A 
treatment is considered promising relative to the control if its hazard ratio (HR) relative to 
control, after adjustment for covariates, is significant at the one-sided significance level of 0.05.  
We are using one-sided testing since this is a phase II trial to identify whether one of these agents 
is promising relative to the control, and we are not interested in detecting treatments that are 
worse than control since they would not be pursued further.  Control rates for GRFS are expected 
to be approximately 23% by one year, based on a recent analysis of CIBMTR data, although we 
considered control rates at one year as high as 35%.  In addition to the final analysis, an interim 


7 
 
analysis for futility will be conducted after 30 patients in each group have 6 months of follow-up, 
anticipated to be approximately 50% through the accrual period assuming uniform accrual over 
30 months.  If fewer than 14 patients are alive and GVHD/relapse free at 6 months, closure of the 
study arm for futility will be considered.   
The operating characteristics of this study design, including the impact of the futility stopping 
rule, were determined in a simulation study.  GRFS was assumed to follow an exponential 
distribution, and follow-up was censored at one year for all patients. The probability of GRFS by 
one year was assumed to be 23% or 35% for the control group, while probabilities of GRFS for 
the treatment groups were 5%, 10%, or 20% higher at one year, depending on the scenario.  
Probabilities of stopping for futility were calculated for each arm, along with the expected 
sample size (ExpN) assuming uniform accrual over 30 months.  Final probabilities of identifying 
a treatment as promising relative to control were estimated, along with the probability of 
identifying at least one treatment as promising.  This latter probability is the same as the 
Familywise Type I error rate when all the treatments have the same GRFS.  Finally, we included 
the probabilities of selecting a particular treatment arm as the winner, among those identified as 
promising, based on having the lowest HR relative to control.  However, this is for illustrative 
purposes only, since it is possible that multiple treatments may be identified as good candidates 
for further study in a follow on phase 3 trial.  This probability is most interpretable when there is 
clear separation in outcomes between the best treatment and the other treatments.  The 
simulation results are shown in Table 1 below.  Adjustment for covariates was not incorporated 
into the simulation study, although it will be used in the final analysis. 
This study design has 81-87% power to identify a treatment as promising when its GRFS at one 
year is 15% better than control.  The probability of stopping an arm for futility is approximately 
37% for treatment arms which are no better than control, when the control is correctly specified 
(23% at one year).  If the control rates are higher, there is less impact of the futility boundary, 
with a 6% likelihood of stopping an arm for futility when it has the same outcome as the control.  
If none of the treatments has GRFS better than the control, the overall (Familywise) type I error 
rate is approximately 11-13%.  When the best treatment has GRFS which is 15% better than the 
other two arms, the probability of correct selection of the winner based on having the best 
observed outcomes is over 80%.  This means that there is at least an 80% chance that the truly 
best treatment will have the best observed outcomes.   When the GRFS for the best treatment is 
only 10% better than the other two treatments, there is a 75-81% chance of correctly selecting 
the winner.   


 
 
 
 
8 
 
TABLE 1: OPERATING CHARACTERISTICS OF STUDY DESIGN 
 
GRFS at 1 Year 
Probability of Stopping 
for Futility 
Individual Power 
Overall 
Probability of Selection 
as Best 
Control 
A 
B 
C 
A 
B 
C 
A 
B 
C 
Power 
A 
B 
C 
ExpN 
0.23 0.23 0.23 0.23 38.3% 37.0% 37.4% 
4.1% 
3.9% 
4.2% 
10.9% 
3.8% 
3.5% 
3.7% 222.6 
0.23 0.38 0.23 0.23 
3.0% 38.0% 37.4% 86.9% 
4.4% 
4.0% 
87.3% 86.5% 
0.4% 
0.4% 237.1 
0.23 0.38 0.38 0.38 
3.2% 
3.2% 36.5% 86.0% 86.2% 
4.0% 
97.0% 48.6% 48.3% 
0.1% 252.0 
0.23 0.38 0.38 0.23 
3.1% 
3.2% 
3.3% 86.8% 86.0% 86.9% 
99.2% 33.4% 32.4% 33.4% 266.0 
0.23 0.38 0.33 0.33 
3.2% 
8.8% 
8.6% 86.0% 58.8% 58.3% 
95.2% 61.7% 17.2% 16.3% 261.3 
0.23 0.38 0.28 0.28 
3.1% 19.3% 18.9% 86.1% 24.5% 24.6% 
89.8% 80.7% 
4.5% 
4.6% 252.7 
0.35 0.35 0.35 0.35 
5.8% 
6.0% 
6.0% 
4.4% 
4.9% 
4.7% 
12.6% 
4.0% 
4.4% 
4.3% 262.5 
0.35 0.50 0.35 0.35 
0.2% 
5.5% 
5.6% 81.3% 
4.6% 
4.5% 
82.0% 80.8% 
0.6% 
0.6% 265.3 
0.35 0.50 0.50 0.35 
0.2% 
0.2% 
5.9% 81.4% 80.8% 
4.2% 
94.4% 46.9% 47.3% 
0.2% 267.4 
0.35 0.50 0.50 0.50 
0.2% 
0.1% 
0.2% 81.5% 81.7% 81.0% 
98.0% 33.2% 33.2% 31.6% 269.8 
0.35 0.50 0.45 0.45 
0.1% 
0.5% 
0.6% 82.5% 52.4% 52.6% 
92.8% 59.7% 16.5% 16.6% 269.5 
0.35 0.50 0.40 0.40 
0.1% 
2.0% 
2.2% 81.0% 20.6% 20.9% 
85.1% 75.2% 
5.1% 
4.8% 268.2 


 
 
 
9 
 
Missing Data 
For time-to-event outcomes, participants who are lost to follow-up before completion of follow-
up are censored at the time of loss to follow-up with definitions detailed in the description of 
each analysis.   
Multiple Comparisons 
Kaplan-Meier curves along with 90% confidence intervals will be constructed to estimate GRFS 
probabilities for each treatment group as well as the control.  The primary analysis will consist of 
a comparison of GRFS for each treatment arm to the control group, based on a multivariate Cox 
regression model.  If none of the treatments has GRFS better than the control, the overall 
(Familywise) type I error rate is approximately 11-13%. 
 
Interim Analyses 
No interim analyses for efficacy are planned for this study. However, an interim analysis for 
futility is planned for the primary outcome of GRFS.  The interim analysis for futility is based on 
the 6 month GRFS when 30 participants in each arm have 6 months of follow-up available.  If 
fewer than 14 are alive and GVHD/relapse free among the first 30 patients on an arm, closure of 
the study arm will be considered.   This futility stopping rule is meant to be a guidance only, 
based on an expected 6 month GRFS of 45-50%.  Formal statistical testing may be considered if 
the stopping rule is triggered.  
Analysis Populations 
The study will enroll a total of 540 participants and all transplanted participants will be included 
in the primary analysis according to the treatment arm and strata at time of randomization 
(modified intent-to-treat analysis).   
 
Secondary analyses will examine the eligible population (EP), 
 
Subgroup Analyses 
Discuss with PIs. 
Adjustment for Covariates 
The primary analysis will consist of a comparison of GRFS for each treatment arm compared to 
the control, based on a multivariate Cox regression model adjusted for age, disease and donor 
type/HLA matching.  The following baseline/demographic factors will also be considered to be 
included in the model: gender, race, ethnicity, conditioning regimen, primary diagnosis, age, 
Karnofsky performance score, HCT-specific comorbidity index score, disease status, 
donor/recipient CMV status, time to transplant, donor/recipient sex match, donor/recipient ABO 


 
 
 
10 
 
match.  The choice of which baseline/demographic factors to include in the model will be 
determined using the stepwise variable selection procedure with a significance level of 10%. 
GRFS is a composite outcome that is calculated using the onset date of acute GVHD, onset date 
chronic GVHD, use of immune suppression drugs date, relapse date, progression date and overall 
survival.  If the GRFS comparison is significant (in a particular treatment arm) then these 
outcomes will also be compared between treatment arm and control using a multivariate Cox 
regression model that contains the same independent variables as in the primary analysis. 
Changes to Planned Analyses 
Table titles and layout are for example purposes only, and may not be the final layout or wording 
chosen for publications or presentations. 
 
[Update as needed] 
 
Analysis of Participant Demographic and Baseline Characteristics 
Descriptive statistics for baseline characteristics will be presented by treatment group.  Formal 
testing for treatment group differences of baseline characteristics will not be conducted. 
Participant Compliance 
A table listing significant protocol deviations will be provided by treatment group.    
Software 
All analyses of the main protocol will be conducted using SAS 9.4 or higher software, or R 
version 3.3.1 or higher. 
Study Operational Tables 
Template tables are provided for the main analyses. 
 
Exhibit 1203-1:  Enrollment  
A graph will be provided showing projected and actual accrual from study initiation to accrual 
closure.  
 
 
 
 


 
 
 
11 
 
 
Figure #. Accrual to 1203 
Number of Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post Study Initiation 
 
An accrual table will provide the number and percentage of centers enrolling 0-10, 11-20, 21-40, 
and 40+ participants. 
Table #. Accrual Information 
Number of Participants 
Enrolled Per Center 
Number of 
Enrolling 
Centers 
% of Enrolling 
Centers 
Total 
XX 
100.0% 
1-10 
 
 
11-20 
 
 
21-40 
 
 
40+ 
 
 
 
The number of centers which were activated but did not enroll participants will be noted 
separately. 


 
 
 
12 
 
Exhibit 1203-2:  Participant Disposition and Follow-Up 
A consort diagram will be provided showing the number of participants and compliance with 
each phase of the protocol.  A table will be provided with descriptive statistics on length of 
follow-up by assigned treatment arm. 
Exhibit 1203-3:  Participant Baseline Characteristics 
Baseline characteristics and demographics will be described by frequencies and percents for 
categorical covariates, and minimum, maximum, median, mean, and standard error for 
continuous covariates.  The following covariates will be included:  
• Treatment Group Assignment 
• Strata (donor type/HLA matching, disease risk) 
• Gender 
• Ethnicity 
• Race  
• Patient Age 
• Karnofsky performance score  
• Planned RIC Regimen 
• Primary Diagnosis 
• Disease Status by Diagnosis 
• Donor/Recipient CMV Status 
• HCT-Specific Comorbidity Index Score 
• Time to Transplant  
• Donor/Recipient Sex Match 
• Donor/Recipient ABO Match 
 
Other baseline covariates will be summarized at the request of the investigators.  P-values for 
treatment group comparisons will not be provided. 
 
The following baseline and demographic characteristics will also be reported for the control 
population. 
• Gender 
• Ethnicity 
• Race 
• Age 
• Karnofsky Performance Score 
• HCT-Specific Comorbidity Index Score 
• RIC Conditioning Regimen 
• Primary Diagnosis 
• Disease Status by Diagnosis 
• Donor/Recipient CMV status 
• Time to Transplant 


 
 
 
13 
 
• Donor Type/HLA matching 
• Primary Diagnosis  
• Donor/Recipient Sex Match 
• Donor/Recipient ABO Match 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
14 
 
Table #. Baseline Characteristics and Demographics of Participants (N = ###) 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Gender 
 
 
 
 
 
Female 
 
 
 
 
 
Male 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
Hispanic or Latino 
 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
 
Unknown 
 
 
 
 
 
Not Answered 
 
 
 
 
 
Race 
 
 
 
 
 
American Indian/Alaskan Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Hawaiian/Pacific Islander 
 
 
 
 
 
Black or African American 
 
 
 
 
 
White 
 
 
 
 
 
More than One Race 
 
 
 
 
 
Other, Specify 
 
 
 
 
 
Unknown 
 
 
 
 
 


 
 
 
 
15 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Not Answered 
 
 
 
 
 
Age, years 
 
 
 
 
 
Mean 
 
 
 
 
 
Std. Dev. 
 
 
 
 
 
Median (Range) 
 
 
 
 
 
Karnofsky Performance Score 
 
 
 
 
 
100 
 
 
 
 
 
90 
 
 
 
 
 
80 
 
 
 
 
 
70 
 
 
 
 
 
HCT-Comorbidity Index Score 
 
 
 
 
 
0 
 
 
 
 
 
1-2 
 
 
 
 
 
3 or greater 
 
 
 
 
 
Donor Type 
 
 
 
 
 
Related Donor 
 
 
 
 
 
Unrelated Donor 
 
 
 
 
 
HLA Match and Donor Type 
 
 
 
 
 


 
 
 
 
16 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Matched Sibling 
 
 
 
 
 
Matched Unrelated 
 
 
 
 
 
Mismatched Unrelated 
 
 
 
 
 
Donor/Recipient CMV Status 
 
 
 
 
 
     Pos/Pos 
 
 
 
 
 
     Pos/Neg 
 
 
 
 
 
     Neg/Pos 
 
 
 
 
 
     Neg/Neg 
 
 
 
 
 
Donor/Recipient Sex Match 
 
 
 
 
 
     Male/Male 
 
 
 
 
 
     Male/Female 
 
 
 
 
 
     Female/Male 
 
 
 
 
 
     Female/Female 
 
 
 
 
 
Donor/Recipient ABO Match 
 
 
 
 
 
     Matched 
 
 
 
 
 
     Minor Mismatched 
 
 
 
 
 
     Major Mismatched 
 
 
 
 
 
Planned RIC Regimen 
 
 
 
 
 


 
 
 
 
17 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Fludarabine/Busulfan 
 
 
 
 
 
Fudarabine/Melphalan 
 
 
 
 
 
Fludarabine/Cyclophosphamide 
 
 
 
 
 
Fludarabine/TBI 
 
 
 
 
 
Fludarabine/Cyclophosphamide/
TBI 
 
 
 
 
 
Total Transplanted 
 
 
 
 
 
Time to Transplant from Dx, 
Months 
 
 
 
 
 
Mean 
 
 
 
 
 
Std. Dev. 
 
 
 
 
 
Median (Range) 
 
 
 
 
 
Primary Diagnosis 
 
 
 
 
 
Acute Lymphoblastic Leukemia 
(ALL) 
 
 
 
 
 
Acute Myelogeneous Leukemia 
(AML) 
 
 
 
 
 
Chronic Myelogenous Leukemia 
(CML) 
 
 
 
 
 


 
 
 
 
18 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Chronic Lymphocytic Leukemia 
(CLL) 
 
 
 
 
 
Myelodysplastic Syndrome 
(MDS) 
 
 
 
 
 
Follicular Lymphoma 
 
 
 
 
 
Diffuse Large B-Cell Lymphoma 
 
 
 
 
 
Mantle Cell Lymphoma 
 
 
 
 
 
Hodgkin’s Lymphoma 
 
 
 
 
 
Disease Status for Acute 
Leukemia Patients 
 
 
 
 
 
Primary Induction Failure 
 
 
 
 
 
First Complete Remission 
 
 
 
 
 
Second/Subsequent Complete 
Remission 
 
 
 
 
 
First Relapse 
 
 
 
 
 
Missing 
 
 
 
 
 
Disease Status for CML Patients 
 
 
 
 
 
First Chronic Phase 
 
 
 
 
 


 
 
 
 
19 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Hematologic Complete 
Remission 
 
 
 
 
 
Accelerated Phase 
 
 
 
 
 
Blast Crisis 
 
 
 
 
 
Missing 
 
 
 
 
 
Disease Status for CLL Patients 
 
 
 
 
 
Nodular Partial Remission 
 
 
 
 
 
Partial Remission 
 
 
 
 
 
No Response/Stable Disease 
 
 
 
 
 
Disease Status for MDS Patients 
 
 
 
 
 
Complete Remission 
 
 
 
 
 
Hematologic Improvement 
 
 
 
 
 
No Response/Stable Disease 
 
 
 
 
 
Progression from Hematologic 
Improvement 
 
 
 
 
 
Missing 
 
 
 
 
 
Disease Status for Lymphoma 
Patients 
 
 
 
 
 
Partial Remission 
 
 
 
 
 


 
 
 
 
20 
 
 
Non-Randomized 
Control Arm 
Randomized Treatment Arms 
 
CIBMTR Controls  
(N=) 
N (%) 
Tac/MTX/ 
Bortezomib 
(N=) 
N (%) 
Tac/MTX/ 
Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
First Complete Remission 
 
 
 
 
 
Second/Subsequent Remission 
 
 
 
 
 
First Relapse 
 
 
 
 
 
Second/Subsequent Relapse 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 


 
 
 
21 
 
Analysis of Endpoints 
 
EXHIBIT 1203-4: GVHD/Relapse or Progression-Free Survival by Treatment Arm 
The time to this event is the time from HSCT to grade III-IV acute GVHD onset, chronic GVHD 
requiring systemic immunosuppressive treatment, disease relapse or progression, death by any 
cause, loss to follow-up or end of 1 year, whichever comes first. The treatment arms will be 
compared using a multivariate Cox regression model adjust for covariates chosen using a model 
building strategy (see adjustment for covariates section).  There will be no overall type III chi-
squared test used to test for differences.  Rather, differences between the treatment arms and 
controls will be directly tested using a one-sided significance level of 0.05 (unadjusted for 
multiple comparisons).  Kaplan-Meier curves along with 90% confidence intervals will also be 
constructed to estimate GRFS probabilities for each treatment arm as well as the controls. 
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
 
Table #. Multivariate Cox PH Regression Model for GRFS (N = ###) 
 
Covariates 
Level 
N 
Coef. 
HR 
90% Conf. Int. 
P-
value 
Treatment 
Overall 
 
 
 
 
#.### 
 
Controls 
## 
##.### 1.00 
(##.## - ##.##)  
#.### 
 
Tac/MTX/Bortezomib 
## 
##.### #.## 
 
#.### 
 
Tac/MTX/Maraviroc 
## 
##.### #.## 
 
#.### 
 
Tac/MMF/Cy 
## 
##.### #.## 
 
 
Age (years) 
 
 
 
 
 
 
Primary Diagnosis 
Overall 
 
 
 
 
 
 
AML 
 
 
1.00 
 
 
 
ALL 
 
 
 
 
 
 
CML 
 
 
 
 
 
 
MS 
 
 
 
 
 
 
CLL 
 
 
 
 
 
 
NHL 
 
 
 
 
 
Donor type/HLA 
Matching 
Overall 
 
 
 
 
 
 
Matched Sibling 
 
 
1.00 
 
 
 
Matched Unrelated 
 
 
 
 
 
 
Mismatched Unrelated 
 
 
 
 
 
 


 
 
 
22 
 
Table #. One-year Kaplan-Meier Estimates (N = ###) 
Group 
Kaplan-Meier 
1-year 
Estimate 
90% Conf. Int. 
Controls 
##.# 
(##.## - ##.##) 
Tac/MTX/Bortezomib 
##.# 
(##.## - ##.##) 
Tac/MTX/Maraviroc 
##.# 
(##.## - ##.##) 
Tac/MMF/Cy 
##.# 
(##.## - ##.##) 
 
 
Figure #. Comparison of Adjusted KM Curves for GRFS by Non-
Randomized CIBMTR Controls with Randomized Treatment Groups 
 
Controls and Tx Arms 
 
 
TMB and Controls 
Probability 
 
 
Probability 
 
 
Months Post HSCT 
 
 
Months Post HSCT 
 
TMM and Controls 
 
 
TMC and Controls 
Probability 
 
 
Probability 
 
 
Months Post HSCT 
 
 
Months Post HSCT 
 
 


 
 
 
23 
 
EXHIBIT 1203-5: Cumulative Incidence of Acute GVHD through Day 180 by Treatment 
Arm 
The cumulative incidence of grade III-IV acute GVHD will only be compared to controls if a 
particular treatment arm compared to controls is significantly better.  If there is a significant 
comparison then the acute GVHD comparison will be made using the same Cox regression 
model covariates as in the GRFS analysis.   Incidence of acute GVHD grade II-IV and grade III-
IV up to 180 days will be estimated with 90% confidence intervals for each treatment as well as 
the controls using the cumulative incidence estimate, treating death prior to aGVHD as a 
competing risk.     
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
Table #. Cumulative Incidence of Acute GVHD through Day 180 by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
## ##.### #.##  
#.### 
 
 
Table #. Incidence of Acute GVHD by Grade and Treatment Arm (N=) 
 
Group 
Acute GVHD  
Cumulative Incidence 
Grade II-IV at 180 
days 
Acute GVHD  
Cumulative Incidence 
Grade III-IV at 180 
days 
90% 
Confidence  
Interval 
Controls 
 
 
 
Tac/MTX/Bortezomib 
 
 
 
Tac/MTX/Maraviroc 
 
 
 
Tac/MMF/Cy 
 
 
 
 
 


 
 
 
24 
 
 
 
 
 
 
 
 
 
 
 
Figure #. Cumulative Incidence of Grade II-IV 
Acute GVHD through Day 180 
Incidence of Grade II-IV Acute GVHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days Post HSCT 
 
 
 
 
 


 
 
 
25 
 
 
 
 
 
 
 
Figure #. Cumulative Incidence of Grade III-IV 
Acute GVHD through Day 180 
Incidence of Grade III-IV Acute GVHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days Post HSCT 
. 
 
 
 
 
 
 
 
 
 


 
 
 
26 
 
EXHIBIT 1203-6: Cumulative Incidence of Chronic GVHD up to 1 year by Treatment 
Arm 
The cumulative incidence of chronic GVHD will only be compared to controls if a particular 
treatment arm compared to controls is significantly better.  If there is a significant comparison 
then the chronic GVHD comparison will be made using the same Cox regression model 
covariates as in the GRFS analysis.   Incidence of chronic GVHD up to 1 year will be estimated 
with 90% confidence intervals for each treatment as well as the controls using the cumulative 
incidence estimate, treating death prior to cGVHD as a competing risk.     
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
 
Table #. Cumulative Incidence of Chronic GVHD by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
Table #. Cumulative Incidence of Chronic GVHD at 1 year by Treatment Arm (N=) 
 
Group 
Chronic GVHD  
Cumulative Incidence at 1 year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
 


 
 
 
27 
 
 
Figure #. Cumulative Incidence of chronic GVHD  
Incidence of chronic GVHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days Post HSCT 
 
EXHIBIT 1203-7: Cumulative Incidence of Chronic GVHD Requiring Systemic 
Immunosuppression by Treatment Arm 
TBD 
EXHIBIT 1203-8: Immunosuppression-free Survival at One Year 
Proportions of patients alive, relapse free, and off immune suppression at one year will be 
described for each treatment group and for the control, along with 90% confidence intervals.  If 
there is censoring prior to one year, multistate models will be constructed to estimate these 
probabilities.  Agreement between this endpoint and the primary endpoint of GRFS will be 
described using cross-tabulation frequencies and assessed using the Kappa statistic. 
 
 
 
 
 


 
 
 
28 
 
Table #. I Proportion Immunosuppression-free Survival at One Year (N=) 
 
Group 
Proportion Immunosuppression-free 
at 1 year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
 
Table #. Measuring Agreement between the Proportions of Patients Alive, Relapse-Free, 
and off Immune Suppression at One Year by GRFS Event (N=) 
 
 
Alive, relapse-free, and IS free at 1 yr 
 
GRFS event 
Yes 
No 
Kappa statistic 
No  
 
 
 
Yes  
 
 
 
 
 
 
EXHIBIT 1203-9: Cumulative Incidence of Relapse/Progression by Treatment Arm 
The cumulative incidence of disease relapse or progression will only be compared to controls if a 
particular treatment arm compared to controls is significantly better.  If there is a significant 
comparison then the disease relapse or progression comparison will be made using the same Cox 
regression model covariates as in the GRFS analysis.   Incidence of disease relapse or 
progression up to 1 year will be estimated with 90% confidence intervals for each treatment as 
well as the controls using the cumulative incidence estimate, treating death prior to disease 
relapse or progression as a competing risk.     
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 


 
 
 
29 
 
Table #. Cumulative Incidence of Relapse/Progression by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
Table #. Cumulative Incidence at 1 year of Relapse/Progression by Treatment Arm (N=) 
 
Group 
Relapse/Progression 
Cumulative Incidence at 1 year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
30 
 
 
Figure #. Cumulative Incidence Relapse/Progression 
Incidence of relapse/progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post HSCT 
 
EXHIBIT 1203-10: Cumulative Incidence of Treatment-related Mortality by Treatment 
Arm 
The cumulative incidence of treatment-related mortality will only be compared to controls if a 
particular treatment arm compared to controls is significantly better.  If there is a significant 
comparison then the treatment-related mortality comparison will be made using the same Cox 
regression model covariates as in the GRFS analysis.   Incidence of treatment-related mortality 
up to 1 year will be estimated with 90% confidence intervals for each treatment as well as the 
controls using the cumulative incidence estimate, treating disease relapse or progression as a 
competing risk.     
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
Table #. Cumulative Incidence of Treatment-related Mortality by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 


 
 
 
31 
 
Table #. Cumulative Incidence at Days 100, 180 and at 1 Year of Treatment-related 
Mortality by Treatment Arm (N=) 
 
Group 
Treatment-related 
Mortality 
Cumulative 
Incidence  
at day 100 [90% CI] 
Treatment-related 
Mortality 
Cumulative 
Incidence  
at day 180 [90% CI] 
Treatment-related 
Mortality 
Cumulative 
Incidence  
at 1 year [90% CI] 
Controls 
 
 
 
Tac/MTX/Bortezomib 
 
 
 
Tac/MTX/Maraviroc 
 
 
 
Tac/MMF/Cy 
 
 
 
 
 
 
Figure #. Cumulative Incidence Treatment-related Mortality 
Incidence of Treatment-related 
Mortality 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post HSCT 
 
 
 
 


 
 
 
32 
 
EXHIBIT 1203-11: Disease-free Survival by Treatment Arm 
Disease-free survival will only be compared to controls if a particular treatment arm compared to 
controls is significantly better.  If there is a significant comparison then the disease-free survival 
comparison will be made using the same Cox regression model covariates as in the GRFS 
analysis.  The model will be for the risk of death or relapse/progression.   Kaplan-Meier curves 
will be constructed to estimate disease-free survival probabilities for each treatment arm as well 
as the controls. 
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
 
Table #. Disease-free Survival by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
 
Table #. Disease-free Survival at 1 year (N=) 
 
Group 
Kaplan-Meier Estimate of  
Disease-free Survival at 1 year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
 
 


 
 
 
33 
 
 
Figure #. Disease-free Survival by Treatment Arm 
Survival Probability 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post HSCT 
 
 
 
EXHIBIT 1203-12: GVHD-free Survival by Treatment Arm 
GVHD-free survival will only be compared to controls if a particular treatment arm compared to 
controls is significantly better.  If there is a significant comparison then the GVHD-free survival 
comparison will be made using the same Cox regression model covariates as in the GRFS 
analysis.  The model will be for the risk of death, grade III-IV acute GVHD or chronic GVHD 
requiring immunosuppressive treatment.   Kaplan-Meier curves will be constructed to estimate 
GVHD-free survival probabilities for each treatment arm as well as the controls. 
Participants who are lost to follow-up or withdraw before the follow-up is complete will be 
censored at the last date available. 
Table #. GVHD-free Survival by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 
 


 
 
 
34 
 
Table #. GVHD-free Survival at 1 year (N=) 
 
Group 
Kaplan-Meier Estimate of  
GVHD-free Survival at 1 year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
Figure #. GVHD-free Survival by Treatment Arm 
Survival Probability 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post HSCT 
 
 


 
 
 
35 
 
 
EXHIBIT 1203-13: Hematologic Recovery 
Probabilities of neutrophil recovery by Day 28 and Day 100 will be described with 90% 
confidence intervals for each treatment group using the cumulative incidence estimate, treating 
death as a competing event.  Similarly, probabilities of platelet recovery by Day 60 and Day 100 
will be described with 90% confidence intervals for each treatment group using the cumulative 
incidence estimate, treating death as a competing event.   
Table #. Probability of Neutrophil Recovery at Day 28 and 100 (N=) 
Group 
Probability of Neutrophil  
Recovery 
at Day 28 [90% CI] 
Probability of Neutrophil  
Recovery 
at Day 100 [90% CI] 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 
Table #. Cumulative Incidence of Platelet Recovery at Day 60 and 100 (N=) 
 
Group 
Cumulative Incidence of  
Platelet Recovery 
at Day 60 [90% CI] 
Cumulative Incidence of 
Platelet Recovery 
at Day 100 [90% CI] 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 


 
 
 
36 
 
 
 
Figure #. Cumulative Incidence Neutrophil Recovery 
Incidence of Neutrophil Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
Days Post HSCT 
 
 
 
 
Figure #. Cumulative Incidence of Platelet Recovery 
Incidence of Platelet Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
Days Post HSCT 
 
 


 
 
 
 
37 
 
 
EXHIBIT 1203-14: Donor Cell Engraftment 
Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized treatment arms will be described numerically 
as median and range for those evaluable as well as according to proportions with full (>95%), mixed (5-95% donor cells), graft 
rejection (<5%), or death prior to assessment of donor chimerism.  Incidence of secondary graft failure (chimerism <5% after initial 
donor cell engraftment) will be described for each arm using frequencies. 
Table #. Donor Cell Engraftment (N=) 
 
Treatment Arm 
 
 
Tac/MTX/Bortezomib 
(N=) 
N (%) 
Tac/MTX/Maraviroc 
(N=) 
N (%) 
Tac/MMF/Cy 
(N=) 
N (%) 
Total* 
(N=) 
N (%) 
Chimerism 
Median (range) 
Median (range) 
Median (range) 
Median 
(range) 
Full (>95% Donor Cells) 
N (%) 
N (%) 
N (%) 
N (%) 
Mixed (5-95% Donor Cells) 
N (%) 
N (%) 
N (%) 
N (%) 
Graft Rejection (<5% Donor Cells) 
N (%) 
N (%) 
N (%) 
N (%) 
Death Prior To Assessment 
N (%) 
N (%) 
N (%) 
N (%) 
Incidence of Secondary Graft Failure 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
 
 
 
 


 
 
 
 
38 
 
 
EXHIBIT 1203-15: Toxicity 
All Grade  3 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade 
overall.  Toxicity frequencies will be described for each time interval as well as cumulative over time. 


 
 
 
 
39 
 
EXHIBIT 1203-16: Infection 
The number of infections and the number of patients experiencing infections will be tabulated for each randomized treatment arm by 
type of infection, severity, and time period after transplant.   
Table #. Summary of Infections by Treatment Arm (N=) 
 
Treatment Arm 
 
Tac/MTX/ 
Bortezomib 
Tac/MTX/ 
Maraviroc 
Tac/MMF/ 
Cyclophosphamid
e 
CIBMTR 
Controls 
Total 
N    %  
N    %  
N    %  
 N % 
 
# Patients Transplanted 
 
 
 
 
 
# Patients with Infections (Grade 2-3) 
 
 
 
 
 
# Patients with Infection Reports 
 
 
 
 
 
           =1 
 
 
 
 
 
           =2 
 
 
 
 
 
           =3 
 
 
 
 
 
           =4 
 
 
 
 
 
           =5 
 
 
 
 
 
           >=6 
 
 
 
 
 
Total Infection Events 
 
 
 
 
 
Maximum Severity by Patient 
 
 
 
 
 


 
 
 
 
40 
 
 
Treatment Arm 
 
Tac/MTX/ 
Bortezomib 
Tac/MTX/ 
Maraviroc 
Tac/MMF/ 
Cyclophosphamid
e 
CIBMTR 
Controls 
Total 
           None 
 
 
 
 
 
           Grade 2 
 
 
 
 
 
           Grade 3 
 
 
 
 
 
Infection by Type (# of patients) 
 
 
 
 
 
           Bacterial 
 
 
 
 
 
           Viral 
 
 
 
 
 
           Fungal 
 
 
 
 
 
           Protozoal 
 
 
 
 
 
           Other 
 
 
 
 
 
Non-microbiologically defined Infections (# of patients) 
 
 
 
 
 


 
 
 
 
41 
 
EXHIBIT 1203-17: Overall Survival 
Overall survival will only be compared to controls if a particular treatment arm compared to controls is significantly better.  If there is 
a significant comparison then the overall survival comparison will be made using the same Cox regression model covariates as in the 
GRFS analysis.  The model will be for the risk of death.   Kaplan-Meier curves will be constructed to estimate overall survival 
probabilities for each treatment arm as well as the controls.  Causes of death will also be summarized by treatment arm using a 
frequency table. 
Participants who are lost to follow-up or withdraw before the follow-up is complete will be censored at the last date available. 
Table #A. Overall Survival by Treatment Arm (N=) 
 
Covariates Level 
N 
Coef. 
HR 
90% Conf. Int. P-value 
Treatment Overall 
 
 
 
 
#.### 
 
Controls 
## ##.### 1.00 (##.## - ##.##)  #.### 
 
Tac/MTX/Bortezomib ## ##.### #.##  
#.### 
 
Tac/MTX/Maraviroc 
## ##.### #.##  
#.### 
 
Tac/MMF/Cy 
 
 
 
 
 
 
 
Table #B. Overall Survival by Treatment Arm (N=) 
 
Covariates 
Level 
N 
Coef. 
HR 
90% Conf. Int. 
P-
value 
Treatment 
Overall 
 
 
 
 
#.### 
 
Controls 
## 
##.### 1.00 
(##.## - ##.##)  
#.### 
 
Tac/MTX/Bortezomib 
## 
##.### #.## 
 
#.### 
 
Tac/MTX/Maraviroc 
## 
##.### #.## 
 
#.### 
 
Tac/MMF/Cy 
## 
##.### #.## 
 
 
Age (years) 
 
 
 
 
 
 
Primary Diagnosis 
Overall 
 
 
 
 
 


 
 
 
 
42 
 
 
AML 
 
 
1.00 
 
 
 
ALL 
 
 
 
 
 
 
CML 
 
 
 
 
 
 
MS 
 
 
 
 
 
 
CLL 
 
 
 
 
 
 
NHL 
 
 
 
 
 
Donor type/HLA 
Matching 
Overall 
 
 
 
 
 
 
Matched Sibling 
 
 
1.00 
 
 
 
Matched Unrelated 
 
 
 
 
 
 
Mismatched Unrelated 
 
 
 
 
 
 
 
Table #. Overall Survival At One Year (N=) 
Group 
Overall Survival 
At One Year 
90% Confidence  
Interval 
Controls 
 
 
Tac/MTX/Bortezomib 
 
 
Tac/MTX/Maraviroc 
 
 
Tac/MMF/Cy 
 
 
 


 
 
 
 
43 
 
 
 
 
Figure #. Overall Survival by Treatment Arm 
Survival Probability 
 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post HSCT 
 
 
 


 
 
 
 
44 
 
 
 
Treatment Arm 
Total 
Tac/MTX/ 
Bortezomib  
Tac/MTX/ 
Maraviroc 
Tac/MMF/ 
Cyclophosphamide 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Recurrence/Persistence 
 
 
 
 
 
 
 
 
Chronic GVHD 
 
 
 
 
 
 
 
 
Infection 
 
 
 
 
 
 
 
 
Bacterial 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
Organism Not Identified 
 
 
 
 
 
 
 
 
Organ Failure 
 
 
 
 
 
 
 
 
Cardiac (Cardiomyopathy) 
 
 
 
 
 
 
 
 
Pulmonary 
 
 
 
 
 
 
 
 
Hemorrhage 
 
 
 
 
 
 
 
 
Intracranial 
 
 
 
 
 
 
 
 
Interstitial Pneumonia 
 
 
 
 
 
 
 
 
Adult Respiratory Distress Syndrome 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
Total Accrual 
 
 
 
 
 
 
 
 
Total Deaths